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Dr.

Wright -- Study Guide for Pathophysiology Final Exam

Note: Slide number refers to the most up-to-date PowerPoint on Canvas.

New Material (From Hemato_Coag_Disorders_Lecture-1 PowerPoint):

o Questions 1 and 2: General question on anemia and tests used to detect (Slides 4 and 5).

Red Cell Disorders


Disorders of red cells can result in anemia or, less commonly, polycythemia
Anemia is defined as a reduction in the oxygen-transporting capacity of blood, which
usually stems from a decrease in the red cell mass to subnormal levels.
Anemia can result from bleeding, increased red cell destruction, or decreased red cell
production.
The decrease in tissue oxygen tension that accompanies anemia triggers increased
production of EPO, which drives a compensatory hyperplasia of erythroid precursors in
the bone marrow.
The rise in marrow output is signaled by the appearance of increased numbers of newly
formed red cells (reticulocytes) in the peripheral blood. By contrast, anemias caused by
decreased red cell production (aregenerative anemias) are associated with subnormal
reticulocyte counts (reticulocytopenia).

Anemias also can be classified on the basis of red cell morphology, including the size,
color and shape of the red cells.
These features are judged subjectively by visual inspection of peripheral smears and also
are expressed quantitatively using the following indices: -
o Mean Cell Volume (MCV)
o Mean Cell Hemoglobin (MCH)
o Mean Cell Hemoglobin Concentration (MCHC)
o Red Cell Distribution Width (RDW)
Depending on the differential diagnosis, a number of other blood tests also may be
performed to evaluate anemia, including:
(1) iron indices
(2) plasma unconjugated bilirubin, haptoglobin, and lactate
dehydrogenase levels,
(3) serum and red cell folate and vitamin B12 concentrations
(4) hemoglobin electrophoresis
(5) Coombs test

o Question 3: What are the features shared by hemolytic anemias (Slides 8-10).

HEMOLYTIC ANEMIAS
Anemias caused by accelerated red cell destruction are termed hemolytic anemias.
Destruction can stem from either intrinsic (intracorpuscular) red cell defects, which are
usually inherited, or extrinsic (extracorpuscular) factors, which are usually acquired.
Features shared by all hemolytic anemias include:
(1) a decreased red cell life span
(2) a compensatory increase in erythropoiesis
(3) the retention of the products of degraded red cells (including iron) by the body.
Hemolytic anemias are associated with erythroid hyperplasia in the marrow and
increased numbers of reticulocytes in the peripheral blood.

Destruction of red cells can occur within the vascular compartment (intravascular
hemolysis) or within tissue macrophages (extravascular hemolysis).
Intravascular hemolysis can result from:
o mechanical forces (e.g., turbulence created by a defective heart valve)
o biochemical or physical agents that damage the red cell membrane
Leads to hemoglobinemia, hemoglobinuria, and hemosiderinuria.
The conversion of heme to bilirubin can result in unconjugated hyperbilirubinemia and
jaundice.
Massive intravascular hemolysis sometimes leads to acute tubular necrosis.

Extravascular hemolysis, the more common mode of red cell destruction, primarily takes
place within the spleen and liver, which contain large numbers of macrophages, the
principal cells responsible for the removal of damaged red cells from the circulation.
o Any reduction in red cell deformability makes passage through the splenic sinusoids
difficult and leads to splenic sequestration and phagocytosis.
Not associated with hemoglobinemia and hemoglobinuria, but often produces jaundice
and, if long-standing, leads to the formation of bilirubin-rich gallstones
In most forms of chronic extravascular hemolysis there is a reactive hyperplasia of
mononuclear phagocytes that results in splenomegaly.

3. Question 4: Specific question on prevalence/mechanism of sickle cell anemia (Slides 14-18).

Sickle Cell Anemia


The prototypical (and most prevalent) hemoglobinopathy.
Stems from a mutation in the -globin gene that creates sickle hemoglobin (HbS).
Normal hemoglobins are tetramers composed of two pairs of similar chains (a2b2).
o HbS is produced by the substitution of valine for glutamic acid at the sixth amino acid
residue of -globin.
The most common familial hemolytic anemia in the world:
o In parts of Africa where malaria is endemic, the gene frequency approaches 30% as a
result of a small but significant protective effect of HbS against Plasmodium
falciparum malaria.
Sickle Cell Anemia
On deoxygenation, HbS molecules form long polymers by means of intermolecular
contacts that involve the abnormal valine residue at position 6.
These polymers distort the red cell, which assumes an elongated crescentic, or sickle,
shape

Sickle Cell Anemia


The sickling of red cells initially is reversible upon reoxygenation.
However, the distortion of the membrane that is produced by each sickling episode leads
to an influx of calcium, which causes the loss of potassium and water and also damages
the membrane skeleton.
Over time, this cumulative damage creates irreversibly sickled cells, which are rapidly
hemolyzed.
The three most important factors that influence the sickling of red cells:
1) The presence of hemoglobins other than HbS.
2) The intracellular concentration of HbS.
3) The transit time for red cells through the microvasculature.

