[box type=”download”] Albumin as a key binding protein and the major contributor to oncotic pressure[/box]
Plasma contains several important proteins.
Most, other than γ-globulins, are synthesized in the liver.
Proteins can ionize as either acids or bases because of the presence of both NH2 and COOH groups.
At pH 7.4 they are mostly in the anionic (acidic) form.
Their ability to accept or donate H+ means they can act as buffers.
Plasma proteins have important transport functions, as they bind many hormones (e.g. cortisol and thyroxine) and metals (e.g. iron). They are classified into albumin, globulin and fibrinogen fractions.
Globulins are further classified as α-, β- and γ-globulins.
[box type=”download”] Role following vessel wall damage Importance of release of 5-HT and thromboxane A2 in haemostasis Fibrin and thrombin’s role in coagulation Detailed knowledge of the coagulation cascade is NOT required[/box]
Haemostasis, a complex process that includes formation of the blood clot, a tough mesh of fibrin entrapping platelets and blood cells.
Platelets play a critical role in haemostasis.
They circulate in the blood but are not true cells, being small (∼3 μm) vesicle-like structures formed from megakaryocytes in the bone marrow.
They have a lifespan of ∼4 days.
Platelets have multiple surface receptors and clearly visible dense granules containing mediators such as serotonin and adenosine diphosphate (ADP), which are released on activation.
The immediate response to damage of a blood vessel wall is vasoconstriction to reduce blood flow.
Damage to the vessel wall exposes collagen, to which a plasma protein called von Willebrand factor (vWF) binds.
Tissue factor (TF) is also exposed.
Platelets have glycoprotein (GP) receptors which avidly bind to vWF, tethering the platelet.
Further receptors including integrins bind directly to collagen.
Together these cause adhesion of the platelet to the damaged area.
Binding to these receptors also initiates platelet activation, partly by increasing intracellular Ca2+.
Platelets change shape, put out pseudopodia and make thromboxane A2 (TXA2) via cyclooxygenase (COX).
TXA2 stimulates release of serotonin (5-HT; 5-hydroxytryptamine), ADP and other compounds from the platelet granules.
TXA2 and serotonin also enhance the vasoconstriction.
The process propagates because ADP directly activates more platelets via purinergic (P2Y) receptors.
It also causes activation of fibrinogen receptors (GPIIb/IIIa) on their surface, which bind to fibrinogen in the plasma causing the platelets to become sticky and aggregate, forming a soft platelet plug.
This is stabilized during clotting by conversion of the fibrinogen to fibrin.
Note that thrombin is also a potent platelet activator.
Formation of the blood clot (coagulation cascade is out of curriculum)
Most clotting factors are produced in the liver, which requires vitamin K, and many (e.g. thrombin, factor X) require Ca2+ to act.
Most of the action occurs on cell or platelet surfaces (The cell-based model of clotting). (Extrinsic and intrinsic pathways – obsolete.)
Tissue factor (TF; thromboplastin) gets exposed to plasma as a result of vascular damage.
Factor VIIa from the plasma is then able to bind to TF (TF:VIIa), and this complex activates factor X.
Factor X combines with cofactor Va to form prothrombinase, that converts prothrombin to thrombin.
The amplification phase takes place on the surface of platelets.
The small amount of thrombin produced above activates nearby platelets, and also cofactor V on their surface.
Cofactor VIII is normally bound to plasma vWF, which protects it from degradation.
Thrombin cleaves factor VIII from vWF and activates it, when it also binds to the platelet surface.
The end product is a large number of activated platelets, covered with the active cofactors, stuck together by fibrinogen.
Thrombin activates a short cascade that leads to activation of factor IX (also activated by TF:VIIa).
Factor IXa forms a complex with cofactor VIIIa on the platelet surface to form tenase, a much more powerful activator of factor X than TF:VIIa.
The Xa binds to cofactor Va on the platelet surface to form prothrombinase.
There is consequently a massive burst of thrombin production.
Thrombin cleaves the fibrinogen bound around the platelets to form fibrin monomers, which spontaneously polymerize to a fibrous mesh of fibrin, entrapping the platelets and other blood cells.
The fibrin polymer is finally cross-linked by factor XIIIa (also activated by thrombin) to create a tough network of fibrin fibres and a stable clot.
Retraction of entrapped platelets contracts the clot by ∼60%, making it tougher and assisting repair by drawing the edges of the wound together.
Multiple inhibitory mechanisms counteract this to prevent inappropriate clotting.
Undamaged endothelium produces prostacyclin and nitric oxide, which impede platelet adhesion and activation.
Plasma antithrombin inhibits thrombin, factor Xa and tenase, and is strongly potentiated by heparin and heparans on endothelial cells.
Thrombomodulin (also on endothelial cells) binds thrombin and converts it so it no longer cleaves fibrinogen but instead activates protein C (APC; activated protein C), which with protein S inactivates factors Va and VIIIa, and hence tenase and prothrombinase.
Finally, the clot is broken down by plasmin, a process called fibrinolysis.
This occurs when plasma plasminogen binds to fibrin, and is converted to plasmin by tissue plasminogen activator (tPA). (Basis of fibrinolysis in CVA or ACS)
Plasmin is itself inactivated by α2-antiplasmin.