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Geriatric(Pharmacy(Review( Module(9( Pharmacotherapy(for(Hematologic(Disorders( (
Geriatric(Pharmacy(Review(
Module(9(
Pharmacotherapy(for(Hematologic(Disorders( (

Accreditation Information

Accreditation Information ASCP is accredited by the Accreditation Council for Pharmacy Education as a provider of

ASCP is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

This home study web activity has been assigned 3 credit hours.

ACPE UPN: 0203-0000-10-029-H01-P

Release Date: 3/8/2010

Expiration Date: 3/8/2013

To receive continuing education credit for this course, participants must complete an on-line evaluation form and pass the on- line assessment with a score of 70% or better. If you do not receive a minimum score of 70% or better on the assessment, you are permitted 4 retakes. After passing the assessment, you can print and track your continuing education statements of credit online.

Geriatric Pharmacy Review courses have not yet been approved for Florida consultant pharmacy continuing education.

Copyright 2011 American Society of Consultant Pharmacists

Current Content Experts:

Content Experts

Barbara Mason, PharmD, FASHP Ambulatory Care Clinical Pharmacist Boise Veterans Affairs Medical Center

&

Professor of Pharmacy Idaho State University, College of Pharmacy

Jarett Szczepanski, PharmD

Specialty Practice Resident, Hematology/Oncology, 2003-2004

The James Cancer Center and Solove Research Institute

The Ohio State University Medical Center

Copyright 2011 American Society of Consultant Pharmacists

Legacy Content Experts:

Content Experts

Robert McNulty, PharmD Specialty Practice Pharmacist, Hematology-Oncology

The James Cancer Center and Solove Research Institute The Ohio State University Medical Center

&

Clinical Assistant Professor

The Ohio State University College of Pharmacy

Tom Snader, PharmD, FASCP President, TCS Pharmacy Consultants

&

Clinical Associate Professor of Clinical Pharmacy

USP - Philadelphia College of Pharmacy

Copyright 2011 American Society of Consultant Pharmacists

Content Expert Disclosure

Barbara Mason has no relevant financial relationships to disclose.

Robert McNulty has no relevant financial relationships to disclose.

Jarett Szczepanski has no relevant financial relationships to disclose.

Tom Snader has no relevant financial relationships to disclose.

Copyright 2011 American Society of Consultant Pharmacists

Red Blood Cell Disorders

Learning Objectives

By the end of this Review Concept you should be able to:

Explain the effect of aging and the role of nutritional and environmental factors on hematopoesis in the older population.

Recognize tests and procedures used in the differential diagnosis of anemia, as well as those results which may indicate anemia.

Compare and contrast the different types of anemias commonly seen in the older population in terms of etiology and presenting signs and symptoms Design and monitor patient-specific pharmacotherapy plans for the treatment of different types of anemia considering comorbidity and other factors

Copyright 2011 American Society of Consultant Pharmacists

Causes of Anemia in the Elderly

NHANES III

11% incidence anemia 1/3 nutritional (iron, B 12 , FA) 1/3 ACD

1/3 unexplained

Hb and Hct values may be lower in elderly but a presumption that they have a lower normal range can result in missing an underlying disorder. Studies have shown increased morbidity and mortality in elderly with anemia. The third National Health and Nutrition Examination Survey (NHANES III) showed that 10-11% of those 65 were mildly anemic. A rate of 28% was found in non-Hispanic blacks.

One-third of the causes were iron, folate or B 12 nutrition deficiencies. Iron deficiency was more than one-half of this group. One-third were related to anemia of chronic diseases. In the remaining one-third, anemia was unexplained. With older adults, evaluation of anemia is often made more difficult by the presence of multiple pathologies. Elderly with the highest incidence are those hospitalized, with the lowest incidence in the community-based groups.

Copyright 2011 American Society of Consultant Pharmacists

Adult Blood Cell Concentration

Red$Blood$Cells

5.21(M)$4.60(F)$$

Hemoglobin$ $ $$

15.7gm/dL(M)$$

13.8gm/dL(F)$$

Hematocrit$ $ $$

46%$(M)$$

40%$(F)$$

Mean$Cell$Volume$(MCV)$ $ $$

80.0G96.1femtoliters/cell$$

Mean$Cell$Hemoglobin$(MCH)$$

27G34$picograms/cell$$$

MCH$ConcentraKon$(MCHC)$$

31.5G36.0$grams/dL $ $$

ErythropoieKn$$

0G19$mU/ml$ $ $$

Factors(that(Impact(Blood(Cell(Concentra3on(Interpreta3on$

Race$

Age$

AlKtude$

Smoking$

Plasma$volume$

Bed$rest$

Salt/fluid$intake$

Excercise$

Copyright 2011 American Society of Consultant Pharmacists

Adult Blood Cell Concentration

Anemias are a group of diseases characterized by a decrease in hemoglobin (Hb) or volume of red blood cells. Anemia is frequently underdiagnosed. Since it may be a sign of underlying pathology, determining the cause of anemia is important. Anemia may also be an independent risk factor for decreased quality of life and survival in the elderly.

The prevalence of anemia is estimated at 11% in geriatrics over age 65 and 20% in age 85 and older. Comorbid conditions such as congestive heart failure, cancer and chronic kidney disease are associated with specific anemias. Anemia of chronic disease is a distinct entity in patients with chronic immune related diseases. Red hematopoieticially active tissue in bone marrow is replaced by yellow inactive marrow with aging. When stimulated with erythropoietin marrow in an elderly increases its iron content to a lesser degree than your younger patients. Oxygen demand for tissue may decrease with aging. Red blood cell survival does not change with aging. Anemia of senescence does not it itself exist and anemia is not an inevitable part of aging. While studies suggest that there is little change in basal hematopoiesis with aging, the ability of the aging hematopoietic system to respond to increasing demands appears to be compromised.

Iron is an essential part of the heme molecule for metabolic processes. Pharmacists are familiar with another heme protein molecule, Cytochrome P-450. With aging, CP-450 is maintained by utilizing dietary heme. With iron deficiency CP-450 is decreased. Iron overload induces heme oxygenase and degrades heme which may decrease CP-450. Iron status in elderly may affect medications metabolized by Cytochrome CP-450.

Copyright 2011 American Society of Consultant Pharmacists

Adult Blood Cell Concentration

Adult Blood Cell Concentration Copyright 2011 American Society of Consultant Pharmacists

Copyright 2011 American Society of Consultant Pharmacists

Etiology of Anemia Prevalence in Aging

Drug use • Alcohol, medication side effects

Undernutrition

Although hemoglobin levels may be normal, decreased marrow reserve may leave elderly vulnerable to anemia. Causes of anemia are not always determined and multiple causes may exist concurrently. Nutritional deficiencies that are not severe enough to be a problem in the younger population may affect the hematopoietic system in the elderly. Elderly are less able to adapt to underfeeding so under nutrition can have a greater impact. Inadequate nutrient intake can be due to social, psychological, psychiatric and pharmacological issues. Edentulous elderly, or those with dysphagia, may have compromised nutritional intake.

Malabsorption of food-protein B-12 in the stomach can be seen in elderly with gastric achlorhydria. Both folic acid and vitamin B12 nutrient deficiencies can affect erythrocyte maturation. Drug induced causes of anemia may be more common because of increased drug use in elderly. Alcohol should be considered a drug. It can be associated with iron deficiency anemia or folic acid anemia.

Copyright 2011 American Society of Consultant Pharmacists

Classification Systems for Anemias

Pathophysiology

Excess blood loss Excess RBC destruction Inadequate RBC production (hypoproliferation)

Morphology

Macrocytic – B12, FA

Microcytic – iron deficiency Normocytic – recent blood loss, bone marrow, anemia of chronic disease

Etiology

Deficiency – iron, B12, FA Central – anemia chronic disease, anemia in elderly

Peripheral – bleeding, hemolysis

The anemias can be classified on the basis of RBC morphology, etiology and pathophysiology. Anemias classified by red blood cell size morphology are macrocytic, normocytic or microcytic. Macrocytic anemias are B 12 deficiency and folic acid deficiency. Iron deficiency is microcytic and normocytic is associated with recent blood loss or chronic disease. Macrocytic anemias are megaloblastic or not as determined microscopically by peripheral blood smear. Etiologic classification can be based on deficiency of iron, vitamin B 12 or folic acid, central caused by bone marrow impairment or peripheral due to bleeding or hemolysis. Pathophysiologic classification is excessive blood loss, excessive red blood cell destruction or inadequate RBC production.

Copyright 2011 American Society of Consultant Pharmacists

CBC with RBC indices • Reticulocyte production index count

TIBC – total iron binding capacity • Serum iron

Laboratory Evaluation

It is vital to identify the type of anemia before treatment. Signs and symptoms can be insidious in onset and diagnosis may be suspected before morphological changes appear. A CBC can first characterize the anemia. If red blood cell changes are accompanied by white blood cell and platelet changes, a primary marrow production may be suspected.

The MCV indices cannot be relied on entirely for cell size detection. A peripheral blood smear may be useful. Red cell diameter width is often unreliable in the elderly. The total reticulocyte count indicates new RBC production. If reticulocytes don’t increase in anemia, it may indicate impaired red blood cell production. A low reticulocyte count may be misleading where blood loss has outstripped supply of nutrients in marrow, resulting in secondary marrow failure.

Examples include iron deficiency, B12, anemia of chronic disease, malnutrition , renal insufficiency or malignancy. An increase in reticulocytes is seen in acute blood loss or hemolysis. Serum levels of iron have day-to-day variation and are best intrepreted with the TIBC. Serum iron decreases with IDA and ACD and increases with hemolytic anemias and iron overload. TIBC (transferrin) saturation is an indirect measurement of the iron-binding capacity of serum transferrin. TIBC is higher when body iron stores are low and high in iron deficiency anemia. Ferritin (storage iron) levels that are low are found in iron deficiency.

Copyright 2011 American Society of Consultant Pharmacists

Algorithm for Anemia Diagnosis

Algorithm for Anemia Diagnosis Copyright 2011 American Society of Consultant Pharmacists

Copyright 2011 American Society of Consultant Pharmacists

Anemia in the Long-Term Care Setting

Anemia in the Long-Term Care Setting Copyright 2011 American Society of Consultant Pharmacists

Copyright 2011 American Society of Consultant Pharmacists

Anemia of Chronic Disease (ACD): Diagnosis and Treatment

Laboratory Findings:

No definitive test confirms the diagnosis • Normocytic, normochromic • Peripheral smear normal, with possible Microcytes

Serum Fe, TIBC - both decreased • Transferrin saturation decreased • Serum ferretin normal to increased

Clinical Manifestations:

Pallor

Tachycardia

Asymptomatic

Treatment:

Treatment of underlying disease • Elimination of nutritional deficiencies, marrow-suppressive drugs • Not responsive to common hematinic drugs

Copyright 2011 American Society of Consultant Pharmacists

Anemia of Chronic Disease (ACD): Diagnosis and Treatment

Chronic diseases that are known to produce anemic conditions include malignancies, infections such as endocarditis, osteomyelitis, or chronic urinary tract infections, collagen vascular disorders, rheumatoid arthritis, and inflammatory bowel disease.These conditions tend to inhibit the mobilization of stored iron, erythropoietin production, and/ or blunt the response to endogenous erythropoietin. Bone marrow reveals an abundance of iron, suggesting the release of iron is the problem.

Cytokines, such as interleukin-1, and tumor necrosis factor may be released and inhibit production or action of erythropoietin. Hepcidin may decrease iron absorption. ACD may coexist with other anemias. Anemias of chronic disease tend to be normocytic and normochromic. Both serum iron and total iron binding capacity are decreased.Ferritin is usually normal, but may be elevated.Patients with anemia of chronic disease can have no signs or symptoms or show signs consistent with any anemic patient, pallor and tachycardia.

Treatment is directed at the underlying cause and at eliminating exacerbating factors such as nutritional deficiencies and marrow-suppressive drugs. Still hematologic and physiologic abnormalities may not be reversed. Iron is only used if deficiency is present and can be ineffective in inflammation. Anemia of chronic disease is one of the most common forms of anemia in the elderly. Since it is associated with other diseases, it can be overlooked or mistaken for iron deficiency. The degree of anemia is generally associated with underlying disease severity. It is a response to stimulation of the cellular immune system.

Erythropoietic agents (EPAs) or erythropoietic stimulating agents (ESAs) have been used in the treatment of anemias of chronic disease, but are not FDA approved. EPO can be effective when the marrow has an adequate supply of iron, colbalamin and folic acid. FDA approved uses for erythropoietic agents include cancer patients on chemotherapy, chronic kidney disease and patients with HIV. Guidelines specific for those types of anemia should be followed.

Copyright 2011 American Society of Consultant Pharmacists

Iron Deficiency Anemia (IDA): Diagnosis and Treatment

Iron(Drug(Interac3ons(

Decrease(Iron(Absorp3on$

Drug(Affected(by(Iron$

Al$

Levodopa$decreased$

Mg$

Levothyroxine$decreased$

Ca$

Penicillamine$decreased$

Antacids$

Fluoroquinolones$decreased$

Laboratory Findings:

Normocytic, normochromic Peripheral smear shows microcytic cells with central pallor MCV 55-74 fL, MCHC 25-30 gm/dL Serum iron < 50 mg/dL Transferrin saturation

Clinical Manifestations:

Fatigue, weakness Pale conjunctivae Tachycardia Apathy Depression Irritability, agitations Dizziness Breathlessness Ankle edema

Copyright 2011 American Society of Consultant Pharmacists

Iron Deficiency Anemia (IDA): Diagnosis and Treatment

Treatment:

Replacement of depleted iron stores:

Treat any underlying disease

325 mg ferrous sulfate, PO t.i.d. between meals for approximately six months • Side effects include constipation, cramping, diarrhea, nausea. • Manage side effects by giving with meals or substituting ferrous gluconate, or ferrous fumarate.

Avoid sustained release or enteric coated preparations. • Approximately 200mg of elemental iron daily in divided doses is used.

 

Parenteral(Iron(

Sodium(Ferric(Gluconate$

Iron(Dextron$

Iron(Sucrose$

62.5$mg$iron/5$mL$

50$mg$iron/mL$

20$mg$iron/mL$

PreservaKve$

No$preservaKve$

No$preservaKve$

No$black$box$warning$

Black$box$warning$

Black$box$warning$

No$IM$

Yes$IM$

No$IM$

Copyright 2011 American Society of Consultant Pharmacists

Iron Deficiency Anemia (IDA): Diagnosis and Treatment

 

Lab(Differences(between(ACD(and(IDA(

 
 

ACD

IDA

Both

Iron

Transferrin

or nl

Transferrin

saturation

Ferritin

or nl

or nl

Iron deficiency results from a negative iron balance or failure to meet increased physiologic iron need. At diagnosis, the cause of IDA should be considered blood loss until proven differently. Occult blood loss from a GI lesion has been demonstrated to be a frequent cause.

Red cell indices are typically low, and microcytosis with central pallor is evident on morphological examination. As expected, serum iron levels are also low.Patients with iron-deficiency anemia may present with fatigue, weakness and shortness of breath. Signs and symptoms of anemia in the elderly my be cardiac predominant although angina is rare. Physiologic changes can compensate for the decrease in hemoglobin which is why symptoms can be marked before they are troublesome. Pallor of skin can be difficult to assess in elderly skin.