Sickle Cell Anemia


Two major consequences arise from the sickling of red cells:
1) the red cell membrane damage and dehydration caused by repeated episodes
of sickling produce a chronic hemolytic anemia.
2) red cell sickling produces widespread microvascular obstructions, which
result in ischemic tissue damage and pain crises.

4. Question 5 and 6: Specific categories (minor, major, etc.) and morphology of -thalassemia
(Slides 20-23).

b-Thalassemia
The mutations associated with -thalassemia fall into two categories:
1) 0, in which no -globin chains are produced
2) +, in which there is reduced (but detectable) -globin synthesis
Persons inheriting one abnormal allele have -thalassemia minor (also known as -
thalassemia trait), which is asymptomatic or mildly symptomatic.
Most people inheriting any two 0 and + alleles have -thalassemia major;
Occasionally, persons inheriting two + alleles have a milder disease termed -
thalassemia intermedia.
In contrast with -thalassemias, gene deletions rarely underlie -thalassemias

The mutations responsible for -thalassemia disrupt -globin synthesis in several


different ways:
Mutations leading to aberrant RNA splicing are the most common cause of -
thalassemia.
Some mutations lie within the -globin promoter and lower the rate of -globin gene
transcription.
Other mutations involve the coding regions of the -globin gene, creating frame-shifts
that lead to termination codons.
Two mechanisms contribute to the anemia in -thalassemia:
1) The reduced synthesis of -globin leads to inadequate HbA formation and
results in the production of poorly hemoglobinized red cells that are pale
(hypochromic) and small in size (microcytic).
o Imbalance in -globin and -globin chain synthesis creates an excess of
unpaired chains that aggregate into insoluble precipitates, which bind and
severely damage the membranes of both red cells and erythroid precursors.
2) A high fraction of the damaged erythroid precursors die by apoptosis a
phenomenon termed ineffective erythropoiesis, and the few red cells that are
produced have a shortened life span due to extravascular hemolysis.
o Ineffective erythropoiesis has another untoward effect: It is associated with an
inappropriate increase in the absorption of dietary iron, which without medical
intervention inevitably leads to iron overload.

5. Question 7: Causes of iron deficiency anemia (Slides 32-33).

Iron Deficiency Anemia


Worldwide, the most frequent cause of anemia is iron deficiency.
The factors responsible for iron deficiency differ in various populations and are best
understood in the context of normal iron metabolism.
The high prevalence of iron deficiency has promoted metabolic pathways that are
strongly biased toward iron retention. There is no regulated pathway for iron excretion,
which is limited to the 1 to 2 mg/day that is lost through the shedding of mucosal and
skin epithelial cells.
o Iron balance is maintained largely by regulating the absorption of dietary
iron.
When the body is replete with iron, most iron entering duodenal cells is handed off to
ferritin, whereas transfer to plasma transferrin is enhanced when iron is deficient or
erythropoiesis is inefficient. This balance is regulated by hepcidin, a small hepatic
peptide that is synthesized and secreted in an iron-dependent fashion.

Chronic blood loss is the most important cause of iron deficiency anemia in the Western
world.
In the developing world, low intake and poor bioavailability due to predominantly
vegetarian diets are the most common causes of iron deficiency.
Increased demands not met by normal dietary intake occur worldwide during pregnancy
and infancy.
Malabsorption can occur with celiac disease or after gastrectomy
Regardless of the cause, iron deficiency develops insidiously. Iron stores are depleted
first, marked by a decline in serum ferritin followed by a decrease in serum iron and a
rise in the serum transferrin. Ultimately, the capacity to synthesize hemoglobin,
myoglobin, and other iron-containing proteins is diminished, leading to microcytic
anemia, impaired work and cognitive performance, and even reduced
immunocompetence.

