COAGULATION PHYSIOLOGY

AND
HEMORRHAGIC DISORDERS

Mansyur Arif, Dept. of Clinical Pathology

Faculty of Medicine, Hasanuddin University,
Makassar
I. COAGULATION PHYSIOLOGY

A. Blood vessel wall rupture  platelet plug

 coagulation factors  coagulation
cascade  fibrin clot.
B. Coagulation factors :
1. >> glycoprotein, pre-enzymatic forms
(zymogens)  serine proteases
Several cofactors, calcium ion (Ca2+)
and phospholipids
 2. Sites of biosynthesis
a. Hepatic synthesis
b. Extrahepatic synthesis
3. Requirements of vitamin K
4. Plasma half – life (see table 1)
C. Coagulation Cascade
1. Pathways : extrinsic pathway
intrinsic pathway
common pathway
Table 1. Plasma coagulation factors

Factor Alternative name Path- Half-life

way (hours)
I Fibrinogen C 90-120
II Prothrombin C 48-120
III Tissue factor I Not available
V Proaccelerin C 12-24
VII Proconvertin E 2-6
VIII Antihemophilic factor I 10-12
IX Christmas factor I 18-30
X Stuart - Prower factor I,E,C 24-60
XI Plasma thromboplastin antecedent I 45-80
XII Hageman factor I 40-70
XIII Fibrin - stabilizing factor I 72-200
HMW kininogen Fitzgerald factor I 150
Prekallikrein Fletcher factor I 48-52
2. Intrinsic factor : F XII, XI, IX and VIII

Prekallikrein, HMWK

3. Extrinsic factor : Tissue F, F VII.

4. Common pathway : F X, V, prothrombin and

fibrinogen.
INTRINSIC SYSTEM
HMWK
XII XII a
Kallikrein

XI XIa EXTRINSIC SYSTEM

VII
IX IXa + VIII TF
Ca 2+ Ca 2+ Ca 2+
PL

X Xa + V
Ca 2+
PL
Prothrombin Thrombin

Fibrinogen Fibrin

XIII XIIIa Stable fibrin clot

Ca 2+
Fig. 1. The coagulation cascade
II. TESTS OF COAGULATION SYSTEM

A. Screening Test
1. Partial thromboplastin time (PTT) and
activated partial thromboplastin time (aPTT)
2. Prothrombin time (PT)
3. Quantitative fibrinogen
4. Thrombin time (TT)
5. Screening test for factor XIII

B. Spesific factor assays

III. 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 [Link]
- 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 :
- Comb. of prolonged BT and a decreased
F VIII : C level  classically
- Comb. of abnormalities of the functional
measures of the vWF – F VIII complex
 variants of vWF (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
IV. 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 [Link]
 b. Diagnosis : mixing study, factor assays
c. Therapy : supportive
3. Lupus anticoagulant  cardiolipin
a. Prolonged PTT, false + serologic test
b. associated with recurrent [Link].
COAGULATION REGULATION
AND
HYPERCOAGULABLE STATES
I. CONTROL MECHANISMS IN COAGULATION

A. Naturally occuring [Link]

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. Fibrinolytic 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 (fig.2)
a. Initiation : pathologic activation of
the coag. cascade
b. Thrombosis
c. Consumption
d. Fibrinolysis
e. Hemolysis
 Diffuse intravascular coagulation

Consumption of coag. Fibrin deposition in

Factors and platelets microcirculation

Secondary fibrinolysis

Bleeding tendency

Ischemic Microangiopathic
tissue hemolytic
damage anemia

Fig. 2. Pathophysiology of DIC

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 (table 4)
 Table 4. Laboratory profiles in acute and chronic DIC
Acute DIC Chronic DIC
• Thrombocytopenia Moderate to severe Mild to severe

• Prothrombin Time (PT) Prolonged N to slightly Prolonged

• aPTT Prolonged Normal to short

• Thrombin Time (TT) Prolonged Normal to moderately

prolonged

• Fibrinogen Decreased Moderately decreased,

Normal or High

• Factor V & VIII Decreased Normal

• Protamine sulfate Test Positive Positive

• Fibrin(ogen) degradation Positive Positive

products (FDP)
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)

>> caused by endothelial damage in microsco-

pic blood vessels
Diagnosis :
~ Thrombocytopenia with normal or increased
numbers of megakaryocytes in marrow.
~ Microangiopathic hemolytic anemia 
marked poikilocytosis (peripheral [Link])
e.g. fragments, helmet cells, burr cells and
elevated serum LDH
~ Fever
~ Renal failure
~ Fluctuating CNS deficits consistent with in-
termittent ischemia
Treatment :
~ Initial th/ is prednison and plasma exchange
~ Aspirin, dipyridamole & sulfinpyrazone  6
month
~ Plasmapheresis  if any of the features of
disease recur
 ~ If thrombocytopenia and hemolysis persist

for 3-4 weeks despite improvement in

other manifestation  splenectomy

C. Heparin thrombocytopenia

D. Hemolytic-uremic syndrome (HUS)

THANK YOU