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BLEEDING DISORDERS

HEMOSTASIS
1. VASCULAR PHASE
2. PLATELET PHASE
3. COAGULATION PHASE
4. FIBRINOLYTIC PHASE
Hemostasis
BV Injury
Platelet
Aggregation
Platelet
Activation

Blood Vessel
Constriction
Coagulation
Cascade
Stable Hemostatic Plug
Fibrin
formation
Reduced
Blood flow
Tissue Factor
Primary hemostatic plug
Neural
Lab Tests
CBC-Plt
BT,(CT)
PT
PTT
Plt Study
Morphology
Function
Antibody
NORMAL CLOTTING
Response to vessle injury
1. Vasoconstriction to reduce blood flow
2. Platelet plug formation (von willebrand factor binds
damaged vessle and platelets)
3. Activation of clotting cascade with generation of fibrin
clot formation
4. Fibrinlysis (clot breakdown)
Normally the ingredients, called factors, act like a row of
dominoes toppling against each other to create a chain
reaction.
If one of the factors is missing this chain reaction cannot
proceed.



CLOTTING CASCADE

VASCULAR PHASE

WHEN A BLOOD VESSEL IS
DAMAGED, VASOCONSTRICTION
RESULTS.
PLATELET PHASE
PLATELETS ADHERE TO THE
DAMAGED SURFACE AND FORM A
TEMPORARY PLUG.
COAGULATION PHASE
THROUGH TWO SEPARATE
PATHWAYS THE CONVERSION OF
FIBRINOGEN TO FIBRIN IS
COMPLETE.
THE CLOTTING MECHANISM
INTRINSIC EXTRINSIC
PROTHROMBIN THROMBIN
FIBRINOGEN
FIBRIN
(II) (III)
(I)
V
X
Tissue Thromboplastin Collagen
VII
XII
XI
IX
VIII
FIBRINOLYTIC PHASE
ANTICLOTTING MECHANISMS ARE
ACTIVATED TO ALLOW CLOT
DISINTEGRATION AND REPAIR OF
THE DAMAGED VESSEL.
HEMOSTASIS

DEPENDENT UPON:
* Vessel Wall Integrity
- Adequate Numbers of Platelets
4 Proper Functioning Platelets
^ Adequate Levels of Clotting Factors
= Proper Function of Fibrinolytic Pathway
LABORATORY EVALUATION
PLATELET COUNT
BLEEDING TIME (BT)
PROTHROMBIN TIME (PT)
PARTIAL THROMBOPLASTIN TIME (PTT)
THROMBIN TIME (TT)
PLATELET COUNT
O NORMAL 100,000 - 400,000 CELLS/MM
3

< 100,000

Thrombocytopenia

50,000 - 100,000 Mild Thrombocytopenia

< 50,000 Sev Thrombocytopenia



BLEEDING TIME

PROVIDES ASSESSMENT OF PLATELET
COUNT AND FUNCTION


NORMAL VALUE
2-8 MINUTES
PROTHROMBIN TIME
Measures Effectiveness of the Extrinsic
Pathway
Mnemonic - PET


NORMAL VALUE
10-15 SECS
PARTIAL THROMBOPLASTIN TIME
Measures Effectiveness of the Intrinsic
Pathway
Mnemonic - PITT
NORMAL VALUE
25-40 SECS
THROMBIN TIME
Time for Thrombin To Convert
Fibrinogen Fibrin
A Measure of Fibrinolytic Pathway
NORMAL VALUE
9-13 SECS


So What Causes Bleeding
Disorders?


OVESSEL DEFECTS
OPLATELET DISORDERS
OFACTOR DEFICIENCIES
OOTHER DISORDERS
?