6. Question 8: General question regarding megaloblastic anemias (Slides 37 and 38).

Megaloblastic Anemias
The morphologic hallmark of megaloblastic anemia is the presence of megaloblasts:
o larger than normal erythroid progenitors (normoblasts) that have delicate,
finely reticulated nuclear chromatin (indicative of nuclear immaturity) and
give rise to abnormally large red cells (macrocytes).

The two principal causes of megaloblastic anemia are folate deficiency and vitamin B12
deficiency.
Both vitamins are required for DNA synthesis and the effects of their deficiency on
hematopoiesis are essentially identical.
Underlying the cellular gigantism associated with megaloblastic anemia is a defect in
DNA synthesis that impairs nuclear maturation and cell division.
This maturational derangement contributes to the anemia in several ways:
1) Many megaloblasts are so defective in DNA synthesis that they undergo
apoptosis in the marrow (ineffective hematopoiesis).
2) Others mature into red cells but do so after fewer cell divisions, further diminishing the
output of red cells.
3) Granulocyte and platelet precursors are also affected (although not as severely) and
most patients present with pancytopenia (anemia, thrombocytopenia, and
granulocytopenia).

7. Question 9: Metabolism of folate (folate cycle) and folate deficiency (Slides 39-42).

Folate Deficiency Anemia


The risk of clinically significant folate deficiency is high in those with a poor diet (the
economically deprived, the indigent, and the elderly) or increased metabolic needs
(pregnant women and patients with chronic hemolytic anemias).
Folate is present in nearly all foods but is destroyed by 10 to 15 minutes of cooking.
Thus, the best sources are fresh uncooked vegetables and fruits.
The principal site of intestinal absorption is the upper third of the small intestine; thus,
malabsorptive disorders that affect this level of the gut, such as celiac disease and tropical
sprue, can impair folate uptake.

The metabolism and functions of folate are complex:


o In brief, after absorption folate is transported in the blood mainly as a
monoglutamate.
o Within cells it is further metabolized to several derivatives, but its conversion
from dihydrofolate to tetrahydrofolate by dihydrofolate reductase is
particularly important. Tetrahydrofolate acts as an acceptor and donor
of one-carbon units in several reactions that are required for the synthesis of
purines and thymidylate, and its deficiency accounts for the defect in DNA
replication that underlies megaloblastic anemia.

The onset of the anemia of folate deficiency is insidious, being associated with
nonspecific symptoms such as weakness and easy fatigability.
The clinical picture may be complicated by the coexistent deficiency of other vitamins,
especially in alcoholics.
Unlike in vitamin B12 deficiency, neurologic abnormalities do not occur.

8. Question 10 and 11: Vitamin B12 absorption and consequences of deficiency (Slides 41 and
43-46).

Vitamin B12 (Cobalamin) Deficiency Anemia (Pernicious Anemia)


Inadequate levels of vitamin B12 (also known as cobalamin) result in a megaloblastic
anemia identical to that seen with folate deficiency.
However, vitamin B12 deficiency can also cause a demyelinating disorder of the
peripheral nerves and the spinal cord.
The term pernicious anemia, a relic of days when the cause and therapy of this condition
were unknown, applies to vitamin B12 deficiency that results from defects involving
intrinsic factor.
Vitamin B12 Deficiency Anemia
Intrinsic factor plays a critical role in the absorption of vitamin B12, a multistep process
that proceeds as follows:
1. Peptic digestion releases dietary vitamin B12, allowing it to bind a salivary protein called
haptocorrin.
2. On entering the duodenum, haptocorrinB12 complexes are processed by pancreatic
proteases; this releases B12, which attaches to intrinsic factor secreted from the parietal
cells of the gastric fundic mucosa.
3. The intrinsic factorB12 complexes pass to the distal ileum and attach to cubulin, a
receptor for intrinsic factor, and are taken up into enterocytes.
4. The absorbed vitamin B12 is transferred across the basolateral membranes of enterocytes
to plasma transcobalamin, which delivers vitamin B12 to the liver and other cells of the
body.