Copyright 2011 American Society of Consultant Pharmacists

Iron Deficiency Anemia (IDA): Diagnosis and Treatment

Nailbeds, buccal or lingual mucosa may be more revealing. Iron deficiency is not just manifested as anemia. Iron regulates protein synthesis and cellular energy. Tissue iron deficiency can manifest as glossitis, atrophic gastritis, small intestine malabsorption, decreased lymphocyte function, and impaired temperature maintenance. Tachycardia and gastrointestinal problems such as atrophic gastritis are not uncommon.

The primary therapeutic goal for patients with iron-deficiency anemia is replacement of depleted iron stores. Remember to start with one dose per day and increase to three times a day over the next 1-2 weeks to minimize gastrointestinal side effects. Taking iron with meals may also reduce GI side effects, but may also decrease absorption.Ferrous gluconate and fumarate are well-tolerated alternatives, probably because they contain less elemental iron per dose than does the sulfate.

Enteric coated preparations should not be used in achlorlhydric patients. Patients with very high iron requirements, poor absorption (gastrectomy patients), or intolerance of oral preparations should receive parenteral iron. Parenteral iron does not lead to a quicker hematologic response than oral iron. Parenteral preparations differ in their molecular size, kinetics, and toxicity profiles. IV iron research is primarily done in hemodialysis patients.

Severe hypersensitivity reactions have been seen with IV iron dextran. Patients should be observed for more than one hour for reactions. Test drug doses may be used. Epinephrine, diphenhydramine, and corticosteroids should always be readily available when using IV iron dextran. Patients have experienced delayed arthralgias, myalgias for one to two weeks after the infusion. Patients with a history of allergies, asthma or inflammatory diseases are at higher risk of reactions to IV iron dextran.

Sodium ferric gluconate and iron sucroseare alternate parenteral iron products

Oral iron should cause a reticulocytosis in 5-7 days with an increase in Hb or 2-4 g/dL every 3 weeks until normalized. Iron therapy needs to continue until iron stores are restored. Usually 3-6 months of therapy is needed. Serum ferritin should be normal before iron is discontinued.

Copyright 2011 American Society of Consultant Pharmacists

Macrocytic Anemia: Diagnosis and Treatment

Macrocytic Anemia

Megaloblastic B 12 deficiency Folic acid deficiency

Myelodysplasia Normoblastic Chronic liver disease Alcoholism

Hypothyroidism Leukemia and myelodysplasia Aplastic anemia

Folic Acid Deficiency Causes

Inadequate intake

Decreased absorption •

Inadequate utilization

Hyperutilization

B12 Deficiency Causes

Inadequate intake

Inadequate utilization

Malabsorption

Drugs that Cause Macrocytosis

Hydroxyurea

Zidovudine

Cytosine

Azathioprine

6-mercaptopurine

Alcohol

Nitrofurantoin

Drugs Associated with Megaloblastic Anemia

Antimetabolite chemotherapy

Cotrimoxazole

Phenytoin

Phenobarbiturates

Triamterene

Copyright 2011 American Society of Consultant Pharmacists

Macrocytic Anemia: Diagnosis and Treatment

Lab Diagnosis: Vitamin B 12 Deficiency

When assessing lab data, a mild leukopenia and thrombocytopenia are often present. Methylmalonic acid (MMA) and homocysteine levels may be elevated in vitamin B 12 deficiency. Elevated homocysteine levels can occur in either B 12 deficiency or folic acid deficiency. MMA increases are more specific for vitamin B12 elevated homocysteine levels have been reported in some studies to be an independent risk factor for different cerebrovascular diseases.

Folic acid deficiency is associated with poor eating habits, alcoholics, chronic illness, dementia and poor socioeconomic status. Hyperutilization can occur in those with chronic inflammatory disorders. Folic acid is readily destroyed by cooking or processing. Without folate intake, body stores can be used up in four to five months. Folate in food is most commonly in the polyglutomate form which needs to be converted to the monoglutamate form in the small intestine. Once absorbed it is converted again to a tetrahydrofolate.

Lab Diagnosis: Folic Acid Deficiency

Essential to rule out vitamin B 12 deficiency

Lab changes similar to B 12 B 12 level normal • Serum folate levels decreased

RBC folate levels decreased • Serum homocysteine levels usually increased • MCV, serum LDH, indirect bilirubin all may be elevated • Peripheral smear may show anisocytosis, poikilocytosis, macryocytes, hypersegmented polymorphonuclear leukocytes • Low reticulocyte count • Low serum vitamin B 12 level

Copyright 2011 American Society of Consultant Pharmacists

Macrocytic Anemia: Diagnosis and Treatment

Treatment:

Vitamin B12 Deficiency Anemia:

1000 mcg cyanocobalamin IM daily X 7 d, then once weekly for 1-2 months, then monthly for maintenance.

Once repleated may switch to PO 1 mg Vit B12 for maintenance therapy. Monitor for fluid retention, hyperuricemia, hypokalemia

Folate Deficiency Anemia:

Folic Acid 1 mg PO daily until corrected (4 months)

Vitamin B 12 and folate deficiencies can lead to macrocytic anemias in the elderly. Because cognitive dysfunction associated with B 12 deficiency may only respond initially, screening for B 12 deficiency in elderly may be warranted. It is also recommended that organic brain syndrome, unexplained psychosis, peripheral neuropathy, prior gastrectomy, macrocytosis or hypersegmented neutrophils be tested for vitamin B 12 deficiency.Pernicious anemia, which increases in prevalence with advancing age, results from malabsorption of vitamin B 12 caused by the absence of intrinsic factor secondary to destruction of gastric parietal cells or as occurs in ileac disease or atrophic gastritis.

Inadequate dietary consumption of vitamin B 12 is not common unless the diet is poor. Malabsorption of cobalamin results in the inability of vitamin B 12 to be cleared and released from proteins in food due to inadequate gastric acid production. Supplemental cobalamin is absorbed since it is not protein bound. Crystallin B 12 does not require gastric acid or enzymes for digestion. Based on usual dietary intake and body stores, it usually takes several years to develop vitamin deprevation.

Copyright 2011 American Society of Consultant Pharmacists

Macrocytic Anemia: Diagnosis and Treatment

Treatment consists of cyanocobalamin once a day for seven days, followed by weekly injections until stores are replenished and hemoglobin and hematocrit are normalized. Parenteral treatment is preferred in patients with neurologic symptoms. Rebound thrombocytosis with B 12 treatment may precipitate thrombotic events. Patients usually respond with improved well being within a few days and glossitis improves quickly. If treated early neuropsychiatric sign and symptoms can be reversible.

Anemias related to folate deficiency are generally the result of protein-energy malnutrition or excessive alcohol consumption. One milligram of folic acid daily is usually sufficient to correct the problem, although doses as high as five milligrams per day may be needed for patients with malabsorption syndromes. Before beginning folate therapy, it is important to exclude B 12 anemia, since folate will correct the anemia but leave the neurological disorders associated with severe vitamin B 12 deficiency untreated.

The red blood cell precursors megaloblasts can have abnormal development in drug induced megaloblastic anemia.

Copyright 2011 American Society of Consultant Pharmacists

Diagnosis:

Sideroblastic Anemia

Reticulocyte count is low • MCV may be low, normal or high • Serum Fe, transferrin, saturation, ferritin levels high

Peripheral smear shows marked anisocytosis, poikilocytosis

Treatment:

Pyroxidine 200mg daily • If unresponsive, treat symptomatically

Sideroblastic anemias may be primary or secondary to other conditions. They are characterized by impaired heme synthesis and the presence of iron deposits in the mitochondria of normoblasts.Since heme isn’t being synthesized, iron accumulates and can damage the mitochondria and cell. Iron accumulation can overload the body.The acquired form is primarily a disease of the elderly and is often a myelodysplastic syndrome or secondary to a hematologic malignancy, B 12 or folate deficiency, or rheumatic disease.

Patients with sideroblastic anemia show marked anisocytosis and poikilocytosis. Serum iron and transferring saturation and ferritin levels are normal or elevated. A hypochromic anemia in an elderly person without iron deficiency is usually sideroblastic anemia. Management of sideroblastic anemias is supportive rather than curative.Patients may respond to two hundred milligram doses of oral pyroxidine daily for one to two months.

Copyright 2011 American Society of Consultant Pharmacists

Hemolytic Anemia

Common Causes of Hemolytic Anemia

Intrinsic (intracorpuscular, usually membrane defect inherited Spherocytosis and elliptocytosis • Hemoglobin defect

Sickle cell anemia • Thalassemia • Metabolic defect • Glucose-6-phosphate dehydrogenase (G6PD) deficiency

Extrinsic (extracorpuscular, acquired) Membrane defect • Autoimmune hemolytic anemia

Oxidants

Lab

Normocytic normochromic • Increased reticulocyte count • Elevated LDH • Elevated indirect bilirubin

Positive coombs test (autoimmune)

Copyright 2011 American Society of Consultant Pharmacists

Hemolytic Anemia

Hemolytic anemia results from decreased RBC survival time secondary to destruction.Increased reticulocyte production usually suggests hemolytic anemia. As the destruction of red blood cells overwhelms the capacity of normal bone marrow to correct falling hematocrit, indirect bilirubin and serum LDH levels increase.

A positive Coombs test is conclusive for autoimmune hemolytic anemia, the most common type among the elderly. Such anemias are likely to be associated with non-Hodgkin’s lymphoma or chronic lymphocytic leukemia. A related disorder of some importance to the elderly is microangiopathic hemolytic anemia. It is usually associated with severe infections or neoplasms, and is characterized by red cell fragmentation, thrombocytopenia, prolonged partial thromboplastin time and hemosiderinuria.

Drug induced immune hemolytic anemia may be caused by penicillin, quinidine, alpha-methyldopa, and cephalosporins. Its onset is variable depending on the drug and mechanism for hemolysis, when it is caused by the hapten/adsorption mechanism it is slower and of mild to moderate severity. If it is the innocent bystander mechanism, it can be sudden and result in renal failure. Other symptoms include fatigue, malaise, pallor, and shortness of breath. Treatment is removal of the offending agent and supportive. Glucocorticoids are sometimes used.

Copyright 2011 American Society of Consultant Pharmacists

For additional information, see:

Resources

Guralnak JM, Eisenstaedt RS, Ferrucci L. Prevalence of anemia in persons 65 years and older in the United States:

Evidence for a high rate of unexplained anemia. Blood. 2004;104:2263-2268.

Steensma DP, Tefferi A. Anemia in the elderly. How should be define it, when does it matter, and what can be done? May Clin Proc. 2007;82:958.

Arronow WS. Homocysteine. The association with atheroschlerotic vascular disease in older persons. Geriatrics.

2003;58:22-28.

Denny SD, Kuchibhatia MN, Cohen HJ. Impact of anemia on mortality, cognition, and function in community-dwelling elderly. Am J Med. 2006;119:327-334.

Gehrs BC, Friedberg RC. Autoimmune hemolytic anemia. Am J Hemotol. 2002;69:258-271.

Culleton BF, Manns BJ, Zhang J, et.al. Impact of anemia on hospitalization and mortality in older adults. Blood.

2006;107:3841-3846.

Park S, Johnson MA. What is an adequate dose of oral vitamin B 12 in older people with poor vitamin B 12 status? Nutr Rev. 2006;64:373-378.

Weiss GW, Goodnough LT. Anemia of chronic disease. N Engl J Med. 2005;35:1011-1023.

Woodman R, Ferrucci L, Guralnik J. Anemia in older adults. Curr Opin Hemotol 2005;12:123-128.

Copyright 2011 American Society of Consultant Pharmacists

Resources

Eisenstaedt R, Penninx BW, Woodman KC. Anemia in the elderly. Current understanding and emerging concepts. Blood Rev. 2006;20:213-226.

Mulligan JE, Greene GW, Caldwell M. Sources of folate and serum folate levels in older adults. J Am Diet Assoc.

2007;107:495-499.

American Medical Directors Association (AMDA). Anemia in the long-term care setting. Columbia (MD). American Medical Directors Association (AMDA). 2007.28p.

Copyright 2011 American Society of Consultant Pharmacists

White Blood Cell Disorders

Learning Objectives:

By the end of this review section, you should be able to:

Explain current notions regarding the effect of aging on white blood cell function.

Describe common causes of abnormally high and low counts of circulating neutrophils.

List medications that are known to cause neutropenia.

Describe common causes of abnormally high and low counts of circulating lymphocytes.

Describe common causes of abnormally high counts of circulating basophils, monocytes, and eosinophils.

List malignant and nonmalignant clonal disorders of the white cells.

Describe signs and symptoms, recommended treatment, prognosis, and survival rate for patients with chronic myelocytic and chronic lymphocytic leukemia.

Describe signs and symptoms, recommended treatment, prognosis, and survival rate for patients with polycythemia vera.

Describe signs and symptoms, recommended treatment, prognosis, and survival rate for patients with acute myeloblastic, acute lymphoblastic leukemia, and acute promyelocytic leukemia.

Describe signs and symptoms and chemotherapeutic treatment for patients with Hodgkin’s disease and non-Hodgkin’s lymphomas.

Copyright 2011 American Society of Consultant Pharmacists

Hematological Profiles of Young and Elderly Adult

Parameter

 

Young Adult

 

Elderly Adult

Neutrophil (x 103/ml)

5.9

± .03

4.5

± 0.6

Leukocyte (x 103/ml)

8.8

± .04

7.6

± 0.5

Lymphocyte (x 103/ml)

1.9

± .08

1.9

± 0.3

Conditions such as chronic lymphocytic leukemia, polycythemia vera, and atypical chronic myelocytic leukemia occur with such frequency in the aged population that they could be considered diseases of the elderly.While superficial comparisons of hematologic profiles between otherwise normal young and old adults reveal no significant differences, research focusing on bone marrow and white cell function in the elderly suggest an age- related reduction in immune response.

Copyright 2011 American Society of Consultant Pharmacists

Age-Related Changes in Reserve Capacity

Age-Related Changes in Reserve Capacity Studies have shown, for example, that while neutrophils from both young

Studies have shown, for example, that while neutrophils from both young and old individuals secrete the same amount of enzymes in the basal state, the number and rate of secretion after stimulation is markedly lower in the elderly.When combined with age-related protein deficiency, this reduced reserve capacity may interfere with the neutrophil’s ability to kill invading bacteria, making the individual more susceptible to disease.

Copyright 2011 American Society of Consultant Pharmacists

Abnormally High Neutrophil Counts (> 6.7 X 103/ml)

Malignant:

Metastatic cancer

Proliferative hematological disorders (e.g., chronic myelocytic leukemia and

polycythemia vera)

Non-malignant:

Acute infections, esp. coccal infections burns • Myocardial infarction • Gout Corticosteroid use

Increased epinephrine secretion or injections

Absolute changes in neutrophil counts produce the same kinds of disorders in the elderly as in younger adults. Neutrophil counts above six point seven times ten to the third neutrophils per microliter (6.7 X 103/ml) produce neutrophilia, which may be the result of malignancies or nonmalignant causes such as acute infections, burns, myocardial infarction and gout.Neutrophilia can also caused by glucocorticoid secretion secondary to infection or corticosteroid treatment.Physiologic neutrophilia is often noted following heightened secretions or injections of epinephrine.A common characteristic of nonmalignant neutrophilias is that immature leukocytes are rarely seen.

