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Bleeding Disorders review Jittiporn purattanamal ,MD. MHJ hosp. HEMOSTASIS 1. VASCULAR PHASE 2. PLATELET PHASE 3. COAGULATION PHASE 4. FIBRINOLYTIC PHASE Lab Tests Hemostasis •CBC-Plt •BT,(CT) •PT •PTT BV Injury Tissue Factor Neural Blood Vessel Constriction Platelet Aggregation Coagulation Cascade Primary hemostatic plug Reduced Platelet Activation Blood flow Fibrin formation Plt Study Stable Hemostatic Plug Morphology Function Antibody NORMAL CLOTTING Response to vessle injury 1. Vasoconstriction to reduce blood flow 2. Platelet plug formation (von willebrand factor binds damaged vessle and platelets) 3. Activation of clotting cascade with generation of fibrin clot formation 4. Fibrinlysis (clot breakdown) CLOTTING CASCADE Normally the ingredients, called factors, act like a row of dominoes toppling against each other to create a chain reaction. If one of the factors is missing this chain reaction cannot proceed. VASCULAR PHASE WHEN A BLOOD VESSEL IS DAMAGED, VASOCONSTRICTION RESULTS. PLATELET PHASE PLATELETS ADHERE TO THE DAMAGED SURFACE AND FORM A TEMPORARY PLUG. COAGULATION PHASE THROUGH TWO SEPARATE PATHWAYS THE CONVERSION OF FIBRINOGEN TO FIBRIN IS COMPLETE. THE CLOTTING MECHANISM INTRINSIC Collagen XII XI EXTRINSI C Tissue Thromboplastin VII IX VIII X FIBRINOGE (I) N V PROTHROMBIN (II) THROMBIN (III) FIBRIN FIBRINOLYTIC PHASE ANTICLOTTING MECHANISMS ARE ACTIVATED TO ALLOW CLOT DISINTEGRATION AND REPAIR OF THE DAMAGED VESSEL. HEMOSTASIS DEPENDENT UPON: Vessel Wall Integrity Adequate Numbers of Platelets Proper Functioning Platelets Adequate Levels of Clotting Factors Proper Function of Fibrinolytic LABORATORY EVALUATION PLATELET COUNT BLEEDING TIME (BT) PROTHROMBIN TIME (PT) PARTIAL THROMBOPLASTIN TIME (PTT) THROMBIN TIME (TT) PLATELET COUNT NORMAL 100,000 - 400,000 CELLS/MM3 < 100,000 Thrombocytopenia Mild Thrombocytopenia 50,000 - 100,000 Sev Thrombocytopenia < 50,000 BLEEDING TIME PROVIDES ASSESSMENT OF PLATELET COUNT AND FUNCTION NORMAL VALUE 2-8 MINUTES PROTHROMBIN TIME Measures Effectiveness of the Extrinsic Pathway Mnemonic - PET NORMAL VALUE 10-15 SECS PARTIAL THROMBOPLASTIN TIME Measures Effectiveness of the Intrinsic Pathway Mnemonic - PITT NORMAL VALUE 25-40 SECS THROMBIN TIME Time for Thrombin To Convert Fibrinogen Fibrin A Measure of Fibrinolytic Pathway NORMAL VALUE 9-13 SECS So What Causes Bleeding Disorders? VESSEL DEFECTS PLATELET DISORDERS FACTOR DEFICIENCIES OTHER DISORDERS ? ? VESSEL DEFECTS VITAMIN C DEFICIENCY BACTERIAL & VIRAL INFECTIONS ACQUIRED & HEREDITARY CONDITIONS Vascular defect - cont. Infectious and hypersensitivity vasculitides - Rickettsial and meningococcal infections - Henoch-Schonlein purpura (immune) PLATELET DISORDERS THROMBOCYTOPENIA THROMBOCYTOPATHY THROMBOCYTOPENIA INADEQUATE NUMBER OF PLATELETS THROMBOCYTOPATHY ADEQUATE NUMBER BUT ABNORMAL FUNCTION THROMBOCYTOPENIA DRUG INDUCED BONE MARROW FAILURE HYPERSPLENISM OTHER CAUSES OTHER CAUSES Lymphoma HIV Virus Idiopathic Thrombocytopenia Purpura (ITP) THROMBOCYTOPATHY UREMIA INHERITED DISORDERS MYELOPROLIFERATIVE DISORDERS DRUG INDUCED FACTOR DEFICIENCIES (CONGENITAL) HEMOPHILIA A HEMOPHILIA B von WILLEBRAND’S DISEASE FACTOR DEFICIENCIES HEMOPHILIA A (Classic Hemophilia) 80-85% of all Hemophiliacs Deficiency of Factor VIII Lab Results - Prolonged PTT HEMOPHILIA B (Christmas Disease) 10-15% of all Hemophiliacs Deficiency of Factor IX Lab Test - Prolonged PTT FACTOR DEFICIENCIES VON WILLEBRAND’S DISEASE Deficiency of VWF & amount of Factor VIII Lab Results - Prolonged BT, PTT OTHER DISORDERS (ACQUIRED) ORAL ANTICOAGULANTS COUMARIN HEPARIN LIVER DISEASE MALABSORPTION BROAD-SPECTRUM ANTIBIOTICS INHIBITORS 30% of people with haemophilia develop an antibody to the clotting factor they are receiving for treatment. These antibodies are known as inhibitors. These patients are treated with high does of FVIIa