Heme-bleeding disorders
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dhemmy Plus on January 25, 2012
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148 terms
Terms | Definitions |
|---|---|
 Bleeding from multiple sites | Suggestive of a systemic defect in hemostasis |
| bleeding limited to the skin and mucosal surfaces | Suggests thrombocytopenia or a defect in platelet or von Willebrand factor function (primary hemostasis) |
| Development of oral mucosal blood blisters | Indication of clinically severe thrombocytopenia |
| Deep tissue bleeding | Suggest effect in soluble coagulation factor response (secondary hemostasis) |
| Retroperitoneal bleeding or hemarthrosis | Particularly associated with significant defects in secondary hemostasis |
| signs of bleeding | Excessive or spontaneous bruising nosebleeds (epistaxis) gum bleeding hematemesis hematuria melena menorrhagia |
| Bleeding tendencies not apparent in the absence of challenge | Mild hemophilia and von Willebrand disease |
| Hemostatic challenges | Surgery major trauma tooth extraction |
| Medications that may contribute to bleeding | Aspirin NSAIDs antiplatelet agents-clopidogrel, glycoprotein 2B/3A inhibitors cold remedies herbal remedies alcohol |
| Underlying medical conditions relevant to bleeding | Liver disease and uremia |
| What to look for on physical exam of the skin | Petechiae generalized purpura or ecchymoses perifollicular purpura (scurvy) striae telandiectasia stigmata of the liver including spider angiomas and palmar erythema |
| Prothrombin time | Measures factors involved in the initial phase of coagulation (extrinsic pathway) sensitive to factors VII, X, V, prothrombin, fibrinogen |
| Selective prolongation of the PT with a normal activated partial thromboplastin time | Factor VII deficiency |
| Prolonged prothrombin time and prolonged activated partial thromboplastin time | Factor X and factor V, prothrombin and/or fibrinogen deficiency = deficiencies in the common pathway |
| Prothrombin time test | Thromboplastin reagent is added to citrated plasma and the time required for fibrin clot formation is determined prothrombin time is usually expressed as a ratio-the international normalized ratio or INR |
| INR | Prothrombin time test-extrinsic pathway |
| Thromboplastin reagent contents | Tissue factor, phospholipid, and calcium |
| Activated partial thromboplastin time (aPTT) | Measures factors involved in the propagation phase and contact activation (intrinsic pathway) sensitive to prekallikrein, high molecular weight kininogen, factor XII, factors XI, IX, VIII, X, V, prothrombin, and fibrinogen |
| deficiencies that may prolong the activated partial thromboplastin time but do not cause bleeding | prekallikrein, high molecular weight kininogen, and factor XII |
| Selective prolongation of the aPTT | Occurs with deficiencies of the contact factors, or factors XI, IX, and VIII |
| aPTT test | Activated partial thromboplastin reagent is preincubated with citrated plasma for 3 min. plasma is then recalcified and the time required for fibrin clot formation is determined |
| Activated partial thromboplastin reagent | Phospholipid plus a surface activator such as silica |
| Mixing tests | If a clotting time is prolonged, repeating the test with a 50-50 mixture of patient plasma and normal plasma can assess whether the prolongation is due to clotting factor deficiency or a coagulation inhibitor |
| when you should perform a mixing test | To evaluate a markedly prolonged aPTT |
| Mechanism of the mixing test | Restoration of 30 to 40% normal levels of anticoagulation factor is sufficient to correct it clotting time; so if a single coagulation factor deficiency is present the mixing test will completely correct prolongation of the clotting time. if the coagulation inhibitor is present, mixing what not correct the clotting time. prolonged clotting time due to multiple factors may not be completely corrected by a mixing test |
| Specific factor activity | If the mixing tests completely corrects the prolonged clotting time the missing factor can be identified by mixing the patients plasma with plasma deficient in specific clotting factors whose deficiency might be responsible for the prolonged clotting time. The way this works is that plasma from a patient deficient in factor VIII will shorten clotting times when added to plasma deficient in any factor except for factor VIII |
| Specific factor activity dilutions | Can be used to quantify the amount of deficient clotting factor by comparing results to those obtained from similar mixtures of normal plasma |
| Platelet count required for normal hemostasis | 60,000-80,000 per microliter |
| Platelet morphology | Can help differentiate between peripheral destruction and bone marrow failure |
| Mean platelet volume increase | Often observed when marrow production is increased to compensate for peripheral destruction |
| Methods of testing platelet function | 1. Template bleeding time 2. PFA-100 3. platelet aggregation testing |
| Template bleeding time | Screening test of primary hemostasis done by making a standardized incision into the skin and measuring the time required for bleeding to stop this test is not predictive of surgical bleeding |