Copyright 2011 American Society of Consultant Pharmacists

Abnormally Low Neutrophil Counts (< 1.4 X 103/ml)

Diminished Neutrophil Supply:

Deficiencies of B12 , folic acid • Cachexia • Alcoholism

Overwhelming bacterial or viral infections MDS, leukemias, myeloproliferative disorders Aplastic anemia Prescription drugs and chemotherapeutic agents

Pseudoneutropenias:

Endotoxemia

Fealty’s syndrome • Idiopathic

Neutropenia is defined as an absolute blood neutrophil count below one point four times ten to the third neutrophils per microliter. Depending on production and distribution factors, neutropenia may be the result of nutritional deficiencies, infections, or hematological disorders. Neutropenias associated with reduced serum B12 or folic acid suggests infections, alcoholism or nutritional deficiencies, and are best managed with appropriate vitamin and/or antibiotic therapy.Acute leukemia and aplastic anemia should be suspected whenever neutropenia is accompanied by other cytopenias, by the presence of immature nucleate cells, and by bone tenderness or splenomegaly.

Copyright 2011 American Society of Consultant Pharmacists

Drug-induced Neutropenia

Ionizing radiation

Chemotherapeutic agents – e.g., methotrexate, vincristine, vinblastine, procarbazine, hydroxyurea • Alkylating agents •

Anthracycline derivatives •

Analgesics • H2 blockers

• • Antibiotics – e.g., chloramphenicol, furadantin, sulfa drugs, penicillins, cephalosporins, gentamicin, metronidazole • Anticonvulsants – e.g., diphenylhydantoin, phenobarbital, carbamazepine • Antithyroid agents – e.g., thiouracils, methimazole, carbimazole

NSAIDs – e.g., indomethacin • Tricyclic and tetracyclic antidepressants – e.g., imipramine • Tranquilizers – e.g., phenothiazines

Antibacterial, diuretic, and hypoglycemic agents – e.g., sulfonamide, linezolid •

Antimetabolites

Colchicine

Antihistamines

Medications are a common source of neutropenia, especially among the elderly.Some chemotherapeutic agents routinely cause neutropenia if prescribed in sufficient quantity.These include alkylating agents, antimetabolites, colchicine, and RNA/DNA synthesis inhibitors.Because of their diminished hemopoietic reserve capacity, elderly patients are especially sensitive to chemotherapy, and may need therapeutically administered cytokines to ameliorate its effects.

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The Role of Lymphocytes in Host Immunity

The Role of Lymphocytes in Host Immunity •   Production of antibodies •   Maintain the

Production of antibodies • Maintain the ability to mount delayed hypersensitivity reactions

Production of cytokines to regulate blood cell production

As with neutrophils, abnormally high or low counts of circulating lymphocytes can have a significant impact on health.Lymphocytes contribute to host immunity by interacting with one another to generate antibodies, by maintaining the ability to mount delayed hypersensitivity reactions, and by producing cytokines, which regulate blood cell production.

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Abnormal Counts of Lymphocytes

High (> 3.22 X 103/ml) Cytomegalovirus infection

Infectious hepatitis Thyrotoxicosis Chronic lymphocytic leukemia

T-cell lymphomas Prolymphocytic leukemia Hairy cell leukemia

Low (> 0.9 X 103/ml) Undernutrition

Tuberculosis Lymphomas AIDS / HIV

Heart failure Acute bacterial infection Corticosteroids

Abnormally high lymphocyte counts, or lymphocytosis, can be caused by malignancies such as chronic lymphocytic leukemia, or by nonmalignant disorders such as transfusion-induced cytomegalovirus infection.Abnormally low lymphocyte counts or lymphopenia may be caused by a variety of conditions, including undernutrition, tuberculosis, lymphomas and AIDS.Less than two hundred C-D-4 T-cells per cubic millimeter indicates severe HIV infection.Acute bacterial infection and the use of corticosteroids also reduce lymphocyte counts.

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Abnormally High Counts of Other White Blood Cells

Eosinophilia (> 0.7 X 103/ml):

Allergic drug reactions Angioneurotic edema Bronchial asthma

Allergic and non-allergic skin conditions Parasitic infections

Monocytosis (> 0.95 X 103/ml):

Listeriosis Tuberculosis Bacterial endocarditis

Malignancies Lymphomas Collagen vascular disease

Sarcoidosis

Basophilia (> 0.09 X 103/ml):

Chronic myelocytic leukemia Polycythemia vera Hodgkin’s disease

Changes in circulating levels of other white blood cells can alert the clinician to a variety of underlying conditions. For example, increases in eosinophil counts are often seen in allergic disorders and drug reactions.

Parasitic infection may also produce eosinophilia. Increases in monocyte counts are associated with listeriosis or tuberculosis, both of which are caused by pathogens that infect monocytes and macrophages.An increase in basophils usually accompanies hematological disorders such as polycythemia vera and Hodgkin’s disease.

While reductions in circulating basophils and monocytes are not necessarily associated with disease, eosinopenia is usually a sign of bacterial infection or some other non-infectious inflammatory process.

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Hematologic Malignancies

Chronic myelocytic leukemia (CML)

Polycythemia vera (PV) • Chronic lymphocytic leukemia (CLL) • Acute myeloblastic leukemia (AML)

Acute promyelocytic leukemia (APL) • Hodgkin’s disease (HD) • Non-Hodgkin’s lymphomas (NHL)

A number of malignant and nonmalignant clonal disorders of the white cells have their greatest incidence in the later years.The peak incidence of chronic myelocytic leukemia, chronic lymphocytic leukemia, and acute myeloblastic leukemia all occur in individuals over age sixty, and increase fourfold by age eighty. Hematologic malignancies such as multiple myeloma and other plasma cell dyscrasias are discussed with thrombotic disorders

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Chronic Myelocytic Leukemia

Signs & Symptoms:

WBC 27 to 1076 X 103/ml • Anemia • Increased neutrophils with very immature

precursors • Splenomegaly and sternal tenderness • Pallor, fatigue, weight loss

Treatment:

Alkylating agents such as busulfan • Interferon-alpha

Hydroxyurea • Marrow transplantation (for younger patients) • Imatinib mesylate

Complications:

Acute leukemia

Infection

Hemorrhage

Elevated total leukocyte counts with neutrophilia may

point to chronic myelocytic leukemia (CML). The

patient often presents with splenomegaly and sternal tenderness, as well as less definitive signs such as pallor, fatigue and weight loss. Very immature neutrophil precursors, blasts, are frequently seen on the blood smear.

CML is usually further categorized as chronic,

accelerated, or blast phases. Many patients present in the chronic phase with abnormal blood counts, positive genetic tests, and little or no other complaints.

Even with treatment, the chronic phase progresses to

the accelerated phase in which new genetic abnormalities are present and more immature cells can be found in the peripheral blood. Generally, there

must be >10% blasts and >20% basophils to be

considered in the accelerated phase.

The disease may further progress to the blast phase, or “blast crisis,” in which >20-30% of the circulating white blood cells are blast cells. Immediate chemotherapy is needed when a patient enters the

blast phase.

Prognosis:

40 months median survival rate

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Chronic Myelocytic Leukemia

Elevated total leukocyte counts with neutrophilia may point to chronic myelocytic leukemia (CML).The patient often presents with splenomegaly and sternal tenderness, as well as less definitive signs such as pallor, fatigue and weight loss.Very immature neutrophil precursors, blasts, are frequently seen on the blood smear.CML is usually further categorized as chronic, accelerated, or blast phases.

Many patients present in the chronic phase with abnormal blood counts, positive genetic tests, and little or no other complaints. Even with treatment, the chronic phase progresses to the accelerated phase in which new genetic abnormalities are present and more immature cells can be found in the peripheral blood. Generally, there must be >10% blasts and >20% basophils to be considered in the accelerated phase. The disease may further progress to the blast phase, or “blast crisis,” in which >20-30% of the circulating white blood cells are blast cells. Immediate chemotherapy is needed when a patient enters the blast phase.

When remission is induced in the chronic phase with chemotherapy, functional status generally improves; however, survival is not necessarily increased.The acute phase is usually resistant even to aggressive therapy. Bone marrow transplantation is usually not a viable option for patients over 65 years old, however, is the preferred treatment modality.If a bone marrow transplant is not an option, the patient may be started on imatinib mesylate, which will be discussed later, or interferon-alpha. Interferon-alpha is an immune system regulator that controls the abnormal white blood cell counts in about eighty percent of patients. Many patients are unable to tolerate the side effects of interferon- alpha which include nausea, flu-like symptoms, and weight loss.

Hydroxyurea, an antimetabolite, has also shown median survival benefit in patients with CML. Hydroxyurea can be used as a single agent, but is commonly used in conjunction with interferon-alpha treatment. Hydroxyurea is a preferred agent, especially for those who may undergo a bone marrow transplant at a later date. There has been some recent speculation that prior treatment with interferon-alpha may contribute to improper bone marrow engraftment if a bone marrow transplant is an option for the patient after disease progression. Alkylating agents such as busulfan are rarely used anymore due to profound pancytopenia and other undesirable side-effects.

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Imatinib mesylate (Gleevec®)

A tyrosine kinase inhibitor

Side effects:

Nausea

Muscle cramps

Diarrhea

Rash

Headaches

Edema

Imatinib mesylate may be used as the primary treatment for patients in the chronic or accelerated phase, or in patients who have failed interferon-alpha therapy. Imatinib is also used in patients whose physical condition or other circumstances render them unable to undergo a bone marrow transplant.Imatinib is a protein-tyrosine kinase inhibitor that inhibits Bcr-Abl, the constitutive abnormal, tyrosine, kinase created by the Philadelphia chromosome, abnormality in chronic myeloid leukemia. Early responses are very promising, however, the survival benefit, long-term toxicities, and durability of response are unknown. The normal dose of imatinib is 400mg once a day, however, doses of 600-800mg a

day or more have been used in the accelerated and blast phases headaches, muscle cramps, and rash.

Common

side effects include nausea, edema,

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Polycythemia Vera

Signs & Symptoms:

WBC >12 X 103/ml Increased hematocrit Headache, dizziness, visual disturbances

Weakness Pruritus, esp. after bathing Ruddiness of the face Splenomegaly

Treatment:

Phlebotomy

Hydroxyurea Interferon-alpha Radioactive phosphorus

Alkylating agents

Complications:

Myelofibrosis Acute leukemia

Polycythemia vera is the result of clonal proliferation of primitive precursors or stem cells from which other blood elements are formed. About forty percent of cases occur in individuals sixty-five or older. Patients present with headache, weakness, visual disturbances and dizziness.

Ruddiness of the face and splenomegaly are common, and patients often complain of itchiness after bathing. Hematologically, the disease is characterized by an increase in circulating red cells and increased hematocrit. Leukocyte counts may also be increased.

Treatment is focused on the reduction of hematocrit values, through phlebotomy or chemotherapy. Hydroxyurea, an antimetabolite, has been effectively used to reduce the number of circulating cells. For patients who cannot tolerate hydroxyurea or for whom the drug does not control the peripheral blood count, interferon-alpha may be an effective option.

Radioactive phosphorus (32P) has a high success rate, however, is used only in elderly patients with life expectancies of less than five years because it causes leukemia in about 10% of patients. Alkylating agents have been used in the past, however are now usually avoided due to the incidence of transformation of polycythemia vera into an acute leukemia.

Prognosis:

12 years median survival rate

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Chronic Lymphocytic Leukemia

Signs & Symptoms:

Lymphocyte count > 10 X 103/ml • Marrow aspirate > 30% lymphocytes • Most peripheral blood lymphocytes with B cell markers

Lymphadenopathy, splenomegaly, and/or hepatomegaly

Fatigue

Complications:

Thrombocytopenia

Lymphocytosis

Chronic lymphocytic leukemia is usually a consequence of malignant clonal proliferation of B-lymphocytes.It is characterized by a sustained blood lymphocyte count above ten times ten to the third per microliter, marrow aspirate of greater than thirty- percent lymphocytes, and a majority of peripheral blood lymphocytes with B cell markers.Patients often complain of fatigue, and lymphadenopathy, splenomegaly, and hepatomegaly are also common.About a fourth of patients who present with chronic lymphocytic leukemia are asymptomatic.

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Chronic Lymphocytic Leukemia

Staging – Rai system (median survival prognosis)

Stage 0: Lymphocytosis alone (>12 yrs) Stage 1: Lymphadenopathy (8.5 yrs)

Stage 2: Hepatomegaly +/- splenomegaly (6 yrs) Stage 3: Hb < 10 g/dl (1.5 yrs) Stage 4: Platelets < 100 x 109/L (1.5 yrs)

CLL is commonly divided into five stages to more accurately describe the progression of the patients malignant disease. Stage 0 is when a patient has a lymphocyte count >15,000 /mm3. When a patient begins to have physically detectable enlarged lymph nodes, he or she has progressed to Stage 1 and is at an intermediate risk of malignant complications. When the liver and spleen become involved, the patient is said to have Stage 2 disease. Stage 3 disease is considered high risk and is present when the patient’s hemoglobin count falls to < 10g/dL. Thrombocytopenia due to CLL is Stage 4 disease and also associated with high risk. Other findings such as a rapid doubling time and poor performance status are important to address when assessing a patient. The entire spectrum of co-morbid conditions will play a part in determining the acuity of disease and intensity of treatment.

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Chronic Lymphocytic Leukemia

Treatment:

Alkylating agents • Chlorambucil, cyclophosphamide • Purine analogs

Bone marrow transplant

• • Radiation therapy

Fludarabine

Corticosteroids

Pharmacotherapy usually involves the use of alkylating agents such as chlorambucil and cyclophosphamide. The purine analogs, such as fludarabine, are now first line treatments for CLL. Fludarabine has shown significant advantages over chlorambucil in the areas of complete remission and duration of remission. Due to a high incidence of opportunistic infection, patients older than 65 years old do not do as well with fludarabine treatment.

Corticosteroids and radiotherapy may also be prescribed along with chemotherapy to combat chronic lymphocytic leukemia. Bone marrow transplants are also being considered more frequently with a goal of complete remission.

Bone marrow transplant is the only treatment that may result in a cure; therefore, pharmacotherapy and radiation are usually delayed until the patient is stage 3 or 4, or has significant symptoms related to either organomegaly or splenomegaly.