Long-standing malabsorption underlies the vast majority of cases of vitamin B12


deficiency.
o Vitamin B12 is abundant in all food derived from animals, including eggs and
dairy products, and is resistant to cooking and boiling. Even bacterial
contamination of water and nonanimal foods can provide adequate amounts.
o As a result, deficiencies due to diet are rare, being confined to strict vegans.
Pernicious anemia is the most frequent cause of vitamin B12 deficiency.
o This disease seems to stem from an autoimmune reaction against parietal cells and
intrinsic factor itself, which produces gastric mucosal atrophy

The metabolic defects responsible for the anemia are intertwined with folate metabolism.
Vitamin B12 is required for recycling of tetrahydrofolate, the form of folate that is needed
for DNA synthesis. In keeping with this relationship, the anemia of vitamin B12
deficiency is reversed with administration of folate.
By contrast, folate administration does not prevent and may in fact worsen the neurologic
symptoms. The main neurologic lesions associated with vitamin B12 deficiency are
demyelination of the posterior and lateral columns of the spinal cord.
The severity of the neurologic manifestations is not related to the degree of anemia.
Indeed, the neurologic disease may occur in the absence of overt megaloblastic anemia.

9. Question 12: General question on neutropenia (Slide 53).

Neutropenia
A reduction in the number of granulocytes in blood is known as neutropenia or, when
severe, agranulocytosis.
Neutropenic persons are susceptible to bacterial and fungal infections; in whom they can
be fatal.
The mechanisms underlying neutropenia can be divided into two broad categories:
1) Decreased granulocyte production.
o Clinically important reductions in granulopoiesis are most often causedby marrow
failure (as occurs in aplastic anemia), extensive replacement of the marrow by
tumor (such as in leukemias), or cancer chemotherapy.
2) Increased granulocyte destruction.
o This can be encountered with immune-mediated injury or in overwhelming
bacterial, fungal, or rickettsial infections.

10. Question 13: Know the different patterns of Chronic Nonspecific Lymphadenitis (Slide 58).

Reactive Lymphadenitis
Chronic Nonspecific Lymphadenitis
o Depending on the causative agent, can assume one of three patterns:
1) Follicular Hyperplasia This pattern occurs with infections or inflammatory
processes that activate B cells, which migrate into B cell follicles and create the
follicular (or germinal center) reaction. Causes of follicular hyperplasia include
rheumatoid arthritis, toxoplasmosis, and early HIV infection.
2) Paracortical Hyperplasia This pattern is caused by immune reactions involving the T
cell regions of the lymph node. Paracortical hyperplasia is encountered in viral
infections, after certain vaccinations, and in immune reactions induced by drugs
3) Sinus Histiocytosis This reactive pattern is characterized by distention and
prominence of the lymphatic sinusoids, owing to a marked hypertrophy of lining
endothelial cells and an infiltrate of macrophages (histiocytes). It often is encountered
in lymph nodes draining cancers.

11. Questions 14-17: Matching between specific types of lymphoid neoplasms and their
definitions. Specifically, I will have a defining feature of ALL (Slides 66 and 67), CLL (Slides
68-70), DLBCL (Slides 73 and 74), and Hodgkin lymphoma (Slides 78-81) that you will have to
match with the respective cancer. Will only match once (i.e. only one option/definition per
cancer to match). It would be a good idea to review the 5 background points listed for all
lymphoid neoplasms (Slides 62-65).
Note: I mentioned at the beginning of the review session that you only needed the
definitions on the summary slide for lymphoid neoplasms. However, since I agreed to
provide this study guide I will be taking the defining feature directly from the slides that
describe each cancer listed above. In other words, study the slides for each cancer that
you will be matching with their defining feature. This could be anything from the
defining mutation to the pathology they exhibit in a peripheral blood smear, etc.

Acute Lymphoblastic Leukemia


Acute lymphoblastic leukemia (ALL) is an aggressive tumor, composed of immature
lymphocytes (lymphoblasts), that occur predominantly in children and young adults.
The principal pathogenic defect in acute leukemia is a block in differentiation. This
maturation arrest stems from acquired mutations in specific transcription factors that
regulate the differentiation of immature lymphoid or myeloid progenitors.
Acute leukemias also are associated with complementary acquired mutations that allow
the tumor cells to proliferate in a growth factor-independent fashion. In B-ALL, one of
the most important mutations of this type is a BCR-ABL fusion gene created by a (9;22)
translocation (the so-called Philadelphia chromosome, for the city of its discovery).
Blasts accumulating in the marrow suppress the growth of normal hematopoietic cells
producing bone marrow failure.

Because of differing responses to therapy, it is of great practical importance to distinguish


ALL from AML.

