Bleeding Disorders


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  • The initial fibrin clot, held together by noncovalent bonds, is soluble in urea. Subsequent transglutamination by factor XIII covalently crosslinks overlapping fibrin strands, which then become resistant to solubilization. The ability of 5M urea or monochloroacetic acid to solubilize the clot reflects deficiency of factor XIII
  • Shapiro, A. and Parameswaran, R. (2007) Miscellaneous Rare Bleeding Disorders, in Textbook of Hemophilia (eds C. A. Lee, E. E. Berntorp, W. K. Hoots and L. M. Aledort), Blackwell Publishing Ltd, Oxford, UK. doi: 10.1002/9780470987124.ch58Editor Information1 Professor of Haemophilia, Director and Consultant Haematologist, Haemophilia Centre and Haemostasis Unit, The Royal Free Hospital, London, UK2 Professor of Hemophilia, Lund University;, Director, Department of Coagulation Disorders, Malmö University Hospital, Malmö, Sweden3 Professor of Pediatrics, University of Texas M.D. Anderson Cancer Center;, Professor of Pediatrics and Internal Medicine, University of Texas Medical School at Houston;, Medical Director, Gulf States Hemophilia and Thrombophilia Center, Houston, TX, USA4 The Mary Weinfeld Professor of Clinical Research in Hemophilia, Mount Sinai School of Medicine, New York, NY, USAPublication HistoryPublished Online: 4 OCT 2007 Published Print: 12 JAN 2005ISBN InformationPrint ISBN: 9781405127691Online ISBN: 9780470987124
  • Bleeding Disorders

    1. 1. An Approach to Bleeding DisordersRekha Parameswaran, MD
    2. 2. ObjectivesI. Clinical aspects of bleedingII. Approach to laboratory work-upIII. Hematologic disorders causing bleeding• Coagulation factor disorders:• Platelet disordersIV. Approach to acquired bleeding disorders• Hemostasis in liver disease• Surgical patients• DIC
    3. 3. Objectives - I Clinical aspects of bleeding
    4. 4. OverviewCause of bleeding can be :Localized pathologic process : Postop bleeding consultsDisorders involving vascular integrity : All coag labsand CBC normalDisorders involving platelet number and/orfunction: CBC, Platelet function assay abnormalDisorders of procoagulant factors: PT/PTTabnormalitiesDefects of fibrinolytic pathway :PT, PTT normal
    5. 5. Clinical Features of Bleeding DisordersPlatelet Coagulationdisorders factor disordersSite of bleeding Skin Deep in soft tissuesMucous membranes (joints, muscles)(epistaxis, gum,vaginal, GI tract)Petechiae Yes NoEcchymoses (“bruises”) Small, superficial Large, deepHemarthrosis / muscle bleeding Extremely rare CommonBleeding after cuts & scratches Yes NoBleeding after surgery or trauma Immediate, Delayed (1-2 days),usually mild often severe
    6. 6. PetechiaeDo not blanch with pressure(cf. angiomas)Not palpable(cf. vasculitis)(typical of platelet disorders)Gernsheimer, MD, T., & Frank, MD, M. B. (2006). Thrombocytopenia. Retrieved from
    7. 7. Ecchymoses(typical of coagulationfactor disorders)
    8. 8. Objectives - II Laboratory approach to workup
    9. 9. Coagulation and FibrinolysisPathwaysHolly, MD, J. L. (2007). Cardiometabolic risk syndrome part v: Fibrinolytic dysfunction. Your Life Your Health - The Examiner, Retrievedfrom
    10. 10. Laboratory Evaluation of BleedingOverviewCBC and smear Platelet count ThrombocytopeniaRBC and platelet morphology TTP, DIC, etc.Coagulation Prothrombin time Extrinsic/common pathwaysPartial thromboplastin time Intrinsic/common pathwaysCoagulation factor assays Specific factor deficiencies50:50 mix Inhibitors (e.g., antibodies)Fibrinogen assay Decreased fibrinogenThrombin time Qualitative/quantitativefibrinogen defectsFDPs or D-dimer Fibrinolysis (DIC)Platelet function von Willebrand factor vWDBleeding time In vivo test (non-specific)Platelet function analyzer (PFA) Qualitative platelet disordersand vWDPlatelet function tests Qualitative platelet disorders
    11. 11. Laboratory Evaluation of theCoagulation PathwaysPartial thromboplastin time(PTT)Prothrombin time(PT)Intrinsic pathway Extrinsic pathwayCommon pathwayThrombin timeThrombinSurface activating agent(Ellagic acid, kaolin)PhospholipidCalciumThromboplastinTissue factorPhospholipidCalciumFibrin clot
    12. 12. Thrombin Time Bypasses factors II-XII Measures rate of fibrinogen conversion to fibrin Procedure:– Add thrombin with patient plasma– Measure time to clot Variables:– Source and quantity of thrombin
