Hemostasis
Hemostasis literally means ―a slowdown of blood flow. There are three basic components of hemostasis: extravascular, vascular and intravascular. The extra-vascular component is mainly the pressure exerted on the blood vessels because of an accumulation of extravasated blood in the tissue space. The efficiency of this component depends upon the bulk of the surrounding tissue, the type of tissue and the tone of the tissue.
The vascular component constitutes the blood vessels themselves. The role played by the blood vessels depends upon their size, the amount of smooth muscle in their wall and the integrity of the lining endothelium. On injury, a blood vessel undergoes vaso-constriction as a neurogenic response, thus decreasing the blood flow. Together with the extra-vascular component, it may stop the blood flow altogether.
The injury exposes collagen and tissue factors that initiate the participation of the intra-vascular components of hemostasis. The key components in intra-vascular hemostasis are the platelets, the coagulation factors, anticoagulants, and fibrinolytic factors. Platelets and coagulation factors promote the formation of a thrombus, which occludes the injured site and results in the arrest of bleeding. Anticoagulant proteins help in limiting the thrombus formation at the injury‘s site, while fibrinolytic factors help in the dissolution of the thrombus. A fine balance between these keeps the blood in a fluid state. A tilt of the balance to one side or the other may result in a failure of coagulation which leads to a bleeding disorder or an increased propensity to coagulation leading to a hypercoagulable state or thrombosis.
The exposure of collagen in the wall of the blood vessel (following the injury) provides a surface for the adhesion of platelets. The platelets that adhere to this surface undergo a metamorphosis and a release reaction which attracts more platelets, leading to an aggregation of platelets that results in the formation of a platelet plug. The numbers, as well as the functional integrity of these platelets, affect this phase of hemostasis. This primary platelet plug is strengthened by the formation of fibrin threads and is converted into a thrombus. Fibrin formation is initiated in two ways. First, the injury to the vessel‘s wall leads to an exposure of tissue factor (TF) or factor III with which combines a plasma protein, factor VII, and initiates an extrinsic pathway of coagulation. The exposure of negatively-charged elements of the vessel wall (collagen) activates another protein, factor XII, which initiates the intrinsic pathway of coagulation.
The two pathways converge on a common pathway, activating factor X that, in turn, complexes with the activated factor V. This complex converts the prothrombin in the plasma into thrombin, which then polymerizes the fibrinogen into fibrin threads. These threads are then stabilized by the action of activated factor XIII. In this cascade, platelets also play a part by providing phospholipid. In all, there are 12 proteins and one metal ion (Ca++), which participate in the coagulation process. These can be divided into three groups that have similar properties, as follows:
1. Contact Group: This includes Prekallikrein, High Molecular Weight Kininogen (HMWK), factor XII and factor XI. These are activated on exposure to negatively-charged surfaces. These are also involved in fibrinolysis and the complement system. The site of their synthesis, (apart from factor XI which is synthesized in the liver), is not clear. These are all serine proteases.
2. Prothrombin Group: This group includes factors II, VII, IX and X. These are all serine proteases and are synthesized in the liver. These require Vitamin K for γ carboxylation of glutamic acid residues in order to convert these into pro-enzymes.
3. Fibrinogen Group: This group includes factors I, V, VIII and XIII. Of these I, V and XIII are synthesized in the liver.
The activation of the coagulation system simultaneously brings into play another set of proteins that have an opposing effect. That is, these obstruct the process of coagulation to prevent an extension of clots beyond the required limit. The most important proteins of this system are Tissue Factor Pathway Inhibitor (TFPI), Antithrombin (AT), Protein C and Protein S. Another group of proteins, which are collectively termed the fibrinolytic system, regulates the deposition & removal of fibrin. The major protein of this system, plasmin, is produced by the action of plasminogen activators on a protein called plasminogen, which is synthesized by the liver. The most important plasminogen activator is the Tissue Plasminogen Activator (t-PA), released by the injured endothelium of the vessel wall.
DISORDERS OF HEMOSTASIS
Based on the physiology of hemostasis, the disorders of hemostasis (as described above) can be grouped into those arising due to:
1. Vascular defects
2. Platelet defects
3. Defects in the coagulation pathway
4. Defects in the anticoagulant pathway
5. Defects in the fibrinolytic pathway
6. Others
Each of these can be subdivided, based on clinical manifestations, into bleeding disorders and hypercoagulable states or thrombophilia. Each sub-group can be further divided, based on etiology, into hereditary/congenital or acquired disorders.