Chronic Lymphocytic Leukemia


Most patients with lymphoid neoplasms fit the diagnostic criteria for CLL, which is the
most common leukemia of adults in the Western world.
CLL is an indolent, slowly growing tumor of mature B cells, suggesting that increased
tumor cell survival is more important than tumor cell proliferation in this disease.
The tumor cells contain high levels of BCL2, a protein that inhibits apoptosis.
Another important pathogenic aspect of CLL is immune dysregulation. Through unclear
mechanisms, the accumulation of CLL cells suppresses normal B cell function, often
resulting in hypogammaglobulinemia.
As time passes the tumor cells tend to displace the normal marrow elements, leading to
anemia, neutropenia, and eventual thrombocytopenia.

Effacement of Lymph Node Architecture


Chronic Lymphocytic Leukemia
In CLL, sheets of small lymphocytes and
scattered ill-defined foci of larger, actively
dividing cells diffusely efface involved lymph
nodes.
The predominant cells are small, resting
lymphocytes with dark, round nuclei, and scanty
cytoplasm.

Diffuse Large B Cell Lymphoma


The most common type of lymphoma in adults, accounting for approximately 50% of
adult NHLs.
About one third of tumors have rearrangements of the BCL6 gene, located on 3q27, and
an even higher fraction of tumors have activating point mutations in the BCL6 promoter.
These mature B cell tumors express pan-B cell antigens, such as CD19 and CD20. Many
also express surface IgM and/or IgG. Other antigens (e.g., CD10, BCL2) are variably
expressed.
Without treatment, diffuse large cell B cell lymphomas are aggressive and rapidly fatal.
With intensive combination chemotherapy and anti-CD20 immunotherapy, complete
remissions are achieved in 60% to 80% of the patients; of these, approximately 50%
remain free of disease and appear to be cured.
The neoplastic B cells are large (at least three to four times the size of resting
lymphocytes) and vary in appearance from tumor to tumor. In many tumors, cells with
round or oval nuclear contours, dispersed chromatin, several distinct nucleoli, and modest
amounts of pale cytoplasm predominate

Hodgkin Lymphoma
Hodgkin lymphoma encompasses a distinctive group of neoplasms that are characterized
by the presence of a tumor giant cell, the Reed-Sternberg cell.
Unlike most NHLs, Hodgkin lymphomas arise in a single lymph node or chain of lymph
nodes and typically spread in a stepwise fashion to anatomically contiguous nodes.
The Reed-Sternberg (RS) cell, a very large cell (15 to 45 m in diameter) with an
enormous multilobate nucleus, exceptionally prominent nucleoli and abundant cytoplasm
is the main morphological marker.
Particularly characteristic are cells with two mirror-image nuclei or nuclear lobes, each
containing a large (inclusion-like) acidophilic nucleolus surrounded by a clear zone,
features that impart an owl-eye appearance.

Hodgkin Lymphoma
Typical RS cells and variants have a characteristic
immunophenotype, as they express CD15 and CD30 and fail to
express CD45 (common leukocyte antigen), B cell
antigens, and T cell antigens.
Nodular sclerosis Hodgkin lymphoma is the
most common form. It is equally frequent in men
and in women and has a striking propensity to
involve the lower cervical, supraclavicular, and
mediastinal lymph nodes. Most patients are
adolescents or young adults, and the overall
prognosis is excellent.
Elegant molecular studies performed on single microdissected RS cells from any given
case possessed the same immunoglobulin gene rearrangements. In addition these studies
revealed that the rearranged immunoglobulin genes had undergone somatic
hypermutation. As a result, it is now agreed that Hodgkin lymphoma is a neoplasm
arising from germinal center B cells.
The characteristic non-neoplastic, inflammatory cell infiltrate is generated by a number of
cytokines, some secreted by RS cells. Conversely, the responding inflammatory cells,
rather than being innocent bystanders, produce additional factors such as CD30 ligand
that aid the growth and survival of RS cells and contribute further to the tissue reaction.
Note: Brentuximab vedotin and CD30

