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Approach to Bleeding TAAAC.pptxggbbjkkkkkg
- 1. Approach to Bleeding! Fatima(Fatuma) Khadadah PGY5 University of Toronto January 23rd 2020
- 2. Disclosures • No relevantdisclosures • Slide credits to all previous TAAAC residents notably Drs Jiajia Liu and Abi Vijenthira
- 3. Objectives • Review themechanisms behind normal and abnormal hemostasis • Develop an approach to the patient with bleeding • Discuss specific hemostatic scenarios and challenges
- 4. When you thinkof hemostasis you think of.. Wikipedia.org Madness!
- 5. Slide from Dr.Michelle Sholzberg
- 6. Hemostasis is composedof 4major events: 1. Primary hemostasis 2. Secondary hemostasis 3. Fibrin clot formation and stabilization 4. Inhibition of coagulation Bloody Easy Coagulation Simplified
- 7. Primary Hemostasis • CollagenVascular Abnormality • Von Willibrand Disease (VWD) • Platelet Deficiency • Quantitative thrombocytopenia • Qualitative platelet dysfunction • Classic: mucocutaneous bleeding (petechiae, purpura, gingival bleeding, menorrhagia) Normal Abnormal
- 8. Secondary Hemostasis Normal Abnormal • Hereditaryor acquired coagulation factor deficiency • Hemophilia: • Factor VIII (Hemophilia A) • Factor IX (Hemophilia B) • Drugs E.g. DOACs • Classic: joint, intramuscular bleeding
- 9. Fibrin Clot Formationand Stabilization • Clot stabilizers • Rare diseases • Classic: Delayed bleeding Normal Abnormal
- 10. Inhibition of Coagulation Normal Abnormal •Hereditary Thrombophilias! • E.g. Factor V Leiden, Protein C and S deficiency • Inhibition of thrombin generation +
- 11. Objectives Review the mechanismsbehind normal and abnormal hemostasis • Develop an approach to the patient with bleeding • Discuss specific hemostatic scenarios and challenges
- 12. Quiroga T, Hematology2012 What is the most common bleeding disorder?
- 13. How to approachbleeding NYD? Location of Bleeding • Primary hemostasis defects • Mucocutaneous bleeding • Easy bruising • Heavy menstrual bleeding • Petichiae (low plts) • Secondary hemostasis defects • Hemarthrosis • Intramuscular bleeding • Retroperitoneal bleeding • CNS bleeding Onset • Chronic/recurrent vs. 1st episode? • Differentiate congenital vs. acquired Severity • Require blood transfusions? PMHx • Previous hemostatic challenges? • Postpartum hemorrhage • Circumcision • Dental procedures • Surgical procedures • Comorbidities • Liver/renal disease Medications • Anticoagulants, Antibiotics, ASA, NSAIDs, valproic acid, SSRI Family History • VWD: predominantly autosomal dominant (male and female affected) • Hemophilia A and B: X-linked (predominately males affected)
- 14. What is themost important test to diagnose a bleeding disorder? • The clinical history! • The PT/INR and PTT are only 1-2% sensitive for bleeding disorders • A bleeding history can be standardised using a Bleeding Assessment Tool
- 15. ISTH Bleeding assessmenttool • Clinician-administered standardized bleeding history and bleeding severity assessment • Studied and sensitive in von Willebrand disease, inherited platelet defects, and mild hemophilia/hemophilia carriers • Score >4 suggestive of a bleeding disorder • Sensitivity for vWD 99% - high NPV! • Specificity 70-80% - > further testing is still needed!
- 16.
- 19. Further testing ifISTH BAT >4 ? • CBC + differential • PT/PTT/fibrinogen • Liver/renal function testing • Von Willebrand factor antigen level, ristocetin cofactor activity, and factor VIII level • Platelet function assay (PFA) • (Platelet aggregation/Platelet secretion/Platelet flow cytometry)
- 20. DDx: Isolated ProlongedaPTT • Heparin or other anticoagulant • Deficiency or inhibitor of: • Factor VIII • Factor IX • Factor XI • Factor XII • Contact factor (XII, PK, HMWK) • Von Willebrand disease (2nd to low FVIII) • Lupus anticoagulant Which of the above do not confer a bleeding risk? Lupus anticoagulant + Factor 12 deficiency!
