HEMOSTATIC DISORDER

I. CONGENITAL HEMORRHAGIC DISORDER

A. Hemophilia A (factor VIII deficiency) and
Hemophilia B (factor IX deficiency)
1. Pathophysiology :
X chromosome, gene defect.
2. Clinical features :
mild, moderate and severe disease
3. Diagnosis :
a. screening tests
b. specific factor assay
4. Therapy : to raise the deficient factor

a. Pharmacologic therapy :

1. Hemophilia A : Desmopressin (dDAVP)

2. Hemophilia B : no effective drugs

b. Replacement therapy :

1. Beware of adverse effects

2. The choice of blood product is critical

 c. Treatment options :
1. Fresh frozen plasma (FFP)
2. Cryoprecipitate
3. Factor concentrates
5. Complication : Arthropathy, Inhibitors,
Liver disease, HIV infection.
6. Interdisciplinary care  hemophilia center
medical care, psychosocial care and
genetic counseling
 B. von Willebrand’s disease

1. Physiology of vWF :
- HMW glycoprotein, 250 kD
- In plasma and in platelets
- as a carrier protein for coag. F VIII
- important for primary hemostasis
- mediates adhesion of platelets to the s.endot
- vWF – F VIII complex : F VIII : C, F VIII : Ag,
F VIII : Cag, F VIII : RCof.
2. Clinical features : >> mucous membrane
bleeding, epistaxis, menorrhagia
3. Diagnosis :
- Combination of prolonged BT and a
decreased F VIII : C level  classically
- Combination of abnormalities of the functional
measures of the vWF – F VIII complex 
variants of vWF (see table 2)
- Ristocetin aggregation
- Diff. of type  F VIII multimer analysis :
type I, IIA, IIB, IIC, III.
Table 2. Laboratory Findings in Hemophilia A
and Severe vWF Disease

Labotatory test Finding

Hemophilia A vWF disease
Bleeding time Normal Prolonged
VIII : C Decreased Decreased
VIII : Ag Normal Decreased
VIII : RCof Normal Decreased
 4. Therapy
a. dDVAP
b. Cryoprecipitate
c. F VIII concentrates

C. Other inherited factor deficiencies

1. F XII, prekallikrein and HMWK
2. F I, II, V, VII, X, XI and XIII
II. ACQUIRED HEMORRHAGIC DISORDER
A. Vitamin K deficiency
1. Etiology
a. dietary deficiency
b. malabsorption
c. antibiotic therapy
d. hemorrhagic disease of the new born
2. Clinical features : severe bruising or
excessive bleeding or asymptomatic
 3. Diagnosis
- severe : prolonged PT and PTT
- early or milder def. : prolonged PT
4. Therapy
- Parenteral vit. K
- FFP
B. Liver disease
1. Etiology
a. decreased synthesis of coag. factors
b. Vit. K def
 c. Functionally abnormal fibrinogens
d. Disseminated Intravasc. Coagulation
(DIC) and consumption of coag. factors
2. Clinical features
- vary with the course of the patient’s liver
disease
- >> GIT bleeding
3. Diagnosis
- Lab. findings  varies widely
 4. Therapy
- trial of parenteral vit K therapy
- Replacement therapy  FFP
C. Clotting factor inhibitors  autoantibodies
1. Inhibitors in hemophilia
2. Inhibitors in patients without preexisting
bleeding disorders
a. Etiology : drugs, autoimmune or
lymphoproliferative disorders,
spontaneous a.coagulants
 b. Diagnosis : mixing study, factor assays
c. Therapy : supportive
3. Lupus anticoagulant  cardiolipin
a. Prolonged PTT, false + serologic test
b. associated with recurrent spont.abortions.
COAGULATION REGULATION AND
HYPERCOAGULABLE STATES
I. CONTROL MECHANISMS IN COAGULATION

A. Naturally occuring a.coagulants

1. Antithrombin III (AT III)  acts as a serine
protease inhibitor
2. Protein C, Protein S  Vit K – dependent
3. Other plasma protease inhibitor : heparin
cofactor II, 2- macroglobulin.
B. Fibrinolitic system

1. Activation :
a. Intrinsic activation : a poorly understood
mechanism of activation
b. Extrinsic Activation : Tissue plasminogen
activator (t-PA), urokinase
c. Exogeneous (therapeutic) activation :
streptokinase, urokinase and t-PA
2. Sites of action
a. Fibrinogen
b. Fibrin

II. THROMBOTIC DISORDER

A. Congenital thrombotic disorder
1. AT III deficiency
2. Protein C deficiency
3. Protein S deficiency
B. AQUIRED THROMBOTIC DISORDER
 THROMBOEMBOLIC DISEASE
1. Risk factors :
a. abnormalities of blood flow
b. abnormalities of the vasculature
c. abnormalities of the coagulation system
2. Clinical manifestations :
a. Venous thrombosis
- superficial thrombosis
- deep vein thrombosis
 b. Pulmonary embolism
c. Arterial thrombosis
d. Other
4. Therapy
a. Agents  treatment and prevention
1. Anticoagulants :
- Heparin
- Warfarin
2. Thrombolytic agents :
- Streptokinase
- Urokinase
- t-PA
b. Treatment approaches
1. Deep vein thrombosis : >> heparin,
thrombolytic agent
2. Pulmonary embolus : heparin, thrombolytic
agent
3. Myocardial infarction : thrombolytic agent
4. Peripheral artery and catheter thrombosis :
thrombolytic agent.
III. THROMBOHEMORRHAGIC DISORDER

A. Disseminated intravascular coagulation(DIC)

1. Pathophysiology (see table 3)
a. Initiation : pathologic activation of
the coag. cascade
b. Thrombosis
c. Consumption
d. Fibrinolysis
e. Hemolysis
Table 3. Conditions that commonly precipitate DIC
Infectious condition
Gram negative septicemia
Other endotoxin-related condition
Obstetric conditions
Abruptio placentae
Amniotic fluid embolism
Retained dead fetus
Vascular conditions
Aneurysm
Giant cavernous hemangioma
Hematologic conditions
Massive hemolysis
Promyelocytic leukemia
Snake venom
Trauma
2. Clinical features  varies widely
a. diffuse bleeding from multiple sites
b. thrombotic lessions
3. Diagnosis  lab. findings vary with time &
circumstances
Severe DIC :
a. Thrombocytopenia
b. Prolonged PT, PTT, TT
c. Decreased fibrinogen
d. FSPs
e. Microangiopathic hemolytic anemia
4. Therapy :
a. Low grade DIC  treatment may not
be necessary
b. Clinically significant bleeding 
replacement of depleted coagulation
factors and cells
c. Thrombosis : heparin
B. Thrombotic thrombocytopenic purpura
(TTP) and hemolytic-uremic syndrome
(HUS)
C. Heparin thrombocytopenia
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