?
VESSEL DEFECTS
O VITAMIN C DEFICIENCY

O BACTERIAL & VIRAL INFECTIONS

O ACQUIRED &
OHEREDITARY CONDITIONS
Vascular defect - cont.
Infectious and hypersensitivity vasculitides
- Rickettsial and meningococcal infections
- Henoch-Schonlein purpura (immune)
PLATELET DISORDERS
O THROMBOCYTOPENIA

O THROMBOCYTOPATHY



THROMBOCYTOPENIA

INADEQUATE NUMBER
OF PLATELETS
THROMBOCYTOPATHY
ADEQUATE NUMBER BUT
ABNORMAL FUNCTION
THROMBOCYTOPENIA
DRUG INDUCED
BONE MARROW FAILURE
HYPERSPLENISM
OTHER CAUSES

OTHER CAUSES
Lymphoma
HIV Virus
Idiopathic Thrombocytopenia Purpura (ITP)
THROMBOCYTOPATHY
UREMIA
INHERITED DISORDERS
MYELOPROLIFERATIVE DISORDERS
DRUG INDUCED
FACTOR DEFICIENCIES
(CONGENITAL)

O HEMOPHILIA A

O HEMOPHILIA B

O von WILLEBRANDS DISEASE
FACTOR DEFICIENCIES
HEMOPHILIA A (Classic Hemophilia)
80-85% of all Hemophiliacs
Deficiency of Factor VIII
Lab Results - Prolonged PTT
HEMOPHILIA B (Christmas Disease)
10-15% of all Hemophiliacs
Deficiency of Factor IX
Lab Test - Prolonged PTT
FACTOR DEFICIENCIES
VON WILLEBRANDS DISEASE
Deficiency of VWF & amount of Factor VIII
Lab Results - Prolonged BT, PTT
OTHER DISORDERS
(ACQUIRED)
O ORAL ANTICOAGULANTS
4COUMARIN
4HEPARIN
O LIVER DISEASE
O MALABSORPTION
O BROAD-SPECTRUM ANTIBIOTICS
INHIBITORS

30% of people with haemophilia develop an antibody to the
clotting factor they are receiving for treatment. These
antibodies are known as inhibitors.

These patients are treated with high does of FVIIa for bleeds or
surgery. This overrides defect in FVIII or FIX deficiency.

Longterm management involves attempting to eradicate
inhibitors by administering high dose FVIII (or FIX) in a
process called immune tolerance




Bleeding Disorders

Clinical Features of Bleeding Disorders
Platelet Coagulation
disorders
factor disorders

Site of bleeding Skin Deep in soft tissues
Mucous membranes (joints, muscles)
(epistaxis, gum,
vaginal, GI tract)
Petechiae Yes No
Ecchymoses (bruises) Small, superficial Large, deep
Hemarthrosis / muscle bleeding Extremely rare Common
Bleeding after cuts & scratches Yes No
Bleeding after surgery or trauma Immediate, Delayed (1-2 days),
usually mild often severe
Platelet Coagulation
Petechiae, Purpura Hematoma, Joint bl.
Petechiae
Do not blanch with pressure
(cf. angiomas)
Not palpable
(cf. vasculitis)
(typical of platelet disorders)
Hemarthrosis
Hematoma
Petechiae
Purpura
Ecchymosis
Senile Purpura
Petechiae in patient
with Rocky Mountain
Spotted Fever
Henoch-Schonlein purpura

Ecchymoses
(typical of coagulation
factor disorders)
CT scan showing large hematoma
of right psoas muscle
Coagulation factor disorders
Inherited bleeding
disorders
4Hemophilia A and B
4vonWillebrands disease
4Other factor deficiencies
Acquired bleeding
disorders
4Liver disease
4Vitamin K
deficiency/warfarin
overdose
4DIC
Hemophilia A and B


Hemophilia A Hemophilia B

Coagulation factor deficiency Factor VIII Factor IX

Inheritance X-linked X-linked
recessive recessive

Incidence 1/10,000 males 1/50,000 males

Severity Related to factor level
<1% - Severe - spontaneous bleeding
1-5% - Moderate - bleeding with mild injury
5-25% - Mild - bleeding with surgery or trauma