| PFA 100 | whole blood is passed through a small glass tube coated with collagen/epinephrine or collagen/ADP at high Shear rates. the time until occlusion of the tube is measured. not predictive of surgical bleeding times |
| Platelet aggregation testing | Detailed assessment of platelet response (aggregation and secretion) to specific platelet agonists used in patients with suspected intrinsic platelet defects not a screening test |
| Renal function tests | Uremia is associated with acquired defect in platelet function |
| ristocetin cofactor activity | Most commonly used test to determine von Willebrand factor activity |
| ristocetin mechanism | Antibiotic that induces a conformational change in von Willebrand factor, triggering binding to platelet Gp Ib and in vitro platelet agglutination |
| Multimer analysis | Used in selected patients to evaluate the size distribution of von Willebrand factor multimers |
| FDP | Fibrin or fibrinogen degradation products |
| D dimer | Specific product that results from plasmin digestion of cross-linked fibrin demonstrates the presence of both Robin and plasmin activity in circulation |
| Fibrinogen level | May be low due to: -congenital deficiency of fibrinogen -liver disease -disseminated intravascular coagulation |
| a2-antiplasmin level | low levels can result from: -genetic deficiency - liver disease - disseminated intravascular coagulation - hyperfibrinolytic states |
| Thrombin time | Performed by addition of thrombin to plasma and measuring the clotting time sensitive to low fibrinogen levels and dysfunctional fibrinogen also sensitive to the presence of heparin |
| factor XIII activity | Screening test is urea clot solubility |
| Single gene defects | Responsible for most inherited bleeding disorders |
| Hemophilia A | Factor VIII deficiency |
| Hemophilia B | Factor IX deficiency |
| Account for 80% of inherited clinical bleeding disorders | Hemophilia B, hemophilia A, von Willebrand disease |
| X-linked bleeding disorders | Hemophilia |
| autosomal dominant bleeding disorder | Von Willebrand disease-most forms |
| Autosomal recessive bleeding disorders | Deficiencies of factors V, VII, X, XI, XIII, and prothrombin do not cause bleeding in the heterozygous state rare |
| Represents 80 to 85% of congenital hemophilia | Hemophilia A/ factor VIII |
| Hemophilia phenotype severity | Depends on specific factor activity |
| Severe hemophilia | <1% activity |
| Moderate hemophilia | 1-5% activity |
| Mild hemophilia | 5-30% activity |
| Characteristics of severe hemophilia | Spontaneous bleeds into joints and deep tissue that require factor replacement on an ongoing basis may develop antibodies against transfused clotting factor |
| Signs of mild hemophilia | May be asymptomatic until challenged by significant trauma or surgery |
| Signs of moderate hemophilia | Minor trauma may lead to symptoms similar to those seen in patients with severe hemophilia |
| Therapy for hemophilia | Specific factor replacement with concentrated factor VIII or IX purified from human plasma and subjected to treatments to inactivate viruses or synthesized using recombinant DNA technology |
| Von Willebrand disease | Collection of disorders in which there is a quantitative or qualitative deficiency of von Willebrand factor usually accompanied by a parallel decrease in factor VIII activity |
| Signs of von Willebrand disease | Generally characterized by mucocutaneous bleeding, but soft tissue/doing tissue bleeding may also be observed in variants associated with severely depressed factor VIII levels |
| Von Willebrand factor affect on factor VIII | Von Willebrand factor acts as a carrier protein that prolongs the plasma half-life of factor VIII fivefold |
| Therapy for type I von Willebrand disease | Administration of DDAVP to stimulate the release of endogenous von Willebrand factor from endothelial cells generally given every 12 to 24 hours for a limited number of doses |
| DDAVP | Desmopression-a vasopressin analog exhibits tachyphylaxis- diminished effects with repeated dosing |
| therapy for forms of von Willebrand with abnormal proteins (type II) or severe forms (type III) | Replacement therapy with clotting factor concentrates that contain the factor VIII-von Willebrand factor complex |
| Type II von Willebrand disease | Qualitative deficiency in von Willebrand factor protein |
| Type III von Willebrand disease | Severe deficiency/quantitative |
| Antifibrinolytic agents/Amicar or tranexamic acid | Useful for mucocutaneous bleeding |
| Glanzmann's thombasthenia | Congenital deficiency of the GP IIb/IIIa complex |
| Hallmark of Glanzmann's thombasthenia | Deficient platelet aggregation in response to multiple agonists - this receptor is critical for the final step in platelet aggregation, the binding of adhesive proteins such as fibrinogen that cross-link platelets |
| Bernard-Soulier syndrome | Congenital deficiency of Gp Ib |
| Hallmark of Bernard-Soulier syndrome | Platelets with the active von Willebrand factor dependent adhesion patients usually have mild thrombocytopenia with large circulating platelets |
