Chapter 12 - Disorders Of Hemostasis Flashcards
What are the components of hemostasis? What do they do?
Hemostasis is a multi step process that involves platelets, plasma clotting factors, naturally occurring anticoagulants, and the inherent properties of the endothelial lining of blood vessels
Platelets - thrombocytes, are large fragments from the cytoplasm of bone marrow cells called megakaryoctyes. There are normally 150000 to 400000 platelets in each micro litre of blood with an average platelet life span of 8-9 days. They dont leave the blood as WBC do, but at any times about 1/3 of them are stored into the circulation as needed. Platelet production is controlled by a protein called thrombopoietin that causes proliferation and maturation of megakaryocytes. It is produced in the liver, kidney, smooth muscle and bone marrow. It’s production and released are regulated by the number of platelets in the circulation. They lack a nucleus, the have many of the structural and functional characteristics of a whole cell. The cell membrane plays an important role in platelet adhesion and the coagulation process, is covered with a surface coat of glycocalyx, consisting of glycoproteins, glycosaminoglycans and several coagulation factors absorbed from the plasma.Glycoprotien IIb/IIIa binds fibrinogen and acts to connect platelets together to form large aggregates. Phospholipids, which are also present in the platelet membrane, provide critical binding sites for calcium and coagulation factors in the intrinsic coagulation pathway. The cell membrane is supported by a network of micro tubules, actin filaments, myosin, and actin binding proteins. They are arranged circumferentially and are responsible for maintaining the platelets disk shape. The central part of the platelet contains mitochondria, enzymes needed for synthesis of ATP and prostaglandin thromboxane, glycogen and two specific types of granules that release mediators for hemostasis. The a granules contain fibrinogen, coagulation factors, plasminogen, plasminogen activator inhibitor and platelet derived growth factors they play an important role in platelet aggregation, blood coagulation and the initial phase of vessel repair. The release of growth factors causes vascular prolliferate and grow. The granules or dense granules, mainly contain adenosine DI phosphate ADP, ATP , ionized calcium, serotonin, and histamine, which facilitate platelet adhesion and vasoconstriction at the site of vessel injury.
the coagulation system. It uses plasma proteins that are present as inactive procoagulation factors. Each are identified by Roman numerals, performs a specific step in the coagulation process. the activation of one procoagulant or pro enzyme is designed to activate the next factor in the sequence cascade effect. Because they are present in the blood the multi step process ensures that a massive episode of intravascular clotting does not occur by chance. It means that abnormalities of the clotting process occur when one or more of the factors are deficient or when conditions lead to inappropriate activation of any of the steps. Most are synthesized in the liver. Vitamin K is necessary for the synthesis of factors VII, IX, X prothrombin and proteins C and S. Calcium is required in all but the first two steps of the clotting process. Inactivation of the calcium ion prevents blood from clotting once removed from the body. A clot is not expected to be a permanent solution to vessel injury; thus blood clotting is accompanied by processes designed to control the coagulation cascade and dissolve the clot once bleeding has been controlled.The plasma also contains a plasma protein called plasminogen that gets activated and converted to plasminogen, and enzyme capable of digesting the fibrin strands of the float.
Endothelium - The blood vessels themselves play an important role in preventing and controlling the formation of blood clots. They are lines with endothelial cells that modulate several, frequently opposing stages of normal hemostasis.They normally maintain an environment that promotes blood flow by blocking platelet adhesion and activation, inhibiting the coagulation process, and losing blood clots. An intact surface prevents platelets and plasma coagulation factors from interacting with the underlying thrombogenic subendothelial extracelllular matrix. If platelets are activated, they are inhibited from adhering to the surrounding uninjured endothelium by endothelial prostacyclin and nitric oxide they are both potent vasodilators and inhibitors of platelet aggregation. they also start an enzyme ADP TBW tdegrades and further inhibits platelet aggregation. Endothelial if injured exhibit procoagulant properties in response to injury and activation. An in port at function of activate endothelial cells is the synthesis of con Willebrand factor, which participates in platelets adhesion and blood clotting.
What are the 5 stages of clot formation and dissolution?
1.
During the process of hemostasis, hairlike fibrin strands glue the aggregated platelets together and intertwine to form the structural basis of the blood clot. In the presence of fibrin, plasma becomes gel like and traps RBC and other formed elements in the blood.Hemostasis is complete when fibrous tissue grows into the clot and seals the hole in the vessel.
