Hemostasis and its Disorders

Sahyuddin

Div of Hematology & Med Oncology - Dept of Int Medicine

Medical Faculty , Hasanuddin University
NORMAL HEMOSTASIS

NORMAL HEMOSTASIS :

MAINTAINS BLOOD IN A FLUID

STATE AND PRODUCES A LOCAL
HEMOSTATIC PLUG AT SITES OF
VASCULAR INJURY
Balance of Hemostasis

Blood lost Blood clot

coagulation
antifibrinolysis

Normal Maintain
hemostasis fibrinolysis normal blood
flow
anticoagulation
Hemostatic Balance

Prot. S
PAI-1
Prot. C
Antiplasmin
TFPI
Tissue factor* Fibrinolytic
System
Clotting
Factors ATIII

Procoagulant Anticoagulant
 Haemostasis
Balance versus imbalance
Thrombophilia Healthy Bleeding tendency
 HEMOSTASIS

I. Primary Hemostasis
- Blood vessel contraction
- Platelet Plug Formation
II. Secondary Hemostasis
- Activation of Clotting Cascade
- Deposition & Stabilization of Fibrin
III. Tertiary Hemostasis
- Dissolution of Fibrin Clot
- Dependent on Plasminogen Activation
Hemostasis

BV Injury

Neural Damage/contact.
Contact

Blood Vessel Platelet Coagulation

Constriction Aggregation Cascade
Primary hemostatic plug

Reduced Platelet
Activation Fibrin
Blood flow formation

Stable Hemostatic Plug

Hemostasis

Consist of :
1. Vascular system &
endothelium
2. Platelet
3. Coagulation
4. Anticlotting Mechanisms
5. Fibrinolytic System
6. Fibrinolytic Inhibitors
I. Vascular system and endothelium

1. Endothelial layer
- endothelial cell
2. Subendothelial layer
- smooth muscle cell
- fibroblast
- ECM (extracellular
matrix); collagen,
adhesion proteins
Endothelial cell

Produce :
- Prostacyclin (Prostagradin I2, PGI2)
- Nitric Oxide (NO)
- Thrombomodulin (thrombin binding protein)
- Heparin-like glycosaminoglycan
- Tissue factor pathway inhibitor (TFPI)
- Tissue plasminogen actibvator (t-PA)
- Plasminogen activator inhibitor-1 (PAI-1)
- Von Willibrand factor (VWF) etc.
Vascular System

1. Vasoconstriction
II. Platelet
Platelet plug formation

1. Platelet adhesion
2. Plt. shape change
3. Plt. release reaction
4. Plt. aggregation
Platelet activation

Fibrinogen
Platelet secretion
2. Platelet activation
3. Haemostatic plug
III. THE COAGULATION CASCADE

 A SERIES OF ENZYME REACTIONS

ULTIMATELY RESULTING IN THE
FORMATION OF THROMBIN WHICH
CONVERTS FIBRINOGEN (SOLUBLE)
INTO FIBRIN (INSOLUBLE)
III. Coagulation pathway
4. Coagulation
5. Stable clot formation
 IV. Natural anticoagulants
Anticlotting Mechanisms
 Antithrombin III (ATIII):
The major inhibitor of the
coagulation cascade.
• Inhibits Thrombin
• Inhibits activated F IX, X, XI, XII.
– Activity is enhanced by heparin.
 TFPI
 Protein C
– Activated by Thrombin /
Thrombomodulin
– Anticoag. & fibrinolytic
activity.
– Vitamin K & Protein S are
cofactors
 Protein S
 V. Fibrinolysis

V. Fibrinolytic System
Plasmin
– Produced from
Plasminogen by
(TPA)
– Degrades Fibrin &
Fibrinogen (FDP)
– Degrades Factors
V, VIII, IX, XI & XII.
– Activity is inhibited
by Antiplasmin.
 VI. Antifibrinolytic process

A. Antiplasmin
– Inactivates plasmin rapidly.
– Inactivates factors XI & XII
slowly.
B. PAI-1
– Inhibits the function of TPA
– Also has some inhibitory
activity against urokinase,
plasmin, thrombin, activated
Protein C, factors & XII,
& kallikrein
6. Clot dissolution
 BLEEDING DISORDER

VASCULAR DEFECT

BLEEDING
PLATELET DEECT
DISORDER

COAGULATION DEFECT
Disorders of Hemostasis

1. Vascular disorders
 Scurvy, easy bruising, Henoch-Schonlein
purpura.
2. Platelet disorders
 Quantitative - Thrombocytopenia
 Qualitative - Platelet function disorders –
Glanzmans
3. Coagulation disorders
 Congenital - Haemophilia (A, B), Von-Willebrands
 Acquired - Vitamin-K deficiency, Liver disease
4. Mixed/Consumption: DIC
A. Vascular disorders :

 Petechiae, purpura, ecchymoses

 Senile purpura
 Vitamin C deficiency (scurvy)
 Connective tissue disorders
 Infections – Meningococcus
 Henoch-Schonlein Purpura-Immune
Senile Purpura
Henoch-Schonlein purpura
B. Platelet Disorders - Features:

 Mucocutaneous bleeding
 Petechiae, Purpura, Ecchymosis.
 spontaneous bleeding after trauma
 CNS bleeding (severe  plt)
 Prolonged bleeding time (BT)
 Petechiae
(typical of platelet disorders)
Disorders of platelets

