THE CASCADE EVENTS

**Hemostasis(BASIC SCIENCES)
THE STEPS AND SEQUENCE


Hemostasis is a process of linked physiologic events aimed at limiting of bleeding. It can be divided into two broad stages.

Primary and secondary hemostasis.
-Primary hemostasis involves the initial clot formation by adherence of platelets to the damaged blood vessel wall.
-Secondary hemostasis includes initiation of the coagulation cascade thrombin generation, and fibrin deposition.
Steps
-The main partners of primary hemostasis are platelets and endothelial cells. Platelets are 1.5 to 3.5µm discoid blood cells without nucleus or DNA that are formed from bone marrow megakaryocytes.
-Their key structure are their secretory granules, contractile cytoskeleton, and outer proteoglycan coat, which contains membrane receptors.
-The intracellular granules are of two types, alpha granules and dense granules (or dense bodies).
-Alphgranules contain platelet thrombospoundin, fibrinogen, fibronectin, platelet factor 4, von Willebrand’s facto (vWf), platelet derived growth factor (PDGF), factors V, X and VIII, and many other.
-Proteins dense granules contain ATP, ADP, GTP, GDP, other phosphates, calcium and serotonin.
-After platelet activation, these contents are released the presence of platelet specific proteins in the serum is the start of platelet activation.
-The endothelium is recognized as a metabolically active tissue that plays a role in coagulation and inflammation.
-The normal endothelium functions to maintain a nonthrombogenic surface in normal blood vessels, and keep a balanced steady state between the continuous process of coagulation and fibrinolysis. --Although the normal endothelium is nonthrombogenic, it secretes a subendothelial matrix gets exposed to the plasma (with break of endothelium), acts as highly thrombogenic.
-Another function of the endothelium (and megakaryocytes) is production of vWf. Stores of vWf are released into the subendothelium when the endothelium is damaged.
This initiates platelet, adhesion, leading to degranulation and further adhesion. Primary hemostasis is further enhanced by the initial vasoeonstriction of the damaged vessels.

Secondary Hemostasis:
Coagulation Cascade
Steps
-Following the initiation of the primary hemostatic process the coagulation cascade is activated which ends with the formation of a stable fibrin clot. Inactive forms of factors in the blood are converted to their active forms and this leads to a cascade effect with progressively larger amounts of coagulation factors produced.
-Fibrin monomers are generated as the final product of this cascade and are physically cross-linked to form the final stable clot.
-Normal state coagulation involves the interaction of many factors and is limited to the vessel wall injured.
This occurs through a series of inhibitory and regulatory substances, with their feedback loops.
The diluting effect of the blood flowing through the affected area is also a factor.
Till now coagulation has been understood to involve two “pathways” intrinsic and extrinsic.
-The intrinsic pathway did not require interaction with the injured vessel wall and resulted in the activation of factor XII as the initiating event for coagulation.
-Activated factor XII then activated factor XI, which in turn activated factor IX. A complex of activated factor VIII (factor VIIIa) and activated factor IX (Factor IXa) with calcium and phospholipid then activated factor X.
-Activated factor X (Factor Xa) then converted prothrombin to thrombin, which in turn converted fibrinogen to fibrin.
-Factor XIIIa converted the fibrin monomers into a cross-linked fibrin clot in the presence of calcium.
In the extrinsic pathway, coagulation is initiated when circulating factor VII interacts with subendothelial tissue factor (TF) in the presence of calcium. Subendothelial TF is exposed to the circulation as a result of endothelial injury.
-The activated factor VII (factor VIIa) TF complex activated factor X. Factor Xa then converts prothrombin to thrombin, and the reaction proceeds as described previously to generate a stable fibrin clot.
It is now felt that the
-The intrinsic pathway play a minor role. Inadequate levels of some of its key components will render standard coagulation tests abnormal but do not result in a clinically significant bleeding disorder.
-However the importance of the TF pathway as the predominant mechanism for in vivo coagulation is supported by recent research.
-The distribution of TF in the subendothelial layer, the epidermis, and myoepithelial cells.
-Thus the intact cells constitutes a “hemostatic barrier”.
-Injury puts TF into contact with factor VII, thus initiating coagulation.
-This concept of a single coagulation pathway (TF pathway) fits with current data and observed clinical syndromes and should replace the older concept of twin pathways**
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