الفهرس 
NORMAL HEMOSTASISOnly 14 pages are availabe for public view
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Abstract
Haemostasis describes the physiology relating to cessation of
bleeding following vessel injury. Upon a breach in vascular integrity, a complex reaction ensues leading to rapid transformation of blood from its fluid state into localized thrombus at the site of tissue damage. Haemostasis is therefore designed to minimize blood loss, restore vascular integrity and ultimately preserve life.
Damage to the blood vessel wall leads to the intricate interplay of four key components: the vascular endothelium, platelets, the coagulation pathway and finally fibrinolysis. When the endothelium is physically disrupted, it switches to a prothrombotic and proinflammatory state . This state is characterized by vasoconstriction, platelet and leucocyte activation and adhesion, promotion of thrombin formation in addition to coagulation and fibrin deposition at the vascular wall. The thrombin formation and proinflammatory state also form the initial steps towards vascular repair. Platelet plug formation if often referred to as primary haemostasis, while secondary haemostasis involves the complex interaction of plasma coagulation factors, which form fibrin strands used to strengthen the platelet plug.
Antithrombotic mechanisms restrict the permanent plug to the site of vessel injury, ensuring that the permanent plug does not inappropriately extend to occlude the vascular tree.
The physiology of the hemostatic system is closely linked to liver function because the liver parenchymal cells produce most of the factors of clotting and of the fibrinolytic systems and because the liver regulates the activation or inhibition of both systems. A disturbed liver parenchymal cell function adversely impacts the hemostasis system, the extent of which correlates with the degree of disease. These changes may be modest in patients with mild liver disease but are severe in patients with grossly compromised liver function.
Patients who have liver disease can present with substantial alterations in the primary hemostatic system. Abnormal platelet numbers and function are common and traditionally have been thought to contribute to impaired hemostasis in both acute and chronic liver disease.
Multiple factors can cause or contribute to the development of thrombocytopenia in patients with chronic liver disease. These include portal hypertension with resulting hypersplenism, cirrhosis, hepatocellular carcinoma and chemotherapy, anti-platelet antibodies, decreased levels or activity of the platelet growth factor thrombopoietin.
A number of coagulation proteins are synthesized by the liver and their synthesis is variably impaired in liver disease . Factor VII, Factors II, V and X are also reduced in acute liver injury, with additional deficiencies of factors IX and XI in chronic liver injury. Conversely, plasma factor VIII levels are elevated in liver disease, This is likely secondary to enhanced vWF synthesis, These procoagulant protein
deficiencies are counter balanced by a deficit in anticoagulant proteins. These proteins are also synthesized within the liver, and their diminished circulating levels swing the coagulopathy pendulum in favor of clotting. Plasma levels of antithrombinIII, protein C (PC) and protein S (PS) are decreased in those with chronic liver disease.
All the proteins involved in fibrinolysis, except for tissue plasminogen activator(tPA) and plasminogen activator inhibitor 1 (PAI 1) ,are synthesized in the liver. Reduced plasma levels of plasminogen,alpha2-antiplasmin, histidine-rich glycoprotein, and factor XIII are found in cirrhosis.
Another plasma protein, thrombin-activatable fibrinolysis inhibitor (TAFI), has been identified. It is synthesized by the liver and plays an important regulatory role in fibrinolysis.
Accelerated Intravascular Coagulation and Fibrinolysis (AICF) is another debated issue. AICF seems to occur predominantly in patients who have moderate-to-severe liver failure but is not detected in compensated patients AICF probably results from the formation of a fibrin clot that is more susceptible to plasmin degradation because of elevated levels of tPA or the presence of dysfibrinogen.
For testing coagulation in liver disease , The prothrombin time (PT) and activated partial thromboplastin time (aPTT) reflect activity of the extrinsic and intrinsic coagulation pathways, respectively. Prolongation of these coagulation times is common in liver disease and reflects reduced synthesis and resultant reduction in plasma levels of coagulation factors. The INR,which is a reliable measure of prothrombin time in patients on anticoagulation, will also continue to be a means of expressing severity of liver disease.The Thromboelastography (TEG) assesses overall hemostasis, the cumulative effects of procoagulant and anticoagulant proteins, fibrinogen, platelets, and red blood cells.
The management of haemostatic abnormalities in patients with liver disease is often difficult and challenging. Therapy is directed at correction of haemostatic defects in patients who are actively bleeding or who require surgery or other invasive procedures.
Fresh-frozen plasma is often used to prevent bleeding during liver biopsy or other potentially hemorrhagic invasive procedures in patients presenting with a prolonged prothrombin and/or partial thromboplastin time. Plasma is also used when patients bleed acutely from esophageal varices. The use of plasma is still a common practice despite the guidelines of the American Association for the Study of Liver Disease and in vitro studies showing that plasma shortens the prothrombin time but does not affect the amount of thrombin formed.
Platelet concentrates are used in the attempt to increase the low platelet count of cirrhosis patients Preliminary results indicate that the thrombopoietin receptor agonist eltrombopag increases platelet counts in cirrhosis more markedly than transfusion, but the study of this drug was interrupted due the occurrence of thrombotic complications.
Recombinant activated factor VII (rFVIIa )was also used because of its capacity to generate a strong thrombin burst at the site of bleeding in clinical conditions such as variceal bleeding and major surgical operations such as hepatectomy and liver transplantation. The use of rFVIIa is not recommended as an adjunctive hemostatic treatment for variceal bleeding, nor for bleeding prophylaxis in patients undergoing liver biopsy, transplantation, or resection.
Concentrates of vitamin K–dependent factors (also called prothrombin complex concentrates) had been used in patients with advanced liver disease, these plasma-derived products shorten or fully correct the prolonged coagulation tests and factor deficiencies, but their clinical effect on actual bleeding is not substantiated, and the risk of thrombosis is significant with them and rFVIIa.
Among the antifibrinolytic drugs, a potential candidate is tranexamic acid, which, given orally or IV, blocks the binding to fibrin of plasminogen and thus the activation of this fibrinolysis proenzyme to the enzyme plasmin.
Transfusional and nontransfusional hemostatic medications have an uncertain role in the prevention and treatment of bleeding in an array of clinical settings associated with end-stage liver disease.
This is not surprising, given the current knowledge that bleeding is
not caused mainly by hemostasis defects, but rather by hemodynamic alterations of portal hypertension, endothelial dysfunction, bacterial infections, and renal failure.
Increasing clinical and laboratory data provide evidence for the concept of rebalanced hemostasis in patients with liver disease. The ‘average’ patient with liver disease has a relatively balanced, effective hemostatic system, preventing both thrombosis and bleeding.But still there is a proportion of patients will be off-balance and be at increased risk for either bleeding or thrombosis.