Section I Normal Haemostasis A Introduction

Haemostasis is a host defence mechanism that protects the integrity of the vascular system after tissue injury. It is responsible for minimising blood loss. It is critical that formation of blood clot in response to a breach in the vascular endothelium occurs rapidly. Systemic activation of the coagulation cascade or extensive local extension of thrombosis resulting in vascular occlusion, however, should not occur. Immediate vasoconstriction of the injured vessel and reflex constriction of adjacent small arteries and arterioles are responsible for an initial slowing of blood flow to the injured area (Fig. 1). The reduced blood flow enables contact activation of platelets and coagulation factors. The vasoactive amines and thromboxane A2 from platelets and the fibrinopeptides produced during fibrin formation

Fig. 1 Scheme of primary haemostatic function.

may also have vasoconstrictive activity.1 Thrombin generated at the site of injury converts soluble fibrinogen into fibrin and potentiates platelet aggregation and secretion. Thrombin also activates factor XI that amplifies the intrinsic pathway activity. Furthermore, it activates factor XIII that covalently cross-links the fibrin meshwork. A meshwork of fibrin anchors and extends the platelet plug. The fibrin component increases as the fused platelets autolyse, and after a few hours the entire haemostatic plug is transformed into a solid mass of cross-linked fibrin.2 During the same time frame, the plug begins to lyse due to the incorporation ofplasminogen and tissue plasminogen-activator (t-PA) in the plug, resulting in plasmin generation.3

Role of endothelium and subendothelium

The active role of "endothelial cells'' in preserving vascular integrity is well-established. This cell provides the basement membrane, collagen, elastin, and fibronectin of the subendothelial connective tissue. Loss of or damage to the endothelial lining results in both haemorrhage and activation of the coagulation cascade. The endothelial cell has an active role in haemostatic response, including synthesis of tissue factor, prostacyclin (Fig. 3), von Willebrand factor (vWF),

Table 1. Platelet Granule Content and Their Biological Functions




Alpha granule

Platelet factor 4

Neutralises heparin effect


Promotes fibroblast chemotaxis


Mitogen for fibroblast; chemotaxis for

growth factor

neutrophils, fibroblasts, and smooth muscle

von Willebrand factor

Adhesion molecule; carrier for factor VIII, protecting it from proteolysis


Promotes platelet-platelet interaction


Adhesion of platelets and fibroblasts

Dense granule


Aggregation of platelets


Source of ATP for energy




Coagulation; platelet function

plasminogen activator, anti-thrombin III, and thrombomodulin (the surface protein responsible for activation of protein C). Furthermore, the endothelium provides agents that are vital to both platelet reaction and blood coagulation.4

Role of platelets

Platelets are derived from the cytoplasm of bone marrow megakaryocytes and are the smallest of blood cells. They are disc shaped, anucleate with a relatively complex internal structure, which reflects their specific haemostatic function (Fig. 2). Normal platelet count is 150-400 x 109/l.

The contents of both alpha and dense granules (Table 1 ) may be released via a system of surface-connecting tubules, during platelet activation.

Platelet reactions and primary haemostatic plug formation

Initial adherence of platelets to exposed connective tissue (Fig. 1) follows endothelial lining breakage. Biochemical pathways for the metabolism of arachidonic acid (Fig. 3) are contained in both platelets and vascular endothelial cells.5 The platelet adhesion is

Surface glycoproteins:

GpIa GpIb


Microtubules &


Dense granules:


Serotonin Ca2+

Microtubules &


Dense granules:


Serotonin Ca2+

Glycogen i_Phospholipid membrane

Open cannalicular system mitochondrion

Fig. 2 Platelet electron microscopic ultrastructure (EM x 30,000).

Glycogen i_Phospholipid membrane

Open cannalicular system a granules:

growth factors fibrinogen factor V vWF


Fig. 2 Platelet electron microscopic ultrastructure (EM x 30,000).

Arachidonic acid

Cyclic endoperoxides

Arachidonic acid

Vessel wall


Cyclic endoperoxides

ÎS Prostacyclin

ÎS Prostacyclin


Thromboxane A2


Inducesplatelet aggregation

Inhibitsplatelet aggregation

Inducesplatelet aggregation c s

Inhibitsplatelet aggregation

Fig. 3 Arachidonic acid metabolism in vascular endothelium and platelets.

potentiated by von Willebrand factor (vWF).6,7 Collagen and thrombin generated at the site of injury cause the adherent platelets to release their granules, including ADP, serotonin, fibrinogen, lysosomal enzymes, and heparin-neutralising factor (PF-4). Collagen and thrombin activate platelet prostaglandin synthesis, leading to the formation of thromboxane A2, which potentiates platelet release reactions and platelet aggregation. It is also a powerful vasoconstrictor.

Fig. 4 Main pathways of platelet activation.

Released ADP causes platelets to swell and aggregate (Fig. 4). Additional platelets from the circulating blood are drawn to the area of injury, resulting in growth of the haemostatic plug that soon covers the exposed connective tissue. Released platelet granule enzymes, ADP, and thromboxane A2 may all contribute to the consolidation of the accumulated platelet plug. Prostacyclin, produced by endothelial and smooth muscle cells in the vessel wall adjacent to the area of damage, is important in limiting the extent of the initial platelet plug. This unstable plug produced is sufficient to provide temporary control of bleeding. Definitive haemostasis is achieved with fibrin formation by blood coagulation and with platelet-induced clot retraction.5'7'8

Role of circulating proteins with procoagulant, anti-coagulant, and fibrinolytic activities


The coagulation cascade involves sequential activation of a number of blood clotting factors, resulting in the formation of fibrin. Figures 5 and 6 show how the coagulation cascade operates in vitro (Fig. 5) with the classical waterfall hypothesis, whereas (Fig. 6) is thought to represent the in vivo process.



Prothrombin Throi


Tissue Factor


Fig. 5 Classical waterfall hypothesis of coagulation.

Fig. 6 The revised hypothesis of coagulation.

Conventionally, the coagulation cascade has been divided into intrinsic, extrinsic, and final common pathways. The intrinsic pathway ensues when the negatively charged subendothelium activates factor XII which, in turn, leads to activation of factor XI that activates factor IX. In association with calcium and with factor VIII as a cofac-tor, activated factor IX activates factor X on the membrane surface provided by platelet phospholipid (platelet factor 3). The intrinsic pathway is mediated via the contact factor system; following limited activation, factor XII activates prekallikrein to kallikrein, which in turn, activates factor XII. High molecular weight kiniogen (HMWK) is a non-enzymatic accelerator of these interactions. In the extrinsic pathway tissue factor activates factor VII, which in turn, activates factor X both directly and indirectly via activating factor IX. The final common pathway is concluded when activated factor X, in association with cofactor factor V on phospholipid surface and calcium, converts prothrombin to thrombin. Thrombin then converts fibrinogen to fibrin.9,10

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