Complications Soft tissue bleeding
Hemophilia
Clinical manifestations (hemophilia A & B are
indistinguishable)

Hemarthrosis (most common)
Fixed joints
Soft tissue hematomas (e.g., muscle)
Muscle atrophy
Shortened tendons
Other sites of bleeding
Urinary tract
CNS, neck (may be life-threatening)
Prolonged bleeding after surgery or dental extractions

Hemarthrosis (acute)
Treatment of hemophilia A
Intermediate purity plasma products
4Virucidally treated
4May contain von Willebrand factor

High purity (monoclonal) plasma products
4Virucidally treated
4No functional von Willebrand factor

Recombinant factor VIII
4Virus free/No apparent risk
4No functional von Willebrand factor
Dosing guidelines for hemophilia A
Mild bleeding
4Target: 30% dosing q8-12h; 1-2 days (15U/kg)
4 Hemarthrosis, oropharyngeal or dental, epistaxis, hematuria

Major bleeding
4Target: 80-100% q8-12h; 7-14 days (50U/kg)
4 CNS trauma, hemorrhage, lumbar puncture
4 Surgery
4 Retroperitoneal hemorrhage
4 GI bleeding

Adjunctive therapy
4 -aminocaproic acid (Amicar) or DDAVP (for mild disease only)
Complications of therapy
Formation of inhibitors (antibodies)
410-15% of severe hemophilia A patients
41-2% of severe hemophilia B patients

Viral infections
4Hepatitis B Human parvovirus
4Hepatitis C Hepatitis A
4HIV Other

Viral infections in hemophiliacs
HIV -positive HIV-negative
(n=382) (n=345)
53% 47%
Hepatitis serology % positive % negative

Negative 1 20
Hepatitis B virus only 1 1
Hepatitis C virus only 24 45
Hepatitis B and C 74 34
Blood 1993:81;412-418
Treatment of hemophilia B
Agent
4High purity factor IX
4Recombinant human factor IX

Dose
4Initial dose: 100U/kg
4Subsequent: 50U/kg every 24 hours
von Willebrand Disease: Clinical Features
von Willebrand factor
4Synthesis in endothelium and megakaryocytes
4Forms large multimer
4Carrier of factor VIII
4Anchors platelets to subendothelium
4Bridge between platelets

Inheritance - autosomal dominant

Incidence - 1/10,000

Clinical features - mucocutaneous bleeding
Laboratory evaluation of
von Willebrand disease
Classification
4Type 1 Partial quantitative deficiency
4Type 2 Qualitative deficiency
4Type 3 Total quantitative deficiency

Diagnostic tests:
vonWillebrand type
Assay 1 2 3

vWF antigen Normal
vWF activity
Multimer analysis Normal Normal Absent
Treatment of von Willebrand Disease
Cryoprecipitate
4Source of fibrinogen, factor VIII and VWF
4Only plasma fraction that consistently contains VWF multimers

DDAVP (deamino-8-arginine vasopressin)
4 plasma VWF levels by stimulating secretion from endothelium
4Duration of response is variable
4Not generally used in type 2 disease
4Dosage 0.3 g/kg q 12 hr IV

Factor VIII concentrate (Intermediate purity)
4Virally inactivated product
Vitamin K deficiency
Source of vitamin K Green vegetables
Synthesized by intestinal flora

Required for synthesis Factors II, VII, IX ,X
Protein C and S

Causes of deficiency Malnutrition
Biliary obstruction
Malabsorption
Antibiotic therapy

Treatment Vitamin K
Fresh frozen plasma
Common clinical conditions associated with
Disseminated Intravascular Coagulation
Sepsis

Trauma
4 Head injury
4 Fat embolism

Malignancy
Obstetrical complications
4 Amniotic fluid embolism
4 Abruptio placentae

