1. Disorders of coagulation II: Acquired

2. Liver disease Liver disease leads to defects of coagulation, platelets and fibrinolysis: Reduced synthesis of vitamin K dependent factors caused by impaired vitamin K absorption Reduced synthesis of vitamin K dependent factors caused by impaired vitamin K absorption Impaired synthesis of other coagulation proteins (factor I and V ). Impaired synthesis of other coagulation proteins (factor I and V ). Thrombocypenia {hypersplenism) and abnormal platelet function (cirrhosis). Thrombocypenia {hypersplenism) and abnormal platelet function (cirrhosis). Fibrinolysis impaired: Fibrinolysis impaired: Reduced levels of proteins C and S. antithromhin and, antiplasmin lead to susceptibility to disseminated mtravas­cular coagulation (DI C). Reduced levels of proteins C and S. antithromhin and, antiplasmin lead to susceptibility to disseminated mtravas­cular coagulation (DI C). Dysfibrinogenaemia may lead to haemorrhage or thrombosis. Dysfibrinogenaemia may lead to haemorrhage or thrombosis.

3. Disseminated intravascular coagulation

4. Background: Disseminated intravascular coagulation (DIC) is a complex systemic thrombohemorrhagic disorder involving the generation of intravascular fibrin and the consumption of procoagulants and platelets where the blood starts to coagulate throughout the whole body. Background: Disseminated intravascular coagulation (DIC) is a complex systemic thrombohemorrhagic disorder involving the generation of intravascular fibrin and the consumption of procoagulants and platelets where the blood starts to coagulate throughout the whole body. DIC is seen in association with a number of well-defined clinical situations, including sepsis, major trauma, and abruptio placenta, and with laboratory evidence of the following: DIC is seen in association with a number of well-defined clinical situations, including sepsis, major trauma, and abruptio placenta, and with laboratory evidence of the following: 1. Procoagulant activation 2. Fibrinolytic activation 3. Inhibitor consumption 4. Biochemical evidence of end-organ damage or failure

5. DIC occurs in acute and chronic forms. DIC occurs in acute and chronic forms. Also called consumptive coagulopathy. Also called consumptive coagulopathy. This depletes the body of its platelets and coagulation factors, and there is paradoxically an increased risk of hemorrhage. This depletes the body of its platelets and coagulation factors, and there is paradoxically an increased risk of hemorrhage.

6. Clinical features Both bleeding and thrombosis may occur. Both bleeding and thrombosis may occur. Tissue damage caused by thrombosis leads to necrosis and further activation of coagulation and fibrinolysis. Tissue damage caused by thrombosis leads to necrosis and further activation of coagulation and fibrinolysis. Purpura, ecchymoses, gastrointestinal bleeding. Purpura, ecchymoses, gastrointestinal bleeding. Bleeding from intravenous sites and following venepuncture may occur as a result of low levels of coagulation factors and platelets resulting from increased consumption.i Bleeding from intravenous sites and following venepuncture may occur as a result of low levels of coagulation factors and platelets resulting from increased consumption.i Renal function may be impaired due to microvascular thrombosis. Renal function may be impaired due to microvascular thrombosis.

7. Etiology Infections: Infections: Sepsis, particularly with gram-negative bacteria Sepsis, particularly with gram-negative bacteria Sepsisgram-negative bacteria Sepsisgram-negative bacteria Viral Viral Malaria Malaria Malaria Rickettsial Rickettsial Rickettsial Obstetric complications (most common cause), with chemicals from the uterus being released into the blood. Obstetric complications (most common cause), with chemicals from the uterus being released into the blood.uterus Tissue trauma such as burns, accidents, surgery, heat stroke or shock. Tissue trauma such as burns, accidents, surgery, heat stroke or shock. shock Liver disease Liver disease Liver Incompatible blood transfusion reactions or massive blood transfusion (when more than the total circulatory volume is transfused) Incompatible blood transfusion reactions or massive blood transfusion (when more than the total circulatory volume is transfused)transfusion reactionsblood transfusion reactionsblood transfusion Graft-versus-host disease Graft-versus-host disease Graft-versus-host disease Graft-versus-host disease Cancers, Cancers, Viral hemorrhagic fevers. Viral hemorrhagic fevers. Viral hemorrhagic fevers Viral hemorrhagic fevers Envenomation by some species of venomous snakes. Envenomation by some species of venomous snakes.speciesvenomous snakesspeciesvenomous snakes

8. Diagnosis Although numerous blood tests are often performed on patients prone to DIC, the important measures are: full blood count (especially the platelet count), fibrin degradation products or D-dimer tests (markers of fibrinolysis), bleeding time and fibrinogen levels. Although numerous blood tests are often performed on patients prone to DIC, the important measures are: full blood count (especially the platelet count), fibrin degradation products or D-dimer tests (markers of fibrinolysis), bleeding time and fibrinogen levels.blood testsfull blood countplateletfibrin degradation productsD-dimerfibrinolysisbleeding time fibrinogenblood testsfull blood countplateletfibrin degradation productsD-dimerfibrinolysisbleeding time fibrinogen

9. 1. Decreased platelets 2. Elevated FDPs or D-dimers (which are produced when fibrin undergoes degradation when blood clots are dissolved by fibrinolysis). fibrinolysis 3. + 4 Prolonged bleeding time and decreased fibrinogen are markers of DIC.

10. Pathophysiology The processes of coagulation and fibrinolysis lose control, and the result is widespread clotting with resultant bleeding. The processes of coagulation and fibrinolysis lose control, and the result is widespread clotting with resultant bleeding. One of the critical mediator of DIC is the release of tissue factor (TF). One of the critical mediator of DIC is the release of tissue factor (TF). TF is present on the surface of many cell types and is not normally in contact with the general circulation, but is exposed to the circulation after vascular damage. TF is present on the surface of many cell types and is not normally in contact with the general circulation, but is exposed to the circulation after vascular damage. This plays a major role in the development of DIC in septic conditions. This plays a major role in the development of DIC in septic conditions. TF is also abundant in tissues of the lungs, brain, and placenta. TF is also abundant in tissues of the lungs, brain, and placenta. This helps to explain why DIC readily develops in patients with extensive trauma. This helps to explain why DIC readily develops in patients with extensive trauma. Upon activation, TF binds with coagulation factors that then trigger both the intrinsic and the extrinsic pathways of coagulation. Upon activation, TF binds with coagulation factors that then trigger both the intrinsic and the extrinsic pathways of coagulation. Excess circulating thrombin results from the excess activation of the coagulation cascade. Excess circulating thrombin results from the excess activation of the coagulation cascade.

