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HAEMOSTASIS; COMPONENTS AND PATHWAY


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INTRODUCTION

  • Haemostasis is the normal physiological response of the human body to blood vessel injury and bleeding that prevents significant blood loss after vascular injury
  • It can be defined as a group of integrated physiological processes by which blood is kept in a fluid state, haemorrhage is arrested and vascular patency is restored when necessary, through clot dissolution. It is the first stage of wound healing
  • Haemostasis is essential for survival and defects of which can result in bleeding or thrombosis formation
  • In healthy people without bleeding disorders, control of bleeding is achieved very quickly and without medical intervention

EVENTS IN HAEMOSTASIS

  • Following injury, series of events take place which are essential for survival
  • There is vasoconstriction, thereby reducing blood flow to the site of injury and promoting repair processes to take place
  • When the endothelium is damaged, the normally isolated, underlying collagen is exposed to circulating platelets, which bind directly to collagen with collagen-specific glycoprotein Ia/IIa surface receptors
  • This adhesion is strengthened further by von Willebrand factor (vWF), which is released from the endothelium and from platelets
  • vWF forms additional links between the platelets’ glycoprotein Ib/IX/V and A1 domains
  • This localization of platelets to the extracellular matrix promotes collagen interaction with platelet glycoprotein VI
  • Platelets aggregate and release its contents forming a temporary haemostatic plug
  • Intricate enzymatic reactions occur involving coagulation proteins
  • Leading to fibrin production to form a stable haemostatic plug
  • Activated platelets release the contents of stored granules into the blood plasma
  • These include ADP, Serotonin, Platelet-Activating factor, vWF
  • Others are Platelet factor-4, Thromboxane A2 (TXA2)
  • They, in turn, activate additional platelets
  • The content of the granules activate a Gq-linked protein receptor cascade, resulting in increased calcium concentration in the platelets’ cytosol
  • The calcium activates protein kinase C, which in turn, activates phospholipase A2 (PLA2)
  • Which then modifies the integrin membrane glycoprotein IIb/IIIa, increasing its affinity to bind fibrinogen
  • The activated platelets change shape from spherical stellate, and the fibrinogen crosslinks with glycoprotein IIb/IIIa
  • This aids in the aggregation of adjacent platelets, completing primary haemostasis COMPONENTS OF HAEMOSTASIS
  • The essential role of the haemostatic system is a rapid reaction to injury such that the effect of injury is confined to the area of damage
  • The objective is the production of a haemostatic plug
  • The substances involving in this regard are normally circulated in the blood in an inactive form and only become activated at the site of vascular injury
  • Normal haemostasis depends on a delicate balance and complex interaction between 5 components
    • Blood vessels
    • The platelets (both in number and function)
    • Coagulation factors including their co-factors
    • Coagulation factors inhibitors
    • The fibrinolytic system
  • A bleeding tendency occurs when there is a;
    • Deficiency of clotting factors and platelets
    • Inhibition of coagulation processes
    • Excessive activity of the fibrinolytic system

 

THE ROLE OF BLOOD VESSELS IN HAEMOSTASIS

  • The blood vessel is composed of endothelial cells which line the intima and rest on a basement membrane of subendothelial microfibrils especially in the capillaries
  • It contain increased amounts of elastin, innervated smooth muscle cells and collagen in large blood vessels

 

  • Endothelium refers to cells that line the interior surface of blood vessels and lymphatic vessels forming an interface between circulating blood cells and the rest of the vessel wall
  • Intact endothelial cells serve primarily to inhibit platelet adherence and blood clotting
  • Injury or activation of endothelial cells however, results in a procoagulant phenotype that augments local clot formation

 

Prothrombotic Properties of Vascular Endothelium

Endothelial cells play very important roles in haemostasis. It has prothrombic properties which include;

  • Production of vonWillebrand factor
  • Production of tissue factor
  • Secretion of plasminogen activator inhibitors

Antithrombic Properties of Vascular Endothelium

Production of;

  • Tissue factor pathway inhibitor
  • Antithrombin
  • Protein S
  • Thrombomodulin
  • Heparin-like molecules – Heparin, Sulphate, Glycosaminoglycans