- 21. DDx: Isolated ProlongedPT • Vitamin K deficiency • Warfarin therapy • Liver disease • Factor VII deficiency/inhibitor
- 22. DDx: Prolonged PT& aPTT • High dose (heparin or) warfarin • Dilutional coagulopathy • DIC • Vitamin K deficiency • Moderate to severe liver disease • Common pathway clotting factor deficiencies/inhibitors:
- 23. Mixing Study • Whatis a Mixing study? • Combine normal plasma + pt plasma 1:1 • Perform PTT afterwards Two possible outcomes: • PTT fully corrects • PTT does not fully correct INHIBITOR FACTOR DEFICIENCY
- 24. Moving on toinpatient bleeding management and cases
- 25. Principles of BleedManagement • ABCs • Ask for help (surgical teams, ICU…) • Intravenous access • CBC, PT, PTT, Blood group and screen • Fluid resuscitation +evaluate need for blood transfusion • Tranexamic acid unless contraindicated • Give targeted hemostatic therapy (factors, etc.) if appropriate
- 26. Tranexamic acid • Evidence •Trauma (CRASH-2) – improves survival if given <3h from trauma • TBI (CRASH-3) – treatment <3 hrs reduces head injury related death • Obstetrics (WOMAN) – reduces death in PPH if given ASAP • Peri-procedural – decrease blood loss, need for blood transfusions, mortality benefit • Elective c-section, TKA, orthognatic surgery, cardiac surgery, spinal surgeries, TURP, hemophilia and dental extractions • Menorrhagia – decreased bleeding, improved quality of life • SAH: decreased rebleeding and mortality • GI bleeding: trend towards decreased mortality • Cancer: safe to give and no increased risk of thrombosis or death (meta-analysis) https://doi.org/10.1016/j.transproceed.2015.05.027.
- 27. Tranexamic acid • Contraindications: •Active thrombus (you want the clot to go away!) • Hematuria (risk of urinary obstruction) • NOT a contraindication: • It is not a procoagulant -> multiple large prospective multicenter trials in high-thrombotic risk populations (trauma, obstetrics) do not show an increased risk of thrombosis • Adverse effects • Lowers seizure threshold • Headache, GI effects
- 28. Case 1 50 yearold man presents to ER with sudden onset severe headache. PMHx 1. Atrial fibrillation Medications 1. Warfarin 5 mg PO daily 2. Metoprolol 25 mg PO BID Investigations • Hemoglobin 9 g/dL • Platelets 200 x109/L • WBC 9 x109/L • INR 13 • aPTT 38 s • Electrolytes, renal, and liver function normal
- 29.
- 30. 3 Step Approachto Life-threatening Bleeding from Warfarin Excess 1. Stabilize - ABCs (incl. call surgeons) - Hold warfarin - Give TXA 2. Vitamin K - 10 mg IV (can repeat in 12h) - Effect in 6-12 h 3. Prothrombin Complex OR Fresh Frozen Plasma Short-term plan – PCC (lasts 6 hours) Long-term plan – Intravenous vitamin K 10mg
- 31.
- 32. Why might hisINR be elevated? • Interference with warfarin metabolism • Heart failure (OR 1.6-3.0) • Liver dysfunction (OR 2.8) • Acute illness – infection, diarrhea (OR 12.8!) • Fever (OR 2.9) • Large day-to-day variations in Vitamin K intake • Vitamin K-rich foods: Basil, green leafy vegetables (kale), scallions, chili powder, asparagus, soybeans (cooked), dried prunes • Drug Drug Interactions!! – including over-the-counter drugs (paracetamol), antibiotics
- 33.
- 34. Warfarin reversal • Warfarin •No bleeding: INR > 10, vitamin K 5mg x 1 orally • Minor bleeding: • INR > 3 - hold warfarin • INR 5-10 - oral Vitamin K 1-2.5mg x 1 • INR > 10 – oral vitamin K 5mg x 1 • Life threatening bleeding • Vitamin K 10mg IV x 1 • PCC = Octaplex/Beriplex or FFP 15cc/kg.