11. The excess thrombin cleaves fibrinogen, which ultimately (at the end ) leaves behind multiple fibrin clots in the circulation. These excess clots trap platelets to become larger clots, which leads to microvascular and macrovascular thrombosis. The excess thrombin cleaves fibrinogen, which ultimately (at the end ) leaves behind multiple fibrin clots in the circulation. These excess clots trap platelets to become larger clots, which leads to microvascular and macrovascular thrombosis. This settling of clots in the microcirculation, in the large vessels, and in the organs is what leads to the ischemia, impaired organ perfusion, and end-organ damage that occurs with DIC. This settling of clots in the microcirculation, in the large vessels, and in the organs is what leads to the ischemia, impaired organ perfusion, and end-organ damage that occurs with DIC.

12. Coagulation inhibitors are also consumed in this process. Decreased inhibitor levels will permit more clotting so that a feedback system develops in which increased clotting leads to more clotting. Coagulation inhibitors are also consumed in this process. Decreased inhibitor levels will permit more clotting so that a feedback system develops in which increased clotting leads to more clotting. At the same time, thrombocytopenia occurs because of the entrapment of platelets. Clotting factors are consumed in the development of multiple clots, which contributes to the bleeding seen with DIC. At the same time, thrombocytopenia occurs because of the entrapment of platelets. Clotting factors are consumed in the development of multiple clots, which contributes to the bleeding seen with DIC. DIC is associated with a poor prognosis and a high mortality rate. DIC is associated with a poor prognosis and a high mortality rate.

13. Treatment The underlying cause must be treated initially. The underlying cause must be treated initially. Anticoagulants are only given when indicated as patients with DIC are prone to bleeding. Anticoagulants are only given when indicated as patients with DIC are prone to bleeding. Platelets may be transfused if counts are very low, and fresh frozen plasma may be administrated. Platelets may be transfused if counts are very low, and fresh frozen plasma may be administrated.transfusedfresh frozen plasmatransfusedfresh frozen plasma The prognosis for those with DIC, depending on its cause, is often grim (bad), leading the initials to be known colloquially as "death is coming". The prognosis for those with DIC, depending on its cause, is often grim (bad), leading the initials to be known colloquially as "death is coming".

14. Other acquired disorders of coagulation 1. Drugs Anticoagulants and drugs affecting anticoagulation can disturb coagulation. Anticoagulants and drugs affecting anticoagulation can disturb coagulation. Chemotherapy Chemotherapy 2. Acquired coagulation inhibitors These antibodies to coagulation factors are idiopathic, com­moner in the elderly, or occur in malignancy (e.g. lym­phoma), connective tissue disease (e.g. SLE) and with paraproteins (e.g. myeloma). These antibodies to coagulation factors are idiopathic, com­moner in the elderly, or occur in malignancy (e.g. lym­phoma), connective tissue disease (e.g. SLE) and with paraproteins (e.g. myeloma). They lead to excessive bleed­ing, both spontaneously and following injury. They lead to excessive bleed­ing, both spontaneously and following injury.

15. 3. Vitamin K deficiency Vitamin K is required to activate factors II, VII, IX and X and protein C and S. Vitamin K is required to activate factors II, VII, IX and X and protein C and S. It is fat-soluble and derived from vegetables in food and intestinal flora. It is fat-soluble and derived from vegetables in food and intestinal flora. Deficiency occurs in patients on poor diets, those taking broad-spectrum antibiotics which reduce the gut flora, in biliary tract disease and with intestinal malabsorption. Deficiency occurs in patients on poor diets, those taking broad-spectrum antibiotics which reduce the gut flora, in biliary tract disease and with intestinal malabsorption. 4. Haemorrhagic disease of the newborn Newborn infants are at an increased risk of bleeding because of hepatic immaturity and low levels of vitamin K. Newborn infants are at an increased risk of bleeding because of hepatic immaturity and low levels of vitamin K. It is normal to give an injection of vitamin K (1 mg) to all newborn infants in the UK. It is normal to give an injection of vitamin K (1 mg) to all newborn infants in the UK.

17. HEPERCOAGULAABILITY STATE. ANTITHROMBIN III DIFICIENCY. ANTITHROMBIN III DIFICIENCY. PROTEIN S DIFICIENCY PROTEIN S DIFICIENCY PROTEIN C DIFICIENCY PROTEIN C DIFICIENCY DYSFIBRINOGENAEMIA DYSFIBRINOGENAEMIA ACTIVATED PROTEIN C-RESISTANCE ACTIVATED PROTEIN C-RESISTANCE HEPARIN COFACTOR DIFICIENCY HEPARIN COFACTOR DIFICIENCY DISPLASMINOGENAEMIA DISPLASMINOGENAEMIA PLASMINOGEN ACTIVATOR DIFICIENCY PLASMINOGEN ACTIVATOR DIFICIENCY PLASMINOGEN ACTIVATOR INHIBITOR EXCESS PLASMINOGEN ACTIVATOR INHIBITOR EXCESS ashjan319 ashjan319

18. Thrombosis and thrombophilia Thrombosis: Thrombosis: Thrombosis is a specific medical term for a blood clot that remains in the place where it formed. Thrombosis is a specific medical term for a blood clot that remains in the place where it formed. Thrombosis is the pathological process whereby platelets and fibrin interact with the vessel wall to form a haemosta­tic plug (clot or thrombus) to cause vascular obstruction, instructing the flow of blood resulting in ischaemia, which means deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel e.g. Myocardial infarction and deep vain thrombosis. Thrombosis is the pathological process whereby platelets and fibrin interact with the vessel wall to form a haemosta­tic plug (clot or thrombus) to cause vascular obstruction, instructing the flow of blood resulting in ischaemia, which means deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel e.g. Myocardial infarction and deep vain thrombosis.clotthrombusbloodclotthrombusblood