SLIDES (62-65):
Lymphoid Neoplasms
Historically, few areas of pathology evoked as much controversy and confusion as the
classification of lymphoid neoplasms, which is perhaps inevitable in view of the intrinsic
complexity of the immune system, from which they arise.
An international working group of pathologists, molecular biologists, and clinicians
working on behalf of the World Health Organization (WHO) has formulated a widely
accepted classification scheme that relies on a combination of morphologic, phenotypic,
genotypic, and clinical features.
Important principles to be considered:
1) B and T cell tumors often are composed of cells that are arrested at or derived from a
specific stage of their normal differentiation
As background, certain important principles need to be considered:
2) The most common lymphomas are derived from germinal center or post-germinal
center B cells. Mature T cells, which are genomically stable, give rise to lymphomas
infrequently.
3) All lymphoid neoplasms are derived from a single transformed cell and are therefore
clonal. Thus, analyses of antigen receptor genes and their protein products can be used to
differentiate clonal neoplasms from polyclonal, reactive processes.
4) Lymphoid neoplasms often disrupt normal immune function. Both
immunodeficiency and autoimmunity may be seen.
5) Although NHLs often manifest at a particular tissue site, sensitive molecular assays
usually show the tumor to be widely disseminated at diagnosis. As a result, with few
exceptions, only systemic therapies are curative.

12. Question 18: General question on multiple myeloma (Slides 75-77).

Multiple Myeloma
Multiple myelomas (and related plasma cell tumors) secrete a single complete or partial
immunoglobulin.
Because these immunoglobulins can be detected in the serum, these disorders are also
referred to as monoclonal gammopathies, and the associated immunoglobulin is often
referred to as an M protein.
Although M proteins may be indicative of overt malignancy, they also are found often in
normal elderly personsa condition called monoclonal gammopathy of undetermined
significance (MGUS).
Collectively, these disorders account for approximately 15% of the deaths that are caused
by tumors of white blood cells. They are most common in middle-aged and elderly
persons.
Multiple myeloma usually manifests with multifocal destructive skeletal lesions, which
most commonly involve the vertebral column, ribs, skull, pelvis, femur, clavicle, and
scapula.
This destructive process in turn often leads to pathologic fractures, most frequently in
the vertebral column or femur.
The bone lesions usually appear as punched-out defects 1 to 4 cm in diameter

Microscopic examination of the marrow reveals increased numbers of plasma cells,


which usually constitute greater than 30% of the cellularity.
Myeloma cells may resemble normal plasma cells but more often show abnormal features
such as prominent nucleoli or abnormal cytoplasmic inclusions containing
immunoglobulin.

Renal involvement (myeloma nephrosis) is associated with proteinaceous casts in the


distal convoluted tubules and the collecting ducts, consisting mostly of Bence Jones
proteins along with variable amounts of complete immunoglobulins

13. Question 19 and 20: Specific question on mutation events and/or peripheral blood smear
pathology in Acute Myeloid Leukemia and Chronic Myelogenous leukemia (Slides 84-87).

Acute Myeloid Leukemia


Most AMLs harbor mutations in genes encoding transcription factors that are required for
normal myeloid cell differentiation.
These mutations interfere with the differentiation of early myeloid cells, leading to the
accumulation of myeloid precursors (blasts) in the marrow.
Example: AMLs that harbor the (15;17) translocation, which results in the fusion of the
retinoic acid receptor (RARA) gene on chromosome 17 and the PML gene on
chromosome 15. The chimeric gene produces a PML/RAR fusion protein that blocks
myeloid differentiation at the promyelocytic stage, probably in part by inhibiting the
function of normal retinoic acid receptors.
Overall survival is only 15% to 30%. Can target AMLs that harbor the (15;17)
translocation with all-trans retinoic acid (ATRA) to overcome this block and induce the
neoplastic promyelocytes to rapidly differentiate into neutrophils.

Acute promyelocytic leukemiabone marrow aspirate. The neoplastic promyelocytes


have abnormally coarse and numerous azurophilic granules. Other characteristic findings
include the presence of bilobed nuclei and multiple needle-like Auer rods.

Chronic Myeloproliferative Disorders


Marked by the hyperproliferation of neoplastic myeloid progenitors that retain the
capacity for terminal differentiation; as a result, there is an increase in one or more
formed elements of the peripheral blood.
A common theme is the association of these disorders with activating mutations in
tyrosine kinases, which generate constitutive signals mimicking those that are normally
produced in response to hematopoietic growth factors.
For example: chronic myelogenous leukemia (CML) is associated with a characteristic
abnormality, the BCR-ABL fusion gene, which produces a constitutively active BCR-
ABL tyrosine kinase. Alternatively, polycythemia vera has activating mutations in the
tyrosine kinase JAK2 (signaling pathway activated by EPO).
Chronic myelogenous leukemiaperipheral blood smear. Granulocytic forms at various
stages of differentiation are present.
The leukocyte count is elevated, often exceeding 100,000 cells/L. The circulating cells
are predominantly neutrophils, metamyelocytes, and myelocytes.