- Vessel spasm - is initiated by endothelial injury and caused by local and by oral mechanisms. Usually lasting less then one minute, that results from neural reflexes and by oral factors released from platelets and traumatized tissue.
- Formation of the platelet plug - the second line of defence, is initiated as platelets come in contact with the vessel wall. Small breaks are often sealed with a platelet plug instead of a blood clot. It involves adhesion, granule release and aggregation of platelets. They are attached to a damaged vessel wall, become activated, and change from smooth disks to spiny spheres, exposing glycoproteins receptors on their surfaces. Adhesion requires a protein molecule called con Willebrand factor vWF. This factor is produced by both megakaryocytes and endothelial cells and circulates in the blood as a carrier protein for coagulation factor VIII. Adhesion to the vessel subendothelial layer occurs when the platelet membrane receptor binds to vWF at the injury site, linking the platelet to exposed collagen fibers. Degranulation and release of the contents of a and b granules occur soon after. The binding of ADP to the platelet membrane indies a conformation change of the gpIIb/IIIa receptors, allowing them to bind fibrinogen and form aggregation. The combined actions of ADP and TXA2 lead to the expansion of the enlarging platelet aggregate, called the primary hemostatic platelet plug. To convert from plug into clot occurs as the coagulation pathway is activated on the surface of the aggregated platelets and fibrinogen is converted to fibrin, thereby creating a fibrin mesh work that cements the platelets and other blood components together.
- Blood coagulation or development of an insoluble fibrin clot - The coagulation cascade is the third step, it is a stepwise process resulting in the conversion of the soluble plasma protein fibrinogen into insoluble fibrin strands. They create a mesh work that cements platelets and other blood components together to form the clot. The process results from the activation of what have traditionally been designated the intrinsic and the extrinsic pathways. The intrinsic is a slow process, begging in the circulation with the activation of Factor XII Hageman factor. Extrinsic is much faster begins with the trauma to the blood vessel or surrounding tissues and the release of an adhesive lipoprotein called tissue factor from the subendothelial cells.In the presence of calcium, factors V and VII form a complex that’s activates factor X. And the conversion of prothrombin II to thrombin IIa. It then acts as the enzyme to convert fibrinogen I to fibrin Ia the material that stabilzes the clot.
- Clot retraction - normally occurs with 20-60 minutes after a clot has formed, contributing to hemostasis by squeezing serum from the clot and joining the edges of the broken vessel. Platelets, through the action of their actin and myosin filaments, also contribute to clot retraction. Therefore requires large numbers of platelets, and failure of clot retraction is indicative of low platelet count.
- Clot dissolution. - begins shortly after its formation; this allows blood flow to be reestablished and permanent tissue repair to take place is called fibrinolysis. Requires a sequence of steps controlled by activators and inhibitors. Plasminogen, the pro enzyme for the fibrinolytic process, normally is present in the blood in its inactive form. It is converted to it active form, plasmin, by plasminogen activators formed in the vascular endothelium, liver and kidneys. The plasmin formed from plasminogen digests the fibrin strands of the clot and certain clotting factors, such as fibrinogen I, factor V factor VIII, prothrombin II, and factor XII. The most important is tissue type plasminogen activator tPA, which is synthesized principally by endothelial cellls and is most active when attached to fibrin. ANother activator is urokinase type plasminogen activator uPA is present in the tissues and can activate it in the fluid phase.
What is hypercoagulability states? What are the two general forms?
Represents an exaggerated form of hemostasis that predisposes to thrombosis and blood vessel occlusion.
Arterial thrombocytes are usually due to turbulence and composed largely of platelet aggregates, whereas venous thrombosis are usually due to stasis of flow and composed of largely of platelet aggregates and fibrin complexes that result from activation of the coagulation cascade.
- Increased platelet function - Predisposes to platelet adhesion, formation of platelet clots and the disruption of blood flow. The causes of inc platelet function include an inc in platelet count and disturbances in blood flow, damage to the vascular endothelium, and inc sensitivity of platelets to factors that cause adhesiveness and aggregation. Thrombocytosis is used to describe elevations in the platelet count above 1000000 An inc in platelet count can occur as a reactive disorder associated with iron-deficiency anemia, especially in children; splenectomy; cancer; and chronic inflammatory conditions such as rheumatoid arthritis and crohn disease. Usually the only clinically apparent signs are those of the underlying disease. Myeloproliferataive disorders such as poly utube is Vera produce excess platelets that may predispose to thrombosis or paradoxically, bleeding when the rapidly produced platelets are defective. Atherosclerotic plaques disturb blood flow, causing endothelial damage and promoting platelet adherence, Platelets adhere to the vessel wall, release growth factors, cause proliferation of smooth muscle, and thereby contribute to the development of atherosclerosis. Smoking, elevated levels of blood lipids and cholesterol, hemodynamic stress, and diabetes mellitus predispose to vessel damage, platelet adherence, and eventual thrombosis.