19. It may he arterial, causing ischemia, or venous leading to stasis. It may he arterial, causing ischemia, or venous leading to stasis. The thrombus may he subsequently lysed by fibrinolysis. The thrombus may he subsequently lysed by fibrinolysis. Thrombosis underlies ischaemic heart. cerebrovascular and peripheral vascular disease: venous occlusion and pulmonary embolism: and it plays an important part in pre-eclampsia. Thrombosis underlies ischaemic heart. cerebrovascular and peripheral vascular disease: venous occlusion and pulmonary embolism: and it plays an important part in pre-eclampsia. It becomes more common with age. It becomes more common with age. Thromboembolism is a general term describing both thrombosis and its main complication which is embolisation. Thromboembolism is a general term describing both thrombosis and its main complication which is embolisation.embolisation

20. The thrombus may he subsequently lysed by fibrinolysis. The thrombus may he subsequently lysed by fibrinolysis. Thrombosis underlies ischaemic heart. cerebrovascular and peripheral vascular disease: venous occlusion and pulmonary embolism: and it plays an important part in pre-eclampsia. Thrombosis underlies ischaemic heart. cerebrovascular and peripheral vascular disease: venous occlusion and pulmonary embolism: and it plays an important part in pre-eclampsia. It becomes more common with age. It becomes more common with age. Thromboembolism is a general term describing both thrombosis and its main complication which is embolisation. Thromboembolism is a general term describing both thrombosis and its main complication which is embolisation.embolisation

21. Causes Causes In classical terms, thrombosis is caused by abnormalities in one or more of the following (Virchow's triad, who is a German physician and pathologist known for his contributions to cell theory and the study of disease): In classical terms, thrombosis is caused by abnormalities in one or more of the following (Virchow's triad, who is a German physician and pathologist known for his contributions to cell theory and the study of disease):Virchow The composition of the blood (hypercoagulability) caused for example, by genetic deficiencies or autoimmune disorders. The composition of the blood (hypercoagulability) caused for example, by genetic deficiencies or autoimmune disorders. Damage of the vessel wall (endothelial cell injury) such as by trauma, infection, or turbulent flow at bifurcations. Damage of the vessel wall (endothelial cell injury) such as by trauma, infection, or turbulent flow at bifurcations. Slowing down of the blood flow (hemostasis) past the point of injury (which may occur after long periods of sedentary behavior - for example, sitting on a long airplane flight). Slowing down of the blood flow (hemostasis) past the point of injury (which may occur after long periods of sedentary behavior - for example, sitting on a long airplane flight).

22. 1 & 2 are most important for venous thrombosis. 1 & 2 are most important for venous thrombosis. 3 is more important for arterial thrombosis. 3 is more important for arterial thrombosis. High altitude has also been known to induce thrombosis. High altitude has also been known to induce thrombosis. Occasionally, abnormalities in coagulation are to blame. Occasionally, abnormalities in coagulation are to blame. Intravascular coagulation follows, forming a mass of red blood cells, leukocytes, and fibrin. Intravascular coagulation follows, forming a mass of red blood cells, leukocytes, and fibrin.

23. Classification: There are two distinct forms of thrombosis: 1- Arterial thrombosis 2- Venous thrombosis

24. Arterial thrombosis A blood clot within an artery is known as an arterial thrombosis. A blood clot within an artery is known as an arterial thrombosis. This occurs in relation to damaged endothelium, where exposed collagen and released tissue factor cause platelet aggregation and fibrin formation. This occurs in relation to damaged endothelium, where exposed collagen and released tissue factor cause platelet aggregation and fibrin formation. Arterial thrombosis is responsible for heart attacks, strokes and peripheral vascular disease (thrombosis in leg arteries). Arterial thrombosis is responsible for heart attacks, strokes and peripheral vascular disease (thrombosis in leg arteries). Heart attacks and strokes are a major cause of death and serious illness. Heart attacks and strokes are a major cause of death and serious illness.

25. The causes of arterial thrombosis: Arterial thrombosis usually affects individuals who already have: 1. Atherosclerosis, or narrowing of the arteries. 2. Stroke Stroke 3. Myocardial infarction (usually coronary thrombosis due to rupture of an atherosclerotic plaque) Myocardial infarction Myocardial infarction 4. Thoracic outlet syndrome (may precipitate arterial thrombosis as well as venous) Thoracic outlet syndrome Thoracic outlet syndrome

26. Risk factors for arterial thrombosis Risk factors for arterial thrombosis The main risk factors for arterial thrombosis include: The main risk factors for arterial thrombosis include: Smoking Smoking High blood pressure High blood pressure Increased levels of cholesterol Increased levels of cholesterol Diabetes Diabetes Increasing age Increasing age Family history Family history Poor diet Poor diet Excess body weight Excess body weight Physical inactivity. Physical inactivity. Of these, the major risk factors are smoking, high blood pressure (hypertension), and increased cholesterol levels.

27. Symptoms of arterial thrombosis Symptoms of arterial thrombosis The build up of atheroma causes the narrowing of the arteries, which can lead to heart disease and heart attacks, strokes or peripheral vascular disease. The build up of atheroma causes the narrowing of the arteries, which can lead to heart disease and heart attacks, strokes or peripheral vascular disease.