1. Decreased Number: Thrombocytopenia

 Decreased Production
 Decreased Survival – Immune (ITP)
 Increased utilization - DIC
2. Defective Platelet function:
 Acquired – Drugs – Aspirin, MPS, MDS
 Congenital – Eg. Thrombasthenia.
C. Coagulation disorders:

 Deficiencies of Clotting factors

 Onset - delayed after trauma
 Deep bleeding
 Into joints - Hemarthroses
 Into deep tissues – Hematoma
 large skin bleed – Ecchymoses
Ecchymoses Hemarthroses

(Typical of coagulation
factor disorders)
Factor VIII Deficiency

 Classic hemophilia (hemophilia A)

 X-linked disorder (affects 1º males)
 Most common - severe bleeding
 Spontaneous hematomas < 1, 5, 75%
 Abnormal aPTT – Intrinsic path.
 Diagnosis - factor VIII assay
 Treatment - factor VIII concentrate
 Cryoprecipitate (less desirable)
Factor IX Deficiency

 Christmas disease (Hemophilia B)

 X-linked recessive disorder
 Requires evaluation of factor VIII and IX
activity levels to diagnose
 Treatment - factor IX concentrate
 Cryoprecipitate if factor IX unavailable
Secondary Hemostatic Disorders

Acquired coagulation disorder:

 Vitamin K deficiency

- neonates - decreased intestinal

flora and dietary intake
- oral anticoagulants (coumadin)
- fat malabsorption syndromes
 Required for factors II, VII, IX, X

 Prolonged PT and aPTT

 Combined Primary and Secondary
Hemostatic Disorders

Severe Liver Disease

 Primary - dysfunctional platelets and/or

thrombocytopenia ( BT)
 Secondary - decrease in all coagulation

factors except vWF ( PT, aPTT)

 Vitamin K will promote synthesis of factors

II, VII, IX, X

Combined Primary and Secondary
Hemostatic Disorders (DIC)

Disseminated Intravascular Coagulation

 Major pathologic processes -

obstetric complications, neoplasms,

infection (sepsis), major trauma
 Primary - platelet consumption

( bleeding time,  platelets)

 Secondary - factor consumption

( PT, aPTT)
 NORMAL HAEMOSTASIS

Intravascular Haemostatic
clot formation mechanisms
TF
TF
TF
Cytokines
TF TF

Activated
Monocyte
monocyte
Activation of monocytes

SYSTEMIC INFLAMMATION
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
 CLINICAL APPROACH

I. HISTORY TAKING
CLINICAL II. PHYSICAL EXAM
APPROACH
III. LABORATORY EXAM
1. INITIAL TX
2. REFERRAL
 HISTORY TAKING

1
LOCAL BLEEDING/ WIDESPREAD
2
FIRST TIME/ LONG STANDING
3
PREVIOUS DISEASE
4
DRUG, HERBS, CHEMICAL
5
FAMILY HISTORY
 PHYSICAL EXAM
1. F EBRIS/ FEVER
2. A NEMIA
3. B LEEDING TYPE
4. I CTERUS/ JAUNDICE
5. O RGANOMEGALY
6. L YMPHADENOPATHY
7. A DDITIONAL SYMPTOMS
 IMPORTANT CLUES

LOCAL, MILD BLEEDING, PETECHIAE/

PURPURA

PLATELET - DEFECT

MULTIPLE LOCATION, SEVERE

BLEEDING (ECHYMOSES/ HEMATOMAS)

COAGULATION DEFECT
Laboratory evaluation in hemostasis disorder

Screening test of hemostasis :

- tourniquet test (also blood vessel integrity)

- whole blood clotting time
- clot retraction time
- clot lysis time
Laboratory evaluation in hemostasis disorder

 Blood vessel integrity

tourniquet test
 Platelet
- platelet count
- platelet function test
platelet aggregation
platelet factor 3 assay
- bleeding time
Laboratory evaluation in hemostasis disorder

 Coagulation pathway
- prothrombin time (PT) => extrinsic pathway
- partial thromboplastin time (PTT) =>
intrinsic pathway
- thrombin time (TT) => fibrinogen or
thrombin inhibition
- factor assay
Laboratory Evaluation of the Coagulation Pathways

Partial thromboplastin time Prothrombin time

(PTT) (PT)

Intrinsic pathway Extrinsic pathway

Thrombin time
Common pathway

Fibrin clot
Initial Evaluation of a Bleeding Patient - 1

Normal PT
Normal PTT

Consider evaluating for:

F XIII deficiency Monoclonal gammopathy
Abnormal fibrinolysis Platelet disorder
(a2 anti-plasmin def) Vascular disorder
Initial Evaluation of a Bleeding Patient - 2

Normal PT
Abnormal PTT

Test for factor deficiency:

Isolated deficiency in intrinsic pathway (factors VIII, IX, XI)
Multiple factor deficiencies (rare)
Initial Evaluation of a Bleeding Patient - 3

Abnormal PT
Normal PTT

Test for factor deficiency:

Isolated deficiency of factor VII (rare)
Multiple factor deficiencies (common)
(Liver disease, vitamin K deficiency, warfarin, DIC)
Initial Evaluation of a Bleeding Patient - 4

Abnormal PT
Abnormal PTT

Test for factor deficiency:

Isolated deficiency in common pathway: Factors V, X,
Prothrombin, Fibrinogen
Multiple factor deficiencies (common)
(Liver disease, vitamin K deficiency, warfarin, DIC)