Vascular disorders

Reaction to toxin (e.g.
snake venom, drugs)

Immunologic disorders
4 Severe allergic reaction
4 Transplant rejection
Activation of both coagulation and fibrinolysis
Triggered by
Disseminated Intravascular Coagulation (DIC)
Mechanism
Systemic activation
of coagulation
Intravascular
deposition of fibrin

Depletion of platelets
and coagulation factors
Bleeding Thrombosis of small
and midsize vessels
with organ failure
Pathogenesis of DIC
Coagulation Fibrinolysis
Fibrinogen
Fibrin
Monomers
Fibrin
Clot
(intravascular)
Fibrin(ogen)
Degradation
Products
Plasmin
Thrombin Plasmin
Release of
thromboplastic
material into
circulation
Consumption of
coagulation factors;
presence of FDPs
aPTT
PT
TT
Fibrinogen

Presence of plasmin
FDP

Intravascular clot
Platelets
Schistocytes
Disseminated Intravascular Coagulation
Treatment approaches
Treatment of underlying disorder

Anticoagulation with heparin

Platelet transfusion

Fresh frozen plasma

Coagulation inhibitor concentrate (ATIII)
Classification of platelet disorders
Quantitative disorders

4Abnormal distribution
4Dilution effect
4Decreased production

4Increased destruction
Qualitative disorders

4Inherited disorders (rare)
4Acquired disorders
Medications
Chronic renal failure
Cardiopulmonary bypass
Thrombocytopenia


Immune-mediated
Idioapthic
Drug-induced
Collagen vascular disease
Lymphoproliferative disease
Sarcoidosis
Non-immune mediated
DIC
Microangiopathic hemolytic anemia

Liver Disease and Hemostasis
1. Decreased synthesis of II, VII, IX, X, XI, and
fibrinogen

2. Dietary Vitamin K deficiency (Inadequate
intake or malabsortion)

3. Dysfibrinogenemia

4. Enhanced fibrinolysis (Decreased alpha-2-
antiplasmin)

5. DIC

6. Thrombocytoepnia due to hypersplenism

Management of Hemostatic
Defects in Liver Disease
Treatment for prolonged PT/PTT
Vitamin K 10 mg SQ x 3 days - usually
ineffective

Fresh-frozen plasma infusion
25-30% of plasma volume (1200-1500 ml)
immediate but temporary effect

Treatment for low fibrinogen
Cryoprecipitate (1 unit/10kg body weight)

Treatment for DIC (Elevated D-dimer, low factor
VIII, thrombocytopenia
Replacement therapy




Vitamin K deficiency due to warfarin overdose
Managing high INR values
Clinical situation Guidelines

INR therapeutic-5 Lower or omit next dose;
Resume therapy when INR is therapeutic

INR 5-9; no bleeding Lower or omit next dose;
Resume therapy when INR is therapeutic

Omit dose and give vitamin K (1-2.5 mg po)

Rapid reversal: vitamin K 2-4 mg po (repeat)

INR >9; no bleeding Omit dose; vitamin K 3-5 mg po; repeat as necessary
Resume therapy at lower dose when INR therapeutic
Chest 2001:119;22-38s (supplement)
Vitamin K deficiency due to warfarin overdose
Managing high INR values in bleeding patients
Clinical situation Guidelines

INR > 20; serious bleeding Omit warfarin
Vitamin K 10 mg slow IV infusion
FFP or PCC (depending on urgency)
Repeat vitamin K injections every 12 hrs as needed

Any life-threatening bleeding Omit warfarin
Vitamin K 10 mg slow IV infusion
PCC ( or recombinant human factor VIIa)
Repeat vitamin K injections every 12 hrs as needed


Chest 2001:119;22-38s (supplement)
Approach to Post-operative bleeding
1. Is the bleeding local or due to a hemostatic failure?
1. Local: Single site of bleeding usually rapid with minimal
coagulation test abnormalities
2. Hemostatic failure: Multiple site or unusual pattern with
abnormal coagulation tests

2. Evaluate for causes of peri-operative hemostatic failure
1. Preexisting abnormality
2. Special cases (e.g. Cardiopulmonmary bypass)

3. Diagnosis of hemostatic failure
1. Review pre-operative testing
2. Obtain updated testing

Laboratory Evaluation of Bleeding
Overview
CBC and smear Platelet count Thrombocytopenia
RBC and platelet morphology TTP, DIC, etc.