28. Embolisation If a bacterial infection is present at the site of thrombosis, the thrombus may break down, spreading particles of infected material throughout the circulatory system (pyemia, septic embolus) and setting up metastatic abscesses wherever they come to rest. If a bacterial infection is present at the site of thrombosis, the thrombus may break down, spreading particles of infected material throughout the circulatory system (pyemia, septic embolus) and setting up metastatic abscesses wherever they come to rest.circulatory systempyemia septic emboluscirculatory systempyemia septic embolus Without an infection, the thrombus may become detached and enter circulation as an embolus, finally lodging (staying) in and completely obstructing a blood vessel (an infarction), where the effects of an infarction depend on where it occurs. Without an infection, the thrombus may become detached and enter circulation as an embolus, finally lodging (staying) in and completely obstructing a blood vessel (an infarction), where the effects of an infarction depend on where it occurs.embolusinfarctionembolusinfarction

29. 2- Venous thrombosis A venous thrombosis is a blood clot that forms within a vein. A venous thrombosis is a blood clot that forms within a vein.blood clotveinblood clotvein Superficial venous thromboses can cause discomfort but generally do not cause serious consequences, unlike the deep venous thromboses (DVTs) that form in the deep veins of the legs or in the pelvic veins. Superficial venous thromboses can cause discomfort but generally do not cause serious consequences, unlike the deep venous thromboses (DVTs) that form in the deep veins of the legs or in the pelvic veins.deep venous thrombosesdeep venous thromboses Since the veins return blood to the heart, if a piece of a blood clot formed in a vein breaks off it can be transported to the right side of the heart, and from there into the lungs. Since the veins return blood to the heart, if a piece of a blood clot formed in a vein breaks off it can be transported to the right side of the heart, and from there into the lungs.bloodheartlungsbloodheartlungs

30. A piece of thrombus that is transported in this way is an embolism: the process of forming a thrombus that becomes embolic is called a thromboembolism. A piece of thrombus that is transported in this way is an embolism: the process of forming a thrombus that becomes embolic is called a thromboembolism.embolism Deep venous thrombosis Deep venous thrombosis Deep venous thrombosis Deep venous thrombosis Renal vein thrombosis Renal vein thrombosis Renal vein thrombosis Renal vein thrombosis hepatic vein thrombosis hepatic vein thrombosis hepatic vein thrombosis hepatic vein thrombosis

31. Risk factors Risk factors General General Older age Older age Female gender Female gender Smoking Smoking Obesity Obesity Pregnancy Pregnancy Minor injuries Minor injuries

32. Medical Medical Surgery Surgery Trauma Trauma Oral contraceptive use Oral contraceptive use Malignancy Malignancy Kidney disorders Kidney disorders Lupus anticoagulant Lupus anticoagulant Paroxysmal nocturnal hemoglobinuria Paroxysmal nocturnal hemoglobinuria Inflammatory bowel disease Inflammatory bowel disease Disseminated intravascular coagulation Disseminated intravascular coagulation

33. Familial Familial Antithrombin III deficiency Antithrombin III deficiency Protein C deficiency/Protein S deficiency Protein C deficiency/Protein S deficiency Protein C deficiency Protein C deficiency APC resistance (Factor V Leiden) APC resistance (Factor V Leiden) Dysfibrogenemia Dysfibrogenemia Hypoplasminogenemia Hypoplasminogenemia Familial homocysteinemia Familial homocysteinemia

34. Thrombophilia It is a term used to describe both: the inheritance and acquired haemostatic disorders which predispose to thrombosis. It is a term used to describe both: the inheritance and acquired haemostatic disorders which predispose to thrombosis. It should be suspected and screened for in patients who are young. Have a positive family history. Have a thrombosis in an unusual site and in females with recurrent fetal loss. It should be suspected and screened for in patients who are young. Have a positive family history. Have a thrombosis in an unusual site and in females with recurrent fetal loss.

35. Inherited thrombophilia: This has been increasingly recognized recently. This has been increasingly recognized recently. Presentation may be during early child-hood or in adulthood, e.g. at commencement of oral contra­ceptives. Presentation may be during early child-hood or in adulthood, e.g. at commencement of oral contra­ceptives. Inheritance of a variant form of factor V (tactor V Leiden) is the most common (up to 5% of the population). Activated factor V Leiden is relatively resistant to inactivation by protein C. Inheritance of a variant form of factor V (tactor V Leiden) is the most common (up to 5% of the population). Activated factor V Leiden is relatively resistant to inactivation by protein C. The risk of thrombosis is increased 5- to 10-fold in heterozygotes. and 50- to I00 fold in homozygotcs. The risk of thrombosis is increased 5- to 10-fold in heterozygotes. and 50- to I00 fold in homozygotcs. Rarer causes include protein protein S or antithrombin deti­ciency or functional abnormality, defective fibrinolysis, mutant prothromhin and homocystinuria. Rarer causes include protein protein S or antithrombin deti­ciency or functional abnormality, defective fibrinolysis, mutant prothromhin and homocystinuria. The combination of two abnormalities often underlies severe cases. The combination of two abnormalities often underlies severe cases.

37. Acquired thrombophilia Post operative venous thrombosis. Post operative venous thrombosis. Venous stasis or immobility. Venous stasis or immobility. Malignancy. Malignancy. Blood disorders: e.g. increased viscosity. Blood disorders: e.g. increased viscosity. Oestrogen therapy. Oestrogen therapy. The Lupus Anticoagulant. The Lupus Anticoagulant. Factor IX concentrates Factor IX concentrates

38. Lupus anticoagulant syndrome Despite its name, this syndrome usually presents with arte­rial or venous thrombosis or recurrent miscarriages. Despite its name, this syndrome usually presents with arte­rial or venous thrombosis or recurrent miscarriages. It may he associated with systemic lupus erythematosus or other connective tissue disorders, with malignancy or infections or the idiopathic. It may he associated with systemic lupus erythematosus or other connective tissue disorders, with malignancy or infections or the idiopathic. Patients may show a spectrum of antibod­ies which interfere with phospholipid-dependent coagula­tion tests in vitro and/or react with cardiolipin. Patients may show a spectrum of antibod­ies which interfere with phospholipid-dependent coagula­tion tests in vitro and/or react with cardiolipin. The A PTT is prolonged and not corrected by a 5o:50 mix of normal plasma in patient plasma. The A PTT is prolonged and not corrected by a 5o:50 mix of normal plasma in patient plasma. Anticoagulant therapy is needed for patients with thrombosis. Anticoagulant therapy is needed for patients with thrombosis. Paradoxically, it is associated with venous or arterial thrombosis and recurrent pregnancy loss due o placenta infarction. Paradoxically, it is associated with venous or arterial thrombosis and recurrent pregnancy loss due o placenta infarction.