1. Vascular Defects: Hereditary, connective-tissue disorders like Ehlers-Danlos Syndrome and Pseudoxanthoma Elasticum are characterized by weak vessel walls and abnormal collagen that is unable to initiate platelet adhesion/coagulation, thus leading to easy bruising and a hemorrhagic state. A similar defect is acquired in old age (Senile Purpura) and Vitamin C deficiency (Scurvy). Hereditary alterations in the vessels‘ wall structure, e.g., Hereditary Haemorrhagic Telangiectasia and Cavernous Haemangiomas lead to a bleeding disorder due to weak vessel walls. A similar weakness may also result from acquired diseases like diabetes mellitus and amyloidosis. A bleeding disorder may also result from damage to the blood vessels by an immune process, as in Henoch-Schonlein Purpura or in chronic bacterial infections. A thrombotic disorder may result from a disease of the vessel walls, e.g., atheroma formation and endothelial injury due to toxins or viruses.
2. Platelet Defects: Platelet defects may be quantitative or qualitative. Thrombocytopenia (decreased platelet count) is one of the most common causes of bleeding diathesis. This may result either from decreased production or increased consumption. The most important causes of Thrombocytopenia are acquired and not hereditary. Of these the most common is auto-immune or idiopathic thrombocytopenic purpura (ITP). The most important causes of qualitative platelet defects are hereditary. These include the Bernard Soulier Syndrome, Glanzmann‟s Thrombasthenia, Von Willebrand‟s Disease and Storage Pool defects. A similar disorder can also result from the repetitive ingestion of aspirin.
3. Defects in the Coagulation Pathway: Although defects in this pathway, e.g. increased levels of coagulation factors that may result in a hypercoagulable state, more important are the defects that result in a bleeding disorder. These can be hereditary or acquired. Hereditary bleeding disorders constitute the most important group. These occur because of a quantitative or qualitative deficiency of coagulation factors. Although a bleeding disorder may occur because of a deficiency of any coagulation disorder, the most common is Haemophilia A (Factor-VIII deficiency) and Haemophilia B (Christmas Disease) because of factor IX-deficiency. Most important of the acquired bleeding disorders are liver disease and disseminated intravascular coagulation (DIC). The liver is the site for synthesizing the majority of the coagulation factors. Extensive damage to hepatocytes will result in a compromised synthesis of coagulation factors, leading to their deficiency. Besides, the liver produces bile (which is required for the absorption of Vitamin K), which in turn is needed for the synthesis of the active forms of factors II, VII, IX and X. Liver disease, particularly obstructive, will therefore also cause a qualitative deficiency of these coagulation factors and lead to a bleeding disorder. Also, some quantitative and qualitative disorders of the proteins of this pathway also result in a hypercoagulable state. The most important of these is a hereditary, qualitative defect of factor V, Factor V Leiden, and Prothrombin Gene Mutation G A20210.
4. Defects in the Anti-Coagulant Pathway: The quantitative deficiencies of the proteins of this pathway result in a hypercoagulable state (thrombophilia). The defects are mostly hereditary in nature. The most important of these are abnormalities of AT, Protein C and Protein S.
5. Defects in the Fibrinolytic Pathway: These defects most commonly result in a thrombotic tendency. These may be hereditary or acquired.
6. Others: Some disorders that lead either to a tendency to bleed or a hypercoagulable state involve more than one of the above groups as well as other elements. The most important of these are Von Willebrand Disease (vWD), DIC and auto-immune diseases like SLE. vWD results from an abnormality or a deficiency of one part of the factor VIII complex, von Willebrand factor (VIII:vWF). This part is independently produced by vascular endothelium and is required for platelet-vessel wall interaction. It results in a bleeding disorder that has the features of disease due to both a platelet defect and a coagulation protein defect. This is a hereditary defect. DIC clinically manifests mainly as a bleeding disorder with a component of the thrombotic state. It results from the initiation of an uncontrolled coagulation process, which results in a consumption of platelets and coagulation proteins. This eventually leads to the deficiency of coagulation factors as well as thrombocytopenia, leading to a bleeding disorder. This is an acquired defect. In the course of some auto-immune diseases, inhibitors of coagulation or anti-thrombotic factors are produced and result in either a bleeding or a hypercoagulable state. The production of lupus anti-coagulants results in a prothrombotic state, whereas the production of factor VIII inhibitors results in a hemophilia-like disorder.
