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Bleeding and Thrombotic Disorders
This document discusses bleeding and thrombotic disorders. It provides information on hemostasis, mechanisms of bleeding, key aspects of diagnosis such as history and clinical characteristics. It covers laboratory testing including platelet count, bleeding time, platelet function assay, prothrombin time, activated partial thromboplastin time, thrombin time and tests for fibrinolysis. It also discusses hereditary and acquired causes of bleeding disorders and provides details on specific conditions like hemophilia, von Willebrand disease and treatments.
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Bleeding and Thrombotic Disorders
- 1. Bleeding and ThromboticDisorders DR. RAKESH VERMA
- 2. HEMOSTASIS Primary vs. Secondaryvs. Tertiary • Primary Hemostasis – Platelet Plug Formation – Dependent on normal platelet number & function • Secondary Hemostasis – Activation of Clotting Cascade Deposition & Stabilization of Fibrin • Tertiary Hemostasis – Dissolution of Fibrin Clot – Dependent on Plasminogen Activation
- 4. MEcHAnISMS Of blEEdIng VascularIntegrity Platelets Clotting factors Fibrinolysis Derangement of any of these factors can cause abnormal bleeding
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- 6. Bleeding history Epistaxis Gingival hemorrhage MucosalBleeding Heavy Menses Child birth Easy bruisability Bleeding following tooth extractions Hematomas Bleeding following surgery Hemarthrosis
- 7. Medication History Aspirin Warfarin NSAIDS B- Lactamantibiotics Clopidogrel and other antiplatelet agents Herbal medications.
- 8. Nutritional history Vit Kdeficiency Vit C deficiency Broad spectrum antibiotics
- 9. Clinical Characteristics Platelet disorder Clottingfactor deficiency Site of bleeding Skin, mucous membranes (gingivae, nares, GI and genitourinary tracts) Deep in soft tissues (joints, muscles) Bleeding after minor cuts Yes Not usually Petechiae Present Absent Ecchymoses Small, superficial Large, palpable Hemarthroses, muscle hematomas Rare Common Bleeding after surgery Immediate, mild Delayed, severe
- 10. Petechiae 1-3mm Purpura 3mm-10mm Ecchymosis >10mm
- 11. HErEdITAry Deficiency of coagulationfactors Hemophilia Fibrinogen deficiency Von Willebrand disease Platelet disorders Glanzmann thrombasthenia Bernard-Soulier syndrome Platelet granule disorders Fibrinolytic disorders Alpha 2 antiplasmin deficiency PAI 1 deficiency Structural disorders Hemorrhagic Telangiectasias Ehler Danlos syndrome
- 12. AcquIrEd Thrombocytopenias Liver disease Vit Kdeficiency Acquired antibodies to coagulation factors DIC Drugs Vascular
- 13. lAb TESTIng Platelet count Bleedingtime-Measure of the interaction of platelets with the blood vessel wall. BT raised in Thrombocytopenia (platelet count usually below 50,000/microL), Qualitative platelet abnormalities (eg, uremia), von Willebrand disease (VWD), Vascular purpura, Severe fibrinogen deficiency
- 14. blEEdIng TIME vS.PlATElET cOunT
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- 16. Platelet function assay Exposeplatelets within citrated whole blood to high shear (5,000 to 6,000/sec) within a capillary tube and monitor the drop in flow rate as the platelets form a hemostatic plug within the center of a membrane coated with collagen and either ADP or epinephrine Abnormal closure times are an indication of platelet dysfunction, they are not specific for any disorder The test is coagulation factor independent PFA-100™ is more sensitive (>70 percent) than the bleeding time (20 to 30 percent) in detecting all subtypes of von Willebrand's disease (vWD) Exception is type 2N vWD, in which the hemostatic defect resides in the Factor VIII binding site on vWF
- 17. Platelet function assay Collagen/epinephrineclosure time (CEPI-CT)- Abnormal in Aspirin intake Collagen/adenosine diphosphate (CADT-CT)- Normal in aspirin intake
- 18. Prothrombin time (10-13sec) Measureof the extrinsic pathway and common pathway Bypasses the intrinsic pathway and uses tissue factor in presence of calcium Within the combined pathway, factors VII, X, and prothrombin are vitamin-K dependent and are altered by warfarin
