Page 334 - Essential Haematology

320 / Chapter 24 Platelets, blood coagulation and haemostasis

Platelet r elease r eaction and a mplifi cation It inhibits platelet activation and promotes vasodila-
Primary activation by various agonists induces tation. Prostacyclin synthesized by endothelial
intracellular signalling, leading to the release of α cells also inhibits platelet function (Fig. 24.8 ) and

granule contents. These have an important role in causes vasodilatation by raising cyclic guanosine
platelet aggregate formation and stabilization and, monophosphate (GMP) levels. An ectonucleotidase
in addition, the ADP released from dense granules (CD39) acts as an ADPase and helps prevent plate-
has a major positive feedback role in promoting let aggregation in the intact vessel wall.
platelet activation.
Th romboxane A 2 (TXA2) is the second of the Blood c oagulation
two major platelet positive feedback loops impor-

tant in secondary amplification of platelet activa-
The c oagulation c ascade
tion to form a stable platelet aggregate. It is formed
de novo upon activation of cytosolic phospholipase Blood coagulation involves a biological amplifi ca-
A 2 (PL A2 ) (Fig. 24.6 ). TXA2 is a labile substance tion system in which relatively few initiation sub-
and lowers platelet cyclic adenosine monophos- stances sequentially activate by proteolysis a cascade
phate (cAMP) levels and initiates the release reac- of circulating precursor proteins (the coagulation
tion (Fig. 24.6 ). TXA2 not only potentiates platelet factor enzymes) which culminates in the generation
aggregation, but also has powerful vasoconstrictive of thrombin; this, in turn, converts soluble plasma

activity. The release reaction is inhibited by sub- fibrinogen into fibrin (Fig. 24.7 ). Fibrin enmeshes

stances that increase the level of platelet cAMP. One the platelet aggregates at the sites of vascular injury
such substance is prostacyclin (PGI 2 ) which is syn- and converts the unstable primary platelet plugs to
thesized by vascular endothelial cells. It is a potent fi rm, defi nitive and stable haemostatic plugs. A list
inhibitor of platelet aggregation and prevents their of the coagulation factors appears in Table 24.1 . Th e
deposition on normal vascular endothelium. operation of this enzyme cascade requires local con-
centration of circulating coagulation factors at the
Platelet p rocoagulant a ctivity site of injury.
After platelet aggregation and release, the exposed Surface - mediated reactions occur on exposed
membrane phospholipid (platelet factor 3) is avail- collagen, platelet phospholipid and tissue factor.
able for two reactions in the coagulation cascade. With the exception of fi brinogen, which is the

Both phospholipid - mediated reactions are calcium - fibrin clot subunit, the coagulation factors are either
ion dependent. Th e first (tenase) involves factors enzyme precursors or cofactors (Table 24.1 ). All the

IXa, VIIIa and X in the formation of factor Xa (Fig. enzymes, except factor XIII, are serine proteases (i.e.
24.7 ). The second (prothrombinase) results in the their ability to hydrolyse peptide bonds depends

formation of thrombin from the interaction of upon the amino acid serine at their active centre;
factors Xa, Va and prothrombin (II). Th e phos- Fig. 24.9 ). The scale of amplification achieved in

pholipid surface forms an ideal template for the this system is dramatic, (e.g. 1 mol of activated
crucial concentration and orientation of these factor XI through sequential activation of factors
proteins. IX, X and prothrombin may generate up to
8
2 × 10 mol of fi brin).
Growth f actor
PDGF found in the α granules of platelets stimu-
Coagulation in v ivo
lates vascular smooth muscle cells to multiply and
this may hasten vascular healing following injury. The generation of thrombin in vivo is a complex

network of amplification and negative feedback
Natural i nhibitors of p latelet f unction loops to ensure a localized and limited production.
Nitric oxide (NO) is constitutively released from Th e generation of thombin is dependent on three
endothelial cells (Fig. 24.8 ) and also from macro- enzyme complexes, each consisting of protease,

phages and platelets. It has a short half - life of 3 – 5 s. cofactor, phospholipids (PL) and calcium. Th ey are