1. EVALUATION OF THE BLEEDING PATIENT HISTORY (inherited or acquired bleeding tendency?) Prior invasive procedures, dental extractions Family history Medications, alcohol PHYSICAL EXAM Mucosal/skin vs soft tissue bleeding? Bleeding from one or multiple sites? Mucosal hemangiomas, skin/joint laxity, etc

2. Platelet defects and vessel disorders: immediate bleeding from skin and mucosal surfaces, petechiae

3. Coagulation factor deficiency: delayed bleeding into soft tissues

4. Bleeding confined to an operative site is usually due to a severed vessel

5. Initial laboratory evaluation Platelet count PT/INR aPTT Fibrinogen Platelet function screen

6. Prothrombin time/INR Long PT/INR –Liver disease –Vitamin K deficiency –Warfarin or warfarin analogs (rat poison) –DIC –Inherited conditions rare –Won’t detect hemophilia, factor VIII inhibitor, heparin at therapeutic concentrations Magnitude of test abnormality usually proportional to clinical severity

7. aPTT Long aPTT –Heparin (therapeutic or contaminant) –Hemophilia A or B –von Willebrand disease (low VIII – but PTT may be normal) –Factor XI deficiency –Factor VIII inhibitor –Contact factor deficiency (do not cause bleeding) –Lupus anticoagulant (does not cause bleeding) –Less sensitive than PT/INR to liver disease, DIC, warfarin Magnitude of test abnormality not necessarily proportional to clinical severity

8. Platelet function screen Replaces the bleeding time Advantages –Ex vivo test (no skin incision) –Better standardized –Better sensitivity and specificity PFA-100

9. Platelet function screen Sensitive to:  Defective platelet adhesion in von Willebrand disease  Platelet dysfunction due to many drugs  Inherited platelet disorders  Not useful in patients with moderate or severe Thrombocytopenia  Rarely the only abnormal test in an acute bleeding disorder

10. Conditions that may cause bleeding with normal or near-normal screening tests Mild hemophilia (factor level 20-30% of normal) Von Willebrand disease Factor XIII deficiency (very rare) Fibrinolytic disorders Vascular disorders (Ehlers-Danlos, amyloid, etc)

11. IMMUNE THROMBOCYTOPENIA

12. ITP Drug-induced purpura Heparin-induced thrombocytopenia Post-transfusion purpura

13. ITP Autoimmune platelet destruction Mild to severe thrombocytopenia A diagnosis of exclusion Bleeding risk low to moderate in most cases –Hospitalization not always needed Rarely begins in hospital Other coag tests normal Few symptoms other than bruising & petechiae

14. ITP: initial treatment Corticosteroids: prednisone 1 mg/kg or pulse high dose dexamethasone IVIG (high dose) Splenectomy Platelet transfusion sometimes effective

15. Drug-induced thrombocytopenia Severe thrombocytopenia (<5K) not uncommon Often begins in hospital, precipitous drop in platelet count Bleeding risk moderate to high Typically occurs within days to weeks of starting a drug Testing for drug-dependent platelet Ab can confirm diagnosis but slow turnaround time

16. DRUGS MOST LIKELY TO CAUSE THROMBOCYTOPENIA Hematology 2009;153 * * * * * *

17. Drug-induced thrombocytopenia management Stop any potentially offending drug –Resolution may take days to weeks Steroids less effective than in ITP IVIG in selected cases

18. Heparin-induced thrombocytopenia Mild to moderate thrombocytopenia with onset during hospitalization in most cases Onset typically 4-7 days after initial heparin exposure (UFH > LMWH) Recent surgery, infection, inflammation increase risk Bleeding risk low, thrombosis risk high Heparin Ab test very sensitive – HIT can be ruled out if negative Rx: Stop heparin (any form), consider alternative anticoagulant (not warfarin)

19. Post-transfusion purpura Severe, precipitous drop in platelet count, usually a few days after blood product exposure (FFP, RBC most common) Most patients are multigravid women –Prior exposure to platelet antigen during pregnancy, recall Rxn after transfusion Most patients lack a common platelet alloantigen called HPA-1 (~ 2% of population) Antibodies directed against HPA-1 on transfused “passenger” platelets, patient’s own platelets are destroyed as “innocent bystanders”

