Approach to Bleeding Diathesis Dr.Nalini K Pati MD, DNB, DCH (Syd), FRCPA Paediatric Haematologist Royal Children’s Hospital Melbourne Australia Objectives Objectives - I I. Clinical aspects of bleeding Clinical aspects of bleeding II. Hematologic disorders causing bleeding • Coagulation factor disorders • Platelet disorders III. Approach to acquired bleeding disorders • Hemostasis in liver disease • Surgical patients • Warfarin toxicity IV. Approach to laboratory abnormalities • Diagnosis and management of thrombocytopenia V. Drugs and blood products used for bleeding Clinical Features of Bleeding Disorders Petechiae Platelet Coagulation (typical of platelet disorders) disorders factor disorders Site of bleeding Skin Deep in soft tissues Mucous membranes (joints, muscles) (epistaxis, gum, vaginal, GI tract) Petechiae Yes No Ecchymoses (“bruises”) Small, superficial Large, deep Hemarthrosis / muscle bleeding Extremely rare Common Do not blanch with pressure Bleeding after cuts & scratches Yes No (cf. angiomas) Bleeding after surgery or trauma Immediate, Delayed (1-2 days), usually mild often severe Not palpable (cf. vasculitis) Ecchymoses (typical of coagulation factor disorders) Objectives - II Hematologic disorders causing bleeding – Coagulation factor disorders – Platelet disorders Coagulation factor disorders Hemophilia A and B Inherited bleeding Acquired bleeding Hemophilia A Hemophilia B disorders disorders Coagulation factor deficiency Factor VIII Factor IX – Hemophilia A and B – Liver disease – vonWillebrands disease – Vitamin K Inheritance X-linked X-linked recessive recessive – Other factor deficiencies deficiency/warfarin overdose Incidence 1/10,000 males 1/50,000 males –DIC Severity Related to factor level <1% - Severe - spontaneous bleeding 1-5% - Moderate - bleeding with mild injury 5-25% - Mild - bleeding with surgery or trauma Complications Soft tissue bleeding Hemarthrosis (acute) Hemophilia Clinical manifestations (hemophilia A & B are indistinguishable) Hemarthrosis (most common) Fixed joints Soft tissue hematomas (e. g., muscle) Muscle atrophy Shortened tendons Other sites of bleeding Urinary tract CNS, neck (may be life-threatening) Prolonged bleeding after surgery or dental extractions HISTORY Bleeding history Forms the basis of the diagnosis Establishing symptoms and therapy of hemorrhagic disorders. A Lead to differential diagnosis HISTORY DOCUMENTING HISTORY Repeated visits to other physicians Epistaxis Previous need for transfusion of - Whole blood Gingival haemorrhage - Packed cells Petechae / bruise - Plasma Tooth extractions - Platelets Documented anemia & prescription Veni Puncture site bleeding DOCUMENTING HISTORY Contd., Hemoptysis Bleeding from minor / major cuts Hematemesis Previous surgical procedure - Excessive bleeding Hematuria - Needed transfusion - Re operation Hematochezia - Wound healing Bleeding at circumcision Melena MENSTRUAL HISTORY CNS bleeding Frequency Duration Ophthalmic bleeding Compared to Peers Hemarthrosis Required transfusions Local causes CHILD BIRTH Neonatal history Pregnancies Spontaneous / Induced abortions Estimated blood loss Medicines Documented anaemia Required Dietary history . Transfusion . D & C . Hysterectomy Family history / pedigree chart . Iron therapy EXAMINATION Age Sex General Examination Systemic examination THROMBOCYTOPENIA THROMBOCYTOPENIA Contd., Other differential diagnosis must be considered - Additional laboratory abnormalities Congenital WBC - abnormal cells, neutropenia . Is the history since birth RBC - Macrocytosis, Fragmentation . IbldiIs bleeding worse th an count - Are there additional clinical feat ures . Is there a family history Lymphadenopathy, splenomegaly Bone pain, Limping . Are there any physical Sick child congenital abnormalities *In the presence of above findings consider marrow examination Treatment of hemophilia A Intermediate purity plasma products Underlying disorders – Virucidally treated -SLE – May contain von Willebrand factor . Auto antibody screen - ANF High purity (monoclonal) plasma products and ds DNA – Virucidally treated Anti-phospholipid syndrome – No functional von Willebrand factor HIV infection Recombinant factor VIII – Virus free/No apparent risk – No functional von Willebrand factor Dosing guidelines for hemophilia A Mild bleeding – Target: 30% dosing q8-12h; 1-2 days (15U/kg) – Hemarthrosis, oropharyngeal or dental, epistaxis, hematuria Major bleeding – Target: 80-100% q8-12h; 7-14 days (50U/kg) – CNS trauma, hemorrhage, lumbar puncture – Surgery – Retroperitoneal hemorrhage – GI bleeding Adjunctive therapy – ε-aminocaproic acid (Amicar) or DDAVP (for mild disease only) Complications of therapy Viral infections in hemophiliacs Formation of inhibitors (antibodies) – 10-15% of severe hemophilia A patients HIV -positive HIV-negative (n=382) (n=345) – 1-2% of severe hemophilia B patients 53% 47% Hepatitis serology % positive % negative Viral infections – Hepatitis B Human parvovirus Negative 1 20 Hepatitis B virus only 1 1 – Hepatitis C Hepatitis A Hepatitis C virus only 24 45 – HIV Other Hepatitis B and C 74 34 Blood 1993:81;412-418 Treatment of hemophilia B von Willebrand Disease: Clinical Features Agent von Willebrand factor – Synthesis in endothelium and megakaryocytes – High purity factor IX – Forms large multimer – Recombinant human factor IX – Carrier of factor VIII – AhAnchors p late lets to su bdhlibendothelium Dose – Bridge between platelets – Initial dose: 100U/kg Inheritance - autosomal dominant – Subsequent: 50U/kg every 24 hours Incidence - 1/10,000 Clinical features - mucocutaneous bleeding Laboratory evaluation of Understanding of VWD von Willebrand disease Classification – Type 1 Partial quantitative deficiency – Type 2 Qualitative deficiency – Type 3 Total quantitative deficiency Diagnostic tests: vonWillebrand type Assay 1 2 3 vWF antigen ⇓ Normal ⇓⇓ vWF activity ⇓⇓⇓⇓ Multimer analysis Normal Normal Absent Treatment of von Willebrand Disease Vitamin K deficiency Cryoprecipitate Source of vitamin K Green vegetables – Source of fibrinogen, factor VIII and VWF Synthesized by intestinal flora – Only plasma fraction that consistently contains VWF multimers Required for synthesis Factors II, VII, IX ,X Protein C and S DDAVP (deamino -8-arginine vasopressin) – ↑ plasma VWF levels by stimulating secretion from endothelium Causes of deficiency Malnutrition – Duration of response is variable Biliary obstruction Malabsorption – Not generally used in type 2 disease Antibiotic therapy – Dosage 0.3 µg/kg q 12 hr IV Treatment Vitamin K Factor VIII concentrate (Intermediate purity) Fresh frozen plasma – Virally inactivated product Common clinical conditions associated with Disseminated Intravascular Coagulation (DIC) Disseminated Intravascular Coagulation Mechanism Activation of both coagulation and fibrinolysis Systemic activation Triggered by of coagulation Sepsis Obstetrical complications – Amniotic fluid embolism Trauma – Abbupopaceruptio placent ae – Head injury Intravascular Depletion of platelets Vascular disorders – Fat embolism deposition of fibrin and coagulation factors Reaction to toxin (e.g. Malignancy snake venom, drugs) Immunologic disorders Thrombosis of small Bleeding – Severe allergic reaction and midsize vessels – Transplant rejection with organ failure Pathogenesis of DIC Release of thromboplastic material into Consumption of circulation coagulation factors; Coagulation Fibrinolysis presence of FDPs ↑ aPTT ↑ PT Fibr inogen ↑ TT Thrombin Plasmin ↓ Fibrinogen Presence of plasmin Fibrin ↑ FDP Monomers Fibrin(ogen) Degradation Intravascular clot Products ↓ Platelets Fibrin Schistocytes Clot (intravascular) Plasmin Laboratory Evaluation of DIC Laboratory Evaluation of DIC- I 1. ASSESS DEPLETION OF COAGULATION • Assess Depletion Of Coagulation Factors FACTORS • PLATELET COUNT 2. ASSESS FIBRINOLYSIS • PROTHROMBIN TIME • PARTIAL THROMBOPLASTIN TIME 3. BLOOD FILM FOR MICRO-ANGIOPATHY • THROMBIN TIME • FIBRINOGEN Laboratory Evaluation of DIC-II Laboratory Evaluation of DIC-III Tests Of Fibrinolysis • Prothrombin activation peptide [Fl.2] CLOT LYSIS • Thrombin anti-thrombin complexes EUGLOBIN LYSIS TIME FIBRIN PLATE LYSIS • AT III levels PARA-COAGULATION FDP These tests are not available for routine D DIMER clinical management. Disseminated Intravascular Coagulation Treatment approaches Classification of platelet disorders Quantitative disorders Qualitative disorders Treatment of underlying disorder – Abnormal distribution – Inherited disorders Anticoagulation with heparin – Dilution effect (rare) – AiddidAcquired disorders Platelet transfusion – Decreased production » Medications Fresh frozen plasma – Increased destruction » Chronic renal failure » Cardiopulmonary bypass Coagulation inhibitor concentrate (ATIII) Thrombocytopenia Approach to the thrombocytopenic patient History Immune-mediated – Is the patient bleeding? Idioapthic – Are there symptoms of a secondary illness? (neoplasm, infection, autoimmune disease) Drug-induced – Is there a history of medications, alcohol use, or recent Collagen vascular disease transfusion? Lymphoproliferative disease – Are there risk factors for HIV infection? Sarcoidosis – Is there a family history of thrombocytopenia? – Do the sites of bleeding suggest a platelet defect? Non-immune mediated DIC Assess the number and function of platelets Microangiopathic hemolytic anemia – CBC with peripheral smear – Bleeding time or platelet aggregation study Bleeding time and