1. Bleeding Diathesis INTRODUCTION Shirazi MH 1/12/2009 K&CH

2. Definition An unusual susceptibility to bleeding Or A disruption of the haemostatic mechanism Or Bleeding that is spontaneous or following tissue injury resulting from local, haematosis abnormalities or fibrinolysis

3. The Normal Clotting Cascade

4. The Normal Clotting Cascade Categorised

5. Cause – Bleeding Diathesis Acquired Anticoagulation with warfarin / heparin Liver failure / Vitamin K deficiency / DIC Snake venom e.g Rattle snake, viper Viral hemorrhagic fever Leukemia Autoimmune Acquired antibodies to coagulation factors Inhibitor directed –Against Factor VIII –Antiphospholipid Genetic Lack of coagulation factor protien producing genes –Haemoplilia (VIIIA, IXB deficiency) –Von willebrand (protein regured for platlet adhesion) –Bernard souller (GpIb), the receptor for vWF) –Wiskott Aldrich (autoimmune haemolytic anaemia-defects in homeostasis) –Glenzmann thromasthenia (platelets lack GP IIb/IIIa. Hence, no fibrinogen bridging

6. Clinical Diagnosis –History To identify presence of condition »History of transfusion »Menorrhagia, Metrorrhagia (15-20 % vWD, immune thrombocytopenic purpura, platelet function defect) »Anaemia »Response to trauma –(excellent screening for inherited hemorrhagic disorder) To identify possible cause –Inherited (Report little bleeding) »Bleeding shortly after birth/During childhood »Positive family history (30-40% haemophilic a –Ve History) »Consistent genetic pattern –Acquired (exaggerated tendency to bleed) »Dietary habits »Antibiotic use »Medication Aspirin (Beta lactamase antibiotics, NSAID,Clopidogrel,Ticloidine,Warfarin) »Thyroid, liver, and kidney disease To rationalise laboratory investigation –Examination

7. Examination Platelet Disease Mucosal/cutaneous bleeding Lack vessel protection by submucosal tissue Bleed immediately after vascular trauma –Petechiae From small capillary In areas of increased venous pressure (dependent parts of the body) Asymptomatic and not palpable D/D small telangiectasias (Angiomas, Vasculitic purpura, Wiskott-Aldrich Syndrome, Leukaemia, Vit K deficiency –Purpura Characteristically purple in colour Small, multiple, and superficial in location Develop without noticeable trauma / not spread into deeper tissues Seen in – (Acute / Chronic leukaemia, Vitamin K deficiency)

8. Examination Coagulation Disorders –Ecchymoses Large palpable ecchymoses Spreading into deep tissue - haematomas – Hemarthrosis- severe coagulation disorder- haemophilia Coagulation disorder bleeding onset may be delayed after surgery

9. Laboratory Test General screening tests 1.Platelet count 2.Bleeding time (BT) 3.Prothrombin time (PT) 4.Activated partial thromboplastin time (aPTT) 5.Thrombin time (TT) Other / Specific tests –Coagulation factor assays –Assessment of factor XIII activity via clot solubility testing. –Tests of fibrinolysis –Measurement of fibrin split - D-dimer levels –Alpha-2-antiplasmin activity –Euglobulin clot lyses time –Tissue Plasminogen activator –Plasminogen activator inhibitor-1 antigens –etc

10. Understanding The Screening Test 1 - Platelet Counting –Detect quantitative/ qualitative (Uraemia) platelet abnormalities –Platelet function analyzer (PFZ-100) –Peripheral smear –Platelet release essays

11. 2 - Bleeding Time –Prolonged bleeding time Interaction of platelets with vessel wall Thrombocytopenia below 50,000/microL, von Willebrand disease (VWD) Vascular Purpura Severe fibrinogen deficiency Acquired –Aspirin/ Clopidogrel

12. 3 - Prothrombin Time –Production of fibrin via the extrinsic pathway and final common pathway –Requires Tissue thromboplastin (tissue factor) Factor VII (extrinsic pathway) Factors X, V Prothrombin (factor II) Fibrinogen –The test bypasses the intrinsic pathway Thromboplastin : platelets Factors VII, X, and II require vitamin-K - altered by warfarin

13. 4 - Activated Partial Thromboplastin Time –Measures the intrinsic and common pathways of coagulation Deficiencies of all coagulation factors (Except VII and XIII) No Thromboplastin Heparin assessment

14. 5 - Thrombin Time Thrombin Time and Reptilase Time –Measure common pathway conversion of fibrinogen to fibrin –The formation of initial clot by thrombin and reptilase –Prolonged due to »Hypofibrinogenemia »Heparin »structurally abnormal fibrinogens (dysfibrinogens) –Heparin prolongs the TT not the RT (helps determining if heparin is the cause of prolonged TT)

