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Pathogenesis, Appr oach to Blee ding Disorders

Normal Hemostasis Fibrinolytic System

When blood vessel injured, 3 mecha nisms operate locally to control bleedi ng
Vessel wall contraction
Platelet plug formation
Fibrin clot formation
Normal physiologic response to vascular injury
Balance between procoagulant & anticoagulant mechanisms
Achieved through
Blood vessels
Platelets
Coagulation, Anticoagulation factors
Fibrinolytic factors
Systems Involved
1° Hemostatic 2° Hemostatic Fibrinolytic
Vascular system Formation of Fibrin Lysis of clot through
Platelets through activation of activation of Defects in Hemostasis
Coagulation cascade plasminogen → plasmin
Natural Anticoagulant
Oppose effect of coagulation cascade

Mechanism of Haemostasis

Hemostasis – Clot Formation, Vessel Repair

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1° Hemostasis 2° Hemostasis

Blood Vessels Simplified Scheme of Blood Cogulation

Endothelial cell function
Subendothelial
Vasoconstriction

Role of Endothelial cell

2° Hemostasis

Platelet

Vessel wall injured, plasma exposed to Tissue Factor

Complex between Factor VIIa, Tissue Factor
Tissue Factor-Factor VIIa (TF-FVIIa) complex
Promote Hemostasis by
catalyzes initial activation of Factor IX, Factor X
Adhesion to subendothelial collagen (via von Willebrand factor)
Once pathway starts, TF-FVIIa activation of Factor X
Platelet shape change
is rapidly shut down by TFPI (produced by Endothelial cells)
• Expose platelet receptors to soluble fibrinogen
Newly produced FIXa binds with cofactor FVIIIa
• Release reaction
on Phosph olipid surface results in Activation of FXa
Vasoconstriction PDGF ADP release
FXa with cofactor FVa with Ca on Phospholipid
Serotonin Initiate vessel wall Stimulate platelet to
convert Prothrombin (FII) to Thrombin (FIIa)
Thromboxane A2 repair stick
Small amount of Thrombin is Initiated by Extrinsic Pathway
Expansion of Thrombin generation occur through Intrinsic Mechanism
Intrinsic limbs of pathway include activation of FXIa by Thrombin
with ultimate generation of ↑ Thrombin using FIXa, FVIIa to Activate FX
FV, FVIII are activated by Thrombin
Activation results in further burst of coagulation activity
Thrombin convert Fibrinogen to Fibrin Monomers
Platelet Aggregation Forming soluble fibrin clot
FXIII crosslinks fibrin monomers to for m insoluble fibrin clot

Platelet Adhesion

1° Hemostasis
Provide a procoagulant surface
(eg. Phospholipid for coagulation cascade to act)
Expression of Factor V, Factor VIII receptors
also initiate propagation of cascade

Regulation of 1° Hemostasis
Prostacyclin
(Potent Inhibitor of Platelet Aggregation)

Regulation of 2° Hemostasis
Serine Protease Inhibitors
Antithrombin
Heparin cofactor II
Tissue Factor Pathway Inhibitor(TFPI)
Inhibits FVII-TF Complex
Protein C Pathway
Fibrinolytic System
Plasmin
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Disorder of Hemostasis

Causes of Abnormal Bleeding Clinical Bleedi ng Disorders

Vessel wall abnormality
Thrombocytopenia
Platelet function disorder
Blood coagulation defective

Assessing
Bleeding Real
Bleeding due to Factor Deficiencies or Platelet Defects
Acquired or Inherited Disorder
Tests

Bleeding
Spontaneous
Prolonged, Excessive bleeding after Surgical procedures, Trauma
Simultaneous bleeding from Multiple sites

Platelet Defects or Factor Deficiencies

Platelet Defects Coagulation Factor Deficiencies
Muco-cutaneous bleedi ng Soft Tissue, Joint Bleeds
Excessive bruising
Gum bleeding
Epistaxis
Bleed excessively from injuries and at Bleed excessively from injuries and at
time of surgery time of surgery

Petechiae Hematoma
Purpura Joint Bleeding
Platelet Defects Coagulation Factor Deficiencies
Mucosal Blee ding Common Rare
Petechiae Common Rare
Deep Hematomas Rare Characteristic
Bleeding from Skin Persistent Minimal
Cuts

Inherited or Acquired Dis order

Inherited Acquired
Present at any time (Birth→Geriatric) Appear suddenly with severe
Classic Haemophilia A, B – Sex Linked bleeding
vWD – Autosomal Newly abnormal coagulation tests
Dominant, Recessive Having other illnesses predispose to
Haemophilia A (Def. Factor VIII) bleeding disorders
Haemophilia B (Def. Factor IX) Liver Disease
Von Willebrand’s disease Vitamin K Deficiency
(Def. vW Factor) Drugs (eg. Warfarin)
DIC

History
Abnormal bruising Haemarthrosis/ Deep Bleeding
Abnormal bleeding - cuts, abrasions Dental extraction bleeding
Epistaxis Surgery bleeding
Gum bleeding/ GIT bleeding Previous anaemia, transfusion
Haematuria Drug history – warfarin, aspirin
Menorrhagia Family history

Physical Examination
Pallor
Purpura, Petechiae, Ecchymoses, Bruises, Haematoma
Fever, Jaundice, Lymphadenopathy, Hepatosplenomegaly
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Screening Tests (Bleeding Disorders)

Activated Partial
Bleeding Time (BT) Prothrombin Time (PT) Thrombin Time (TT)
Full Blood Picture (FBP) Thromboplastin Time (APTT)
(3-8 mins) (10-14 secs) (14-16 secs)
(30-40 secs)
Thrombocytopenia Detect Measures (Extrinsic) Measures (Intrinsic) Detect
(establish cause) Abnormal Platelet Function Factor VII Factor VIII Deficiency of Fibrinogen
Anaemia Abnormal Blood Vessel Factor X Factor IX Inhibition of Thrombin
Leukaemia Ivy Template Method* Factor V Factor XI Diluted Thrombin added to
DIC Prolonged BT Prothrombin Factor XII citrated plasma
Thrombocytopenia Fibrinogen Factor X Prolonged TT
Platelet dysfunction Tissue Facter V Hypofibrinogenaemia
von Willebrand disease Thromboplastin + Calcium Prothrombin Dysfibrinogenaemia
Vascular abnormalities added to citrated plasma Fibrinogen Heparin
Prolonged PT Phospholipid + a surface Fibrin Degradation Products
Deficiency of Coagulation F. activator (kaolin) + calcium
Warfarin added to citrated plasma
Liver Disease Prolonged APTT
DIC Deficiency of Coagulation F.
Heparin
Liver Disease
* Ivy Template Method
After application of 40mmHg pressure to upper arm with a BP cuff,
two 1-mm deep, 1 cm long incisions are made
In the flexor surface of forearm skin

Further Test (Mixing Test) Tests

Prolonged PT/ APTT
Test Plasma + Normal Plasma
Normalised Prolonged
Coagulation Deficiency/ Defect Presence of Inhibitor

Special Tests
Bleeding Disorders Platelet Function
Coagulation Factors Assay Platelet Aggregation
Platelet Function Tests Platelet Adhesion,
DIC Tests Adhesion-Aggregation
vW Factor Assay Storage Pool,
Tests for Inhibitor Release Reaction of Platelets
Tests for Pathological Fibrinolysis Platelet Factor 3