- 20. Prolonged Pt Vitamin Kdeficiency Liver disease, which decreases the synthesis of both vitamin K-dependent and -independent clotting factors. Deficiency or inhibition of factors VII, X, II (prothrombin), V, or fibrinogen Heparin does NOT prolong the PT
- 21. aPtt Measures the intrinsicand common pathways of coagulation Uses partial thromboplastins Prolonged in deficiency of the clotting factors inhibitor to any of the clotting factors except for factor VII deficiency of prekallikrenin, high molecular weight kininogen Lupus Anticoagulant. Used to monitor heparin activity
- 24. thrombin time Measureconversion of fibrinogen to fibrin monomers and the formation of initial clot by thrombin Prolonged in Hypofibrinogenemia Dysfibrinogenenimia Increased fibrin split products (inhibit polymerisation of fibrin monomers) Heparin; increases TT but not Reptilase Time
- 26. factor deficiencies/ inhibitors Aprolonged aPTT can be due to a deficiency (or absence) of a coagulation factor or the presence of a coagulation factor inhibitor Mixing studies helps in differentiation. Patient sample is mixed with normal plasma in 1:1, and if PT or PTT get corrected shows deficiency of factors PT or PTT get corrected partially or uncorrected shows inhibitors Lupus anticoagulants (antibody against phospholipids) can result in a prolonged aPTT that is not correctable by the addition of normal plasma
- 27. fibrinolysis Fibrin and fibrinogen degradationproducts (FDP) are protein fragments resulting from the action of plasmin on fibrin or fibrinogen Activator Inhibitor Pathway
- 28. fibrinolysis FDP assays donot differentiate between fibrin degradation products and fibrinogen degradation products Fibrin D-dimers are degradation products of cross-linked fibrin D-dimers specifically reflect fibrinolysis of cross-linked fibrin (ie, the fibrin clot) – so are more reliable indicators of thrombosis
- 29. Normal PT aNdPTT Thrombocytopenia Factor 13 deficiency Platelet dysfunction Vascular purpuras Psychogenic purpura
- 30. Normal PT aNdProloNged aPTT Hemophilia A Hemophilia B Factor XI deficiency Factor VIII inhibitor Malignancy, Clonal lymphoproliferative disorders, Pregnancy, Rheumatologic disorders Lupus anticoagulant
- 31. ProloNged PT aNdNormal aPTT Factor VII deficiency Warfarin therapy Early liver disease Early DIC
- 32. ProloNged PT aNdPTT Vit K deficiency Liver disease Acquired inhibitor to factor V Factor X deficiency DIC
- 33. HemoPHilia Hemophilia A (85%)and B(10-15%) are X-linked recessive diseases Severe disease -<1 % factor activity; bleeding is often spontaneous Moderate disease - 1 to 5 %; require mild trauma to induce bleeding Mild disease - >5 %; prolonged bleeding after dental work, surgery, or injuries from moderate trauma. The most common sites are into joints and muscles and from the gastrointestinal tract The hallmark of hemophilia is the hemarthrosis
- 34. •Some female carriersof hemophilia A or hemophilia B will have sufficient reduction of their factor VIII or factor IX through lionization of the X chromosome to produce mild bleeding disorders in carriers •In severe hemophilia, APTT is usually two to three times the upper limits. other screening tests platelet count, bleeding time, prothrombin time, and thrombin time are normal. Specific assay for factors will confirm the diagnosis. •Evaluation for inhibitors should also be performed. In such patients the quantitative Bethesda assay for inhibitor should be performed.
- 35. TreaTmeNT The two componentsto therapy are treatment of active bleeding and inhibitor ablation via immune tolerance induction Cryoprecipitate has high levels of factor VIII Porcine Factor VIII Recombinant human Factor VIII A recombinant factor VIIa is for treating factor VIII or factor IX inhibitor patients. The choice of factor VIII product usually is based upon safety, purity, and cost. Prophylaxis is the Standard care of treatment for severe disease Mild hemophilia A - Desmopressin acetate. Desmopressin is ineffective in hemophilia B. The prevention of trauma, avoidence of Aspirin and other nonsteroidal anti-inflammatory drugs.
- 36. dosiNg One international unit(IU) of clotting factor is that amount present in 1 mL of pooled normal plasma Dose of F VIII (IU) = Weight (kg) x (Desired % increase) x 0.5 Dose of F IX (IU) = Weight (kg) x (Desired % increase) x 1.4 Depends on the presence or absence of inhibitors.