40. Protein C

41. Protein C is a major physiological anticoagulant. Protein C is a major physiological anticoagulant.anticoagulant It is a vitamin K-dependent serine protease enzyme, that is activated by thrombin into activated protein C (APC). It is a vitamin K-dependent serine protease enzyme, that is activated by thrombin into activated protein C (APC).vitamin Kserine protease enzymethrombinvitamin Kserine protease enzymethrombin The activated form (with protein S and phospholipid as a cofactor) degrades Factor Va and Factor VIIIa. The activated form (with protein S and phospholipid as a cofactor) degrades Factor Va and Factor VIIIa.protein ScofactorFactor VaFactor VIIIaprotein ScofactorFactor VaFactor VIIIa It should not be confused with C peptide or c- reactive protein or protein kinase C. It should not be confused with C peptide or c- reactive protein or protein kinase C.C peptidec- reactive protein kinase C peptidec- reactive protein kinase C The protein C pathway’s key enzyme, activated protein C, provides physiologic antithrombotic activity and exhibits anti-inflammatory. The protein C pathway’s key enzyme, activated protein C, provides physiologic antithrombotic activity and exhibits anti-inflammatory.anti-inflammatory Its actions are related to development of thrombosis and ischemic stroke. Its actions are related to development of thrombosis and ischemic stroke. thrombosisischemic stroke thrombosisischemic stroke

42. Role in disease

43. The Protein C Anticoagulant Pathway: Thrombin escaping from a site of vascular injury binds to its receptor thrombomodulin (TM) on the intact cell surface. Thrombin escaping from a site of vascular injury binds to its receptor thrombomodulin (TM) on the intact cell surface. As a result, thrombin loses its procoagulant properties and instead becomes a potent activator of protein C. As a result, thrombin loses its procoagulant properties and instead becomes a potent activator of protein C. Activated protein C (APC) functions as a circulating anticoagulant, which specifically degrades and inactivates the phospholipid-bound factors Va and VIIIa. Activated protein C (APC) functions as a circulating anticoagulant, which specifically degrades and inactivates the phospholipid-bound factors Va and VIIIa. This effectively down-regulates the coagulation cascade and limits clot formation to sites of vascular injury. This effectively down-regulates the coagulation cascade and limits clot formation to sites of vascular injury. T = Thrombin, PC= Protein C, Activated Protein C= APC, PS= Protein S T = Thrombin, PC= Protein C, Activated Protein C= APC, PS= Protein SGenetics The PROC gene is located on the second chromosome. The PROC gene is located on the second chromosome.chromosome

44. Protein C deficiency Protein C deficiency is a rare genetic feature that predisposes to venous thrombosis and habitual abortion. It was first described in 1981. The disease belongs to a group of genetic disorders know as thrombophilias. The prevalence of protein C deficiency has been estimated to about 0.2% to 0.5% of the general population. Protein C deficiency is a rare genetic feature that predisposes to venous thrombosis and habitual abortion. It was first described in 1981. The disease belongs to a group of genetic disorders know as thrombophilias. The prevalence of protein C deficiency has been estimated to about 0.2% to 0.5% of the general population.venousthrombosishabitual abortionthrombophiliasvenousthrombosishabitual abortionthrombophilias Protein C deficiency is associated with an increased incidence of venous thromboembolism, whereas no association with arterial thrombotic disease has been found. Protein C deficiency is associated with an increased incidence of venous thromboembolism, whereas no association with arterial thrombotic disease has been found.

45. Activated protein C resistance is the inability of protein C to cleave factors V and/or VIII. This may be hereditary or acquired. The best known and most common hereditary form is Factor V Leiden. Acquired forms occur in the presence of elevated Factor VIII concentrations. Activated protein C resistance is the inability of protein C to cleave factors V and/or VIII. This may be hereditary or acquired. The best known and most common hereditary form is Factor V Leiden. Acquired forms occur in the presence of elevated Factor VIII concentrations. Activated protein C resistanceFactor V Leiden Activated protein C resistanceFactor V Leiden Warfarin necrosis is acquired protein C deficiency due to treatment with the vitamin K inhibitor anticoagulant warfarin. In initial stages of action, inhibition of protein C may be stronger than inhibition of the vitamin K-dependent coagulation factors (II, VII, IX and X), leading to paradoxical (impossible) activation of coagulation and necrosis of skin areas. Warfarin necrosis is acquired protein C deficiency due to treatment with the vitamin K inhibitor anticoagulant warfarin. In initial stages of action, inhibition of protein C may be stronger than inhibition of the vitamin K-dependent coagulation factors (II, VII, IX and X), leading to paradoxical (impossible) activation of coagulation and necrosis of skin areas. Warfarin necrosiswarfarinnecrosis Warfarin necrosiswarfarinnecrosis

46. Pathophysiology The main function of protein C is its anticoagulant property as an inhibitor of coagulation factors V and VIII. The main function of protein C is its anticoagulant property as an inhibitor of coagulation factors V and VIII.protein CVVIIIprotein CVVIII There are two main types of protein C mutations that lead to protein C deficiency: There are two main types of protein C mutations that lead to protein C deficiency: Type I: Quantitative defects of protein C (low production or short protein half life) Type I: Quantitative defects of protein C (low production or short protein half life) Type II: Qualitative defects, in which interaction with other molecules is abnormal. Defects in interaction with thrombomodulin, phospholipids, factors V/VIII and others have been described. Type II: Qualitative defects, in which interaction with other molecules is abnormal. Defects in interaction with thrombomodulin, phospholipids, factors V/VIII and others have been described. thrombomodulin Homozygous protein C mutations often causes a severe thrombotic disorder known as purpura fulminans. Homozygous protein C mutations often causes a severe thrombotic disorder known as purpura fulminans.purpura fulminanspurpura fulminans protein c deficiency has only had 16 cases before 1999 protein c deficiency has only had 16 cases before 1999

47. Protein S. Protein S is a vitamin K-dependent plasma glycoprotein synthesized in the liver. Protein S is a vitamin K-dependent plasma glycoprotein synthesized in the liver.vitamin Kglycoproteinvitamin Kglycoprotein In the circulation, Protein S exists in two forms: a free form and a complex form bound to complement protein C4b In the circulation, Protein S exists in two forms: a free form and a complex form bound to complement protein C4bcomplement