- 35. Prothrombin Complex (Octaplex, Beriplex) CONTENTS: •Factor 2, 7, 9, 10, PrC, PrS, heparin • Specific for warfarin reversal INDICATION • Warfarin reversal or vit K deficiency with life threatening bleeding and INR > 1.5 or emergency surgery within < 6 hrs ***Contraindicated if HITT ***Lasts 6 hours DOSE and PRACTICAL TIPS • INR 1.5-2.99: 1000 units over 5 mins • INR 3-4.99: 2000 units over 10 mins • INR ≥ 5: 3000 units over15 mins (this is max dose) • If INR unknown and serious bleeding 2000 units over 10 mins Fresh Frozen Plasma CONTENTS • All clotting factors + fibrinogen • INR of FFP = 1.6 INDICATION • Liver disease and bleeding and INR > 1.5 • Warfarin reversal if no PCC OR patient has hx of HITT **DON’T give plasma for: • Bleeding/procedure & INR < 1.5 • NOT bleeding and INR > 1.5 DOSE and PRACTICAL TIPS • 15 cc/kg round to nearest 250 mL • Each unit of 250 mL will increase factor levels by 20% • Max. effect only 5-6 hrs corresponding to shortest half-life (factor VII!) • Beware of transfusion reactions • TACO, TRALI, AHTR • Minor urticarial give anti-histamine, NOT a contraindication to more plasma
- 37. DOACs and bleeding •General tips • Local measures • TXA 1g IV q8h • When was the last dose and what is their creatinine clearance? It may already be out of their system! • Rivaroxaban or Apixaban • If likely to still have anti-Xa on board: PCC 50 IU/kg or 2000 IU • (andaxanet alfa) • DABIGATRAN • Idarucizumab 5g IV (2 vials)
- 38. Case 2 • 19M presents with weakness in left leg and flank bruising. No trauma. • PMHx: • History of intermittent joint swelling and pain since childhood • Meds: nil • FMHx: younger brother had appendectomy last year and required +++ blood transfusions • O/E: HR 110, BP 120/80, T 36.8, RR 22, O2 100%
- 39. Case continued PTT 50s INR 1 Mixing study: PTT CORRECTS Factor VIII level < 1%, Factor XI level 80% • consistent with Hemophilia A Overview of treatment • Factor replacement (recombinant or plasma-derived) • Cryoprecipitate (or Fresh frozen plasma)
- 40. Hemophilia A andB • Hemophilia A • FVIII deficiency • Prevalence 1/5 000 • X-linked inheritance • Hemophilia B • FIX deficiency • Prevalence 1/30 000 • X-linked inheritance • Classified by severity • World Federation of Hemophilia updated guidelines 2013 Severity Factor Level Bleeding Episodes Severe < 1% Spontaneous bleeding into joints or muscles, predominantly in the absence of identifiable hemostatic challenge Moderate 1-5% Occasional spontaneous bleeding; prolonged bleeding with minor trauma or surgery Mild 5-40% Severe bleeding with major trauma or surgery. Spontaneous bleeding is rare.