20. Post-transfusion purpura If suspected notify blood bank to arrange for appropriate testing and transfusion therapy Test for HPA-1 antibodies in patient serum Do NOT give platelet transfusion If RBC transfusion needed give washed RBC High dose IVIG Steroids generally not helpful

21. www.ouhsc.edu/platelets

22. DISSEMINATED INTRAVASCULAR COAGULATION

23. Rapid formation & lysis of intravascular fibrin Consumption of clotting factors, platelets, inhibitors Life-threatening underlying disease Bleeding due to uncontrolled fibrinolysis, thrombocytopenia, clotting factor consumption and tissue injury from underlying disease Tissue injury/necrosis due to microvascular occlusion, hypotension, cytokine-mediated endothelial damage Most deaths due to underlying disease

24. PUPURA FULMINANS Pneumococcal sepsis in splenectomized patient NEJM 2001;344:1593

25. DIAGNOSIS OF DIC 1.Underlying disease capable of causing DIC? 2.Evidence of accelerated clotting factor and platelet consumption, and increased fibrinolysis? If both present DIC is likely

26. SCREENING FOR DIC D-dimer (most sensitive) PT/INR (PTT less helpful) Fibrinogen CBC/platelet count Fibrin monomer (most specific)

27. TREATMENT OF DIC TREAT UNDERLYING DISEASE! Clotting factor & inhibitor replacement for patients with significant bleeding:  Fresh frozen plasma (goal INR ≤ 1.6)  Cryoprecipitate (goal fibrinogen ≥ 100)  Platelets (goal platelet count 50-75K) Pharmacologic inhibitors (selected pts with refractory bleeding)  Heparin (low dose)  Antifibrinolytics (Amicar, tranexamic acid)

28. THROMBOTIC THROMBOCYTOPENIC PURPURA (TTP)

29. TTP Microangiopathic hemolytic anemia Thrombocytopenia Organ dysfunction (CNS, renal, other) due to small vessel occlusion Untreated mortality rate >90% With treatment mortality < 20% 1-2 cases/yr @ UWHC

30. TTP Caused by autoimmune destruction of ADAMTS-13 protease that modulates von Willebrand factor multimer size Very large multimers clump platelets Microthrombi damage RBC and block vessels

31. TTP Thrombocytopenia (may be severe) Intravascular hemolysis (high LDH, low haptoglobin, schistocytes in blood smear) INR, PTT, fibrinogen usually normal Organ dysfunction –Neurologic symptoms –Renal dysfunction (hematuria, proteinuria) –Cardiac (arrhythmia) ADAMTS-13 activity low (usually <5%)

32. TTP - DDX Cancer (may be occult) Pregnancy complications (HELLP, etc) Hemolytic-uremic syndrome (kidney most prominent target organ) –Shiga toxin –“Atypical” HUS: genetic component, complement- mediated Vasculitis (SLE, scleroderma) HIV infection DIC Drugs (calcineurin inhibitors, mitomycin C, interferon, clopidogrel, ticlopidine)

33. TTP Urgent plasma exchange –Plasma infusion if PE not immediately available Immunosuppression –Corticosteroids –Rituximab for patients with resistant, refractory or relapsed disease Do not transfuse platelets unless there is lifethreatening bleeding

34. HEMOPHILIA

35. HEMOPHILIA Inherited deficiency of factor VIII (hemophilia A) or factor IX (hemophilia B) Sex-linked inheritance; almost all patients male Most bleeding into joints, muscles; mucosal and CNS bleeding uncommon Severity inversely proportional to factor level: < 1%: severe, bleeding after minimal injury 1-5%: moderate, bleeding after mild injury > 5%: mild, bleeding after significant trauma or surgery (may not be diagnosed until adulthood)

36. HEMOPHILIA Treatment of bleeding episodes Unexplained pain in a hemophilia should be considered due to bleeding unless proven otherwise External signs of bleeding may be absent Treatment: factor replacement, pain control –Most adult patients self-administer factor Test for inhibitor (antibody vs factor) if unexpectedly low response to factor replacement –Most inhibitors occur in children