48. Function Function The best characterized function of Protein S is its role in the anti coagulation pathway, it functions as a cofactor to Protein C in the inactivation of Factors Va and VIIIa. The best characterized function of Protein S is its role in the anti coagulation pathway, it functions as a cofactor to Protein C in the inactivation of Factors Va and VIIIa.coagulationProtein CFactors VaVIIIacoagulationProtein CFactors VaVIIIa Only the free form has cofactor activity. Only the free form has cofactor activity. The property of Protein S enhances the phagocytosis of the apoptotic cell, allowing it to be removed 'cleanly' without any symptoms of tissue damage such as inflammation occurring. The property of Protein S enhances the phagocytosis of the apoptotic cell, allowing it to be removed 'cleanly' without any symptoms of tissue damage such as inflammation occurring.inflammation

49. Protein S deficiency Protein S deficiency Protein S deficiency is a disorder associated with increased risk of venous thrombosis. Protein S deficiency is a disorder associated with increased risk of venous thrombosis.venous thrombosisvenous thrombosis Protein S, a vitamin K-dependent physiological anticoagulant, acts as a nonenzymatic cofactor to activated protein C in the proteolytic degradation of factor Va and factor VIIIa. Protein S, a vitamin K-dependent physiological anticoagulant, acts as a nonenzymatic cofactor to activated protein C in the proteolytic degradation of factor Va and factor VIIIa.vitamin K factor Vafactor VIIIavitamin K factor Vafactor VIIIa Decreased (antigen) levels or impaired function (activity) of protein S, leads to decreased degradation of factor Va and factor VIIIa and an increased propensity (tendency) to venous thrombosis. Decreased (antigen) levels or impaired function (activity) of protein S, leads to decreased degradation of factor Va and factor VIIIa and an increased propensity (tendency) to venous thrombosis.protein Sfactor Vafactor VIIIaprotein Sfactor Vafactor VIIIa Protein S circulates in human plasma in two forms: approximately 60 percent is bound to complement component C4b while the remaining 40 percent is free. Protein S circulates in human plasma in two forms: approximately 60 percent is bound to complement component C4b while the remaining 40 percent is free. Only free protein S has activated protein C cofactor activity. Only free protein S has activated protein C cofactor activity.

50. Types: Hereditary and Acquired Hereditary and Acquired a) There are three types of hereditary protein S deficiency. a) There are three types of hereditary protein S deficiency. Protein S deficiency can also be acquired due to : Vitamin K deficiency or Treatment with warfarin which generally also impairs the coagulation system itself (factors II, VII, IX and X), and therefore predisposes to bleeding rather than thrombosis. Vitamin K deficiency or Treatment with warfarin which generally also impairs the coagulation system itself (factors II, VII, IX and X), and therefore predisposes to bleeding rather than thrombosis.warfarin bleedingwarfarin bleeding Systemic sex hormone therapy and pregnancy Systemic sex hormone therapy and pregnancy Liver disease and certain chronic infections (for example HIV). Liver disease and certain chronic infections (for example HIV).

51. Protein S deficiency is the underlying cause of a small proportion of cases of disseminated intravascular coagulation (DIC), deep venous thrombosis (DVT) and pulmonary embolism (PE). Protein S deficiency is the underlying cause of a small proportion of cases of disseminated intravascular coagulation (DIC), deep venous thrombosis (DVT) and pulmonary embolism (PE).disseminated intravascular coagulationdeep venous thrombosispulmonary embolismdisseminated intravascular coagulationdeep venous thrombosispulmonary embolism Hereditary PSD is an autosomal dominant condition, resulting in a 50 percent chance of passing the disease to progeny. Hereditary PSD is an autosomal dominant condition, resulting in a 50 percent chance of passing the disease to progeny.autosomal dominantautosomal dominant Less than half of those diagnosed with PSD will experience thrombosis, and those who do usually are affected only from the age of the late teens onwards. Less than half of those diagnosed with PSD will experience thrombosis, and those who do usually are affected only from the age of the late teens onwards.thrombosis Screening of young children is usually deferred because early testing is often inaccurate, and it is better to wait until they are old enough to decide for themselves whether they want to be tested. Screening of young children is usually deferred because early testing is often inaccurate, and it is better to wait until they are old enough to decide for themselves whether they want to be tested.

52. Factor V Leiden mutation Factor V Leiden (sometimes Factor VLeiden) is the name given to a variant of human factor V that causes a hypercoagulability disorder. Factor V Leiden (sometimes Factor VLeiden) is the name given to a variant of human factor V that causes a hypercoagulability disorder.factor V hypercoagulabilityfactor V hypercoagulability In this disorder the Leiden variant of factor V, cannot be inactivated by activated protein C. Factor V Leiden is the most common hereditary hypercoagulability disorder amongst Eurasians. In this disorder the Leiden variant of factor V, cannot be inactivated by activated protein C. Factor V Leiden is the most common hereditary hypercoagulability disorder amongst Eurasians.factor Vfactor V

53. Pathophysiology In the normal person, factor V functions as a cofactor to allow factor X to activate an enzyme called thrombin. Thrombin in turn cleaves fibrinogen to fibrin, which polymerizes to form the dense meshwork that makes up the majority of a clot. In the normal person, factor V functions as a cofactor to allow factor X to activate an enzyme called thrombin. Thrombin in turn cleaves fibrinogen to fibrin, which polymerizes to form the dense meshwork that makes up the majority of a clot. cofactorfactor Xenzymethrombin fibrinogenfibrinclot cofactorfactor Xenzymethrombin fibrinogenfibrinclot Activated protein C (aPC) is a natural anticoagulant that acts to limit the extent of clotting by cleaving and degrading factor V. Activated protein C (aPC) is a natural anticoagulant that acts to limit the extent of clotting by cleaving and degrading factor V.protein C anticoagulantprotein C anticoagulant Such mutation makes factor V less suseptable to cleavage by APC. Such mutation makes factor V less suseptable to cleavage by APC. Factor V Leiden is an autosomal dominant condition in which the coagulation factor cannot be destroyed by aPC. Factor V Leiden is an autosomal dominant condition in which the coagulation factor cannot be destroyed by aPC.autosomal dominantautosomal dominant

