Bleeding Diathesis

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. ExaminationPlatelet DiseaseMucosal/cutaneous bleedingLack 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. ExaminationCoagulation 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 • Platelet count • Bleeding time (BT) • Prothrombin time (PT) • Activated partial thromboplastin time (aPTT) • 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 • 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 • Fibrinogen • Levels are measured by immunologic assays – dysfibrinogenemia • 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 • 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 • 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 • Low platelets -<50,000/micrL(Thrombocytopenia most common acquired Diathesis) • 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 TestUnknown 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