for bleeds or surgery. This overrides defect in FVIII or FIX deficiency. Longterm management involves attempting to eradicate inhibitors by administering high dose FVIII (or FIX) in a process called immune tolerance Bleeding Disorders Clinical Features of Bleeding Disorders Platelet Coagulation disorders factor disorders Site of bleeding tissues Skin Mucous membranes Deep in soft (joints, muscles) (epistaxis, gum, vaginal, GI tract) Petechiae Yes No Ecchymoses (“bruises”) Small, superficial Large, deep Hemarthrosis / muscle bleeding Extremely rare Common Bleeding after cuts & scratches Yes No Bleeding after surgery or trauma Immediate, Delayed (1-2 Platelet Coagulation Petechiae, Purpura Hematoma, Joint bl. Hemato ma Petechiae Purpura Senile Purpura Petechiae in patient with Rocky Mountain Spotted Fever Henoch-Schonlein purpura Ecchymoses (typical of coagulation factor disorders) Coagulation factor disorders Inherited bleeding disorders – Hemophilia A and B – vonWillebrands disease – Other factor deficiencies Acquired bleeding disorders – Liver disease – Vitamin K deficiency/warfarin overdose – DIC Hemophilia A and B Hemophilia A Hemophilia Factor VIII Factor IX X-linked recessive X-linked recessive 1/10,000 males 1/50,000 B Coagulation factor deficiency Inheritance Incidence males Severity Related to factor level <1% - Severe - spontaneous bleeding 1-5% - Moderate - bleeding with mild injury 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 Treatment of hemophilia A Intermediate purity plasma products – Virucidally treated – May contain von Willebrand factor High purity (monoclonal) plasma products – Virucidally treated – No functional von Willebrand factor 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 – -aminocaproic acid (Amicar) or DDAVP (for mild disease only) Complications of therapy Formation of inhibitors (antibodies) – 10-15% of severe hemophilia A patients – 1-2% of severe hemophilia B patients Viral infections – Hepatitis B parvovirus – Hepatitis C – HIV Human Hepatitis A Other Viral infections in hemophiliacs HIV -positive HIV- negative (n=382) (n=345) 53% 47% Hepatitis serology negative Negative 20 Blood 1993:81;412-418 Hepatitis B virus only % positive 1 1 % Treatment of hemophilia B Agent – High purity factor IX – Recombinant human factor IX Dose – Initial dose: 100U/kg – Subsequent: 50U/kg every 24 hours von Willebrand Disease: Clinical Features von Willebrand factor – – – – – Synthesis in endothelium and megakaryocytes Forms large multimer Carrier of factor VIII Anchors platelets to subendothelium Bridge between platelets Inheritance - autosomal dominant Incidence - 1/10,000 Clinical features - mucocutaneous bleeding Laboratory evaluation of von Willebrand disease Classification – Type 1 – Type 2 – Type 3 Partial quantitative deficiency Qualitative deficiency Total quantitative deficiency Diagnostic tests: vonWillebrand type 2 Assay 3 1 vWF antigen vWF activity Multimer analysis Normal Normal Normal Treatment of von Willebrand Disease Cryoprecipitate – Source of fibrinogen, factor VIII and VWF – Only plasma fraction that consistently contains VWF multimers DDAVP (deamino-8-arginine vasopressin) – plasma VWF levels by stimulating secretion from endothelium – Duration of response is variable – Not generally used in type 2 disease – Dosage 0.3 µg/kg q 12 hr IV Factor VIII concentrate (Intermediate purity) – Virally inactivated product Vitamin K deficiency Source of vitamin K Green vegetables Synthesized by intestinal flora Required for synthesis Factors II, VII, IX ,X Protein C and S Causes of deficiency Malnutrition Biliary obstruction Malabsorption Antibiotic therapy Treatment Vitamin K Fresh frozen plasma Common clinical conditions associated with Disseminated Intravascular Coagulation Activation of both coagulation and fibrinolysis Triggered by 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 rejection Disseminated