Pathogenesis Bleeding Disorders
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Pathogenesis, Appr oach to Blee ding Disorders Normal Hemostasis When blood vessel injured, 3 mechanisms operate locally to control bleeding 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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Pathogenesis Bleeding Disorders
Transcript of Pathogenesis Bleeding Disorders
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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