Coagulation Prothrombin time Extrinsic/common pathways
Partial thromboplastin time Intrinsic/common pathways
Coagulation factor assays Specific factor deficiencies
50:50 mix Inhibitors (e.g., antibodies)
Fibrinogen assay Decreased fibrinogen
Thrombin time Qualitative/quantitative
fibrinogen defects
FDPs or D-dimer Fibrinolysis (DIC)

Platelet function von Willebrand factor vWD
Bleeding time In vivo test (non-specific)
Platelet function analyzer (PFA) Qualitative platelet disorders
and vWD
Platelet function tests Qualitative platelet disorders



Laboratory Evaluation of the
Coagulation Pathways
Partial thromboplastin time
(PTT)
Prothrombin time
(PT)
Intrinsic pathway Extrinsic pathway
Common pathway
Thrombin time
Thrombin
Surface activating agent
(Ellagic acid, kaolin)
Phospholipid
Calcium
Thromboplastin
Tissue factor
Phospholipid
Calcium
Fibrin clot
Coagulation factor deficiencies
Summary
Sex-linked recessive
4 Factors VIII and IX deficiencies cause bleeding
Prolonged PTT; PT normal

Autosomal recessive (rare)
4 Factors II, V, VII, X, XI, fibrinogen deficiencies cause bleeding
Prolonged PT and/or PTT

4 Factor XIII deficiency is associated with bleeding and
impaired wound healing
PT/ PTT normal; clot solubility abnormal

4 Factor XII, prekallikrein, HMWK deficiencies
do not cause bleeding


Thrombin Time
Bypasses factors II-XII

Measures rate of fibrinogen conversion to fibrin

Procedure:
4Add thrombin with patient plasma
4Measure time to clot

Variables:
4Source and quantity of thrombin

Causes of prolonged Thrombin Time
Heparin
Hypofibrinogenemia
Dysfibrinogenemia
Elevated FDPs or paraprotein
Thrombin inhibitors (Hirudin)
Thrombin antibodies
Classification of thrombocytopenia
Associated with bleeding
4Immune-mediated
thrombocytopenia (ITP)
4Most others
Associated with thrombosis
4Thrombotic thrombocytopenic
purpura
4Heparin-associated
thrombocytopenia
4Trousseaus syndrome
4DIC
Bleeding time and bleeding
5-10% of patients have a prolonged bleeding time

Most of the prolonged bleeding times are due to
aspirin or drug ingestion

Prolonged bleeding time does not predict excess
surgical blood loss

Not recommended for routine testing in
preoperative patients




Drugs and blood products used for
bleeding
Treatment Approaches to
the Bleeding Patient
Red blood cells
Platelet transfusions
Fresh frozen plasma
Cryoprecipitate
Amicar
DDAVP
Recombinant Human factor VIIa

RBC transfusion therapy
Indications
Improve oxygen carrying capacity of blood

4Bleeding

4Chronic anemia that is symptomatic

4Peri-operative management

Red blood cell transfusions
Special preparation



CMV-negative CMV-negative patients Prevent CMV
transmission

Irradiated RBCs Immune deficient recipient Prevent GVHD
or direct donor

Leukopoor Previous non-hemolytic Prevents reaction
transfusion reaction
CMV negative patients Prevents transmission


Washed RBC PNH patients Prevents hemolysis
IgA deficient recipient Prevents anaphylaxis
Red blood cell transfusions
Adverse reactions