54. Mutation of the gene encoding factor V—a single nucleotide substitution —changes the protein's 506th amino acid from arginine to glutamine. Mutation of the gene encoding factor V—a single nucleotide substitution —changes the protein's 506th amino acid from arginine to glutamine. Mutationgenenucleotideproteinamino acidarginineglutamine Mutationgenenucleotideproteinamino acidarginineglutamine Since this amino acid is normally the cleavage site for aPC, the mutation prevents efficient inactivation of factor V. Since this amino acid is normally the cleavage site for aPC, the mutation prevents efficient inactivation of factor V. When factor V remains active, it facilitates overproduction of thrombin leading to excess fibrin generation and excess clotting. When factor V remains active, it facilitates overproduction of thrombin leading to excess fibrin generation and excess clotting. The excessive clotting that occurs in this disorder is almost always restricted to the veins, where the clotting may cause a deep vein thrombosis (DVT). The excessive clotting that occurs in this disorder is almost always restricted to the veins, where the clotting may cause a deep vein thrombosis (DVT).veinsdeep vein thrombosisveinsdeep vein thrombosis If the venous clots break off, these clots can travel through the heart to the lung, where they block a pulmonary blood vessel and cause a pulmonary embolism. If the venous clots break off, these clots can travel through the heart to the lung, where they block a pulmonary blood vessel and cause a pulmonary embolism.heartlungpulmonary blood vessel pulmonary embolismheartlungpulmonary blood vessel pulmonary embolism Women with the disorder have an increased risk of miscarriage and stillbirth. Women with the disorder have an increased risk of miscarriage and stillbirth. Studies have found that about 5% of caucasians in North America have factor V Leiden. Studies have found that about 5% of caucasians in North America have factor V Leiden. Up to 30% of patients who present with vein thrombosis have this condition. Up to 30% of patients who present with vein thrombosis have this condition.vein thrombosisvein thrombosis It is also known as protein C-resistance (APC-R) It is also known as protein C-resistance (APC-R)

55. The presence of acquired risk factors for venous thrombosis -- including smoking, use of estrogen-containing (combined) forms of hormonal contraception use, and recent surgery -- further increase the chance that an individual with the factor V Leiden mutation will develop DVT. The presence of acquired risk factors for venous thrombosis -- including smoking, use of estrogen-containing (combined) forms of hormonal contraception use, and recent surgery -- further increase the chance that an individual with the factor V Leiden mutation will develop DVT.smokinghormonal contraceptionsurgerysmokinghormonal contraceptionsurgery Women with Factor V Leiden have a substantially increased risk of clotting in pregnancy (and on estrogen containing birth control pills or hormone replacement) in the form of deep vein thrombosis and pulmonary embolism. Women with Factor V Leiden have a substantially increased risk of clotting in pregnancy (and on estrogen containing birth control pills or hormone replacement) in the form of deep vein thrombosis and pulmonary embolism. pregnancyestrogen pregnancyestrogen

56. They also have an increased risk of preeclampsia, as well as miscarriage and stillbirth due to clotting in the placenta, umbilical cord, or the fetus. They also have an increased risk of preeclampsia, as well as miscarriage and stillbirth due to clotting in the placenta, umbilical cord, or the fetus. preeclampsiamiscarriage stillbirth preeclampsiamiscarriage stillbirth Heterozygote patients have 5 folds increased risk of thrombosis. Heterozygote patients have 5 folds increased risk of thrombosis. Homozygote patients have around 50- folds risk of thrombosis Homozygote patients have around 50- folds risk of thrombosis

57. Diagnosis Diagnosis Suspicion of factor V Leiden being the cause for any thrombotic event should be considered in any white patient below the age of 45, or in any person with a family history of venous thrombosis. Suspicion of factor V Leiden being the cause for any thrombotic event should be considered in any white patient below the age of 45, or in any person with a family history of venous thrombosis. This disease can be diagnosed by watching the aPTT as activated protein C is added. With a normal patient, adding APC increases the aPTT. In patients with factor V Leiden, adding APC to plasma of Factor V leiden will fail to prolong APTT. This disease can be diagnosed by watching the aPTT as activated protein C is added. With a normal patient, adding APC increases the aPTT. In patients with factor V Leiden, adding APC to plasma of Factor V leiden will fail to prolong APTT. aPTT There is also a simple genetic test that can be done for this disorder, and will give a quick diagnosis. There is also a simple genetic test that can be done for this disorder, and will give a quick diagnosis.

58. Antithrombin (AT) deficiency Antithrombin (AT) is a small protein molecule that inactivates several enzymes of the coagulation system. Antithrombin (AT) is a small protein molecule that inactivates several enzymes of the coagulation system.coagulation It is a glycoprotein produced by the liver and consists of 432 amino acids, and contains three disulfide bonds. It is a glycoprotein produced by the liver and consists of 432 amino acids, and contains three disulfide bonds.glycoproteinliverdisulfide bondsglycoproteinliverdisulfide bondsFunction The physiological target of antithrombin are those of the contact activation pathway (formerly known as the intrinsic pathway), namely the activated forms of Factor X (Xa), Factor IX (IXa), Factor XI (XIa), Factor XII (XIIa) and Factor II (thrombin) (IIa) and also the activated form of Factor VII (VIIa) from the tissue factor pathway (formerly known as the extrinsic pathway).[7] The physiological target of antithrombin are those of the contact activation pathway (formerly known as the intrinsic pathway), namely the activated forms of Factor X (Xa), Factor IX (IXa), Factor XI (XIa), Factor XII (XIIa) and Factor II (thrombin) (IIa) and also the activated form of Factor VII (VIIa) from the tissue factor pathway (formerly known as the extrinsic pathway).[7] contact activation pathwayFactor XFactor IXFactor XIFactor XIIFactor IIFactor VIItissue factor pathway[7] contact activation pathwayFactor XFactor IXFactor XIFactor XIIFactor IIFactor VIItissue factor pathway[7]

59. Pathology: Autosomal Dominant inheritance. Autosomal Dominant inheritance. Antithrombin (AT) deficiency usually causes recurrent venous thrombosis usually start early in adult live. Antithrombin (AT) deficiency usually causes recurrent venous thrombosis usually start early in adult live. Occasionally causes arterial thrombosis. Occasionally causes arterial thrombosis. Many molecular variants of AT are known and are associated with varying degree of thrombosis. Many molecular variants of AT are known and are associated with varying degree of thrombosis.