Intravascular Coagulation (DIC) Mechanism Systemic activation of coagulation Intravascular deposition of fibrin Thrombosis of small and midsize vessels with organ failure Depletion of platelets and coagulation factors Bleeding Pathogenesis of DIC Release of thromboplastic material into circulation Coagulation Fibrinolysis Fibrinogen Plasmin Thrombin Fibrin Monomers Fibrin Clot (intravascular) Consumption of coagulation factors; presence of FDPs aPTT PT TT Fibrinogen Presence of plasmin FDP Fibrin(ogen) Degradation Products Plasmin Intravascular clot Platelets Schistocytes Disseminated Intravascular Coagulation Treatment approaches Treatment of underlying disorder Anticoagulation with heparin Platelet transfusion Fresh frozen plasma Coagulation inhibitor concentrate (ATIII) Classification of platelet disorders Quantitative disorders – Abnormal distribution – Dilution effect – Decreased production – Increased destruction Qualitative disorders – Inherited disorders (rare) – Acquired disorders Medications Chronic renal failure Cardiopulmonary bypass Thrombocytopenia Immune-mediated Idioapthic Drug-induced Collagen vascular disease Lymphoproliferative disease Sarcoidosis Non-immune mediated DIC Microangiopathic hemolytic anemia Liver Disease and Hemostasis 1. Decreased synthesis of II, VII, IX, X, XI, and fibrinogen 2. Dietary Vitamin K deficiency (Inadequate intake or malabsortion) 3. Dysfibrinogenemia 4. Enhanced fibrinolysis (Decreased alpha-2-antiplasmin) 5. DIC 6. Thrombocytoepnia due to hypersplenism Management of Hemostatic Defects in Liver Disease Treatment for prolonged PT/PTT Vitamin K 10 mg SQ x 3 days usually ineffective Fresh-frozen plasma infusion 25-30% of plasma volume (12001500 ml) immediate but temporary effect Treatment for low fibrinogen Cryoprecipitate (1 unit/10kg body weight) Treatment for DIC (Elevated D-dimer, Vitamin K deficiency due to warfarin overdose Managing high INR values Clinical situation Guidelines INR therapeutic-5 Lower or omit next dose; Resume therapy when INR is therapeutic INR 5-9; no bleeding Lower or omit next dose; Resume therapy when INR is therapeutic Omit dose and give vitamin K (1-2.5 mg po) Rapid reversal: vitamin K 2-4 mg po (repeat) INR >9; no bleeding Omit dose; vitamin K 3-5 mg po; repeat as necessa Resume therapy at lower dose when INR therapeut Chest 2001:119;22-38s (supplement) Vitamin K deficiency due to warfarin overdose Managing high INR values in bleeding patients Clinical situation Guidelines INR > 20; serious bleeding Omit warfarin Vitamin K 10 mg slow IV infusion FFP or PCC (depending on urgency) Repeat vitamin K injections every 12 hrs as ne Any life-threatening bleeding Omit warfarin Vitamin K 10 mg slow IV infusion PCC ( or recombinant human factor VIIa) Repeat vitamin K injections every 12 hrs as ne Chest 2001:119;22-38s (supplement) Approach to Post-operative bleeding 1. Is the bleeding local or due to a hemostatic failure? 1. 2. Local: Single site of bleeding usually rapid with minimal coagulation test abnormalities Hemostatic failure: Multiple site or unusual pattern with abnormal coagulation tests 2. Evaluate for causes of peri-operative hemostatic failure 1. 2. Preexisting abnormality Special cases (e.g. Cardiopulmonmary bypass) 3. Diagnosis of hemostatic failure 1. 2. Review pre-operative testing Obtain updated testing Laboratory Evaluation of Bleeding Overview CBC and smear Coagulation pathways Platelet count RBC and platelet morphology Thrombocytopenia TTP, DIC, etc. Prothrombin time Extrinsic/common Partial thromboplastin time Intrinsic/common Coagulation factor assays 50:50 mix Fibrinogen assay Thrombin time Specific factor deficiencies Inhibitors (e.g., antibodies) Decreased fibrinogen Qualitative/quantitative fibrinogen defects Fibrinolysis (DIC) pathways FDPs or D-dimer Platelet function disorders von Willebrand factor vWD Bleeding time In vivo test (non-specific) Platelet