- 41. Principles of TreatingBleeding Hemophilia Patient • Acute bleeds should be treated as soon as possible, preferably within 2 hours. If in doubt, treat. • In severe bleeding that may be life-threatening, treat with factor immediately even before diagnostic assessment is completed • Watch for critical sites that can be life- or limb-threatening (ex. neurovascular compromise in MSK bleeding) – may still need surgical opinion • Tranexamic acid • Specific factor replacement • If not available, can use cryoprecipitate or FFP if hemophilia A, and FFP if hemophilia B
- 42. How To DoseFactor Concentrate Disease Half-Life Yield Products Hemophilia A (VIII) 8-12 hours 2% / u / kg Kogenate Advate Hemophilia B (IX) 18-24 hours 0.5-1% / u / kg Benefix
- 43. How To DoseFactor Concentrate Bleed Severity Example Treatment Target Dosing (if severe deficiency) Major GI Bleed Retroperit. Bleed CNS Bleed 80-100% HA = 50 u/kg HB = 100 u/kg Moderate Hemarthrosis 60-80% HA = 30 u/kg HB = 60 u/kg Minor Dental Work 50-60% Consider DDAVP Tranexamic Acid
- 44. If specific factorreplacement unavailable: • What contains VIII • Cryoprecipitate (VIII, XIII, FBG, VWF) • DDAVP (boosts plasma levels of FVIII and VWF) – 0.3 mcg/kg IV or SC can raise FVIII by 3-6 times • What contains IX • Prothrombin Complex Concentrate • What contains (or helps) both • FFP – 1 cc FFP contains 1 unit of factor activity, but difficult to achieve FVIII or FIX levels above 25-30% • (Tranexamic Acid)
- 45. So how muchfactor does our patient need? • Assuming weight is 70 kg • Assume close to 0% VIII activity • Factor VIII 70 kg x 2% /u / kg = 70 kg x 50 u / kg = 3500 units IV
- 46. How long totreat for? • Hemarthrosis – 1-2 treatments (40-60%) • Muscle hemorrhage – 2-3 days, sometimes much longer if at critical site or if rehabilitation needed • Throat / neck – 7-14 days • UGIB – 7-14 days • CNS – 7-21 days • World Federation of Hemophilia Recommendations
- 47. Case 3 • A23 F presents to the ER after experiencing epistaxis and easy bruising for three days. She noted petechiae on her arms and legs • Exam reveals: • Wet purpura • Petechiae, ecchymoses • Normal spleen size
- 48. Investigations: • CBC: Hg120, WBC 10, Platelets 2 • Biochemistry: Electrolytes N, Creatinine 80 • Coags: Fibrinogen 2, INR 1, PTT 30
- 49. Life-threatening thrombocytopenia • Thromboticmicroangiopathies (look for anemia, AKI, blood film!) • TTP • aHUS • DIC (always do PT/PTT/fibrinogen in thrombocytopenic patient) • HELPP • Isolated thrombocytopenia • ITP • HIT (if recent heparin exposure) • Malignancy: Acute leukemia
- 51. Immune Thrombocytopenia (ITP) •Diagnosis of exclusion • An acquired immune-mediated disorder • Isolated thrombocytopenia • Platelet count less than 100 * 109/L, and the absence of any obvious initiating and/or underlying cause • Clinically: mucocutaneous bleeding. ICH rare (estimates 1.5%) but fatal
- 52. Investigations • Exclude otherdiagnoses • Look for secondary cause! • HIV, HCV, H.pylori • Ancillary • APLA, ANA • Quantitative Ig (look for CVID) • DAT, IAT • Bone marrow if older, no response to steroids, clinical concern RE: malignancy
- 53. Emergency Management ofITP 1. SUPPORTIVE MEASURES • Tranexamic acid 500-1000 mg PO TID if bleeding • Platelet transfusion in life/limb threatening 2. STEROIDS • Prednisone 1 mg/kg PO OD OR dexamethasone 40 mg PO OD * 4 days 3. IVIG if need a rapid platelet count increase • IVIG 1 g/kg * 2 days • NB. Risks of IVIG • May use Anti-D alternatively (50-75 mcg/kg IV) in RH + non- splenectomized patients • Concern for hemolysis
- 54. Transfusion Thresholds forThrombocytopenia • Non active bleeding - nonimmune • Active bleeding or going for OR • CNS bleed, eye bleed • For patients in DIC, try to keep counts NOT evidence based!! 10 50 100 > 30- 50
- 55. Objectives Review the mechanismsbehind normal and abnormal hemostasis Develop an approach to the patient with bleeding Discuss specific hemostatic scenarios and challenges
- 56. Conclusions • 3 cases 1.Bleeding on anticoagulants 2. Inherited factor deficiencies 3. Bleeding and thrombocytopenia • Give tranexamic acid unless contraindicated – improves outcomes in all studied groups • Always evaluate for causes and consequences of bleeding • History crucial in patients with abnormal bleeding
- 57. Thank you! • You’vestopped the bleeding!