60. AT concentrate are available and are used to prevent thrombosis during surgery or childbirth. AT concentrate are available and are used to prevent thrombosis during surgery or childbirth. It leads to increased prothrombin levels. It leads to increased prothrombin levels. It increases the risk of thrombosis by at least 2-folds. It increases the risk of thrombosis by at least 2-folds. Such mutation + high concentrations of factor VII, IX and XI will lead to sustained generation of thrombin which will lead reduction in the regulation of fibrinolysis and finally to thrombosis. Such mutation + high concentrations of factor VII, IX and XI will lead to sustained generation of thrombin which will lead reduction in the regulation of fibrinolysis and finally to thrombosis.

61. Hyperhomocysteinemia Definition: An amino acid produced by the body, derived from the digestion of protein-rich foods. Definition: An amino acid produced by the body, derived from the digestion of protein-rich foods. Homocystein is derived from dietary methionin and is metabolized either by the remethylation or the trans-sulphuration pathways. Homocystein is derived from dietary methionin and is metabolized either by the remethylation or the trans-sulphuration pathways. As a consequence of the biochemical reactions in which homocysteine is involved, deficiencies of the vitamins folic acid, pyridoxine (B6), or B12 (which use as cofactors) can lead to high homocysteine levels. As a consequence of the biochemical reactions in which homocysteine is involved, deficiencies of the vitamins folic acid, pyridoxine (B6), or B12 (which use as cofactors) can lead to high homocysteine levels.folic acidpyridoxineB12folic acidpyridoxineB12

62. Supplementation with pyridoxine, folic acid, B12 or trimethylglycine (betaine) reduces the concentration of homocysteine in the bloodstream. Supplementation with pyridoxine, folic acid, B12 or trimethylglycine (betaine) reduces the concentration of homocysteine in the bloodstream.trimethylglycine Normal fasting homocysteine plasma levels are between 5,0 and 15,9 mmol/l. Normal fasting homocysteine plasma levels are between 5,0 and 15,9 mmol/l. Hyperhomocysteinemia is a medical condition characterized by an abnormally large level of homocysteine in the blood. Hyperhomocysteinemia is a medical condition characterized by an abnormally large level of homocysteine in the blood.homocysteinebloodhomocysteineblood

63. Classical Hyperhomocysteinemia: Is a rare autosomal recessive disorder Is a rare autosomal recessive disorder Vascular disease and thrombosis are major features of the disease. Vascular disease and thrombosis are major features of the disease. Higher levels can be genetic or acquired. Higher levels can be genetic or acquired. Such Higher levels are associated with increased risk of both venous and arterial thrombosis. Such Higher levels are associated with increased risk of both venous and arterial thrombosis. Acquired risk factors: Decreased folate levels. Decreased folate levels. Decreased vitamin B12 levels. Decreased vitamin B12 levels. Decreased vitamin B6 levels. Decreased vitamin B6 levels. Drugs (e.g. cyclosporine). Drugs (e.g. cyclosporine). Renal damage. Renal damage. Smoking. Smoking. The risk is increased with age and it is higher in men and menopausal women. The risk is increased with age and it is higher in men and menopausal women.

64. Hypercoagulable state. Definition of Hypercoagulable state: Definition of Hypercoagulable state: A hypercoagulable state is the medical term for a condition in which there is an abnormally increased tendency toward blood clotting (coagulation). A hypercoagulable state is the medical term for a condition in which there is an abnormally increased tendency toward blood clotting (coagulation). Hypercoagulation disorders may be acquired or hereditary. Hypercoagulation disorders may be acquired or hereditary. Some of the primary or hereditary disorders that lead to hypercoagulation are: Some of the primary or hereditary disorders that lead to hypercoagulation are: Abnormal clotting factor V. Abnormal clotting factor V. Variations in fibrinogen. Variations in fibrinogen. Deficiencies in proteins C and S. Deficiencies in proteins C and S.

65. Other body system diseases may also lead to these disorders, including Other body system diseases may also lead to these disorders, including Diabetes. Diabetes.Diabetes Sickle cell anemia, Sickle cell anemia, Sickle cell anemia Sickle cell anemia Congenital heart disease, Congenital heart disease, Congenital heart disease Congenital heart disease Lupus. Lupus. Thalassemia, Thalassemia, Thalassemia Polycythemia rubra vera, and others. Polycythemia rubra vera, and others. Polycythemia Antithrombin III deficiency. Antithrombin III deficiency. Secondary or acquired hypercoagulable states are acquired during life, usually in an individual who is unwell or immobile. Secondary or acquired hypercoagulable states are acquired during life, usually in an individual who is unwell or immobile.

66. The common causes of a secondary hypercoagulable state fall into three main categories: The common causes of a secondary hypercoagulable state fall into three main categories: Venous stasis caused by: Venous stasis caused by: Immobility Immobility Obesity Obesity Congestive cardiac failure Congestive cardiac failure Posteroperative bedrest Posteroperative bedrest Coagulation factor activation caused by: Coagulation factor activation caused by: Malignant disease Malignant disease Pregnancy Pregnancy Oestrogen and oral contraceptive use Oestrogen and oral contraceptive use Nephrotic syndrome Nephrotic syndrome Antiphospholipid syndrome Antiphospholipid syndrome

67. platelet activation caused by: platelet activation caused by: Myeloproliferative disorders Myeloproliferative disorders Thrombotic thrombocytopenic purpura Thrombotic thrombocytopenic purpura Commonly an acute thrombotic episode results in an individual who acquires a hypercoagulable state on the background of a primary hypercoagulability. Commonly an acute thrombotic episode results in an individual who acquires a hypercoagulable state on the background of a primary hypercoagulability.