37. TREATMENT OF BLEEDS IN HEMOPHILIA Administer appropriate clotting factor concentrate –20-40 U/kg for minor bleeds, repeat daily for 2-3 days –40-50 U/kg for major bleeds, repeat daily for 4-7 days –50 U/kg q 12 hours for life-threatening bleeds 1 U/kg should increase plasma level of factor by about 2% –Initial dose higher with factor IX concentrate (greater volume of distribution, but longer half-life)

38. TREATMENT OF HEMOPHILIACS WITH INHIBITORS Call a hematologist Recombinant factor VIIa High dose factor VIII (if low titer inhibitor) Induce tolerance with daily factor infusion ± immunosuppression

39. ACQUIRED FACTOR VIII DEFICIENCY Autoantibody to factor VIII (most common autoimmune factor deficiency) Most patients elderly Often presents with severe soft tissue or mucosal bleeding (different bleeding pattern than inherited hemophilia) Laboratory: prolonged aPTT not corrected by mixing with normal plasma, factor VIII activity typically < 10% –Bleeding risk not proportional to factor level –Normal INR and platelet count Treatment: rVIIa, immunosuppression

40. BLOOD PRODUCTS AND DRUGS IN THE TREATMENT OF BLEEDING DISORDERS

42. BLOOD COMPONENT TRANSFUSION TO TREAT OR PREVENT BLEEDING Platelets: –Active bleeding: if platelet count < 50K –Prophylaxis: when platelets <10-20K –Patient having surgery: if platelets < 50-100K FFP (active bleeding): –When INR > 1.6 Cryoprecipitate (active bleeding): –Goal fibrinogen level 100

43. DDAVP (Desmopressin) Vasopressin analogue, stimulates VWF/factor VIII release from endothelium Intravenous or intranasal administration Increases plasma VWF/factor VIII levels for 18-24h, enhances platelet adhesion Effective in –Type I VWD (usually not in type 2, never in type 3) –Mild hemophilia A –Platelet dysfunction (variably effective) HA, flushing, hyponatremia with repeated dosing

44. AMICAR AMICAR (epsilon aminocaproic acid) Antifibrinolytic: inhibits plasmin formation and binding to fibrin Uses –Treating DIC with hyperfibrinolysis, or bleeding after thrombolytic drugs –Prophylaxis in severe thrombocytopenia –GI tract bleeding –Menorrhagia –Prophylaxis after dental extraction in hemophilia –Decrease bleeding after major trauma Short half-life, needs frequent dosing (4-24 grams/d) Oral or intravenous administration Alternative: tranexamic acid (longer half-life)

45. Recombinant Factor VIIa (rFVIIa) Augments tissue factor-induced coagulation FDA approved for treatment of Factor VIII inhibitor w/bleeding Off-label use is common, efficacy unclear: –Other coagulation inhibitors (including drugs) w/bleeding –Emergency reversal of coagulopathy (eg, warfarin) in patients with lifethreatening bleeding Potent procoagulant → risk of thrombosis Very expensive!

47. Prothrombin complex concentrate (PCC) Mixture of vitamin K dependent procoagulant factors: II, IX, X,VII Used to rapidly correct warfarin effect (or severe vitamin K deficiency) in acutely bleeding patient or prior to urgent surgical procedure Advantages vs FFP: –Less volume –No risk of TRALI, low risk of allergic rxn –Less risk of virus transmission

48. VITAMIN K Indications: 1.Correction of vitamin K deficiency 2.Treatment of warfarin or superwarfarin overdose 3.Prophylaxis in patients at risk for vitamin K deficiency Oral or IV administration (unreliable absorption with subcutaneous injection)

49. ANTICOAGULANT-RELATED BLEEDING

50. BLEEDING RISK VS INR <22.0-2.93-4.44.5-6.9>7 INR 0 50 100 150 200 Bleeding events/100 patient-yr Lancet 1996; 348:423

