Pathogenesis, Appr oach to Blee ding Disorders

Normal Hemostasis

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

through activation of

Coagulation cascade

Lysis of clot through

activation of

plasminogen → plasmin

Platelets

Natural Anticoagulant

Oppose effect of coagulation cascade

Mechanism of Haemostasis

Hemostasis – Clot Formation, Vessel Repair

Fibrinolytic System

Defects in Hemostasis

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1° Hemostasis

Blood Vessels

Endothelial cell function

Subendothelial

Vasoconstriction

Role of Endothelial cell

Platelet

Promote Hemostasis by

Adhesion to subendothelial collagen (via von Willebrand factor)

Platelet shape change

• Expose platelet receptors to soluble fibrinogen

• Release reaction

Vasoconstriction PDGF ADP release

Serotonin Initiate vessel wall

repair

Stimulate platelet to

stick Thromboxane A2

Platelet Aggregation

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)

2° Hemostasis

Simplified Scheme of Blood Cogulation

2° Hemostasis

Vessel wall injured, plasma exposed to Tissue Factor

Complex between Factor VIIa, Tissue Factor

Tissue Factor-Factor VIIa (TF-FVIIa) complex

catalyzes initial activation of Factor IX, Factor X

Once pathway starts, TF-FVIIa activation of Factor X

is rapidly shut down by TFPI (produced by Endothelial cells)

Newly produced FIXa binds with cofactor FVIIIa

on Phospholipid surface results in Activation of FXa

FXa with cofactor FVa with Ca on Phospholipid

convert Prothrombin (FII) to Thrombin (FIIa)

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

Forming soluble fibrin clot

FXIII crosslinks fibrin monomers to for m insoluble fibrin clot

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

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

Excessive bruising

Gum bleeding

Epistaxis

Soft Tissue, Joint Bleeds

Bleed excessively from injuries and at

time of surgery

Bleed excessively from injuries and at

time of surgery

Petechiae

Purpura

Hematoma

Joint Bleeding

Platelet Defects Coagulation Factor Deficiencies

Mucosal Blee ding Common Rare

Petechiae Common Rare

Deep Hematomas Rare Characteristic

Bleeding from Skin

Cuts

Persistent Minimal

Inherited or Acquired Disorder

Inherited Acquired

Present at any time (Birth→Geriatric) Appear suddenly with severe

bleeding Classic Haemophilia A, B – Sex Linked

vWD – Autosomal

Dominant, Recessive

Newly abnormal coagulation tests

Having other illnesses predispose to

bleeding disorders Haemophilia A (Def. Factor VIII)

Haemophilia B (Def. Factor IX) Liver Disease

Von Willebrand’s disease

(Def. vW Factor)

Vitamin K Deficiency

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

Clinical Bleedi ng Disorders

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Screening Tests (Bleeding Disorders)

Full Blood Picture (FBP) Bleeding Time (BT)

(3-8 mins)

Prothrombin Time (PT)

(10-14 secs)

Activated Partial

Thromboplastin Time (APTT)

(30-40 secs)

Thrombin Time (TT)

(14-16 secs)

Thrombocytopenia

(establish cause)

Detect

Abnormal Platelet Function

Abnormal Blood Vessel

Measures (Extrinsic)

Factor VII

Factor X

Factor V

Prothrombin

Fibrinogen

Measures (Intrinsic)

Factor VIII

Factor IX

Factor XI

Factor XII

Factor X

Facter V

Prothrombin

Fibrinogen

Detect

Deficiency of Fibrinogen

Inhibition of Thrombin Anaemia

Leukaemia Ivy Template Method* Diluted Thrombin added to

citrated plasma DIC Prolonged BT

Thrombocytopenia

Platelet dysfunction

von Willebrand disease

Vascular abnormalities

Prolonged TT

Hypofibrinogenaemia

Dysfibrinogenaemia

Heparin

Fibrin Degradation Products

Tissue

Thromboplastin + Calcium

added to citrated plasma

Prolonged PT

Deficiency of Coagulation F.

Warfarin

Liver Disease

DIC

Phospholipid + a surface

activator (kaolin) + calcium

added to citrated plasma

Prolonged APTT

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)

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,

Adhesion-Aggregation DIC Tests

vW Factor Assay Storage Pool,

Release Reaction of Platelets Tests for Inhibitor

Tests for Pathological Fibrinolysis Platelet Factor 3

Tests

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