function analyzer (PFA) Qualitative platelet and vWD Platelet function tests Qualitative platelet Laboratory Evaluation of the Coagulation Pathways Partial thromboplastin time (PTT) Prothrombin time (PT) Surface activating agent (Ellagic acid, kaolin) Phospholipid Calcium Thromboplastin Tissue factor Phospholipid Calcium Intrinsic pathway Extrinsic pathway Thrombin time Common pathway Thrombin Fibrin clot Coagulation factor deficiencies Summary Sex-linked recessive Factors VIII and IX deficiencies cause bleeding Prolonged PTT; PT normal Autosomal recessive (rare) Factors II, V, VII, X, XI, fibrinogen deficiencies cause bleeding Prolonged PT and/or PTT Factor XIII deficiency is associated with bleeding and impaired wound healing PT/ PTT normal; clot solubility abnormal Factor XII, prekallikrein, HMWK deficiencies do not cause bleeding 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 Causes of prolonged Thrombin Time Heparin Hypofibrinogenemia Dysfibrinogenemia Elevated FDPs or paraprotein Thrombin inhibitors (Hirudin) Thrombin antibodies Classification of thrombocytopenia Associated with thrombosis – Thrombotic thrombocytopenic purpura – Heparin-associated thrombocytopenia – Trousseau’s syndrome – DIC Associated with bleeding – Immune-mediated thrombocytopenia (ITP) – Most others Bleeding time and bleeding 5-10% of patients have a prolonged bleeding time Most of the prolonged bleeding times are due to aspirin or drug ingestion Prolonged bleeding time does not predict excess surgical blood loss Not recommended for routine testing in preoperative patients Drugs and blood products used for bleeding Treatment Approaches to the Bleeding Patient Red blood cells Platelet transfusions Fresh frozen plasma Cryoprecipitate Amicar DDAVP Recombinant Human factor VIIa RBC transfusion therapy Indications Improve oxygen carrying capacity of blood – Bleeding – Chronic anemia that is symptomatic – Peri-operative management Red blood cell transfusions Special preparation CMV-negative CMV-negative patients Prevent CMV transmission Irradiated RBCs Immune deficient recipient or direct donor Prevent GVHD Leukopoor Previous non-hemolytic transfusion reaction CMV negative patients Prevents reaction PNH patients IgA deficient recipient Prevents hemolysis Prevents anaphylaxis Washed RBC Prevents transmission Red blood cell transfusions Adverse reactions Immunologic reactions Hemolysis Anaphylaxis Febrile reaction Urticaria Non-cardiogenic pulmonary edema RBC incompatibility Usually unknown; rarely against IgA Antibody to neutrophils Antibody to donor plasma proteins Donor antibody to leukocytes Red blood cell transfusions Adverse reactions Non-immunologic reactions Congestive heart failure Volume overload Fever and shock contamination Bacterial Hypocalcemia transfusion Massive Transfusion-transmitted disease Infectious agent Risk HIV Hepatitis C Hepatitis B Hepatitis A HTLV I/II CMV Bacteria Creutzfeld-Jakob disease Others ~1/500,000 1/600,000 1/500,000 <1/1,000,000 1/640,000 50% donors are sero-positive 1/250 in platelet transfusions Unknown Unknown Platelet transfusions Source – Platelet concentrate (Random donor) – Pheresis platelets (Single donor) Target level – Bone marrow suppressed patient (>1020,000/µl) – Bleeding/surgical patient (>50,000/µl) Platelet transfusions complications Transfusion reactions – Higher incidence than in RBC transfusions – Related to length of storage/leukocytes/RBC mismatch – Bacterial contamination Platelet transfusion refractoriness – Alloimmune destruction of platelets (HLA antigens) – Non-immune refractoriness Microangiopathic hemolytic anemia Coagulopathy Splenic sequestration Fresh frozen plasma Content - plasma (decreased factor V and VIII) Indications – – – – Multiple coagulation deficiencies (liver disease, trauma) DIC Warfarin reversal Coagulation deficiency (factor XI or VII) Dose (225 ml/unit) – 10-15 ml/kg Note – Viral