14. Question 21 and 22: Know the mechanisms that cause DIC and the two main consequences.
Understand what consumptive coagulopathy means (Slides 92-95).

DISSEMINATED INTRAVASCULAR COAGULATION


DIC is caused by the systemic activation of coagulation and results in the formation of
thrombi throughout the microcirculation. As a consequence, platelets and coagulation
factors are consumed and, secondarily, fibrinolysis is activated.
DIC can give rise to either tissue hypoxia and microinfarcts caused by myriad
microthrombi or to a bleeding disorder related to pathologic activation of fibrinolysis and
the depletion of the elements required for hemostasis (consumptive coagulopathy).
Causes bleeding more commonly than all of the congenital coagulation disorders
combined.

DIC usually is triggered by either (1) the release of tissue factor or thromboplastic
substances into the circulation or (2) widespread endothelial cell damage.
(1) Thromboplastic substances can be released into the circulation from a variety of
sourcesfor example, the placenta in obstetric complications or certain types of cancer
cells. In gram-negative and gram-positive sepsis (important causes of DIC), endotoxins
or exotoxins stimulate the release of tissue factor from monocytes. Activated monocytes
also release IL-1 and TNF, both of which stimulate the expression of tissue factor on
endothelial cells and simultaneously decrease the expression of thrombomodulin.

DIC usually is triggered by either (1) the release of tissue factor or thromboplastic
substances into the circulation or (2) widespread endothelial cell damage.
(2) Severe endothelial cell injury can initiate DIC by causing the release of tissue factor
and by exposing subendothelial collagen and von Willebrand factor. Widespread
endothelial injury can be produced by the deposition of antigen-antibody complexes (e.g.,
in systemic lupus erythematosus), by temperature extremes (e.g., after heat stroke or burn
injury), or by infections (e.g., due to meningococci or rickettsiae).
DIC is most often associated with sepsis, obstetric complications, malignancy, and major
trauma

Whatever the pathogenic mechanism, DIC has two consequences. First, there is
widespread fibrin deposition within the microcirculation. Second, a bleeding
diathesis results from the depletion of platelets and clotting factors and the secondary
release of plasminogen activators.

15. Question 23: Specific question on one of the 3 causes of thrombocytopenia that I wanted you
to know Immune thrombocytopenic purpura, heparin-induced thrombocytopenia, or thrombotic
thrombocytopenic purpura (Slides 96-98).

THROMBOCYTOPENIA
Clinically important thrombocytopenia is confined to (1) disorders with reduced
production or (2) increased destruction of platelets.
When the cause is accelerated destruction of platelets, the bone marrow usually reveals a
compensatory increase in the number of megakaryocytes. Hence, bone marrow
examination can help to distinguish between these two major categories of
thrombocytopenia.
Note: thrombocytopenia is one of the most common hematologic manifestations of AIDS.
A count less than 150,000 platelets/mL generally is considered to constitute
thrombocytopenia.
Platelet counts 20,000 to 50,000 platelets/mL associated with increased risk of post-
traumatic bleeding, and spontaneous bleeding becomes evident when counts fall below
20,000 platelets/mL.
Most bleeding occurs from small, superficial blood vessels and produces petechiae or
large ecchymoses in the skin, the mucous membranes of the gastrointestinal and urinary
tracts, and other sites.
Larger hemorrhages into the central nervous system are a major hazard in those with
markedly depressed platelet counts.

16. Question 24 and 25: Specific questions on mechanism/consequences of vWF disease and
hemophilia A (Slides 99-103).
COAGULATION DISORDERS
Result from either congenital or acquired deficiencies of clotting factors.
Acquired deficiencies are most common and often involve several factors simultaneously
(e.g., vitamin K deficiency, hepatic parenchymal diseases, DIC).
Hereditary deficiencies of each of the coagulation factors have been identified. Only von
Willebrand disease, hemophilia A (a deficiency of factor VIII), and hemophilia B
(Christmas disease, a deficiency of factor IX) are sufficiently common to warrant further
consideration.

Hemophilia A and von Willebrand disease are caused by qualitative or quantitative


defects involving the factor VIIIvon Willebrand factor (vWF) complex.
The most important function of vWF is to facilitate the adhesion of platelets to damaged
blood vessel walls. vWF also stabilizes factor VIII.

von Willebrand Disease


Presents as spontaneous bleeding from mucous membranes, excessive bleeding from
wounds, and menorrhagia.
It is underrecognized, as the diagnosis requires sophisticated tests and the clinical
manifestations often are quite mild.
It is estimated that approximately 1% of people in the United States have von Willebrand
disease, making it the most common inherited bleeding disorder.