    13. 13. Causes of prolonged Thrombin Time Hypofibrinogenemia Dysfibrinogenemia
    14. 14. Pre-analytic errors Problems with blue-top tube– Partial fill tubes– Vacuum leak and citrateevaporation Problems with phlebotomy– Heparin contamination– Wrong label– Slow fill– Underfill– Vigorous shaking Biological effects– Hct ≥55 or ≤15– Lipemia, hyperbilirubinemia,hemolysis Laboratory errors– Delay in testing– Prolonged incubation at 37°C– Freeze/thaw deterioration
    15. 15. Initial Evaluation of a Bleeding Patient - 1Normal PT, Abnormal PTTNormal thrombin timeTest for factor deficiency:Isolated deficiency in intrinsic pathway (factors VIII, IX, XI)Multiple factor deficiencies (rare)Repeatwith50:50mix50:50 mix is normal50:50 mix isabnormalTest for inhibitor activity:Specific factors: VIII,IX, XINon-specific (anti-phospholipid Ab)
    16. 16. Initial Evaluation of a Bleeding Patient - 2Abnormal PT, Normal PTTNormal thrombin timeTest for factor deficiency:Isolated deficiency of factor VII (rare)Multiple factor deficiencies (common)(Liver disease, vitamin K deficiency, warfarin, DIC)Repeatwith50:50mix50:50 mix is normal50:50 mix isabnormalTest for inhibitor activity:Specific: Factor VII (rare)Non-specific: Anti-phospholipid (rare)
    17. 17. Initial Evaluation of a Bleeding Patient - 3Abnormal PT, Abnormal PTTNormal or abnormal thrombin timeTest for factor deficiency:Isolated deficiency in common pathway: Factors V, X,Prothrombin, FibrinogenMultiple factor deficiencies (common)(Liver disease, vitamin K deficiency, warfarin, DIC)Repeatwith50:50mix50:50 mix is normal50:50 mix isabnormalTest for inhibitor activity:Specific : Factors V, X, Prothrombin,fibrinogen (rare)Non-specific: anti-phospholipid (common)
    18. 18. Tests are normal-Now what?Factor XIII deficiencyalpha-2-antiplasmin deficiencyPAI-1 deficiencymild factor deficiencyvascular disorders: hereditary hemorrhagictelangiectasia
    19. 19. Initial Evaluation of a Bleeding Patient - 4Normal PT, Normal PTTNormal thrombin timeConsider evaluating for:Mild factor deficiency Monoclonal gammopathyAbnormal fibrinolysis Platelet disorder( 2 anti-plasmin def) Vascular disorderElevated FDPsUreasolubilityNormalAbnormalFactor XIII deficiency
    20. 20. PAI-1 deficiencyAutosomal recessiveGlycoprotein serpin synthesized in liverBleeding in homozygotes with wide spectrum ofclinical symptomsMeasure PAI-1 activity
    21. 21. Alpha-2 AntiplasminAutosomal recessiveSingle chain glycoprotein synthesized in the liverBleeding in homozygotesIntracranial hemorrhage in full term neonatesIntramedullary hematomas of long bonesMeasure alpha 2 antiplasmin levelShapiro, A. and Parameswaran, R. (2007) Miscellaneous Rare Bleeding Disorders, in Textbook of Hemophilia (eds C. A. Lee, E. E.Berntorp, W. K. Hoots and L. M. Aledort), Blackwell Publishing Ltd, Oxford, UK. doi: 10.1002/9780470987124.ch58
    22. 22. Factor XIII deficiency Composed of 2 subunits A and B: A synthesis is in hematopoieticcells and B synthesis in the Liver FXIII-A def is know as Type 2 , FXIII-B def os Type-1(<%5). Associated with delayed bleeding Autosomal recessiveHsieh , L., & Nugent , D. (2008). Factor xiii deficiency. Haemophilia, 14(6), 1190-200. doi: 10.1111/j.1365-2516.2008.01857.x
    23. 23. Rare Clotting Factor DeficienciesWhat are rare clotting factor deficiencies?. (2012, May). Retrieved from
    24. 24. Platelet Function Analyzer 100® Tests primary hemostasis in artificial vessel The PFA-100® system was designed to measure primary hemostasis in vitro byuniquely simulating the in vivo hemodynamic conditions of platelet adhesion,activation and aggregation. Results are of Collagen/Epinephrine and Collagen/ADP Results may distinguish between normal, a drug effect, and inherentplatelet dysfunction
    25. 25. PFA 100Normal Aspirin vWD GlanzmannsThrombastheniaCollagen/Epi Normal Abnormal Abnormal AbnormalCollagen/ADP Normal Normal Abnormal Abnormal Closure Time was abnormal in 64% of patients diagnosed with vWD ascompared to 43% by Bleeding Time. Some studies indicate poor discrimination between normal control andpatients with platelet dysfunction. The best “test” for detection of platelet dysfunction is medical history.