Immunologic reactions

Hemolysis RBC incompatibility
Anaphylaxis Usually unknown; rarely against IgA
Febrile reaction Antibody to neutrophils
Urticaria Antibody to donor plasma proteins
Non-cardiogenic Donor antibody to leukocytes
pulmonary edema


Red blood cell transfusions
Adverse reactions





Non-immunologic reactions

Congestive heart failure Volume overload

Fever and shock Bacterial contamination

Hypocalcemia Massive transfusion
Transfusion-transmitted disease



Infectious agent Risk

HIV ~1/500,000
Hepatitis C 1/600,000
Hepatitis B 1/500,000
Hepatitis A <1/1,000,000
HTLV I/II 1/640,000
CMV 50% donors are sero-positive
Bacteria 1/250 in platelet transfusions
Creutzfeld-Jakob disease Unknown
Others Unknown
Platelet transfusions
Source
4Platelet concentrate (Random donor)
4Pheresis platelets (Single donor)


Target level
4Bone marrow suppressed patient (>10-20,000/l)
4Bleeding/surgical patient (>50,000/l)



Platelet transfusions - complications
Transfusion reactions
4Higher incidence than in RBC transfusions
4Related to length of storage/leukocytes/RBC mismatch
4Bacterial contamination

Platelet transfusion refractoriness
4Alloimmune destruction of platelets (HLA antigens)
4Non-immune refractoriness
Microangiopathic hemolytic anemia
Coagulopathy
Splenic sequestration
Fever and infection
Medications (Amphotericin, vancomycin, ATG, Interferons)
Fresh frozen plasma
Content - plasma (decreased factor V and VIII)
Indications
4Multiple coagulation deficiencies (liver disease, trauma)
4DIC
4Warfarin reversal
4Coagulation deficiency (factor XI or VII)
Dose (225 ml/unit)
410-15 ml/kg
Note
4Viral screened product
4ABO compatible
Cryoprecipitate
Prepared from FFP
Content
4Factor VIII, von Willebrand factor, fibrinogen
Indications
4Fibrinogen deficiency
4Uremia
4von Willebrand disease
Dose (1 unit = 1 bag)
41-2 units/10 kg body weight
Hemostatic drugs
Aminocaproic acid (Amicar)
Mechanism
4 Prevent activation plaminogen -> plasmin
Dose
4 50mg/kg po or IV q 4 hr
Uses
4 Primary menorrhagia
4 Oral bleeding
4 Bleeding in patients with thrombocytopenia
4 Blood loss during cardiac surgery
Side effects
4 GI toxicity
4 Thrombi formation
Hemostatic drugs
Desmopressin (DDAVP)
Mechanism
4 Increased release of VWF from endothelium
Dose
4 0.3g/kg IV q12 hrs
4 150mg intranasal q12hrs
Uses
4 Most patients with von Willebrand disease
4 Mild hemophilia A
Side effects
4 Facial flushing and headache
4 Water retention and hyponatremia
Recombinant human factor VIIa (rhVIIa; Novoseven)
Mechanism
4 Direct activation of common pathway

Use
4 Factor VIII inhibitors
4 Bleeding with other clotting disorders
4 Warfarin overdose with bleeding
4 CNS bleeding with or without warfarin

4Dose
490 g/kg IV q 2 hr
4Adjust as clinically indicated

Cost (70 kg person) - $1 per g
4 ~$5,000/dose or $60,000/day

Approach to bleeding disorders
Summary
Identify and correct any specific defect of
hemostasis
4 Laboratory testing is almost always needed to establish the cause of
bleeding

4 Screening tests (PT,PTT, platelet count) will often allow placement
into one of the broad categories

4 Specialized testing is usually necessary to establish a specific
diagnosis
Use non-transfusional drugs whenever possible

RBC transfusions for surgical procedures or large
blood loss

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