Protein C System

The protein C system is responsible for the inactivation of the activated co-factors Va and VIIIa. Protein C and S are vitamin K-dependent factors. The system is represented in Figure HA.19.

Thrombin behaves as an anti-coagulant when it binds to thrombomodulin, which is present on the endothelial surface. The resulting complex activates protein C, which in the presence of protein S inactivates factors Va and VIIIa by cleavage. Thus thrombosis is prevented from propagating along normal vessel close to a point of injury.

Reduced plasma levels of protein C and S are associated with thrombosis and can be inherited in an autosomal dominant fashion. Deficiency of thrombomodulin has not been described and probably results in non viability. The most common inherited cause of a thrombotic tendency is a mutation of factor V (Factor V-Leiden) which alters the activated protein C (APC) cleavage site, this results in reduced APC induced cleavage and demonstrated in vitro by the APC resistance (APCR) test. Once again this is an autosomal dominant trait.

Endothelial »II

Thnofinbomodu Ii n ^Binding

Thrombin

^Forma cornpien ftolein C -► Activated proton C

Protein S

Fgctgri V Factor*

to Vila IrflctiV V|<

Endothelial »II

Figure HA.19 Protein C system

Fibrinolysis

A scheme for the fibrinolyic system is shown in Figure HA.20. Intrinsic activation of fibrinolysis, via kallikrein, is possible but the physiological relevance is uncertain. Tissue-type plasminogen activators (t-PA) are of greatest importance; t-PA is synthesized by endothelial cells. Its release is stimulated by venous occlusion, thrombin, adrenaline, vasopressin and strenuous exercise. Its biological activity increases dramatically when bound to fibrin.

In vivo activity of the fibrinolytic system is routinely assessed in clinical situations by measuring fibrin degradation products (FDPs) which usually include the products of fibrinogen degradation and, therefore, does not rely on the presence of fibrin. D-dimers, on the other hand, are only produced by digestion of cross-linked fibrin and are, therefore, a more specific indicator of fibrinolysis which has been exploited recently in the assessment of suspected pulmonary embolism.

Platelets

Platelets are responsible for forming the primary haemostatic plug following injury. They are produced in the bone marrow by the cytoplasmic budding of megakaryocytes. They are bi-convex discs with a diameter of 2-4 ^m and volume of 5-8 fl. The normal life span of a platelet is between 8 and 14 days. They contain granules of which the most numerous are a granules (the contents of which are listed in Figure HA.21). Dense bodies are less numerous but of

Ploimin

Fibrirt Fibrinogen

Fibrin > degrodatior products

Figure HA.20 Fibrinolytic system

CONTENTS OF PLATELET ALPHA GRANULES

• Adhesive proteins - von Willebrand's factor, fibrinogen, fibronectin, vitronectin

• Growth factors

- platelet-derived growth factor (PDGF)

- platelet factor 4 (PF4)

- P thromboglobulin

Figure HA.21

importance as their deficiency (storage pool disease) can result in significant haemorrhage. Dense bodies contain platelet nucleotides (ADP, ATP, 5-HT).

Platelets function by adhesion to sites of injury, they change shape and release their granules and then aggregate together forming the platelet plug. They also provide the surfaces that enhance the coagulation reaction and growth factors contained in the a granules stimulate tissue repair. Global platelet function can be tested by measuring the bleeding time, which is best performed by experienced laboratory staff using the template method (normal < 9 min). It should be remembered that thrombocytopenia results in prolongation of the bleeding time. Qualitative platelet defects can be assessed by platelet aggregometry to various stimuli.

Platelet Adhesion

Blood vessel injury results in exposure of subendothelial collagen and microfibrils. Larger von Willebrand's factor (vWF) molecules bind to the microfibrils and platelets adhere to the vWF via platelet glycoprotein (GP) 1b. Following this, the glycoprotein IIb-IIIa complex becomes exposed which increases adhesion (and is also involved in aggregation).

Platelet Shape Change

This occurs within seconds of adhesion; the platelet becomes more spherical and spikey which enhances interaction between platelets. The platelet granules migrate towards the surface.

Platelet Release Reaction

This follows immediately and involves the release of the contents of platelet granules, it is sustained for several minutes. Thus coagulation factors, adhesive proteins, growth factors and nucleotides are delivered to the site of injury.

Platelet Aggregation

At the site of injury ADP is released from damaged cells (and following platelet release reaction), this binds to platelets and exposes the GP Ilb-IIIa complex. Fibrinogen binds to this receptor, and as it is a dimeric molecule is capable of forming bridges between platelets. The other main physiological inducer of platelet aggregation is thromboxane A2, this is a product of arachidonic acid metabolism in the platelet.

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