What is inc clotting activity? What are inherited disorders and acquired disorders?
Thrombus formation due to activation of the coagulation system can result from primary or secondary disorders affecting the coagulation components of the blood clotting process.
Inherited disorders (primary) Mutation in the factor V and prothrombin genes are the most common. In this the mutant factor Va cant be inactivated by protein C; as a result, an important anti thrombotic counter regulatory mechanism is lost. Approx. 2-5% of Caucasians carry a specific factor V mutation (Leiden mutation). The defect predisposes to venous thrombosis, and among persons with recurrent deep vein thrombosis, and among persons with recurrent deep vein thrombosis, the frequency of the mutation may be as high as 60%. A single nucleotide change in the prothrombin gene, which affects 1-2% of the population, is associated with elevated prothrombin levels and an almost three fold inc in venous thromboses. Another hereditary defect results in high circulating levels of homocysteine, which predisposes to venous and arterial thrombosis by activating platelets and altering antithrombotic mechanisms.
Acquired disorders - multiple conditions often predispose pt to acquired (secondary). Stasis of blood and accumulation of platelets and activated clotting factors are common in situation such as with prolonged bed rest and immobility. Hyperviscosity syndromes and deformed RBC in sickle cell disease inc the resistance to flow and cause small vessel stasis. Hypercoagulability is associated with oral contraceptive use and the hyper estrogen if state of pregnancy, probably related to the inc synthesis of coagulataion factors and reduced synthesis of anti thrombin III. The incidence of stroke , thromboemboli, and myocardial infarction is greater in women who use oral contraceptives and over 35 and smoke. In disseminated cancer, release of procoagulant tumor products predisposes to thrombosis. Smoking and obesity promote hypercoagulability for unknown reasons.
What is antiphospholipid syndrome?
Another cause of inc venous and arterial thrombosis is the syndrome. This condition is associated with a family of autoantibodies directed against several negatively charged phospholipids, causing an inc in coagulation activity. It is unclear how it leads to it but possible explanations include direct platelet activation, endothelial cell activation or injury, or interference with the phospholipids binding proteins involved in the regulation of blood coagulation. Common features include recurrent thrombosis, repeated fetal loss, and thrombocytopenia. Can be primary or secondary condition and is most often associated with systemic lupus.
Clinical manifestations, typically those characterized by reecurrent venous and arterial thrombi. Cardiac valvular vegetation associated with thrombi adherence and thrombocytopenia due to excessive platelet consumption may also occur Venous thrombosis, especially in the deep leg veins, occurs in up to 50% with the syndrome, half of whom develop pulmonary emboli. Arterial thromboses and most frequently manifest with features of ischemia and infarction. The cerebral arteries are the most commonly affected. other sites are coronary arteries of the heart and the retinal, renal and peripheral arteries.
In most the thrombotic events occur as a single episode at one anatomic site. Occassionally, pt may present with multiple vascular occlusion involving many organ systems. Catastrophic antiphospholipid syndrome and has a high mortality rate.
Treatment focuses on the removal or reduction in factors to thrombosis, including smoking estrogen contraceptives. Acute event is treated with anticoagulants and immune suppression in refractory cases. Aspirin and anticoagulant drugs may be used to prevent future thrombosis.
What is bleeding disorders? What are platelet disorders? What is thrombocytopenia?
Bleeding disorders can result from defects in any of the factors that contribute to hemostasis. Bleeding can occur as a result of disorders associated with platelet count, platelet function, coagulation factors, or blood vessel injury.
