8.5 Haemostasis

Platelets are key players in haemostasis, the process by which the body seals a ruptured blood vessel and prevents further loss of blood. Although rupture of larger vessels usually requires medical intervention, haemostasis is quite effective in dealing with small, simple wounds and small internal bleeds. There are three steps to the process: vascular spasm, the formation of a platelet plug, and coagulation (blood clotting). Failure of any of these steps will result in haemorrhage—excessive bleeding. The vascular response and platelet plug formation are referred to as primary haemostasis and coagulation is referred to a secondary haemostasis.

Vascular Spasm

When a blood vessel is severed or punctured, or when the wall of a vessel is damaged, vascular spasm occurs. In vascular spasm, the smooth muscle in the walls of the vessel contracts dramatically. This smooth muscle has both circular layers; larger vessels also have longitudinal layers. The circular layers tend to constrict, which narrows the vessel lumen, and slows the flow of blood. The longitudinal layers, when present, draw the vessel back into the surrounding tissue, often making it more difficult for a surgeon to locate, clamp, and tie off a severed vessel. The vascular spasm response is believed to be triggered by several chemicals called endothelins that are released by vessel-lining (endothelial) cells and by pain receptors in response to vessel injury. This phenomenon typically lasts for up to 30 minutes, although it can last for hours.

Formation of the Platelet Plug

In the second step, platelets, which normally float free in the plasma, encounter exposed underlying connective tissue and collagenous fibres at the site of blood vessel damage. The platelets bind (adhesion) to the exposed collagen and become activated. Activated platelets are spiked and sticky and bind to other activated platelets (aggregation) and the endothelial lining. Platelet adhesion is assisted by a glycoprotein released from neighbouring endothelial cells called von Willebrand factor, which helps stabilise the growing platelet plug. Platelet aggregation is aided by the plasma protein, fibrinogen, which forms bridges between adjacent platelets at the site of bleed vessel damage. As platelets collect, they simultaneously release chemicals from their granules into the plasma that further contribute to haemostasis.

A platelet plug can temporarily seal a small opening in a blood vessel. Plug formation, in essence, buys the body time while more sophisticated and durable repairs are being made. In a similar manner, even modern naval warships still carry an assortment of wooden plugs to temporarily repair small breaches in their hulls until permanent repairs can be made.

Coagulation

Those more sophisticated and more durable repairs are collectively called coagulation, the formation of a blood clot. The process is sometimes characterised as a cascade, because one event prompts the next as in a multi-level waterfall. The result is the production of a gelatinous but robust clot made up of a mesh of fibrin—an insoluble filamentous protein derived from fibrinogen, the plasma protein introduced earlier—in which platelets and blood cells are trapped. Figure 8.11 summarises the three steps of haemostasis.

Clotting Factors Involved in Coagulation

In the coagulation cascade, plasma proteins called clotting factors (or coagulation factors) prompt reactions that activate still more coagulation factors. The process is complex, but is initiated along two basic pathways.

Both of these pathways merge into a third pathway, referred to as the common pathway (see Figure 8.11b). All three pathways are dependent upon the 12 known clotting factors, including Ca2+ and vitamin K (Table 8.2). Clotting factors are secreted as inactive enzymes primarily by the liver and the platelets. The liver requires the fat-soluble vitamin K to produce many of them. Vitamin K (along with biotin and folate) is somewhat unusual among vitamins in that it is not only consumed in the diet but is also synthesised by bacteria residing in the large intestine. The calcium ion, considered factor IV, is derived from the diet and from the breakdown of bone. Some recent evidence indicates that activation of various clotting factors occurs on specific receptor sites on the surfaces of activated platelets.

The 12 clotting factors are numbered I through XIII according to the order of their discovery.

Table 8.2 Clotting factors

*Vitamin K Required

[table id=5 /]

Common Pathway

Both the intrinsic and extrinsic pathways lead to the common pathway, in which fibrin is produced to seal off the vessel. Once factor X has been activated to become the enzyme prothrombinase (factor Xa) by either the intrinsic or extrinsic pathway, it converts factor II, the inactive enzyme prothrombin, into the active enzyme thrombin. (Note that if the enzyme thrombin were not normally in an inactive form, clots would form spontaneously, a condition not consistent with life.) Then, thrombin converts factor I, the soluble plasma protein fibrinogen, into the insoluble protein fibrin protein strands. Fibrin molecules spontaneously join together to form a mesh, which is stabilised by cross-linking reactions catalysed by Factor XIIIa.

Fibrinolysis

The stabilised clot undergoes contraction via the action of contractile proteins within platelets. As these proteins contract, they pull on the fibrin threads, bringing the edges of the clot more tightly together, somewhat as we do when tightening loose shoelaces. This process also wrings out of the clot a small amount of fluid called serum, which is blood plasma without its clotting factors.

To restore normal blood flow as the vessel heals, the clot must eventually be removed. The process by which the clot is gradually degraded is called fibrinolysis. Like coagulation, fibrinolysis involves a fairly complicated series of protein catabolising reactions. During this process, the inactive protein plasminogen, released by endothelial cells around the site of blood vessel damage, is converted into the active enzyme plasmin, which gradually breaks down the fibrin of the clot. Additionally, bradykinin, a vasodilator, released from damaged tissues as a pain signal, reverses the effects of the serotonin and prostaglandins secreted by the platelets. This allows the smooth muscle in the walls of the vessels to relax and helps to restore the circulation.

Plasma Anticoagulants

An anticoagulant is any substance that opposes coagulation. Several circulating plasma anticoagulants play a role in limiting the coagulation process to the region of injury and restoring a normal, clot-free condition of blood. For instance, a cluster of proteins collectively referred to as the protein C system inactivates clotting factors involved in the intrinsic pathway. TFPI (tissue factor pathway inhibitor) inhibits the conversion of the inactive factor VII to the active form in the extrinsic pathway. Antithrombin inactivates factor X and opposes the conversion of prothrombin (factor II) to thrombin in the common pathway. And as noted earlier, basophils release heparin, a short-acting anticoagulant that also opposes prothrombin. Heparin is also found on the surfaces of cells lining the blood vessels.

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