PLATELET ROLE IN HAEMOSTASIS

  • Platelets contain a number of coagulation factors;
    • Within the α granules

 Fibrinogen  Factor V  vWF

  • Or in the cytosol

 Factor XI

 Factor XIII

  • Intact platelets have little or no intrinsic clot promoting activity, but within seconds of onset of aggregation and adhesion, a reorientation of the membrane phospholipids occur
  • In small blood vessels, platelet aggregation, together with local vasoconstriction is usually sufficient to achieve and maintain haemostasis by forming platelet plug and sealing of endothelial bridge

 

BLOOD COAGULATION

  • There are 2 pathways of blood coagulation – intrinsic and extrinsic
  • About 13 coagulation proteins are involved which are present in plasma in inactive forms
  • They are either enzyme precursors, or co-factors except fibrinogen
  • All the enzymes are serine proteases except factor XIII which is a transglutaminase
  • Their ability to hydrolyze peptide bonds depend upon the amino acid serine at their active center
  • The international committee on nomenclature of blood clotting factors in 1962 assigned roman numerals to the coagulation proteins

Coagulation Factors and Synonyms

I

Fibrin subunit

Fibrinogen

II

Serine protease

Prothrombin

III

Receptor

Thromboplastin

IV

-

Calcium

V

Co-factor

Proaccelerin/Labile factor

VI

 

NOT identified

VII

Serine protease

Proconvertin/Stable factor

VIII

Co-factor

Antihaemophilic

IX

Serine protease

Christmas factor

X

-

Stuart prower

XI

-

Plasma thromboplastin antecedent

XII

-

Hageman factor

XIII

Transglutaminase

Fibrin stabilizing

Prekallikren

HMWK

Serine, Co-f

Fletcher, Fitzgerald

 

 

 

  • The coagulation cascade of secondary haemostasis has 2 initial pathways which lead to fibrin formation
  • These are the contact activation pathway (also known as the intrinsic pathway), and the tissue factor pathway (also known as the extrinsic pathway), which both lead to the same fundamental reactions that produce fibrin
  • It was previously thought that the 2 pathways of coagulation cascade were of equal importance
  • But it is now known that the primary pathway for the initiation of blood coagulation is the tissue factor (extrinsic) pathway
  • The pathways are a series of reactions, in which a zymogen (inactive enzyme precursor) of a serine protease and its glycoprotein co-factor are activated to become active components that then catalyze the next reaction in the cascade, ultimately resulting in cross-lined fibrin

 

 

NATURALLY OCCURRING INHIBITORS OF BLOOD COAGULATION

  • Though normal blood clots readily when withdrawn from the body or when extravasated into damaged tissue, in the vessels it remains fluid in the living body
  • There are effective mechanisms for limiting coagulation in vivo

Serine Protease Inhibitors (Serpins)

  • Antithrombin                                     -IIa, IXa, Xa, XIa, XIIa
  • Heparin co-factor                                     -IIa
  • A1 antitrypsin                                                -X, XI, Plasmin
  • C-esterase inhibitor                                     -KK, XI
  • α2 antiplasmin                                     -Plasmin, KK, XI, XII
  • A2 macroglobulin                                     -KK, II
  • TFPI[1]                                                 -TF-VII

Inhibitors of Co-factors

  • Protein C
  • Protein S – through binding to thombomodulin

Fibrinolytic System

  • This system is very efficient in preventing excess deposition of fibrin in the vascular bed which can culminate in occlusion of blood vessels
  • The excess fibrin is either prevented or rapidly removed, so as not to compromise blood circulation
  • It is a localized surface bound phenomenon which is being catalyzed by the presence of fibrin

Factors Involved in Fibrinolysis

  • Tissue plasminogen activator
  • Urokinase plasminogen activator
  • Plasminogen activator inhibitor - type I & II
  • Streptokinase
  • α2-Antiplasmin
  • Histidine rich glycoprotein
  • Apoprotein
  • Intrinsic activation of plasminogen
    • Factor XII
    • Kallikrein
  • Extrinsic activation of plasminogen
    • Tissue plasminogen activator
    • Urokinase plasminogen activator

The Fibrinolytic System

 

 

[1] TFPI – Tissue Factor Pathway Inhibitor