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Acute Myeloblastic and Acute Lymphoblastic Leukemia

Signs & Symptoms:

Elevated WBC,> 100 X 103/ml in 20% of cases • Neutropenia and thrombocytopenia • Blast cells evident in blood smear

Fever, pallor, weight loss • Petechiae, ecchymoses, epistaxis

Treatment:

Anthracycline derivatives (daunorubicin) • Bone marrow transplant • Standard or high-dose cytarabine

Etoposide

Complications:

Perirectal abscess • Necrotizing colitis

Prognosis:

Varied

Acute myeloblastic leukemia and acute lymphoblastic leukemia are both diseases of the elderly.Clinical presentation is based on the cytopenias that occur in the absence of normal red blood cell production.Total leukocyte count is elevated in over fifty percent of cases. Patients are typically anemic, with thrombocytopenia and neutrophilia. Fever and pallor are common, and weight loss, petechiae, ecchymoses, and epistaxis occur in about half of patients. Some patients may experience bowel problems secondary to leukemic involvement of the colon. Treatment of acute myeloblastic leukemia is relies on the use of multiple chemotherapeutic agents.Standard-dose cytarabine (100-200mg/m2/day for 5-7 days) cytarabine or high-dose (1-1.5g/m2/dose for 4-6 doses) cytarabine with daunorubicin (50mg/m2 on days 1-3) have been tested in international trials.

Both regimens have approximately equal response rates, however, the duration of response is significantly increased with the high-dose cytarabine regimen. Due to increased toxicity of the high-dose cytarabine regimen, most patients over the age of sixty receive the standard-dose treatment. Etoposide may also be added to the cytarabine/daunorubicin regimen. Etoposide does not increase the percentage of remissions, however may increase the durability of remission. Following chemotherapy, bone marrow is often destroyed with the leukemic population, leaving the patient extremely cytopenic and at risk for infection. In spite of this drawback and increased sensitivity of elderly patients to toxic effects of chemotherapy, remission is induced in fifty to sixty percent of cases.

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Acute Promyelocytic Leukemia

Signs & Symptoms:

Fever, pallor, weight loss

Increasing WBC, >10 X 103/µ L

Blasts evident in blood smear (>30% blasts)

Shortness of breath, hypoxemia

Pleural effusions

Coagulation abnormalities

Disseminated intravascular coagulopathy

Treatment:

ATRA (all-trans retinoic acid)

Chemotherapy (anthracycline and cytarabine), Arsenic trioxide

Bone marrow transplant

Acute promyelocytic leukemia (APL) is a subgroup of acute myeloblastic leukemia (AML), known as AML-M3. APL commonly presents with bleeding problems or severe respiratory complications. ATRA, or all-trans retinoic acid, is the first line treatment agent that stimulates terminal differentiation of promyelocytes to mature neutrophils leading to eventual apoptosis. When combined with chemotherapy, there is an 80-95% chance of complete remission. ATRA is often associated with liver and skin complications. Arsenic trioxide is most commonly used in patients who have experienced a relapse after conventional therapy. Arsenic also promotes cell differentiation and eventually cell apoptosis. Arsenic is known to cause QT interval prolongation, retinoic acid syndrome, and gastro-intestinal complaints. Allogenic bone marrow transplant can also be used to treat APL.

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Hodgkin’s Disease

Hodgkin’s Disease Primary populations affected: Ages 20 - 30 years 70 - 80 years (men >

Primary populations affected:

Ages 20 - 30 years

70 - 80 years (men > women)

The incidence of Hodgkin’s disease peaks with two different age groups: young adults aged twenty to thirty, and elderly adults aged seventy to eighty. Men far outnumber women in late onset Hodgkin’s disease. Although a specific etiologic factor has not been found for either group, there is some evidence to suggest a different mechanism at work in each case. Studies show a greater mix of histologic types in elderly patients compared with their younger counterparts. In all age groups, adenopathy is the most common presenting sign.

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Clinical Presentation of Hodgkin’s Disease

Early signs and symptoms:

Fever

Sweats

Lymphadenopathy

Splenomegaly

EtOH intolerance • Abnormal white blood cell counts

Advanced Signs and Symptoms:

Unexplained persistent fever* • Weight loss > 10% body weight in 6 months*

Recurrent drenching night sweats* • Lymphoma present in bone marrow biopsy • “B Symptoms”

One of the first presenting symptoms of Hodgkin’s disease is a painless swelling of the lymph nodes. The typical sites of lymphadenopathy are the neck, axillae, chest, and inguinal areas. Patients with more advanced disease also present with fever, loss of appetite and noticeable weight loss, and drenching night sweats. These signs are commonly dubbed “B symptoms.” Definitive diagnosis is made through abnormal blood counts, lymph node biopsies, and malignant cell morphology, such as the presence of large Reed-Sternberg cells.

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Ann Arbor Staging System

Stage I

Stage II

Stage III

Stage IV

Staging of Hodgkin’s Lymphoma

Stage II Stage III Stage IV Staging of Hodgkin’s Lymphoma (A/B) – absence/presence of “B” symptoms

(A/B) – absence/presence of “B” symptoms

>Fever >Drenching night sweats >Weight loss >Fatigue >Appetite loss >Red patches on the skin >& severely itchy skin often affecting the legs/feet.

(E)

– extranodal involvement

(X)

– bulky disease, >10cm

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Staging of Hodgkin’s Lymphoma

The Ann Arbor staging system was developed in 1971 for the staging of Hodgkin's disease. This staging system focuses on the number of tumor sites (nodal and extranodal), location, and the presence or absence of systemic "B" symptoms.

Stage I refers to NHL involving a single lymph node region (stage I) or a single extralymphatic organ or site (stage IE).

Stage II refers to two or more involved lymph node regions on the same side of the diaphragm (stage II) or with localized involvement of an extralymphatic organ or site (stage IIE).

Stage III refers to lymph node involvement on both sides of the diaphragm (stage III), or with localized involvement of an extralymphatic organ or site (stage IIIE).

Stage IV refers to the presence of diffuse or disseminated involvement of one or more extralymphatic organs (e.g., liver, bone marrow, lung), with or without associated lymph node involvement.

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Some Chemotherapeutic Regimens Used to Treat Hodgkin’s Disease

MOPP:

Nitrogen mustard, Oncovin (vincristine), Procarbazine, prednisone

ABVD:

Adriamycin (doxorubicin), bleomycin, Vinblastine, dacarbazine (DTIC)

MOPP/ABVD:

Nitrogen mustard, Oncovin (vincristine), Procarbazine, prednisone, Adriamycin DTIC

BCVPP:

(doxorubicin), bleomycin, vinblastine,

BCNU, cyclophosphamide, vinblastine, procarbazine, prednisone

Bone marrow transplant

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Some Chemotherapeutic Regimens Used to Treat Hodgkin’s Disease

Treatment of Hodgkin’s disease depends on adequate staging. Patients with early stage disease (IA or IIA) are effectively treated with radiation therapy. Patients with later disease (IIB, III, IVA, or IVB) are treated with combination chemotherapy alone.

Patients of any stage with a large mass in the chest are usually treated with combined chemotherapy and radiation therapy. The use of chemotherapy and/or radiotherapy has led to a 75% cure rate in patients with Hodgkin’s disease, with 94% of patients worldwide expected to survive at least ten years. Older chemotherapeutic regimens included the use procarbazine and prednisone; in combination with either nitrogen mustard and Oncovin, or cyclophosphamide and vinblastine. National randomized trials have shown that ABVD-containing regimens are superior to MOPP. ABVD is now used first-line, with the option of using MOPP as a salvage regimen. Alternating and hybrid regimens using these medications are common.

Vinblastine and methotrexate are not well tolerated, possibly due to decreased renal function and drug clearance. Despite poorer survival rates and increased risk of toxicity, elderly patients may be successfully treated through these techniques. Bone marrow transplant is used as a salvage therapy in younger patients, however, is not usually an option in the elderly.

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Non-Hodgkin’s Lymphomas

Well differentiated lymphocytic lymphoma

Nodular, poorly differentiated, lymphocytic lymphoma

Non-Hodgkin’s lymphomas are a varied group of proliferative disorders that involve clonal expansion of lymphoid cells.The twenty-five percent increase in incidence since 1950 parallels the growth of both the elderly population and AIDS-related malignancies. The most common lymphomas in older adults are the low grade lymphomas, either well- differentiated lymphocytic lymphoma, or nodular, poorly differentiated lymphocytic lymphoma.Both originate from B- cells.The median age of patients with these kinds of tumors is fifty-five, although the poorly differentiated variety rarely occurs after age seventy. Histology more important in defining prognosis:Low; intermediate; high grade lymphomas.

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Clinical Presentation of Non-Hodgkin’s Lymphoma

Early Signs and Symptoms (rare):

Fever

Sweats

Weight loss

Advanced Signs and Symptoms:

Multiple lymph node involvement

Splenomegaly • Lymphomas in bone marrow biopsy

Because early symptoms are rare, patients with non-Hodgkin’s lymphomas typically present with signs of advanced disease. The involvement of multiple lymph nodes in the neck, axillae, inguinal area, mediasternum, and paraaortic area. Splenomegaly will often be present, and bone marrow biopsy will reveal lymphoma in the majority of cases. Non- hodgkin’s lymphoma is commonly staged using a system similar to the Ann Arbor Staging System for Hodgkin’s disease. One of the differences is that an “S” is used to reflect splenic involvement (ex. Stage IIIS). Patients in the latter stages of non-Hodgkin’s lymphoma are rarely curable, and the median survival is five to eight years.

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Some Chemotherapeutic Regimens Used to Treat Non-Hodgkin’s Lymphoma

CVP

Cytoxan, vincristine, prednisone

COPP

Cyclophosphamide, Oncovin (vincristine), Procarbazine, prednisone

CHOP

Cyclophosphamide, Adriamycin (doxorubicin), Oncovin (vincristine), prednisone

ICE

Ifosfamide, carboplatin, etoposide

ESAP

Etoposide, methylprednisolone, cytarabine, Cisplatin

R

Rituxumab

Radioimmunotherapy

Zevalin (ibritumomab-Y90)

Bexxar (tositumomab-I161)

Copyright 2011 American Society of Consultant Pharmacists

Some Chemotherapeutic Regimens Used to Treat Non-Hodgkin’s Lymphoma

Treatment of non-Hodgkin’s lymphomas is less dependent on precise pathological staging than it is for Hodgkin’s disease, since curative radiation therapy is not a viable option. Chemotherapeutic options vary from less aggressive single agent therapy to more aggressive multiagent regimens. Appropriate treatment protocols should be consulted for current dosing and administration guidelines.

While early, aggressive treatment does not produce permanent remission, such treatment may be beneficial to patients with significant symptomatology. CHOP or CHOP+R have become standard first line therapies in the treatment of low- grade non-Hodgkin’s lymphomas. These regimens are commonly used in elderly patients because of favorable toxicity profiles and superior remission rates. ICE and ESAP are non-cross resistant salvage regimens that can be used in patients who relapse after initial cycles of chemotherapy.

Radioimmunotherapy is a new treatment option for the patients with non-Hodgkin’s lymphoma that have relapsed after at least two previous chemotherapy regimens. These drugs consist of CD20 antibodies that have been chemically linked to a radioisotope of either iodine or yttrium. CD20 is a transmembrane protein that is expressed on most malignant B cells.

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For additional information, see:

Resources

Beutler, E. et al. William’s Hematology, 6th ed. New York: McGraw-Hill. 2001.

Ershler, W. B.(1994). Malignant lymphoma, Hodgkin’s disease, and multiple myeloma.In Hazzard, W. R., Bierman, E.L., Blass, J. P., Ettinger, W. H. & Halter, J. B. (Eds.). Geriatric Medicine and Gerontology, 3rd ed.New York:McGraw-Hill:

763-773.

Hamblin, T. (1993). Recent advances in the management of myelodysplastic syndromes. Hematol Oncol; 11(Suppl 1):

27-31.

Ravel, Richard (1995). Clinical Laboratory Medicine, Clinical Application of Laboratory Data, 6th Ed. Mosby.

Rothstein, G.(1994). White cell disorders.In Hazzard, W. R., Bierman, E.L., Blass, J. P., Ettinger, W. H. & Halter, J. B. (Eds.). Geriatric Medicine and Gerontology, 3rd ed.New York:McGraw-Hill: 749-761.

Scott, R. B. (1993). Common blood disorders: a primary care approach. Geriatrics; 48(4): 72-6, 79-80.

South Bank University’s Radiology Museum: Hodgkin’s Disease

Cells Alive

National Comprehensive Cancer Network

http://www.nci.nih.gov

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Disorders of Hemostasis

Learning Objectives:

By the end of this review concept, you should be able to:

Describe possible hemostatic etiologies which can explain the presence of petechiae, ecchymoses, major bleeding and hemorrhage.

Recognize signs and symptoms, as well as current treatment options, for von Willebrand's disease, disseminated intravascular coagulation and ITP.

Recognize signs and symptoms of vitamin K deficiency, warfarin overanticoagulation, or adverse event of heparin/ LMWH use.

Design a treatment plan, and monitor and evaluate the effects of interventions for a senior patient experiencing vitamin K deficiency, warfarin overdose or adverse effect with a heparin product or LMWH.

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Assessment of Patient for Bleeding Diathesis

1. History of transfusions or bleeding problems

Time from onset to cessation of bleeding • Interventions required to stop the bleeding • Whether bleeding recurred after stopping

2. History of iron responsive anemia

3. Thorough physical examination

The clinical evaluation of an elderly patient with a bleeding disorder requires a thorough history and physical examination, followed by appropriate laboratory studies. A medication history significant for past iron use may suggest anemias or past history of bleeding. Pertinent history includes determining the time from onset to cessation of bleeding, interventions required to stop the bleeding, and whether bleeding recurred after stopping. Spontaneous, excessive or delay in onset of bleeding after injury may be due to a hemostatic disorder. Vascular integrity, platelet function and number, coagulation factors and fibrinolysis may be involved.

A

history of bleeding or need for blood transfusions after a simple procedure is significant. However, a negative history

is

only pertinent if the patient actually was at risk of a bleed. A history of a tooth extraction without abnormal bleeding

supports the absence of inherited bleeding disorder. Careful assessment can identify if bleeding is inherited, acquired, or related to hemostasis. This can guide laboratory testing. A patient without a history of significant trauma or surgery must be considered an unknown entity.

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Laboratory Studies to Assess Clotting Function:

Prothrombin Time (PT) • Activated Partial Thromboplastin Time (aPTT)

Thrombin Time (TT) •

Coagulation Factor Levels

Coagulation Factor Inhibitor Levels • Platelet Count • Bleeding Time •

Fibrinogen Degradation Products (FDP) • Fibrin D-dimers

Fibrinogen

Fibrin

http://www.manfred.maitz-online.de/Publications/Presentations/Blood-Clotting-Cascade.ppt

Hemostasis is maintained through vascular, platelet and coagulation components. Generally, coagulation defects in the elderly are treated as they are in any other group.

Prothrombin time and activated partial thromboplastin time are the routine tests to access clotting function. The protime reflects changes in the extrinsic clotting system and the common pathway.

The aPTT is altered by changes in factor levels in the intrinsic pathway and the common pathway.

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Laboratory Studies to Assess Clotting Function:

The thrombin time is affected by thrombin’s ability to convert fibrinogen to fibrin.

Immunologic and functional assays can measure levels of coagulation factors and coagulation factor inhibitors.

Fibrinogen and the various clotting factor levels can be measured to determine if an abnormality in aPTT is the result of low levels of a given clotting protein. Functional activity can be measured as well as levels of structural fibrinogen.

Platelet counts can be direct or fully electronic automation methodology. Peripheral blood smear is the only way to truly identify quantitative and qualitative platelet abnormalities.