    26. 26. Platelet aggregation assay overview of lab diagnosis in bleeding disorders: Platelet function tests. (2003).Retrieved from
    27. 27. Platelet aggregation patternsModified with permission from: Rodgers, GM. Qualitative platelet disorders and von Willebrands disease. In: Practical Diagnosis of Hematologic Disorders,2nd ed., Kjeldsberg, C, Foucar, K, McKenna, RW, et al. (Eds), ASCP Press, Chicago 1995. Copyright © 1995-2010 American Society forClinical Pathology and ASCP Press.
    28. 28. Vascular DisordersHereditary hemorrhagic telangiectasiascurvyEhlers-Danlos syndrome?Henoch-Schonlein purpurathe un-diagnosable fibrinolytic defect
    29. 29. Coagulation factor deficienciesSummarySex-linked recessive Factors VIII and IX deficiencies cause bleedingProlonged PTT; PT normalAutosomal recessive (rare) Factors II, V, VII, X, XI, fibrinogen deficiencies cause bleedingProlonged PT and/or PTT Factor XIII deficiency is associated with bleeding andimpaired wound healingPT/ PTT normal; clot solubility abnormal Factor XII, prekallikrein, HMWK deficienciesdo not cause bleeding
    30. 30. Objectives - III Approach to acquired bleeding disorders– Hemostasis in liver disease– Acquired thrombocytopenia– Surgical patients– DIC– Warfarin toxicity
    31. 31. Liver Disease and Hemostasis1. Decreased levels of II, VII, IX, X, XI, andfibrinogen except factor VIII ( synthesized invascular endothelial cells and sinusoidal livercells)2. Dietary Vitamin K deficiency (Inadequateintake or malabsortion)3. Dysfibrinogenemia4. Enhanced fibrinolysis (Decreased alpha-2-antiplasmin)5. DIC6. Thrombocytopenia due to hypersplenism
    32. 32. Common clinical conditions associated withDisseminated Intravascular Coagulation Sepsis Trauma– Head injury– Fat embolism Malignancy Obstetrical complications– Amniotic fluid embolism– Abruptio placentae Vascular disorders Reaction to toxin (e.g.snake venom, drugs) Immunologic disorders– Severe allergic reaction– Transplant rejectionActivation of both coagulation and fibrinolysisTriggered by
    33. 33. Thrombocytopenia Many competing causes to consider in setting of multipledrugs and multiple comorbidities in our patients withconcomitant bleeding and thrombosis risks Confusion can prevail : Drug-induced, DIC,HIT, ITP,TTP Arriving at correct diagnosis almost always a process ofexclusion
    34. 34. When do we worry about bleeding?
    35. 35. ThrombocytopeniaImmune-mediatedIdioapthicDrug-inducedCollagen vascular diseaseLymphoproliferative diseaseSarcoidosisNon-immune mediatedDICMicroangiopathic hemolytic anemia
    36. 36. Warkentin, T. E. Hematology 2006;2006:408-414Platelet count nadirs in heparin-induced thrombocytopenia (HIT),quinine-induced immune thrombocytopenic purpura (Q-ITP), andthrombotic thrombocytopenic purpura (TTP) with absentADAMTS-13 activityWarkentin, MD, T. E. (n.d.). Think of hit. American society of hematology, 2006(1), 408-414 . doi:10.1182/asheducation-2006.1.408
    37. 37. Approach to the thrombocytopenic patient History– Is the patient bleeding?– Are there symptoms of a secondary illness? (neoplasm,infection, autoimmune disease)– Is there a history of medications, alcohol use, or recenttransfusion?– Are there risk factors for HIV infection?– Is there a family history of thrombocytopenia?– Do the sites of bleeding suggest a platelet defect? Assess the number and function of platelets– CBC with peripheral smear– Bleeding time or platelet aggregation study
    38. 38. How I begin an approach to suddensevere thrombocytopenia at the bedsideSudden severe dropin platelets <10-20Kwithout hemolysisImmuneDrugsIdiopathic orAutoimmuneSepsis DICTransfusion
    39. 39. Bleeding time and bleeding Essentially an obsolete test
    40. 40. Approach to Post-operative bleeding1. Is the bleeding local or due to a hemostatic failure?1. Local: Single site of bleeding usually rapid with minimalcoagulation test abnormalities2. Hemostatic failure: Multiple site or unusual pattern withabnormal coagulation tests2. Evaluate for causes of peri-operative hemostatic failure1. Preexisting abnormality2. Special cases (e.g. Cardiopulmonmary bypass)3. Diagnosis of hemostatic failure1. Review pre-operative testing2. Obtain updated testing
    41. 41. Approach to bleeding disordersSummary Detailed clinical history will help direct you toidentify a defect of hemostasis– Laboratory testing is almost always needed to establish the cause ofbleeding– Screening tests (PT,PTT, thrombin time, platelet count) will oftenallow placement into one of the broad categories– Specialized testing is usually necessary to establish a specificdiagnosis
    42. 42. SummaryHistory & Physical ExaminationLaboratory tests– screening tests– specific diagnostic testsDiagnosis-specific therapy– Factor replacement– Drugs