People with von Willebrand disease have compound defects in platelet function and
coagulation, but in most cases only the platelet defect produces clinical findings.
The classic and most common variant of von Willebrand disease (type I) is an autosomal
dominant disorder in which the quantity of circulating vWF is reduced.
Type II is divided into several subtypes characterized by the selective loss of high-
molecular-weight multimers of vWF.

Hemophilia AFactor VIII Deficiency


An X-linked recessive disorder caused by reduced factor VIII activity primarily affecting
males.
Severe hemophilia A is observed in people with marked deficiencies of factor VIII
(activity levels less than 1% of normal). Milder deficiencies may only become apparent
when other predisposing conditions, such as trauma, are also present. The varying
degrees of factor VIII deficiency are explained by the existence of many different
causative mutations. As in the thalassemias, several types of genetic lesions (e.g.,
deletions, inversions, splice junction mutations) have been identified.
There is a tendency toward easy bruising and massive hemorrhage after trauma or
operative procedures. In addition, spontaneous hemorrhages frequently are
encountered in tissues that normally are subject to mechanical stress, particularly the
joints.
Hemophilia A is treated with factor VIII infusions.
Comprehensive Material (From
Wright_Hematopoeisis_Coagulation PowerPoint):
17. Question 26: General question over the regulation of iron metabolism (Slides 17-20).

Iron Metabolism
Iron is key component of many enzymes, including hemoglobin (Hgb) (largest amount
of iron in the body), myoglobin, cytochromes, catalase, etc.

STORAGE FORMS:

Ferritin = Apoferritin (24 subunits; 450 kDa) + hydrous ferric


oxide phosphate (4,000 atoms/ferritin). Aggregates are called
hemosiderin (1/3 of normal stores); primarily in macrophages in
reticuloendothelial system and liver.

Transferrin -- 76 kDa 1-glycoprotein; two binding sites for ferric iron;


binds to receptor and transports iron into cell via endocytosis pathway;
iron released in acid environment of endosomes.
REGULATION --
o Iron taken up by small intestine via apical DMT1 (divalent metal transporter
1) and transferred to mucosal ferritin or it is transported across the basolateral
membrane by Ferroportin to plasma transferrin; latter step is inhibited by
Hepcidin, a 25-aa peptide made in the liver.
Transferrin receptor/ferritin/hepcidin expression levels fluctuate with iron:
o Iron excess -- high ferritin & hepcidin, low transferrin receptor
o Iron shortage -- low ferritin & hepcidin, high transferrin receptor
Iron stores highly conserved; only 10% excreted (mainly GI) in men over one year, more
in women due to menstruation.
o RBC life span = 120 days; afterwards cells are degraded, and iron is released
back to the transferrin and ferritin pools.
18. Question 27: Know the two clinical assays for coagulation time and the coagulation pathway
that each tests for. Also, know what each assay monitors for (e.g. heparin vs. vitamin K-
reductase inhibitors) (Slide 43).

Coagulation
Clinical Assays:
1) Activated Partial Thromboplastin Time (APTT) Ca2+-chelated plasma (Na citrate)
is recalcified and incubated with negatively-charged PL & aluminum silicate (nr 26-33s).
2) Prothrombin Time (PT) recalcified plasma incubated with PL + TF, i.e.
thromboplastin (nr 12-14s).

19. Question 28: General question on hematopoiesis (Slides 7-10).

Hematopoiesis
Hematopoiesis is the formation and development of red and white blood cells from stem
cells. Occurs in bone marrow.
Hematopoietic stem cells are pluripotent and thereby generate erythrocytes, granulocytes,
monocytes, mast cells, lymphocytes, and megakaryocytes.

Pluripotent stem cells differentiate along one of two pathways, giving rise to either a
lymphoid stem cell or a myeloid stem cell. These in turn differentiate into
progenitor cells.
Nonhematopoietic cells in the bone marrow, known as stromal cells, support the growth
and differentiation of hematopoietic cells.

Stromal cells influence differentiation by providing a microenvironment consisting of a


cellular matrix and either membrane-bound or diffusible cytokines (growth factors).
Among the cytokines involved in this process are a family of acidic glycoproteins known
as the colony-stim factors (CSF), a glycoprotein called erythropoietin (EPO), and
several interleukins (IL).

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