Bleeding time measures the platelet interaction with the blood vessel wall. This test is subject to technical blood factors and a normal bleeding time doesn’t predict safety of surgical procedures and an abnormal one doesn’t predict excess bleeding.

Increased levels of fibrin and fibrinogen degradation products are seen in states of fibrinolysis. These protein fragments result from plasmin activity on fibrin or fibrinogens. Fibrin D-dimers concentrations are degradation products of cross-linked fibrin.

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Possible Etiology: Thrombocytopenia

Platelet dysfunction • Autoimmune disorder • Myelodysplastic syndrome

Acute leukemia

Chronic lymphocytic leukemia

Medications

Infection

HIV

Petechiae and Ecchymoses

Medications   Infection   HIV Petechiae and Ecchymoses Though not always conclusive, certain clinical signs and

Though not always conclusive, certain clinical signs and symptoms suggest a hemostatic disorder. For example, petechiae or minor bleeding usually indicates thrombocytopenia or a defect in the interaction between platelets and the vessel walls.

Bleeding associated with defects in platelet number or function typically present as mucocutaneous signs such as nose bleeds, bleeding from the gums, vaginal bleeding, blood in urine or stool, or bleeding under the skin. Older adults have more friable skin and greater capillary fragility and therefore tend to exhibit ecchymoses on the forearms.

The etiology of thrombocytopenia can be divided into two broad groups: under production or excess destruction. Under production could be a result of myelodysplastic syndromes or leukemias. Usually the red or white cells will also be affected if the low platelet count is due to one of these bone marrow diseases.Excess destruction can be related to autoimmune disorders or drug induced thrombocytopenia. Recurrent infections or immune deficiency states may indicate neutropenia.

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Petechiae and Ecchymoses

Platelets are essential to maintain hemostasis, with a minimum number needed to ensure vascular integrity. Platelets adhere to sites of vascular injury and release mediators that recruit more platelets to the site. Platelet abnormalities result in bleeding immediately after trauma. Delayed bleeding would indicate a coagulation disorder.

Having a low platelet count doesn’t cause symptoms. The bleeding caused by a low platelet count can cause pinpoint red spots or petechiae on the skin (can look like a rash), bruising or purplish areas on the skin called purpura. Petechiae usually result in areas of increased venous pressure and dependent parts of the body, such as feet and ankles. Purpura can also occur with platelet abnormalities. The most common purpuras in elderly are non- thrombocytopenic.

Senile purpura is a nonpalpable ecchymotic area commonly found on the extensor forearms of elderly that is not associated with altered platelet function or quantity.

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Drug-Induced Thrombocytopenia

(NON-CHEMOTHERAPY)

Amiodorone

Chlorpromazine

Indinivir

Procainamide

Amphotericin B

Cimetidine

Interferon

Quinidine

Ampicillin

Danazol

Linezolid

Sulfas

Captopril

Gold

Lithium

Trimethoprim

Carbamazepine

Heparin

Piperacillin

Valproic Acid

Ranitidine

Quinine

Acetamenophen

Ticlopidine

Chlorpropamide

Hydrochlorothiazide

Stop the offending agent!

With new onset thrombocytopenia, any currently administered medications should be reviewed for a possible role in causing the low count. Treatment is simple: stop the offending agent.

Much of the information on drug-induced thrombocytopenia is based on case reports. In assessing this literature, be sure to assess whether the candidate drug preceded the thrombocytopenia and recovery was complete upon discontinuation, etiologies were excluded, other drugs were excluded, re-exposure occurred, and the platelet count was provided.

Patients should be educated that allergic reactions to medicines (Rx and OTC) can decrease platelet counts.

Medications can decrease the number of platelets, cause platelet dysfunction, aplastic anemia or vascular purpura.

Copyright 2011 American Society of Consultant Pharmacists

Abnormal Bruising and Bleeding

Possible Etiology:

Common Medications:

Acquired factor VIII inhibitor

Medications

Aspirin

Clopidogrel

Vitamin K deficiency •

Non-steroidal anti-inflammatory drugs

Heparin

Liver disease

Warfarin

DIC

Malnutrition

• • Senile purpura

Rare Medications:

Ginkgo biloba

Gold

Disorders:

Interferon

Penicillins

Platelet function disorder

Selective serotonin inhibitors (SSRI’s) •

Propothiouricil

Quantitative platelet disorders • factor deficiencies • factor inhibitors

Testosterone

• • Tricyclic antidepressants

Connective tissue • Blood vessel integrity

Important Diagnostic Tests:

Prothrombin Time (PT), Activated Partial Thromboplastin Time (aPTT), , Complete Blood Count (CBC) with platelet count

Copyright 2011 American Society of Consultant Pharmacists

Abnormal Bruising and Bleeding

Abnormal bruising and bleeding are frequent complaints that should prompt a thorough medication history and family history to guide the laboratory evaluation. A standardized bleeding score system is used by physicians as a clinical decision rule.

Patients who present with major bruising suggest a deficiency in one or more coagulation factors.Possible diagnoses include acquired factor VIII inhibitor, vitamin K deficiency, liver disease and disseminated intravascular coagulation.Prothrombin time and partial thromboplastin time are the most useful tests in such cases.

thromboplastin time are the most useful tests in such cases. The PT reflects alterations in clotting

The PT reflects alterations in clotting factors in the extrinsic and common pathways.

APTT reflect alterations in the intrinsic and common pathways.

For platelet function evaluation, Platelet Function Analyzer-100 is used. This should be used with a normal PT and aPTT. With a normal PT and abnormal aPTT, a PTT mixing study should be done. If PTT normalizes, factor VIII, IX and XI assays should be done. If PTT does not normalize lupus anticoagulant and factor VIII inhibitor screening should be done. With an abnormal screening PT and normal PTT, malnutrition or Vitamin K deficiency may be seen. With an abnormal PT and PTT, DIC should be considered.

Copyright 2011 American Society of Consultant Pharmacists

Immune Thrombocytopenic Purpura (ITP)

Lab testing:

Thrombopoietin (TPO) Complete blood count Peripheral blood smear

Symptoms:

Petechiae

Purpura

Ecchymoses

http://www.ouhsc.edu/platelets/

Diagnosis of exclusion:

Familial thrombocytopenia

Hypersplenism Systemic lupus erythematosis Drug-induced HIV

Myelodysplastic Syndrome

Immune thrombocytopenia or ITP was formerly known as idiopathic thrombocytopenic purpura.ITP is an autoimmune disorder characterized by low platelet counts, usually in an otherwise healthy person. A normal complete blood count, white blood cell differential and peripheral blood smear should be found. Incidence rate appears to increase with age, with the highest-age-specific incidence in patients older than age 60.Life-threatening bleeding is more common in older patients.

Frequency of platelet count monitoring is a factor that can greatly influence patient quality of life. Lack of response to treatment can lead to frustration on the part of the patient and health care professional. What may be a safe platelet count for a sedentary elder patient, may be a risky count for an active elder patient. Helicobacter pylori infection may be associated with chronic ITP. Eradication is an option that my improve platelet counts in some patients.

Complication of ITP can be prevented by avoiding medicines such as aspirin or non-steroidal anti-inflammatory agents that can affect platelets.

The process of platelet destruction is accelerated in ITP; with suboptimal platelet production.

Copyright 2011 American Society of Consultant Pharmacists

Immune Thrombocytopenic Purpura (ITP)

Thrombopoietin (TPO) is a growth factor that causes platelet counts to rise. Endogenous TPO drives platelet production on progenitor cells and megakaryocytes. TPO levels may be decreased, normal or slightly inceased in

patients with ITP. This is different than the compensatory increase in TPO seen with thrombocytopenia from other

causes.

is the target of a newly released drug eltrombopag (Promacta ® ). This drug is an oral non-peptide thrombopoietin- receptor agonist that stimulates bone marrow to produce megokaryocytes which are precursors to platelets. A drug with the same mechanism administered subcutaneously once weekly is romiplostim (Nplate ® ).

The failure of compensating platelet production makes ITP unique. The TPO pathway is disrupted in ITP and

Copyright 2011 American Society of Consultant Pharmacists

Therapy of ITP

• • Immune globulin, intravenous immunoglobulin (IVIG)

Rho(D) Immune globulin (IGIV) (WinRho ® ) (anti-Rho(D) antibody to red cell antigen Rho(D) •

Immunosuppressants

Glucocorticoids

Rituximab

Splenectomy

Patients greater than 60 years old have the same therapeutic benefit from steroids, but universally experience greater side effects. Side effects of steroids, especially pertinent to the elderly include: osteoporosis and risk of fracture, risk for serious infection, and accelerated development of cataracts. Blood pressure evaluation is important since risk for hemorrhagic stroke could be increased.

Medical treatment is effective for some patients. Others relapse and others do not respond to medical treatment resulting in splenectomy. The treatment goal for ITP is to treat or prevent bleeding and not to correct the underlying disease. Platelet counts provide information about the risk for bleeding and can guide treatment. Generally, patients with platelet counts greater than 30,000/uL only require treatment if they are symptomatic or have risk factors. Risk factors are : age>60 years, lifestyle (prone to falls) associated coagulation defects, surgery or trauma, uncontrolled hypertension, infection or peptic ulcer disease.

The ideal drug would stimulate platelet production and not suppress the immune system. Treatment of ITP can be worse than the disease. Ever since antiplatelet antibodies were first identified, ITP therapy has been directed at inhibiting platelet destruction. Treatment approaches are to inhibit antiplatelet antibodies or alter the function of macrophages in the reticuloendothelial system.

Copyright 2011 American Society of Consultant Pharmacists

MOA:

Glucocorticoids

Decreased Fc receptor sensitivity • Decreased antibody production • Increase platelet production by impairing bone marrow macrophage

Platelet destruction

Side Effects:

Glucose intolerance •

Psychosis Immunosuppression • Osteoporosis

Steroids appear to lessen Fc receptor sensitivity so that platelets tagged with antibody survive longer.Antibody production may also be decreased. Initial treatment of ITP typically includes steroids. For profound thrombocytopenia with signs of bleeding, very high dose steroids, in the form of methylprednisone 1 gm IV every 24 hours for 3 days is used. High dose dexamethasone 40mg (po or IV) for 4-8 days in cycles has also been used. For less acute cases, prednisone 1 mg/kg daily will be started. This is also the dose that will be started after the high dose protocol. Therapy then will be continued for weeks to months, with a very slow taper in an attempt to avoid a relapse. There is no standard regimen for tapering, but it may be reasonable over 4-6 weeks after achieving a normal platelet count. Patients treated for over three months, should receive calcium and Vitamin D supplementation and bone mineral density monitoring.

Steroids have a long list of potential side effects, including glucose intolerance, mental status changes, increased risk of infection, and bone loss with long term therapy, to list just a few.

Copyright 2011 American Society of Consultant Pharmacists

Intravenous Immune Globulin (IVIG)

MOA:

Decreased Fc receptor sensitivity • Decreased antibody production • Activates inhibitory receptor Fc so platelet clearance is impaired

Side Effects:

Rigors

Fever

Chills

Renal failure

Hypotension

IV immuneglobulin may be useful in a patient with life threatening bleeding or in preparation for surgery. It has even been used for non-FDA labeled indications such as Alzheimer’s disease. Dosing is usually 1gm/ kg for one to two days. Responses are generally seen in 1-5 days, and can last for 2-4 weeks. Infusion related symptoms are the most commonly encountered complications. It is hypothesized that an antigen-antibody reaction and symptoms are described as “rigors”. This is an exacerbation of chills leading to shaking and pain and convulsive-like muscle contractions. Fever occurs next with a physiologic increase in prostaglandins and cytokine release. Meperdine has been used to treat this but would not be recommended for the elderly due to risk of toxicity. Renal failure is rarely associated with sucrose containing products. Side effects additionally include headache, nausea, and vomiting.

Copyright 2011 American Society of Consultant Pharmacists

Rho(D) immune Globulin (IGIV) (WinRho) ®

MOA:

Fc receptor blockade

Patient selection:

Spleen intact • Rh + • Hemoglobin > 8 Gm/dl

Side Effects:

Hemolysis

Renal failure • Fever, chills

Anti-Rho(D) WinRho ® is an alternative to IV immunoglobulin in patients whose red cells are Rho(D) positive. Because of limited available information, this drug is not included in the American Society Hematology guidelines for treatment of ITP. Rho(D) IGIV may be more cost effective for long term maintenance than IGIV. It has the advantage of being administered with less fluid, more rapidly and tends to cost less.Patient selection is important as the patient must have a spleen, and be Rh+.Because hemolysis is expected, patients should have hemoglobin above 8 Gm/dl.Doses are 50 to 75 mcg/kg IV (62.5 u/kg-300.0 u/kg) but should be reduced if the hemoglobin is between 8 and 10 gm/dl. Rho(D)- negative red cells should be used if a Rho(D) positive patient who received WinRho requires red cell transfusion.

Copyright 2011 American Society of Consultant Pharmacists

MOA:

Reduce antibody formation

Side Effects:

• • Hypotension (infusion related)

Fever

Chills

Rituximab

Rituximab is an antibody against CD20, a cell marker on the B lymphocyte. Rituximab is approved for treatment of non- hodgkin’s lymphoma, but has been found to be effective in refractory ITP patients. It is considered an alternative to splenectomy in those at high risk or unwilling to undergo splenectomy. Responses may be delayed for as much as one month after starting therapy. Doses used are 375 mg /m2 IV once weekly x4.

Copyright 2011 American Society of Consultant Pharmacists

Vincristine

Mycophenolate

Cyclophosphamide

Azathioprine

Danazol

Immunosuppressants

A variety of other immunosuppressants have also been employed in refractory patients. These would normally be considered third line therapies. Results from one series of patients suggest that elderly patients respond better to danazol than do younger patients. Danazol is thought to increase the number of T helper/inducer lymphocytes, which may modify the immune processes resulting in platelet destruction. Doses of 400-800 mg per day in divided doses have been used. Most data is anecdotal. Liver dysfunction and thromboembolism are the more serious side effects seen with danazol.

Copyright 2011 American Society of Consultant Pharmacists

MOA:

Splenectomy

Splenectomy reduces platelet removal from circulation

Side Effects:

Risk from surgery • Risk of infection

Splenectomy is a rapid means of elevating the platelet count in ITP patients. The count can begin returning to normal during surgery.In patients older than 60 years, the response to splenectomy may be slightly lower and elderly patients may have more post-operative complications.Long term disadvantages of splenectomy involve immune function changes, since the spleen plays a role in removing encapsulated organisms from the circulation.Consequently, vaccination against hemophilus, meningococcal, pneumococcal and influenza are suggested. The spleen plays a major role in presenting antigen so that antibody production is optimal.If possible, it is better to vaccinate 1 – 2 weeks before splenectomy. Unfortunately, vaccination normally occurs when we are also administering immunosuppressants (i.e. steroids) so you always have to wonder if patients get maximum benefit from the vaccines.

Copyright 2011 American Society of Consultant Pharmacists

Von Willebrand Disease

Most common inherited bleeding disorder • Autosomal dominant – 3 phenotypes 1, 2, 3 with 1 being most common

Von Willebrand factor functions to help platelet adhesion in injured blood vessel walls and stabilize factor VIII in plasma.