| mechanisms of quantitative platelet defects/thrombocytopenia | 1.Decreased production 2. sequestration 3. increased destruction/utilization |
| examples of decreased production of platelets | Congenital primary bone marrow disorders such as leukemia aplastic anemia myelodysplastic syndrome secondary bone marrow suppression due to cite toxic drugs, radiation, viral infection, nutritional deficiencies, marrow replacement by fibrosis, malignancy |
| in most cases of decreased platelet production there is also this | Pancytopenia |
| test performed to evaluate decreased platelet production | Bone marrow biopsy or aspirate |
| characteristic of increased platelet sequestration | Splenomegaly |
| Disorders associated with splenomegaly | Hematologic malignancies like myeloproliferative disease infection secondary enlargement due to liver disease with portal hypertension |
| Splenomegaly effect on platelets | Disorders associated with large spleen result in mild to moderate thrombocytopenia |
| Increased destruction/utilization of platelets | Includes the most common any allergies of thrombocytopenia which include both immune and non-immune mediated mechanisms |
| causes of immune mediated thrombocytopenia | Idiopathic thrombocytopenic purpura drugs autoimmune disease viral infections including HIV |
| causes of nonimmune mediated thrombocytopenia | Sepsis disseminated intravascular coagulation (DIC) thrombotic thrombocytopenic purpura (TTP) |
| Platelet count associated with mild thrombocytopenia | 60,000-150,000 per microliter |
| Platelet count associated with moderate thrombocytopenia | 20,000-50,000 per microliter |
| That account associated with severe thrombocytopenia | <20,000 |
| Bleeding risk associated with mild thrombocytopenia | Does not represent significant hemostatic defect and is generally asymptomatic |
| Bleeding risk associated with moderate thrombocytopenia | Bleeding risk associated with challenge |
| Bleeding risk associated with severe thrombocytopenia | Associated with spontaneous bleeding symptoms |
| Platelet count <10,000 per microliter | Signification risk of life-threatening hemorrhage candidate for prophylactic platelet transfusion |
| Why is decreased production associated with higher risk than increased destruction of platelets? | because in cases of increased instruction the surviving platelets are likely to be younger, larger, and more active due to high turnover rate |
| Most common cause of isolated thrombocytopenia in otherwise healthy people | ITP |
| Autoimmune destruction of platelets in the presence of normal bone marrow production | ITP |
| Diagnosing ITP | Diagnosis of exclusion of other conditions that may cause thrombocytopenia |
| Mechanism of ITP | Antiplatelet autoantibodies often directed at Gp Ib or IIA/IIIB complexes result in antibody and FC dependent platelet destruction by the reticuloendothelial system primarily in the spleen |
| ITP in children | Typically an acute form of the disease following infection that resolves spontaneously in the majority of cases |
| ITP in adults | Chronic relapsing form of ITP usually controlled with therapy spontaneous remissions are unusual |
| ITP and pregnancy | Maternal autoantibody IgG can cross the placenta and cause neonatal thrombocytopenia |
| ITP therapy | Depends on the severity of thrombocytopenia - includes observation in mild cases - glucocorticoids - intravenous immunoglobulin - splenectomy - various forms of immune suppression - synthetic thrombopoietic growth factor |
| drugs that cause drug-induced immune thrombocytopenia | Penicillin or sulfonamide quinine tonic water |
| Mechanism of drug induced immune thrombocytopenia | Drug dependent antibody mediated destruction of platelets similar to drug induced immune hemolysis |
| Drug use during the evaluation of thrombocytopenia | Stop all nonessential drugs |
| Timeline for recovery after stopping offending drug in drug-induced immune thrombocytopenia | 5 to 7 days |
| Microangiopathic hemolytic anemia (MAHA) | Defined by the presence of red blood cell fragmentation (schistocytes) on a blood smear, varying degrees of anemia, elevated LDH, and usually elevated reticulocyte counts |
| Mechanism of MAHA | Physical destruction/shearing of red blood cells due to deposition of rum by in small vessels, or diffuse endothelial injuries |
| thrombocytopenia and microangiopathic hemolytic anemia in the presence of prolonged coagulation times | Suggests DIC |
| Thrombocytopenia and microangiopathic hemolytic anemia in the absence of prolonged coagulation times | Suggests thrombotic thrombocytopenic purpura hemolytic uremic syndrome disease endothelial injury due to malignant hypertension, organ rejection or vasculitis |
| Coagulopathy | Prolonged coagulation time |
| Thrombotic thrombocytopenic purpura | Complication of acquired severe deficiency (<5% activity) of the von Willebrand factor cleaving protease ADAMTS-13 usually caused by the development of autoantibody inhibitors against ADAMTS-13 |
| Acute episodes of TTP | Triggered by infection, pregnancy, medications, or other endothelial injury |