Platelet disorders - reflects the failure of activated platelets to bring about hemostasis through the formation of a platelet plug at the site of injury to the blood vessel wall,
Thrombocytopenia - refers to a dec in the number of circulating platelets to a level less than 100000 The greater the dec in platelet count, the greater the risk of bleeding. Spontaneous bleeding usually does not occur until the platelet count falls below 20000. The sites are the intercellular junction in the postcapillary venules. Key molecules in the junctions include adhesive proteins and associated intracellular binding components. Different vascular beds with varying functions require different vascular beds with varying functions require different types of junctions. Sites are the skin, mucous membranes of the nose, mouth, GI tract, and uterine cavity. Cutaneous bleeding is seen as purple areas of bruising and pinpoint hemorrhages in dependent areas where the capillary pressure is higher. Petechiae are seen in platelet deficiency, not platelet dysfunction. They are also seen in conditions of poor collagen synthesis and impaired formation of capillary intercellular junctions. Major causes are dec platelet production, decrease platelet survival, splenic sequestration, and dilution. Dec platelet production due to loss of bone marrow function may occur because of congenital anemia, acquired anemia, bone marrow infiltration by malignant cells or bone marrow depression. Reduced platelet survival is caused by a variety of immune and nonimmune mechanisms. Destruction may be caused by antiplatelet antibodies. In acute disseminate I grew secular clotting or thrombotic thrombocytopenia outputs TTP, excessive platelet consumption leads to deficiency.
What is immune thrombocytopenia Purpura? What is drug induced thrombocytopenia? What is thrombotic microangiopathies? What is impaired platelet function?
Is an autoimmune disorder that results in platelet antibody formation and excess destruction of platelets. Is thought to result from multiple mechanisms, including anti platelet antibodies against glycoproteins in the platelet membrane. They are made more susceptible to phagocytosis because of the antibodies and are subsequently destroyed in the spleen. Can be both primary or secondary and acute or chronic. AIDS, lupus, antiphospholipid syndrome, chronic lymphocytic leukemia, lymphoma, hepatitis C and drugs such as heparin and quinidine. ITP in children usually follows a viral infection, in adults is often a chronic disorder and not after a virus. Manifestation - a history of easy bruising, bleeding from the gums epistaxis, melena, and abnormal menstrual bleeding in miserably reduced platelet counts. Splenic enlargement may occur. 1/2 of adults have platelet count of less then 10000 and risk internal hemorrhage. Diagnosis on severe 20000 - 30000 and exclusion of other causes. Treatment depends on platelet count and the degree of bleeding. Use corticosteroids as initial therapy; IV immune globulin. Might require a splenectomy .
Drug induced thrombocytopenia - Some drugs such as quinine, quinidine, and certain shots containing antibiotics may induce thrombocytopenia. These drugs act a halter to induce an antigen antibody response and formation of immune complexes that cause platelet destruction by complement mediated lysis. There is a fall in platelet count 7 or more days after initiating therapy with a given drug for the first time. Usually rise rapidly if drug is discontinued. Heparin has been inc implicated in thrombocytopenia and paradoxically in thrombosis. Discontinuing drug and using a different anticoagulants.
Thrombotic microangiopathies. - encompasses a spectrum of clinical syndromes that include thrombotic thrombocytopenia purpura TTP and hemolytic uremic syndrome. TTP is associated with a combination of manifestations that includes fevers, thrombocytopenia, microangiopathies hemolytic anemia, renal failure, and transient neurological abnormalities. Is widespread formation of hyaline thrombi in the micro circulation that are composed primarily of dense aggregates of platelets surrounded by fibrin. The narrowing of the blood vessels by the platelet rich thrombi results in the microangiopatahic hemolytic anemia. Occurs at any age but most common in women 40-50. Onset is abrupt and can be fatal. Clinical include purpura, petechiae, vaginal bleeding and neurological symptoms ranging from headache to seizures and altered consciousness. Anemia is universal and may be marked. Emergency treatment includes plasmapheresis, involves removal of plasma from withdrawn blood and replacement of fresh frozen plasma. If done complete recovery of 80% of cases. HUS is usually following E. coli infection same treatment as above.
Thrombocytopenia may result from inherited disorders of adhesion (von Willebrand disease) or acquired defects caused by drugs, disease or surgery involving extracorporeal circulation Defective platelet function is also common in uremia, presumably because of non eliminated waste products. The use of aspirin and other NSAIDs is the most common cause of platelet dysfunction Aspirin produces irreversible acetylation of platelet cyclooxygenase activity and consequently the synthesis of TXA which is required for platelet aggregation. The NSAIDs are reversible.
What are coagulation disorders? The inherited disorders? And acquired disorders?
Defects can result from deficiencies or impaired function of one or more of the clotting factors, including vWF. They typically occur after injury or trauma.
Hemophilia A and con Willebrand disease are tow of the most common. They are caused by defects involving the factor VII- vWF complex. VWF is synthesized by the endothelium and megakaryocytes, is required for platelet adhesion to the subendothelial matrix of the blood vessel.