Signs & Symptoms:

Mucocutaneous bleeding (nose, vaginal, dental, GI) • Prolonged bleeding time.

Postoperative bleeding

Bruising

Treatment:

DDAVP (desmopressin) , synthetic analog of the antidiuretic hormone vasopressin • Humate P@40-80 Units/kg IV every 12 hours

• • Cyroprecipitate

Alphanate

Koate ®

Copyright 2011 American Society of Consultant Pharmacists

Von Willebrand Disease

Von Willebrand’s disease is a genetic disorder that disrupts hemostasis by prolonging bleeding time. It is less common than hemophilia and bleeding is not usually as severe. Bleeding time is a test which can be used to monitor platelet function. Von Willebrand’s factor (vWF) serves as a carrier protein for factor VIII as well as provides the backbone for platelet aggregates.Without von Willebrand’s factor, platelet plugs are not stable.

The goal of therapy is to increase vWF levels. In patients with a mild form of the disease, desmopressin can stimulate the release of vWF as well as autologous factor VIII from storage sites.Both the IV and intranasal route can be used. A test dose can help predict the patient response. Changes in vWF levels can vary from no change to up to 10 fold increase.The average being approximately a 3 fold increase above baseline. IV doses are 0.3mcg/kg intravenously in 50ml of normal saline infused over 15-30 minutes. 300mcg intranasally is dosed every 12 hours with a peak 60-90 minutes after administration.

Tachyphylaxis can occur with repetitive dosing, possibly due to depletion of the storage sites.Watch for high blood pressure and signs of water intoxication which are predictable effects of an antidiuretic hormone analogue.

VWF can also be increased using cryoprecipitate. Cryoprecipitate should only be used in emergency, life-or-limb threatening situations if antihemophilic factor (Human) is not available.

Humate P is a concentrated clotting factor product containing factor VIII and vWF. The product is labeled with both VIII content and vWF content. Ultrapure forms of factor VIII, monoclonal and recombinant products do not contain vWF.Humate P is generally reserved for use in patients with von Willebrand’s Disease since it is a human source product with the accompanying risk of viral transmission. That risk is reduced by viral inactivation methods. For clarity of dosing, it is best to base the dosage calculations on vWF content, and to express the dose on the label as units of vWF. For example, a typical dose would be 80 units/kg of vWF or 5600 Units vWF in 70 kg patients.Usual frequencies of administration are every 12 hours, sometimes every 8 hours. The amount of Von Willebrand factor – Ristocetin Cofactor (vWF:RCo) and factor VIII contained in each vial is indicated on product labels and may vary depending on manufacturing lot.

Copyright 2011 American Society of Consultant Pharmacists

Von Willebrand Disease

Humate-P ® and Alphanate ® contain both antihemophilic factor and Von Willebrand factor. Koate ® -DVI has a high content of Von Willebrand factor and may also be used. Very high purity, antihemophilic factor (human) immunoaffinity preparations and antihemophilic factor (recombinant) do not contain Von Willebrand factor and should not be used.

Although vWF levels can be measured, factor VIII levels are frequently used to monitor therapy. The goal is to keep the factor VIII level greater than 30% or in cases of major surgery, 50% at all times.

Copyright 2011 American Society of Consultant Pharmacists

Acquired Hemophilia (Factor VIII Autoantibodies)

Acquired Factor VIII Deficiency:

Unexplained prolonged aPTT with normal PT • Spontaneous bleeding (muscle hematoma, soft tissue ecchymoses, mucosol bleeding, GI bleeding)

Clotting Factor Levels:

In the general population, there is a 50-200% range in normal clotting factor levels.

Mild hemophilia • 5-50% normal clotting factor levels Moderate • 1-5% normal clotting factor levels

Severe • <than 1% normal clotting factor levels

Hemophilia is usually an inherited disorder. The availability of recombinant or plasma derived clotting factors has lengthened the life span of hemophilia patients. In the 1980’s, clotting factors manufactured from human blood did not have adequate viral inactivation. Blood borne infections, such as Hepatitis C, and HIV resulted in high mortality rates. Disability rates with hemophilia can be high since bleeding into muscles and joints can lead to chronic pain and joint

disease.

(autoantibodies) in patients with previously normal levels.

Acquired hemophilia is a rare disorder whereby antibodies spontaneously develop to factor VIII

Sometimes an elderly patient without a previous history of clotting disorders will present with an inability to clot after surgery or trauma. The levels fluctuate and may be misleading and underestimate the need for replacement therapy. Factor VIII levels may be decreased due to antibody mediated destruction.

Copyright 2011 American Society of Consultant Pharmacists

Acquired Hemophilia (Factor VIII Autoantibodies), Treatment

Antihemophilic Factor (Human) • Antihemophilic Factor (recombinant)

Activated Prothrombin complex concentrates (APCC) • FEIBA and Autoplex • Factor VIIa (NovoSeven)

Immunosuppressive Therapy (corticosteroids with or without cylophosphamide, vincristine, cyclosporine, interferon alfa)

Hemophilia patients may be treated on a regular basis with scheduled prophylactic treatment or only at the time of a bleed. Decisions are based on bleeding patterns, age, activity level and response to therapy. Comorbidities such as Hepatitic C and HIV complicate management. Clotting factor prescriptions are usually written as ranges to account for variables in dosing such as severity of hemophilia, patient weight and clotting factor manufacturer. Different sites of bleeding require different doses.Insurance coverage and lifetime benefit caps for these expensive medications need evaluation for individual patients.

Based on pharmacy inventory, there can be large cost differentials with small clotting factor dose changes. Adverse effects in patients receiving antihemophilic factor (human) include headache, flushing, tachycardia, paresthesias, back pain, hypotension, somnolence vision disturbance and chest constriction. Incidence seems to be infusion rate related. Clinical studies have not included sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients.

Copyright 2011 American Society of Consultant Pharmacists

Acquired Hemophilia (Factor VIII Autoantibodies), Treatment

An alternative is to employ activated prothrombin complexe concentrates (APCC) to bypass factor VIII in the clotting cascade to form a blood clot. FEIBA and Autoplex are such products. Laboratory monitoring is not helpful in guiding therapy so clinical assessment is the only tool we have to manage FEIBA therapy. FEIBA and Autoplex are human derived plasma products and although prepared with virus inactivation techniques, are still considered to be potential sources for viral infection.

Factor VIIa (NovoSeven) is a recombinant biosynthetic preparation. Patients with an acquired factor VIII deficiency may respond to immunosuppressive therapy to reduce antibody levels.

No single treatment is suitable for bleeding in all patients with acquired hemophilia. The autoantibodies may in fact spontaneously disappear, making it hard to evaluate therapy responsiveness.

Copyright 2011 American Society of Consultant Pharmacists

Warfarin Bleeding Adverse Effect

Most Common Bleeding Sites:

• • Oral pharynx • Soft tissue

• • Urinary tract

Nose

GI

Risk Factors for Bleeding:

Higher frequency in first three months of therapy • Intensity of anticoagulation • History of GI bleeding

Serious comorbid disease • Concurrent ASA or NSAID

Management:

INR 5.0<9.0 with no bleeding

Omit next one or two doses. Resume therapy at lower dose when INR is therapeutic or omit a dose and give vitamin K (1-2.5mg po). For more rapid reversal (patient requires surgery) vitamin K 5mg orally will reduce INR within 24 hours. If INR is still high, add vitamin K (1-2mg orally).

Copyright 2011 American Society of Consultant Pharmacists

Warfarin Bleeding Adverse Effect

INR >9.0 and no significant bleeding

Hold warfarin and give vitamin K 2.5-5mg orally. Additional vitamin K may be needed if the INR isn’t therapeutic within 24-48 hours.

Elevated INR and serious or life threatening intracranial hemorrhage

Irrespective of magnitude of elevation, hold warfarin and give vitamin K (10mg) by slow infusion supplemented with fresh frozen plasma, prothrombin complex concentrate or recombinant factor VIIa. Vitamin K can be repeated every 12 hours for persistent INR elevation.

Age and bleeding risk is controversial. In general, older adults tend to be more sensitive to the drug warfarin. Patients and caregivers need to pay careful attention to signs and symptoms of bleeding. Overanticoagulation management depends on how the patient presents. Dose interruption may be sufficient depending on the presence or absence of bleeding and degree of INR elevation.

Factors associated with a longer time to return of INR to therapeutic range are: age, lower maintenance dose requirements, higher INR, decompensated heart failure, active malignancy, or use of medication that potentiates warfarin A balance must be found so that overanticoagulation is corrected without prolonged resistance to warfarin. especially those with borderline vitamin K deficiency.In most cases, dietary supplements of eighty to one hundred micrograms of vitamin K reduce the hypersensitivity to warfarin. ACCP guidelines recommend management of nontherapeutic INRs based on value and presence of absence of bleeding.

Warfarin bleeding can be minor or life threatening and occur anywhere in the body. Criteria vary when defining bleeding as major or minor. Major bleeding is usually an event that requires hospitalization, transfusion of two or more blood units or leads to a drop in hemoglobin great than 2g/dL. The intensity of anticoagulation therapy is the most powerful risk factor for bleeding. Wide variability in anticoagulation response may also be related to bleeding risk.

Copyright 2011 American Society of Consultant Pharmacists

Disseminated Intravascular Coagulation (DIC)

Clinical Manifestations:

Asymptometic

petechiae and purpura Bleeding Thrombosis

Aneurysms

Lab values:

D-Dimer

increased

Platelets

decreased

Fibrinogen

decreased

PT

prolonged

aPTT

prolonged

Antithrombin

decreased

Disseminated intravascular coagulation or DIC is a process whereby excessive generation of thrombin leads to clots forming in the microvasculature that are then lysed by the fibrinolytic system. A bleeding tendency results because clotting factors are being consumed and anticoagulants such as fibrin degradation products are being created.

The clinical picture can be confusing since a spectrum of presentations can result. The condition can be chronic or acute. Patients can be asymptomatic, can be bleeding or can be thrombosing or can be bleeding and thrombosing at the same time. The most descriptive term heard to describe it is a thrombohemorrhagic disorder.

Microvascular thrombosis results in tissue ischemia and end organ dysfunction.

In the clearest presentation, clotting factors, fibrinogen and platelets are low; fibrin degradation products are elevated with an increase in the aPTT. In chronic DIC, however, compensation by the body may allow adequate synthesis of various factors to blunt some of the findings, so the platelet count may be decreased but not markedly, fibrinogen might even be normal and the PT and the aPTT likewise may be closer to normal than anticipated.

Usually, an underlying condition is causing DIC. Examples of conditions include: myocardial infarction, prosthetic devices, infections, heat stroke, chronic inflammatory diseases and pulmonary embolism. In the elderly, mucin- producing tumors such as prostate cancer can cause DIC. Likewise, DIC has been seen in patients with aneurysms.

Copyright 2011 American Society of Consultant Pharmacists

Disseminated Intravascular Coagulation (DIC)

Treatment:

Base on predominant symptoms (bleeding or clotting) • Fresh frozen plasma, platelets to replace clotting factors • Low dose heparin to control excess thrombin activity

When a patient has symptoms of bleeding or requires invasive procedures, providing platelets and clotting factors with fresh frozen plasma may be necessary.

Treatment is controversial with underlying disease treatment and diagnosis the ultimate goal. Ideally, knowledge of whether hemorrhage or thrombosis is dominating will help guide therapy. Bleeding may be the most obvious symptom, but it is the thrombosis that is associated with most of the mortality. Just as challenging is using lab tests to monitor therapy. Heparin use is limited by bleeding potential and in contraindicated in patients with life-threatening bleeding. Patients with solid tumors and persistent coagulation abnormalities may benefit. If given, heparin can be used IV or subcutaneous at full dose although monitoring is challenging since the aPTT is already elevated. Cryoprecipitate has been used as a source of fibrinogen. Antithrombin concentrate may be useful in some patients. Antifibrinolytic agents such as aminocaproic acid or tranexamic acid are not routinely used to treat DIC as they may increase the risk of thrombosis of a major organ.

Copyright 2011 American Society of Consultant Pharmacists

Liver Disease and Coagulopathy

Treatment Prior to an Invasive Procedure

10mg vitamin K for one to two days • Fresh frozen plasma and platelets • Prothrombin plasma concentrate, 10 u. cryoprecipitate

As with vitamin K deficiency, liver dysfunction can result in reduced levels of procoagulants. Before an invasive procedure or when overt bleeding occurs, PT and a PTT may need to be corrected. Following surgery or even relatively minor procedures, some patients can have difficulty forming a clot.Patients with mild disease may respond to short-term therapy with phytonadione. In more severe cases, phytonadione will usually not have an effect. So prior to invasive procedures or surgery, fresh frozen plasma can replenish clotting factors in patients with liver dysfunction. In patients with more serious liver disease, prothrombin plasma concentrate, cryoprecipitate, and platelets may be needed.

Recombinant factor VIIa or (NovoSeven) has also been used in liver failureto shorten the PT and correctthe bleeding diathesis. Due to its short half-life, the effect is brief. A typical regimen would be 90 mcg/kg IV prior to a procedure and every 2 hours times 1-2 doses following the procedure.

Copyright 2011 American Society of Consultant Pharmacists

Possible Etiology:

Hemorrhage

Generalized – thrombocytopenia, platelet disorder, DIC • Localized – anatomical defect (e.g.,peptic ulcer, tumor, surgery, laceration, trauma) • Surgery

Treatment

Systemic Biologic Hemostatic Agents

Blood Products

Fresh frozen plasma

Cryoprecipitate

Platelets • Factor Concentrates • Plasma derived

Factor VIII • Factor XIII • Recombinant Factor VIIa • Lysine Analogs

E-Aminocaproic Acid • Tranxemic Acid • Vasopressin Agonist Desmopressin

Copyright 2011 American Society of Consultant Pharmacists

Hemorrhage

If the patient is hemorrhaging, it is important to determine whether the bleeding is generalized or localized. Correction of the defect is then required to restore hemostasis.

Blood loss is a major postoperative problem, with cardiac surgery and liver transplantation particularly at high risk. Transfusion of red blood cells are used to restore lost oxygen-carrying capacity but they have a variety of complications. These include: allergic reactions (mild or life threatening), transmission of infectious disease, hemolytic transfusion reactions, circulatory volume overload, immune modulation and transfusion related acute lung injury.

Systemic biologic hemostatic agents that mimic and enhance stages of the coagulation cascade are available to restore hemostasis. The American Society of Anesthesiologists recommends use of hemostatic agents to promote coagulation and minimize blood loss. Fresh frozen plasma is used with active bleeding, elevated PT and aPTT. Platelets are used for thrombocytopenia (platelets <50 x 10 9 /L). Cryoprecipitate containing concentrated fibrinogen, Factor VIII, von Willebrand Factor (VWF) and Factor XIII is indicated for isolated hypofibrinogenemia (fibrinogen levels <80-100 mg/dL). Recombinant Factor VIIa is a vitamin K dependent glycoprotein structurally similar to human plasma derived Factor VIIa.