- 37. Other clotting factordeficiencies Factor Feature Management Factor XI Haemophilia C deficiency autosomal, deficiency associated with mild to moderate bleeding symptoms FFP Factor V Para-hemophilia mucocutaneous bleeding and hematomas are the most common symptoms, rarely hemarthroses; severe menorrhagia is a frequent symptom in women FFP Factor VII homozygous state, deficiency may have spontaneous intracranial hemorrhage and frequent mucocutaneous bleeding Recombinant factor VIIa Factor X rare autosomal disorder that results in mucocutaneous and post-traumatic bleeding FFP Factor XIII (Fibrin-Stabilizing Factor or Transglutaminase Deficiency) symptoms of delayed hemorrhage, patients will have trauma one day and then develop a bruise or hematoma on the following day. Diagnosed by clot solublility in the presence of 5 M urea FFP or cryoprecipitate Contact factors XII,PK,HMWK Prolong PTT but no bleeding No treatment
- 38. voN WillebraNd’s disease Mostcommon of the inherited bleeding disorders 1% -2% in general population. In 1926, Erik von Willebrand described the disease. Multimeric molecules, synthesises in Platelets’ alpha granules Endothelial cell’s Weibel – Palade bodies Von Willebrand factor (VWF) binds to both platelets and endothelial components, forming an adhesive bridge between platelets and vascular subendothelial structures and between adjacent platelets at sites of endothelial injury
- 40. von Willebrand diseasesubtypes Type Defect Genetic s Bleeding symptoms Response to DDAVP Type 1 (common) Quantitative: Decreased vWF AD Mild Good Type 2 (uncommon) Qualitative: Normal vWF levels 2A vWF not "sticky" enough AD/AR Variable Mild to mod. 2B vWF too "sticky" AD Potentially severe Contraindicated 2M Lacking receptor for platelet binding AD Fairly mild Mild to mod. 2N Lacking receptor for factor VIII binding AR Similar to hemophilia A Mild Type 3 (rare) Absent vWF AR Severe No Response
- 41. Condition Prothrombin timePartialthromboplastin timeBleeding time Platelet count Vitamin K deficiency or warfarin Prolonged Normal or mildly prolonged Unaffected Unaffected Disseminated intravascular coagulation Prolonged Prolonged Prolonged Decreased Von Willebrand disease Unaffected Prolonged or unaffected Prolonged Unaffected Hemophilia Unaffected Prolonged Unaffected Unaffected Aspirin Unaffected Unaffected Prolonged Unaffected Thrombocytopenia Unaffected Unaffected Prolonged Decreased Liver failure, early Prolonged Unaffected Unaffected Unaffected Liver failure, end-stage Prolonged Prolonged Prolonged Decreased Uremia Unaffected Unaffected Prolonged Unaffected Congenital afibrinogenemia Prolonged Prolonged Prolonged Unaffected Factor V deficiency Prolonged Prolonged Unaffected Unaffected Factor X deficiency as seen in amyloid purpura Prolonged Prolonged Unaffected Unaffected Factor XII deficiency Unaffected Prolonged Unaffected Unaffected DIC Prolonged Prolonged Prolonged Decreased Laboratory findings in various platelet and coagulation disorders
- 42. Blood component therapy ComponentConstituent Indications Dose FFP All clotting factors Many coagulation factor deficiency state 15ml/kg (gives 20- 30%) Cryoprecipitate I, VIII, XIII, vWF Corresponding deficiencies 30ml/kg Random donor plateletI (RDP) Platelet atleast 5.5x1010 Thrombocytopenia 1unit/10kg Raise 30,000- 50,000/cumm Single donor platelet (SDP) Platelet atleast 3x1011 Thrombocytopenia 1 collection equals 6RDP Whole blood All Acute blood loss Severe trauma
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- 44. IdIopathIc (autoImmune) thrombocytopenIc purpura Themost common cause for acute onset of thrombocytopenia in an otherwise well child
- 45. Presentation •1-4 yr child •Suddenonset of generalized petechiae and purpura. •leeding from the gums and mucous •Splenomegaly is rare •Chronic ITP or thrombocytopenia may be manifestation of a systemic illness such as SLE. Investigations •Severe thrombocytopenia •Platelet size is normal or increased •Prolong bleeding time •Hb, WBC, DLC can be normal •Normal or increased numbers of megakaryocytes Management •70-80% with acute ITP, spontaneous resolution will occur within 6 mo •Platelet transfusion •Intravenous immunoglobulin - dose of 0.8-1 g/kg/day × 1-2 days •Prednisone. •IV Anti- D Therapy
