Hemostasis

Pathophysiology of hemostasis.

Primary hemostasis with formation of a deposition thrombus. Injury to the vessel wall with discontinuity of the endothelium and exposure of collagen leads to initial release of ADP. This leads to an activation of the thrombocytes.

At this first step of hemostasis the factors:

• Thromboxan A2, which is released from the platelets themselves
• PAF (platelet activating factor) from phospholipids of the cell membrane
• adenosine diphosphate (ADP)
• Adrenalin

involved. A vasospasm occurs with slowing of the blood flow, which lasts about 10 seconds; this stimulates the adhesion of platelets to the von Willebrand factor (vWF) of the endothelium. This factor is released together with factor VIII from the so-called Weibel-Palade corpuscles of the endothelium. The von Willebrand factor initiates the aggregation of activated platelets by attaching itself to the GPllb/GPIIIa receptors. Especially under high shear stress, vWF binds to these platelet receptors. If the shear stress subsides, the platelets bind increasingly directly to the exposed collagen of the endothelial defect.

Vasospasm is reduced, resulting in an improvement in blood flow and the rapid formation of a (white) separation thrombus with many thrombocytes. After adhesion and after activation of the thrombocytes, the integrin receptors GpIIb/GPIIIa are activated. The platelet-activating substances such as thrombin, ADP, thrombboxan A2, collagen, PAF, serotonin and adrenalin cause a conformational change in the GPIIb/GPIIIa receptors, so that high-affinity binding sites for fibrin are activated.

Fibrin binds to the thrombocytes via these receptors, whereby the fibrin polymers cross-link the thrombocytes with each other. In addition, the fibrin receptor also binds to the fibronectin in the subendothelial area. Platelet aggregation occurs on the one hand through contact adhesion. It has been shown that thrombocytes are also brought together and aggregate over distances of 25 um by electrical attraction. The first phase of platelet aggregation is called viscous metamorphosis.

The attachment of fibrin to the GPIIb/GPIIIa receptors leads to a cross-linking of the thrombocytes. At this stage the fibrin is soluble. By the action of factor XIIIa, the polymers become solidified and insoluble. This process is called the first phase of aggregation. Erythrocytes are now bound into this cross-linked thrombus (red thrombus). The process of thrombocyte attachment is initially carried out via a loose contact, the "tetherin", followed by "platelet rolling" for final attachment. In a further step, the thrombus is retracted and solidified and cross-linked.

In the phase in which the vasospasm subsides, the platelet thrombus grows very quickly because the improved blood circulation brings more platelets to the site of action. The flow forces in the area of the lesion cause smaller thrombi, whose fibrin fibres are not yet sufficiently stabilised, to be torn off and carried away. These small embolisms are called "white bodies". The platelets, which increasingly contribute to the thrombus and quickly attach themselves, empty the alpha granules and the "dense bodies", so that large amounts of thrombaxan A2, platelet activating factor (PAF) and adenosine phosphate are rapidly released through membrane channels, which in turn accelerate the process.

Second phase of thrombus formation: Fibrinogen, fibronectin, vWF, high molecular weight kininogen, factor V and plasminogen activator inhibitor 1 are released from the alpha-granules. A further activation of the platelets takes place by thrombin and collagen. They cause procoagulant phospholipids to be pushed from the inside of the platelet membrane to the outside. This activation process binds the factors IXa, VIIa, Xa and Va so that the tenase and prothrombinase complex can be formed. At the same time, thrombospondin is released, which binds fibrinogen, fibronectin, VWF and collagen more strongly via glycoprotein IIb/IIIa.

The third phase of thrombus formation consists in the retraction of the thrombocyte plug. This first stabilizes the loose structure of the platelet aggegate and binds it more strongly to the vessel wall. The thrombocytes stick to each other and lose their original shape, transforming from round discs into elongated bodies. The serum lying between the fibrin-platelet net is squeezed out, lysosomes of the thrombocytes are released, the lesion of the vessel wall is closed.

1. HA Neumann (2014) The coagulation system. ABW-Scientific Publisher GmbH Berlin