It acts by binding tissue factor and generating thrombin which activates platelets and promotes conversion of fibrinogen to fibrin. It has been studied but is not approved for intracerebral hemorrhage. Lysine analogs promote hemostasis by inhibiting plasminogen activation. Adverse effects are gastrointestinal. A Cochrane review suggests there is no data to recommend one drug over another.

Desmopressin causes a dose dependent increase in plasma levels of Factor VIII and von Willebrand Factor to promote platelet aggregation and increase tissue plasminogen activity. It has been used in minimizing surgical blood loss with mixed results.

Copyright 2011 American Society of Consultant Pharmacists

For additional information, see:

Resources

Barclay L, Martin N. Management of bleeding and bruising disorders. Am Fam Physician. 2008;77:1117-24.

Andres, E. Idiopathic thrombocytopenic purpura: a retrospective analysis in 139 patients of the influence of age on the response to corticosteroids, splenectomy and danazol. Drugs Aging. 2003; 20(11):841-6.

Bolton-Maggs, PH, Haemophilias A and B. Lancet. 2003 May 24; 361(9371):1801-9.

Batlle, J. Advances in the therapy of von Willebrand disease. Haemophilia. 2002 May; 8(3):301-7.

Huber, MR. Treatment advances in adult immune thrombocytopenic purpura. Ann Hematol. 2003 Dec; 82(12):723-37.

Narang. M. Refractory autoimmune thrombocytopenic purpura: responses to treatment with a recombinant antibody to lymphocyte membrane antigen CD20 (rituximab). Am J Hematol. 2003 Dec; 74(4):263-7.

Kumar. S. Acquired von Willebrand disease. Mayo Clin Proc. 2002 Feb; 77(2):181-7.

Taylor FB The diagnosis and management of disseminated intravascular coagulation. Curr Hematol Rep. 2002 Sep; 1(1):34-40.

Copyright 2011 American Society of Consultant Pharmacists

Resources

National Hemophilia Foundation’s Medical and Scientific Advisory Council (MASAC)

Bloodline

http://cjp.com/blood/

Goodnoogh LT, Brecher ME, Kanter MH, Nubudon JP. Transfusion Medicine. First of two parts – blood transfusion. N Engl J Med . 1999;340(6):438-47.

American Society of Anesthesiologists Task Force on Perioperative Blood Transfusion and Adjuvant Therapies/ Practice guidelines for perioperative blood transfusion and adjuvant therapies. www.asahq.org/publicationsand services/ BCTGuidesFinal.pdf

George JN, Woolf SH, Raskob GE, Wasser J, Aledort LM, Ballem PJ, Blanchette VS, Bussel JB, Cines DB, Kelton JG, Lichtin AE, McMillan R, Okerbloom JA, Regan DH, Warner I. Idiopathic thrombocytopenic purpuras: A practice guideline developed by explicit methods for the American Society of Hematology. Blood. 1996;88:3-40.

National Institutes of Health, National Heart, Lung nd Blood Institute (NHLBI). The diagnosis, evaluation and management of von Willebrand disease. Bethesda, MD. 2007 Dec. 112p.

Copyright 2011 American Society of Consultant Pharmacists

Learning Objectives

Thrombotic Disorders

By the end of this review section, you should be able to:

Compare and contrast immediate, short-term and long-term risk factors for venousthombosis.

Recognize therapeutic strategies for the prevention and management of thombosis, as well as those which should and should not be used in the senior population.

Design a monitoring plan for a senior patient receiving prevention or treatment therapies for a thrombotic disorder, as well as educate the patient and caregiver in regards to the therapy employed.

Copyright 2011 American Society of Consultant Pharmacists

Thrombotic Disorders

Venous thromboembolism (VTE):

Deep vein thrombosis Pulmonary embolus

Pathophysiology of venous thrombosis

Virchow’s Triad

Intimal injury • Hypercoagulability

Stasis

Arterial thromboembolic Disease:

Acute myocardial infarction

Peripheral Artery Disease • Coronary Artery Disease • Atrial Fibrillation or Valvular Heart Disease • Stroke

Microvascular thrombosis:

DIC

Disease •   Stroke Microvascular thrombosis: •   DIC Copyright 2011 American Society of Consultant Pharmacists

Copyright 2011 American Society of Consultant Pharmacists

Thrombotic Disorders

Thrombotic disorders are the result of blood clots which can form in any part of the circulatory system, for example the veins, arteries, heart or microcirculation. Venous thrombi are made up of red blood cells and large amounts of fibrin but few platelets. Venous clots usually start in the lower extremities. Arterial clots consist mostly of platelet aggregates held together with fibrin strands.Arterial thrombi typically occur in association with pre-existing cardiovascular disease such as atherosclerosis.Intracardiac clots, associated with atrial fibrillation or cardiomyopathies, resemble venous clots and consist more of fibrin and RBC’s than platelets.

The complications of thrombosis result from local obstruction of the vessel, distant embolism from the primary clot, or uncommonly, consumption of pro-coagulant components, such as clotting factors, fibrin, and platelets.

It is important to understand thrombosis risk in the elderly as it relates to Virchow’s triad. Stasis in the elderly can occur with immobilization, limb paralysis (stroke), heart failure, or varicose veins. Anything that affects blood viscosity such as polycythemia can contribute to stasis and thrombosis. Internal injury can be direct as a result of surgery (knee, hip esp), trauma, hysterectomy, prostatectomy, extremity fracture, or a central venous cathether. It may also be indirect due to chemotherapy, sepsis, vasculitis or hyperhomocysteinemia.

Anticoagulants are the mainstay of venous thrombosis treatment, but by understanding the pathophysiology, you can see that platelet dependent arterial thromboses need a different therapeutic approach.

VTE may cause no symptoms and sudden death can be the first manifestation. VTE survivors are at risk for complications such as post-thrombotic syndrome and chronic pulmonary hypertension. Goals in the older patient should be to improve morbidity and maybe even delay mortality.VTE is the target of public awareness campaigns and quality initiatives. Current guidelines recommend that hospitals adopt an opt-out policy in terms of VTE prevention. In this case, patients would routinely get VTE prevention unless doctors actively discontinue the treatment.

Copyright 2011 American Society of Consultant Pharmacists

Risk Factors for Venous Thromboembolism

High risk:

Fracture of hip or leg Hip/knee replacement Spinal cord injury

History of VTE

Major trauma Major general surgery Age 75 years

Venous Statsis – varicose veins, surgery, obesity, CHF

Vascular Injury – surgery, trauma, indwelling venous catheters

Moderate risk:

Arthroscopic knee surgery

Thrombophilia

Paralytic CVA

Hormone Replacement Therapy

History TE, DVT

Respiratory Failure

Malignancy

Antiphospholipid Antibody

CHF

Antithrombin Deficiency Catheter

Central Venous

Copyright 2011 American Society of Consultant Pharmacists

Risk Factors for Venous Thromboembolism

Low risk:

Obesity

Varicose veins • Laparoscopic surgery

Drug Therapy - estrogens

Venous thromboembolism (VTE) can occur as a single entity or may be associated with other medical conditions and surgical procedures. Low, moderate and high risk classifications are used for medical patients based on condition and comorbidities. There is not a risk assessment model for medical patients like there is for surgical patients. One tool used in emergency departments is the Kucher VTE risk score that assigns points to various risk factors. Risk factors can be evidence based or consensus based which explains discrepancies. The type of surgical procedure determines the greatest amount of risk, with orthopedic procedures carrying the greatest risk. Prior to surgery, these factors should be considered in weighing the decision as to whether to use prophylactic anticoagulation in this patient.

VTE disproportionately affects the elderly. Since elderly are the fastest growing age group, the risk of VTE events and deaths will be increasing. The incidence of venous thromboembolism doubles in each decade of life over age 50. IArterial thrombotic events are confounded by age based on the elderly prevalence of associated diseases, such as diabetes, hypertension and hyperlipidemia. Risk can be five times greater for those over age 70 compared with those under the age of 55. In general, they also have a lower tolerance for pulmonary emboli. Preoperative illness, malignancy or coagulation activity, as well as postoperative immobility, also serve to heighten the risks of venous thrombosis. Elevated hematocrit (Hct) can result in increased clotting. Pulmonary disorders, dehydration and polycythemia increase Hct in elderly. Protein C resistance is a hypercoagulable state that may first occur in elderly that is linked to an increased incidence of VTE. Hypercoaguable states can be hereditary or acquired. Hereditary examples are Protein C, Protein S, Factor V Leiden and antithrombin III deficiency. Acquired hypercoagulability occurs with malignancy, hormone replacement, or nephrotic syndrome.

Copyright 2011 American Society of Consultant Pharmacists

Assessment of Venous Thromboembolism

Standardized clinical probability assessments • Radio-contrast venography (phlebography)

Color Doppler ultrasonography • Impedence plethysmography • Magnetic resonance angiography

Monoclonal antibody assays i.e. D-Dimer assay

Assessment of Pulmonary Embolism

Ventilation – perfusion (V/Q) scanning • Computed tomography (CT) scans

(V/Q) scanning •   Computed tomography (CT) scans Standardized clinical probability assessments are used

Standardized clinical probability assessments are used before imaging tests. Examples are the Wells Clinical Probability Score and Geneva Scoring for Pulmonary Embolism. The gold standard for establishing the presence of venous thrombosis is radio contrast venography. Venography may not be possible to perform in patients with significant edema and is contraindicated with creatinine >3mg/dL. Good hydration for 6-8 hours after the test is important. Contrast studies in ill patients may cause hypertension and cardiac arrhythmias. Since it is invasive, it is rarely used. Color Doppler ultrasonography is a viable alternative.When the probability of thrombosis is low, noninvasive tests such as serial impedance plethysmography is preferred.Magnetic resonance angiography may be able to provide images of vessels with little or no contrast material, reducing the risk of dye induced renal failure.

Ventilation perfusion and CT scans are used to diagnose PE. V/Q scans measure the distribution of blood and air flow to lungs. A V/Q scan can rule out a PE, but not itself confirm the diagnosis.

Copyright 2011 American Society of Consultant Pharmacists

Assessment of Venous Thromboembolism

D-Dimer assays based on monoclonal antibody technology provide a quick and easy way to test for a byproduct of thrombin generation, which is a degradation product of fibrin blood clots. The D-Dimer test has a high sensitivity of 98-99% for thrombosis and has a high negative predictive value. In other words, a negative D-dimer can rule out deep vein thrombosis (DVT), but a positive test does not rule in the diagnosis. Scoring systems exist to assess pretest probability of DVT and PE based on clinical features. For example, the Charlotte Rule for D-dimer testing is a decision rule to determine if D-dimer testing is safe to use.

Copyright 2011 American Society of Consultant Pharmacists

Treatment of Venous Thromboembolism

Heparins((UFH(vs.(LMWH)(

$Heparin$(UFH)$$

UFH$IV$or$SQ$$

Enoxaparin$ $ $$

LMWH$$

Dalteparin$

LMWH$$

Tinzaparin$$

LMWH$$

Direct Thrombin Inhibitors:

Lepirudin

Argatroban

Bivalirudin

Indirect Acting Factor Xa inhibitor:

Fondaparinux – synthetic heparin pentasaccharide

Warfarin

Mechanical:

Intermittent pneumatic compression • Transvenous filters in vena cava (i.e. Greenfield Filter) • Graded Compression Stockings

Copyright 2011 American Society of Consultant Pharmacists

Treatment of Venous Thromboembolism

Treatment of venous thrombosis is directed at not only blocking extension of the clot within the vein, but also minimizing the embolization of the clot to vital organs, the most common being the lungs. Post phlebitic syndrome results in pain in the extremity, venous stasis, peripheral edema, and stasis ulcers. Effective anticoagulation minimizes the risk of this long term complication of DVT.

Heparin has been the standard agent, and activity of the other agents is normally compared to heparin.

Other agents include the low molecular weight heparins, direct thrombin inhibitors, and indirect acting Factor Xa inhibitors.And of course, warfarin still has a role in the long term maintenance therapy of venousthromboembolism Dabigatran etexilate is an investigational oral direct thrombin inhibitor. Filters in the vena cava are indicated when anticoagulants aren’t effective or safe. An occlusive filter called a Greenfield filter is percutaneously inserted into the femoral or jugular vein. Filters can be permanent or removable and it is controversial whether patients with a permanent filter should be on anticoagulant therapy. Compression stockings must fit to be effective and can be difficult to put on. Ambulation is encouraged with their use. Intermittent pneumatic compression can be effective but in reality, use is frequently not optimal. Devices are often disconnected for patient comfort, or when the patient gets diagnostic tests or ambulates.

Copyright 2011 American Society of Consultant Pharmacists

Pharmacology of Heparins

UFH: large size

Binds antithrombin III and facilitates antithrombin III mediated inactivation of Factors IIa, Xa, IXa and XIIa.

aPTT: not required for prophylactic doses except in small frail elderly (< 45 kg), used for monitoring treatment doses routinely.

(< 45 kg), used for monitoring treatment doses routinely. Copyright 2011 American Society of Consultant Pharmacists

Copyright 2011 American Society of Consultant Pharmacists

Pharmacology of Heparins

LMWH: one-third the size of UFH

Preferentially inhibits Factor Xa

aPTT: not needed or useful for monitoring

Absorption: improved availability; providing a more predictable anticoagulant response ADR:HIT & osteopenia (lower incidence) since they don’t bind platelets as well as UFH

incidence) since they don’t bind platelets as well as UFH Copyright 2011 American Society of Consultant

Copyright 2011 American Society of Consultant Pharmacists

Pharmacology of Heparins

Unfractionated heparin is a heterogenous mixture of sulfated glycosaminoglycans with molecular weights ranging from 3 to 30,000 daltons, with an average weight of 15,000.Heparin acts as a co-factor for Antithrombin. Antithrombin binds to a variety of clotting factors: II, X, IX, XI and inactivates them.Heparin binds to both clotting factor II, and to antithrombin, facilitating the binding of the two agents together before uncoupling and moving on.The clinical effect of heparin seems to rely most on inactivating IIa (thrombin) and Xa.

Because of the binding to IIa, the aPTT serves as a laboratory test to measure the effect of heparin.Since the effect on Xa is not measured by the aPTT, the test does not completely reflect the anticoagulant activity of heparin in vivo. There is considerable interlaboratory in the aPTT and institution specific therapeutic ranges should be used. The ACT (activated clotting time) may be needed when higher doses of heparin are used. Bleeding risk is related more to risk factors than to high aPTTs.

The larger fragments of heparin can bind to other proteins.This may explain the substantial inter- and intra-patient variability in anticoagulation. This tendency to bind to other proteins explains some of the adverse effects.HIT, or heparin induced thrombocytopenia results from heparin binding to platelet factor 4 (PF4) and forming a complex with IgG which then activates platelets. Platelet activation causes the release of prothrombotic particules, platelet consumption and thrombocytopenia. Osteopenia results from heparin binding to osteoblasts, ultimately resulting in osteoclast overactivity and bone resorption. Osteopenia puts elderly with osteoporosis at a risk for fractures.

Low molecular weight heparins are 2 -10,000 daltons in size with an average of 5000 daltons.Their size limits their activity against thrombi , so they work by binding to antithrombin.As a result, there is relatively more inactivation of Xa and less IIa with LMWH than UFH. LMWH’s have greater anti-factor Xa activity.