15. Other/Specific Tests 1.Coagulation Factor Tests (How Identified) –Deficiency / Inhibitor of a coagulation factor –Correctable by addition of normal plasma to patient plasma for tested (1:1) –Immunologic assays also used to measure factor levels –Antibodies suspected when test does not or partially corrects 2.Fibrinogen –Levels are measured by immunologic assays – dysfibrinogenemia 3.Urea clot solubility –initial fibrin clot is non-covalent bonded and soluble in urea –Factor XIII creates covalently cross links fibrin - resistant to solubilisation with urea 4.Tests for fibrinolysis –Fibrin / fibrinogen degradation products (FDP)- plasmin - fibrin or fibrinogen –Do not differentiate between fibrin / fibrinogen degradation products- Possible ELISA –Quantitative FDP levels - more sensitive than D-dimer levels as indicator of degree of fibrinolytic activity 5.More specific tests of the fibrinolytic system –Tissue plasminogen activator (t-PA) –Alpha-2 antiplasmin –Plasminogen activator inhibitor-1 (PAI-1) –Thrombin-activatable fibrinolysis inhibitor (TAFI).

16. Diagnostic Approach Diagnosing Bleeding Diathesis –Mostly apparent from history and physical examination –Confirmed with the appropriate specific tests –When not apparent Screen with – Platelet Count – PT and aPTT

17. Interpreting Screening Results 1.Low platelets -<50,000/micrL(Thrombocytopenia most common acquired Diathesis) 2.Normal Platelet Count and PT, aPTT + mucocutaneous bleeds Platelet dysfunction –Qualitative disorders –Morphology –Aggregation/Function –Common acquired causes of dysfunction »Aspirin, NSAID, Beta-lactam antibiotics »Uraemia »myeloproliferative and myelodysplastic syndromes. –Uncommon causes of dysfunction »Bernard-Soulier syndrome »Glanzmann's thrombasthenia Platelet aggregation »Wiskott-Aldrich syndrome von Willebrand's disease (vWD) –XIII Other disorders –Factor XIII deficiency (Bleeding delayed by 24-36hr) –alpha-2 antiplasmin deficiency - plasminogen activator inhibitor-1 deficiency

18. Interpreting Screening Results Normal PT and APTT +Prolonged BT –Vascular purpura –Screening tests are usually normal in bleeding disorders of vascular tissue abnormalities –Include Hereditary hemorrhagic telangiectasia Ehlers-Danlos disease Osteogenesis imperfecta Scurvy Steroid-induced purpura Small vessel vasculitis Purpura associated with the presence of paraproteins

19. Interpreting Screening Results Normal PT and Prolonged aPTT Disorders intrinsic pathway of coagulation – Inherited disorders hemophilia A, von Willebrand disease, IX (hemophilia B), and XI. Hemophilia A and B –Life-long recurrent soft tissue and joint bleeding –Frequent replacement therapy –Factor XI deficiency presents with a variable and unpredictable bleeding commonly seen following surgery –Disorders prolonging aPTT not associated with excessive bleeding Factor XII deficiency Prekallikrein High molecular weight kininogen –rheumatologic disorders

20. Diagnostic Approach Screening Results Prolonged PT and Normal aPTT –An indicative of an abnormality in the extrinsic pathway –(factor VII deficiency) Manifestations - no excessive bleeding to a severe hemorrhagic tendency Acquired inhibitors of factor VII –Warfarin therapy –Early liver disease –Vitamin K deficiency –Early cases of DIC.

21. Interpreting Screening Results Prolonged PT and aPTT –Disorder Inherent common pathway Mucocutaneous bleeding - Abate with age Low fibrinogen level Deficiency factor X, factor V, Prothrombin –Treatable with fibrinogen replacement –Disorder Acquired common pathway Supratherapeutic warfarin / heparin- thromboembolic disease Vitamin K deficiency (Factor II, VII,IX and X) –Liver disease –DIC, Fibrinolysis Evaluation prolonged PT and aPTT –Exclude or identify abnormality of fibrinogen –Deficiencies of factor V, factor X, and prothrombin (specific factor assays). –Acquired inhibitors to prothrombin and factor X

22. Diagnostic Approach screening Test Unknown cause Some patients are encountered with a significant bleeding history for which there is no explanation –self-inflicted –some disorders of haemostasis escape detection with currently available methods –Psychogenic purpura may be among these disorders Gardener Diamond Syndrom –Other acquired antibodies Antiphospholipid antibodies Autoerythrocyte sensitization, painful bruising syndrome Antibodies to factor VIII (acquired hemophilia), IX, and XI Malignancy Clonal lympho-proliferative disorders Pregnancy

23. Speak to Haematology