| Circulation of ultra large vWF multimers which predispose to the formation of spontaneous platelet aggregates and the deposition of platelet and vWF rich thrombi in small vessels leading to microangiopathy and organ dysfunction due to ischemia | caused by a deficiency of ADAMTS-13 |
| Characteristics of TTP | Thrombocytopenia MAHA fever organ dysfunction- especially the kidney mental status change and seizures |
| Coagulation assays in TTP | Normal |
| TTP therapy | Includes plasma exchange or plasma infusion with vWF-cleaving protease steroids other immunosuppressive therapy |
| TTP mortality rate before plasma exchange | 90% |
| PPP mortality rate with plasma exchange | 20% |
| Hemolytic uremic syndrome | Kidneys are the dominant organ involved |
| Prodrome of HUS | Bloody diarrhea resulting from infection with enterohemorrhagic bacteria expressing Shiga like toxin especially E. coli 0157:H7 |
| Acquired defects in platelet function | Uremia NSAIDs and aspirin |
| Uremia | Results in defective platelet function |
| Treatment of uremia induced thrombocytopenia | Dialysis-can raise hematocrit to >30% conjugated estrogens DDAVP |
| Mechanism of drug-induced thrombocytopenia | Block thromboxane production by the platelet in a reversible (NSAID) or irreversible (aspirin) fashion causing prolonged bleeding time |
| Aspirin induced antiplatelet effect | Because it irreversibly inhibits Cox 1 effect can last for up to 7 to 10 days/the lifespan of the platelets |
| Other drugs that inhibit platelet function | clopidogrel-Inhibit ADP mediated platelet activation Gp IIb/IIIa antagonists such as abciximab, tirofiban, eptifibatide - which block platelet aggregation by blocking fibrinogen binding |
| Causes of thrombocytosis | Reactive myeloproliferative disorders-essential thrombocythemia postsplenectomy/asplenia iron deficiency |
| Reactive thrombocytosis | Associated with chronic underlying inflammation (rheumatoid arthritis) or major trauma generally no therapy is required |
| postsplenectomy/asplenia thrombocytosis | Associated with Howell Jolly bodies and mild leukocytosis |
| Iron deficiency thrombocytosis | Resolves with replacement therapy |
| Acquired coagulopathies | Vitamin K deficiency liver disease disseminated intravascular coagulation |
| vitamin K | required for the production of prothrombin, factors VII, IX, and X, and the anticoagulant proteins C and S |
| Mechanism for the anti-thrombotic effect of warfarin | Antagonism of vitamin K dependent post-translational modifications of factors VII, IX, X |
| PT and PTT in vitamin K deficiency | Prolonged |
| Conditions associated with vitamin K deficiency | Antibiotic therapy malnutrition biliary obstruction malabsorption syndromes ingestion of warfarin |
| Serious bleeding associated with vitamin K deficiency | Treat with fresh frozen plasma or prothrombin complex concentrate |
| Time it takes for oral or parenteral vitamin K to replete coagulation factors | 2 to 3 days |
| Clotting factors affected by severe liver disease | Most including fibrinogen, prothrombin, and factors V, VII, IX, X, and XI |
| Treatment of bleeding in patients with severe liver disease | Fresh frozen plasma vitamin K replacement does not help |
| Conditions that may complicate acute or chronic liver disease | DIC and hyperfibrinolysis |
| DIC | Syndrome in which from then and plasmin are generated at a rate that exceeds the ability of their natural inhibitors, antithrombin and a2-antiplasmin, to neutralize them usually caused by exposure of blood to excessive amounts of tissue factor |
| DIC mechanism | Thrombin and/or plasmin activity is present in systemic circulation and generation of fibrin and platelet activation occur in a disorganized manner |
| Consequence of excessive systemic generation of thrombin and plasmin in DIC | Consumption of coagulation factors and platelets depletion of inhibitors bleeding deposition of fibrin in small vessels with resulting microangiopathy varying degrees of organ dysfunction |
| Underlined disease is associated with DIC syndrome | Infection solid tumors like adenocarcinomas leukemia obstetric complications acute hemolytic transfusion reactions severe liver disease massive trauma surgery shock |
| Chronic DIC | Particularly common in patients with solid tumors |
| Laboratory findings in DIC | Thrombocytopenia prolonged PT/INR and PTT elevated FTP and D dimer decreased fibrinogen schistocytes |
| Treatment of DIC | Treat the underlying condition replacement of depleted clotting factors with fresh frozen plasma platelet transfusion in severe cases |
| Acquired coagulation inhibitors | Usually circulating immunoglobulins of the IgG class can be alloantibodies that arise spontaneously without pre-existing coagulation defects usually in the elderly |
| Laboratory findings in acquired coagulation inhibition | Failure to correct the prolonged coagulation time in mixing studies |
| Spontaneous coagulation inhibitors | Usually directed against factor VIII-hemophilia A are associated with severe or fatal bleeding |
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