- 46. WELLWELL Decrease synthiesis •TAR •Wiskott Aldrich •X- linked Amegakayocyte •Toxins •Radiations Decrease synthiesis •TAR •WiskottAldrich •X- linked Amegakayocyte •Toxins •Radiations Consumption •ITP •Secondary to SLE •drug induced •Maternal ITP •NATP •2B vWD Consumption •ITP •Secondary to SLE •drug induced •Maternal ITP •NATP •2B vWD Large platelet Normal Hb & WBC Large platelet Normal Hb & WBC Small platelet Increase MCV Congenital anomalies Small platelet Increase MCV Congenital anomalies chIldhood thrombocytopenIa Differential diagnosis
- 47. IllIll Decrease synthiesis Malignancy Storage disorder Decrease synthiesis Malignancy Storage disorder Consumption HUS TTP Thombosis Sepsis Consumption HUS TTP Thombosis Sepsis DecreaseFibrinogen Increase FDPs Large platelet Decrease Fibrinogen Increase FDPs Large platelet Small platelet Hepato-spleenomegaly Small platelet Hepato-spleenomegaly Sequestration Haemangioma Hyperspleenism Sequestration Haemangioma Hyperspleenism MassMass chIldhood thrombocytopenIa Differential diagnosis
- 48. Feature HUS TTP Ageusually <3 yr usually 3rd decade Gender M=F F>M Prodrome infection, diarrhea less common Recurrence rare common Diagnosis Triad: Acute renal failure, thrombocytopenia, microangiopathic anemia. Pentad: CNS disturbance, thrombocytopenia, microangiopathic anemia, renal dysfunction, fever. Etiologic factors E. Coli (verotoxin), Shigella gastroenteritis, pneumococcus Pregnancy, autoimmune disease, malignancy, drugs. Decrease ADAM-TS Treatment Renal dialysis, corticosteroids do not help, transfuse only if necessary. Plasma exchange, corticosteroids, avoid transfusions. Prognosis Good Poor mIcroangIopathIc haemolytIc anemIa
- 49. Congenital Abnormalities ofPlatelet Function Condition Platelet aggregation studies Platelet count Other Glanzmann thrombasthenia Abnormal to all agonists Normal Bernard-Soulier syndrome Abnormal to ristocetin Decreased Giant platelets. Storage pool defect 1.Dense body deficiency 2.Gray platelet syndrome Abnormal 2nd phase of aggregation Normal Abnormal platelet granules on electron microscopy ASA/NSAID Abnormal COX or Tx synthase Abnormal to arachidonic acid and abnormal secondary aggregation to ADP and epinephrine Normal Drug induced enzyme effect inhibiting platelet granule release. This is the most common cause of platelet dysfunction. Managment Desmopressin platelet transfusions recombinant factor VIIa stem cell transplants
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- 52. A hereditary predispositionto thrombosis can be caused by deficiencies of the regulatory proteins: •Protein C •Protein S •Antithrombin III •Plasminogen; •Factor V Leiden •Prothrombin mutation (G20210A) •Homocystinuria. •Lipoprotien (a) Investigations no screening tests specific testing is required for each component family history Genetic DNA testing for factor V Leiden and the prothrombin mutation Treatment Fresh frozen plasma Protein C concentrate, Warfarin
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- 54. A conditions resultingin consumption of clotting factors, platelets, and anticoagulant proteins. Causing widespread intravascular deposition of fibrin leading to tissue ischemia and necrosis, a generalized hemorrhagic state, and hemolytic anemia. Clinical Manifestations. Bleeding frequently occurs from venipuncture or surgical incision. Petechiae and ecchymoses. Infarction of skin, subcutaneous tissue, or kidneys. Anemia caused by microangiopathic hemolytic anemia. Lab prolongation of the PT, PTT and TT. Platelet counts may be profoundly depressed. Smear shows fragmented, burr, and helmet-shaped, schistocytes. FDPs, D-dimers elevated (The D-dimer is more specific for activation of coagulation and fibrinolysis than the FDP ) Treatment – two steps (1) treat the trigger that caused the DIC (2) restore normal homeostasis by correcting the shock, acidosis, and hypoxia that usually complicate the DIC Blood components In DIC associated with sepsis, activated protein C (APC) drotrecogin alpha can be given Heparin in patient who have vascular thrombosis