51. Treatment of warfarin-induced coagulopathy in the non-bleeding patient Dentali et al, J Thrombos Haemost 2006;4:1853

52. Treatment of warfarin-induced coagulopathy in the bleeding patient Dentali et al, J Thrombos Haemost 2006;4:1853

53. Reversal of heparin and LMWH Heparin: –FFP won’t help –Protamine sulfate: 1 mg/100U heparin –Neutralizes 80% of heparin LMWH –FFP won’t help –Protamine neutralizes 40% of LMWH

54. New anticoagulant drugs: Dabigatran, rivaroxaban, apixaban, edoxaban If PT and aPTT normal overdose is unlikely No specific antidote (some in development) Activated charcoal if drug taken recently PCC ~ 50 U/kg (rivaroxaban, apixaban, edoxaban) Consider dialysis (dabigatran only) FFP likely to be ineffective, risk of volume overload, TRALI

55. TRANSFUSION REACTIONS

56. Intravascular lysis of transfused rbcs by complement, IgM Causes:  Transfusion of ABO-incompatible blood  Transfusion of ABO-incompatible plasma  Non-ABO antibodies Clinical manifestations:  Fever (but most febrile reactions not hemolytic)  Back pain  Dark or red urine (hemoglobinuria)  Bronchospasm  Shock  DIC  Organ failure (esp kidneys)  Death IMMEDIATE HEMOLYTIC TRANSFUSION REACTION

57. Check blood product/paperwork to ensure correct product given Notify blood bank/transfusion service Obtain blood and urine samples:  Plasma and urine hemoglobin  Direct Coombs test  Repeat crossmatch/antibody screen  Repeat ABO/Rh typing Evaluation of suspected cases

58. IMMEDIATE HEMOLYTIC TRANSFUSION REACTION Stop transfusion immediately IV crystalloid or colloid Maintain BP, heart rate Maintain airway Diuresis  fluid, loop diuretic (mannitol may cause volume overload) Monitor renal and coagulation status Management

59. DELAYED HEMOLYTIC TRANSFUSION REACTION IgG-mediated lysis of transfused red cells (usually extravascular, non-ABO) Usually begins 5-10 days after transfusion Jaundice, falling Hct, positive direct Coombs test, fever Not generally life-threatening

60. FEBRILE, NONHEMOLYTIC TRANSFUSION REACTION Cause: cytokines released by leukocytes during storage; antibodies to HLA antigens on transfused or donor PMNS Incidence: ≤0.5% of units transfused More common in multiply transfused recipients Fever, chills, respiratory distress in severe reactions Reduced incidence/severity with leukocyte-poor product

61. TRANSFUSION-RELATED ACUTE LUNG INJURY (TRALI) Hypoxemia with bilateral pulmonary infiltrates No increase in central venous or pulmonary artery pressures Usually begins acutely within 6 hours of transfusion Clinical: acute respiratory distress, fever, chills Pathophysiology: 1. Underlying lung injury (eg, sepsis, pneumonia) causes PMNs to adhere to pulmonary capillaries 2. Mediators in transfused blood product (neutrophil antibodies, cytokines) activate PMNs with resultant capillary injury

62. TRANSFUSION-RELATED ACUTE LUNG INJURY

63. TRANSFUSION-RELATED ACUTE LUNG INJURY (TRALI) Risk: FFP > platelets > RBC Treatment: stop transfusion (if still in progress); oxygen; ventilatory support if necessary; pulse corticosteroids

64. OTHER ACUTE NON-INFECTIOUS COMPLICATIONS OF TRANSFUSION Allergic reactions Anaphylaxis (IgA-deficient recipient) Lung damage from microaggregates (massive transfusion) Transfusion-associated circulatory overload (“TACO”) Bacterial infection (mainly with platelet transfusion) Hypothermia (rapid infusion of refrigerated blood) Citrate toxicity/hypocalcemia (massive transfusion or apheresis) Graft-vs-host disease Air embolism

65. Transfusion-related deaths 2005-2010 TRALITACOHTR (non-ABO) HTR (ABO) Bacterial Infection Anaphylaxis 200529116680 20063589371 20073452362 200816371073 200913128461 20101882224 TRALI – Transfusion-associated lung injury TACO – Transfusion-associated circulatory overload HTR – Hemolytic transfusion reaction