Von Willebrand Disease is a relatively common hereditary bleeding disorder charaacterized by a deficiency or defect in vWF. It is transmitted as an autosomal dominant disorder, but several rare autosomal recessive variants have been identified. Clinical manifestations include spontaneous bleeding from the nose, mouth and GI tract; excessive menstrual flow; and a prolonged bleeding times in the presence of a normal platelet count. It is usually mild and no treatment is needed Desmopressin acetate DDAVP a synthetic analog of the hormone vasopressin is used in treatment during survives and dental procedures.
Hemophilia A. Is an x linked recessive disorder that primarily affects males. A new mutation may have arisen per 30% have no familial tie. 90% produce insufficient quantities and 10% produce a defective form. If severe can bleed in the soft tissues, the GI tract, the hip, knee, elbow and ankle joints. When they begin to walk it causes inflammation of the synovium with acute pain and swelling. Without proper treatment chronic bleeding and inflammation cause joint fibrosis and Cl fractures, leading to disability. The prevention of trauma is important.. Aspirin and NSAID should be avoided. Factor VIII replacement therapy can be prevention rather then after the episode.
Acquired disorders - coagulation factors II, V, VII, IX, X, Xi, and XII prothrombin II and fibrinogen I are synthesized in the liver. In liver disease, synthesis of these clotting factors is reduced, and bleeding may result. they all require vitamin K for normal activity. Vitamin K defiiency can happen to newborns before flora is there and antibotic therapy that destroy intestinal flora. It may also result from impaired fat absorption caused by liver or gallbladder disease.
What is bleeding associated with vascular disorders?
Called nonthrombocytopenic purpura is from a vascular disorders and is relatively common and results in mild bleeding disorders. The may occur because of structurally weak vessel walls or because of damage to vessels by inflammataion or immune responses. they are characterized by easy bruising and the spontaneous apperance of petechiae and purpura of the skin and mucous membranes. The disorders are hemorrhagic telangiectasia, vitamin C deficiency (scurvy), Cushing disease, and senile purpura. Hemorrhagic telangiectasia is an uncommon autosomal dominant disorder that is characterized by thin walled dilated capillaries and arterioles. Vitamin C is a reversible reducing agent that is an essential cofactor for the hydroxylation of proline in collagen synthesis. A severe vitamin C deficiency results in poor collagen synthesis and failure of the capillary cells to be cemented together properly, which in turn causes a fragile vascular wall. Cushing disease causes protein wasting and loss of vessel tissue support because of excess cortisol. Senile purpura is caused by impaired collagen synthesis due to the aging process.
What is disseminated intravascular coagulation?
DIC is a paradox in the hemostatic sequence characterized by widespread coagulation and bleeding. It is not a primary disease but a complication of many different disorders. Begins with massive activation of the coagulation sequence, which leads to fibrin deposition and formation of thrombi in the micorcirculation of the body. The widespread deposition of fibrin leads to tissue ischemia and hemolytic anemia from fragmentation of red cells as they squeeze through the narrowed micorvasculature. A consequence of the thrombotic process, there is consumption of platelets and coagulation factors and the activation of plasminogen that leads to a hemorrhagic diathesis. It can be initiated by activation of the intrinsic or extrinsic pathway or both. Extrinsic occurs with liberation of tissue factors and is associated with obstetric complication, trauma, bacterial sepsis, and cancer. Intrinsic may be activated through extensive endothelial damage, with activation of factor XII. Can be caused by viruses, infections , immune mechanisms, stasis of blood or temp extremes. Impaired anti coagulation pathways are also associated with reduced levels of anti thrombin and the protein C anticoagulant system. Clinical conditions hypoxia, shock, and acidosis that may coexist also contribute by causing endothelial injury. Gram negative bacterial infections that release endotoxins, which activate both pathways. The inhibit the activity of protein C. Although coagulation and formation of microemboli DIC, its acute manifestations usually are. More directly related to the bleeding problems that occur. It may be present as petechiae, purpura, oozing from punter sites, or sever hemorrhage. Micoremboli may obstruct blood vessels and cause tissue hypoxia and necrotic damage to organ structures, So signs may be renal, circulatory, respiratory, or coma and convulsions Treatment is directed toward managing the primary disease, replacing clotting components, and preventing further activation of clotting mechanisms. Transfusion of fresh frozen plasma, platelets or fibrinogen containing cryoprecipitate may correct the clotting factor deficiency. Heparin may be given to dec blood coagulation, it is controversial as risk for hemorrhage may limit its use.