Copyright 2011 American Society of Consultant Pharmacists

Pharmacology of Heparins

Clinically, this means the aPTT is not a useful measure of LMWH effect. Predictability of response actually removes the need to have a monitoring laboratory test.Anti-factor Xa level monitoring may be needed in patients with renal impairment, weight less that 50kg, obese (>150kg or those who require therapy longer than 14 days. Because of the lower molecular weight, binding is no longer the predominant method of clearance.Renal clearance becomes a notable route of elimination. This might be important in elderly patients as renal function declines with age.Dosage adjustment guidelines for LMWH in renal insufficiency have not been well defined to date.

Heparin induced thrombocytopenia is less likely to occur with LMWH.Theory has it that the MW must be > 4000 daltons to form the PF4-IgG- heparin complex.(HIT antibodies) LMWH should be avoided in patients with HIT. Periodic platelet counts should be monitored. Osteopenia also appears to be less likely with LMWH, possibly due to less activation of osteoclasts, thereby causing less bone loss.

Copyright 2011 American Society of Consultant Pharmacists

Clinical Comparison of Heparin (UFH) vs. LMWH

Low Molecular Weight Heparins:

> Are at least as effective.

> Have more predictable anticoagulation response.

> Can be given SQ with good bioavailability.

> Long half life

> Have a lower incidence of thrombocytopenia.

> Less laboratory monitoring

So, how do LMWH and UFH compare clinically?For the prevention and treatment of venous thrombosis, the LMWH are at least as effective as heparin with a predictable response.The LWMH have the advantage of better bioavailability following subcutaneous injection. This translates into two advantages: monitoring with a laboratory test is not necessary; and the subcutaneous route allows for outpatient therapy.

The LMWH appear to have the same or slightly lower risk of major bleeding. And because of the lower binding to proteins and cells, the incidence of thrombocytopenia is lower.

ACCP Guidelines (8 th edition) recommend the use of unfractionated heparin (UFH) instead of LMWH in patients with severe renal insufficiency (CrCl <30ml/min). If LMWH are used, a dose 50% of the recommended should be used. A FDA warning has been made for an increased risk for death with tinzaparin in renal impaired elderly.

Copyright 2011 American Society of Consultant Pharmacists

Direct thrombin inhibitors, Indirect Acting Factor Xa inhibitors

Fondaparinux – treatment and prevention of VTE after surgeryLepirudin, Argatroban – used in patients with HIT • Bivalirudin unstable angina – PCI in patients with or at risk for HIT

Direct(Thrombin(Inhibitors(Lab(Monitoring(

Lepirudin$

aPTT$two$hours$aaer$iniKaKon$of$therapy$and$each$dose$change$therapeuKc$

range$1.5G2.5x$baseline$

Argatroban$

aPTT$two$hours$aaer$iniKaKon$of$$therapy$and$each$dose$change$therapeuKc$

range$1.5G3x$baseline$

Bivalirudin$

ACT$five$minutes$aaer$IV$bolus$

Indirect Acting Factor Xa Inhibitor Lab Monitoring

Fondaparinux – baseline CBC, platelet count, INR, S Cr, aPTT

Copyright 2011 American Society of Consultant Pharmacists

Direct thrombin inhibitors, Indirect Acting Factor Xa inhibitors

Fondaparinux has FDA approval for treating and preventing VTE after major orthopedic surgery, hip fracture surgery or abdominal surgery. It is not approved for patients with HIT. It is also used for NST and ACS in patients at high risk for bleeding. Fondaparinux does not affect thrombin, a platelet activator. It selectively inhibits factor Xa. By binding to antithrombin, fondaparinux is a refined synthesized variant of heparin whose structure is based on the pentasaccharide region of heparin. It has a fast onset of action, can be given once a daily subcutaneously and routine monitoring is not

required.

than 50kg need extra monitoring.

Fondaparinux is contraindicated with CrCl <30mL/minutes. Elderly greater than age 75 and patients less

Argatroban and Lepirudin have FDA approval for treating patients with HIT.Their role is likely to be limited to this patient population because they have a higher risk of bleeding than heparin.

Lepirudin is a recombinant protein modified and derived from hirudin. It is an irreversible direct thrombin inhibitor with the longest half life of all direct thrombin inhibitors. The direct thrombin inhibitor, lepirudin or desirudin, requires dosage reduction patients with renal insufficiency (CrCl <60ml/min) but >30mL/min.) It should not be used in severe renal insufficiency (CrCl <30 Uml/min) because of the risk of anaphylaxis. Since it can accumulate in renal insufficiency, Argatroban is preferred in that situation. Argatroban is a synthetic reversible direct thrombin inhibitor derived from L- arginine. Advantages over other direct thrombin inhibitors include: rapid onset of action, lack of antigenicity, short half life, and predictable pharmacokinetic response. It not only prevents further thrombotic events, but reduces extension of existing thromboses. Bivalirudin is a semi-synthetic analogue of hirudin. Advantages include: direct elimination and a short half life. It is only FDA approved for anticoagulation in patients with or at risk for HIT thrombosis syndrome undergoing PCI, with concomitant aspirin use. Repeated use of these drugs is not recommended.

Copyright 2011 American Society of Consultant Pharmacists

Types of Heparin Induced Thrombocytopenia (HIT)

Type I (heparin-associated thrombocytopenia)

Up to 30% patients • Non-immune-mediated reaction • Present within one-two days of heparin use asymptomatic

Mild to moderate transient decline (rare below 100,000mcL) • Spontaneous resolution with therapy discontinuation

Type II (heparin-induced thrombocytopenia)

Immune mediated • Severe form

Heparin(Induced(Thrombocytopenia(

 

Type(I(

Type(II(

Frequency(

10G20%$

2G30%$

Timing(

1G4$days$

5G10$days$

Platelet(Count(

100,000/mcL$

30,000G55,000/

mcL$

An3body(mediated(

No$

Yes$

Thromboembolic(

No$

30G80%$

Complica3ons(

Bleeding(Complica3ons(

No$

Rare$

Management(

Monitor$

D/C$heparin$

Copyright 2011 American Society of Consultant Pharmacists

Types of Heparin Induced Thrombocytopenia (HIT)

Disorders Similar to HIT

Pulmonary embolism • Diabetic ketoacidosis • Thrombolytic therapy

Adenocarcinoma

DIC

Endocarditis

• • Post-transfusion purpura

Thrombocytopenia occurring 3-5 days into therapy is marked by a depression in platelet counts to 50 to 100,000 cells/ mm3 and accompanied by other symptoms is usually a mild, self limiting condition.

Thrombocytopenia accompanied by signs of thrombosis can be limb or life threatening. Stopping heparin and switching to the direct thrombin inhibitors is the usual manner of managing these patients. Heparin flushes of intravascular catheters or heparin bonded catheters should also be considered. LMWH has a high potential for cross-reactivity. Patient records should be documented as “heparin allergy” to prevent incidental exposure.

For patients receiving heparin with a risk of heparin induced thrombocytopenia, platelet count monitoring should be done. Patients who have received UFH in the last 100 days need a baseline platelet count to be repeated in 24 hours of starting heparin. Platelet monitoring should be continued at least every two-three days until heparin is stopped.

HIT should be suspected if patients are receiving or have received heparin within the last two weeks and the platelet count falls by 50% and/or a thrombotic event occurs between day 5-14 of heparin.

Copyright 2011 American Society of Consultant Pharmacists

Types of Heparin Induced Thrombocytopenia (HIT)

The frequency of HIT is dependent on four risk factors: duration of use (begins at day 5 and peaks between 10 and 14), type of heparin (bovine UFH > porcine UFH > LMWH, type of patient population (surgical > medical > obstetrical), patient sex (F > M).

The presence of HIT antibodies does not necessarily mean a patient has HIT. Clinical manifestations such as skin reactions at the heparin injection sites or fever, chills, cardiorespiratory distress after intravenous administration are needed to confirm HIT. Assays that can assist in the diagnosis are a functional serotonin release assay (SRA) or antigenic, enzyme-linked immunosorbent assay (ELISA).

Copyright 2011 American Society of Consultant Pharmacists

Specific Disorders of Arterial Thromboembolism

Acute myocardial infarction • Ischemic Stroke

Peripheral artery disease • Coronary artery disease • Atrial fibrillation

Prevention of arterial thromboembolic disease is important for the elderly. The functional and cognitive loss from these diseases affect quality of life in the geriatric population.

diseases affect quality of life in the geriatric population. Copyright 2011 American Society of Consultant Pharmacists

Copyright 2011 American Society of Consultant Pharmacists

Acute Myocardial Infarction (AMI) Acute Coronary Syndrome (ACS)

ST Segment Elevation Myocardial Infarction (STEMI) Non ST Segment Elevation Myocardial Infarction (NSTEMI)

Unstable Angina (UA)

ACUTE(Coronary( Syndrome(
ACUTE(Coronary(
Syndrome(
ACUTE$Coronary$ Syndrome$
ACUTE$Coronary$
Syndrome$
NSTEMI(
NSTEMI(
STEMI$
STEMI$
UA(
UA(
Myocardial$ infarcKon$
Myocardial$
infarcKon$

Algorithms exist for treatment of each arm and are distinguished by initial invasive strategies or initial conservative strategies.

Copyright 2011 American Society of Consultant Pharmacists

Acute Myocardial Infarction (AMI) Acute Coronary Syndrome (ACS)

Risk Factors for Endothelial Dysfunction and Atherosclerosis:

Dyslipidemia

Male

Hypertension

Age

Diabetes

Obesity

Tobacco Use

Risk Factors for STEMI in patients > 75 years:

Previous MI •

Female • Low body weight

Anterior wall infarct • Killip Class III or IV • Hypertension

Treatment:

Thrombolytic agents, such as streptokinase,alteplase, reteplase, or tenecteplase

www.HeartCenterOnline.com Go to Heart Risk Factors and Animations/Illustrations

Copyright 2011 American Society of Consultant Pharmacists

Acute Myocardial Infarction (AMI) Acute Coronary Syndrome (ACS)

Acute myocardial infarction is a manifestation of ischemic heart disease that results in coronary artery occlusion. Endothelial dysfunction and atherosclerosis are involved in coronary artery occlusion and risk factors for ischemic heart disease. Risk factors are familiar: hyperlipidemia, hypertension, obesity, smoking, and lack of exercise, to name a few. Acute coronary syndrome consists of unstable angina and non-ST segment elevation MI or ST segment elevation MI.

In addition to risk factors for STEMI in patients over age 75, there are common comorbidities in this age group. They include stroke, heart failure, hyperlipidemia and previous percutaneous coronary intervention. Elderly often delay seeking medical assistance and their clinical presentation may be atypical. Chest discomfort may be less likely and shortness of breath, syncope and nausea may be more common. With respect to treatment, the use of thrombolytic agents has been tempered by concerns over intracranial bleeding. With the use of streptokinase, there is additional concern over the effect of antistreptokinase antibodies. Other thrombolytic agents have their limitations, including cost. Plasminogen activators are more fibrin specific.

STEMI patients presenting to a PCI capable hospital should be treated within 90 minutes. For those hospitals without PCI capability that can’t be transferred, fibrinolytic (thrombolytic) therapy should be used with 30 minutes unless contraindicated. Early treatment emphasis with reperfusion therapy is strong. Rescue PCI is to be used if the 90 minute electrocardardiogram shows clinical evidence for unsuccessful fibrinolytic therapy. Patients undergoing reperfusion with fibrinolytics should receive anticoagulant therapy for a minimum of 48 hours and preferably for the duration of the hospitalization up to eight days. Established regimens include UFH, enoxaparin and fondaparinux. Elderly should be treated as aggressively as other age groups.

Copyright 2011 American Society of Consultant Pharmacists

Coronary Artery Occlusion Management

Coronary Fibrinolytic Therapy • Percutaneous Coronary Intervention (PCI)

Coronary Artery Bypass Graft (CABG)

MECHANISM OF ACTION OF ASPIRIN

Blocks the enzyme cyclooxygenase by permanently acetylating the enzyme in the platelet.

MECHANISM OF ACTION OF CLOPIDOGREL Selective, irreversible inhibition of adenosine diphosphate (ADP)-induced platelet aggregation.

GlycoproteinIIb-IIIa Receptor Blockers

Receptor site on the platelet surface for von Willebrand’s factor, fibrinogen and other platelet aggregation modulators is blocked, preventing aggregation.

Eptifibatide

Tirofibon

abciximab

Copyright 2011 American Society of Consultant Pharmacists

Coronary Artery Occlusion Management

Coronary artery occlusion can be treated, medically, surgically or with angioplasty.

Thrombolytic therapy is a pharmacological option for opening an obstructed arterybut its use can be controversial in patients over age 75. Stroke and intracranial hemorrhage risk is increased in elderly. Some of the first trials of thrombolytic therapy did not include elderly patients. Elderly may have a higher precedence of relative contraindications but they also have higher mortality post MI. Benefit versus risk must be assessed before thrombolytics are used. An AHA Scientific Statement found a mortality benefit with fibrinolysis in patients up to age 85.

Antiplatelet therapy has a major role in preventing re-occlusion of the artery. Aspirin, clopidogrel or both in combination are considered the front line therapies.Ticlopidine, due to hematologic and hepatic adverse effects, is limited to use in patients who cannot tolerate either of these drugs.

Eptifibatide, tirofiban, abciximab block platelet glycoprotein IIb-IIIa receptors, inhibiting the final common pathway of platelet aggregation.These agents have been effective for short term use in situations such as Acute Coronary Syndrome, Percutaneous Coronary Intervention, or Unstable Angina. Abciximab is the first line GPII b/IIIa receptor inhibitor for STE ACS patients undergoing primary PCI who have not received fibrinolytics. Tirofiban or eptifibitide is recommended for high-risk NSTE ACS patients not being revascularized. Abciximab or eptifibatide is recommended for NSTE ACS patients getting PCI.

Copyright 2011 American Society of Consultant Pharmacists

Coronary Artery Occlusion Management

Thienopyridines (clopidogel) should be added to aspirin in patients with STEMI regardless of whether or not reperfusion therapy is used. It should continue for 14 days. Dual antiplatelet therapy with clopidogrel 75mg and aspirin is used in unstable angina, non-STEMI and STEMI. Oral loading doses of clopidogrel 300mg are used in patients <75 who receive fibrinolytic therapy. One year maintenance therapy with clopidogrel is used in STEMI patients. Patients older than 75 were not enrolled in studies so safety is unknown.

The American Heart Association has 2007 guidelines for cardiovascular disease prevention in women with recommendations specific for women over age 65 years.

Drug eluting and bare metal stents differ in their need for antiplatelet therapy drug, dose and duration. Triple therapy with aspirin, clopidogrel and warfarin may be used in patients with atrial fibrillation or a prosthetic valve.

ACE inhibitors may be used in patients with normal left-ventricular function, low-risk profile, acute coronary syndrome, recent revascularization or left ventricular dysfunction with or without HF symptoms or unless contraindicated. Beta blockers post-MI, are recommended indefinitely in all patients.

Copyright 2011 American Society of Consultant Pharmacists

Ischemic (most common) •

CT scan determines which type

Hemorrhagic

Stroke Subtype Classification intracerebral hemorrhage •