screened product – ABO compatible Cryoprecipitate Prepared from FFP Content – Factor VIII, von Willebrand factor, fibrinogen Indications – Fibrinogen deficiency – Uremia – von Willebrand disease Dose (1 unit = 1 bag) – 1-2 units/10 kg body weight Hemostatic drugs Aminocaproic acid (Amicar) Mechanism – Prevent activation plaminogen -> plasmin Dose – 50mg/kg po or IV q 4 hr Uses – – – – Primary menorrhagia Oral bleeding Bleeding in patients with thrombocytopenia Blood loss during cardiac surgery Side effects – GI toxicity – Thrombi formation Hemostatic drugs Desmopressin (DDAVP) Mechanism – Increased release of VWF from endothelium Dose – 0.3µg/kg IV q12 hrs – 150mg intranasal q12hrs Uses – Most patients with von Willebrand disease – Mild hemophilia A Side effects – Facial flushing and headache – Water retention and hyponatremia Recombinant human factor VIIa (rhVIIa; Novoseven) Mechanism – Direct activation of common pathway Use – Factor VIII inhibitors – Bleeding with other clotting disorders – Warfarin overdose with bleeding – CNS bleeding with or without warfarin – Dose – 90 µg/kg IV q 2 hr – “Adjust as clinically indicated” Cost (70 kg person) - $1 per µg – ~$5,000/dose or $60,000/day Approach to bleeding disorders Summary Identify and correct any specific defect of hemostasis – Laboratory testing is almost always needed to establish the cause of bleeding – Screening tests (PT,PTT, platelet count) will often allow placement into one of the broad categories – Specialized testing is usually necessary to establish a specific diagnosis Use non-transfusional drugs whenever possible RBC transfusions for surgical procedures Clinical Approach When did it start ? Dental history Spontanous bruising Bleeding at surgery Bleeding into joints Menstrual bleeding Epistaxis One site only? Where ? When ? High yield questions Family history Pattern of bleeding - where Difficult to stop or Re-bleeds Drug history Alcohol intake Co Morbid disease Physical Examination in Bleeding Disorders Check sites of bleeding Is it local or generalized ? what are the manifestations, petichiae, ecchymoses, hematoma ? Are there vessel wall abnormalities, telangectasia, “palpable purpura, perifollicular hemorrhages” ? Are there signs of a connective disease process Are There signs of a systemic disease Laboratory testing History and physical Type of tests guided by clinical features Screening tests Further tests Definitive tests Screening Tests INR Extrinsic pathway PTT (activated partial thromboplastin time) intrinsic pathway Thrombin time final pathway Platelet count Laboratory tests further testing INR PTT TT thrombin time Factor assays Tests of fibrinolysis platelet count platelet function tests Special tests Who is likely to bleed Obvious Cirrhosis Renal dysfunction Age Drugs Right heart failure Interpretation of tests If isolated abnormality likely a single defect eg PTT - possible hemophilia, vWd If unexplained do mixing test for inhibitor IF more than one abnormality then more complex eg. INR and PTT - vitamin K- Coumadin eg. PTT,TT heparin eg INR , PTT, TT, Platelets DIC or liver disease (Cirrhosis) New anticoagulants Dabigatran, Rivaroxaban Efficacy of route of administration Reversing INR with vitamin K Depends on clinical scenario Complete reversal Partial reversal (too high INR) IV or oral forms prefered For complete reversal 5-10 mg IV q12h for 2 doses will reverse completely in 36-48 hours. 1-2 mg will decrease INR to therapeutic Level within 12-24 hrs ITP Immune thromboctopenic purpura What is needed for diagnosis Bone marrow examination Anti platelet antibodies When isolated and very low ITP is most likely diagnosis Could be a part of another disease but not likely (SLE , inf mono) Does it require hospitalization ? ITP continued If mucosal bleeding platelets are less than 6 Needs action Steroids IVIG Anti D What about splenectomy New treatments Rituximab TPO agonists
