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Coagulopathy Reversal (Nonwarfarin Agents), Emergency Medicine

Basics

Description

- FXa inhibitors - Binds to antithrombin III, catalyzing FXa inhibition - No direct inhibitory effect on thrombin - Half-life 12-21 hr in normal renal function

- Patient on anticoagulants with active bleeding - Indications for reversal - Serious or life-threatening bleeding - Trauma - GI bleeding - Intracerebral hemorrhage (ICH)

- Give slowly IV over 1-3 min not to exceed 50 mg in any 10-min period - Short half-life, may need to re-dose - Protamine reversal effectiveness is compound specific for LMWH (does not reverse enoxaparin completely) - 1 mg for each 1 mg/100 IU LMWH given in last 8 hr - If 8-12 hr since LMWH, use 0.5 mg for each 1 mg/100 IU LMWH - If >12 hr since LMWH, no protamine suggested - For LMWH, if PTT remains prolonged, may repeat with half of the 1st dose - High or excessive dosing can have a paradoxical anticoagulant effect - Rapid administration can cause hypotension, bradycardia, and anaphylaxis - Anaphylaxis is more likely with a fish allergy or prior exposure to protamine and if concerned, can premedicate with corticosteroids and antihistamines

- Desmopressin (DDAVP) - Induces the release of von Willebrand factor and factor VIII - 0.3 μg/kg IV over 15 min - Effect is immediate - Multiple doses associated with tachyphylaxis, hyponatremia, and seizures

- Platelets - Transfuse to increase count by 50,000/μL (on average, 1 U increases platelet count by 10k) - May need to repeat transfusions daily - Risks include infection transmission, acute lung injury, and allergic reactions

- FDA approved for bleeding episodes in patients with hemophilia B - Dose 25-50 U/kg not to exceed 2 mL/min - Give 1-2 U FFP for factor VIIa component - Effect in <30 min - Limited data to support use in trauma - Vary widely in composition - Long-term safety has not been assessed - Associated with risk of thrombosis - Allergic reactions may occur

  • Patient on anticoagulant medications with minor, major, or clinically significant bleeding needing close monitoring +/- anticoagulant reversal
  • Anticoagulant medicationIndirect inhibitors of thrombinUnfractionated heparin (UFH)Low-molecular-weight heparin (LMWH)EnoxaparinDalteparinTinzaparinAnti-platelet agentsAspirinClopidogrel hydrogen sulfate (Plavix)Factor Xa inhibitors (FXa inhibitors)Fondaparinux (Arixtra)Rivaroxaban (Xarelto)Direct thrombin inhibitors (DTIs)ArgatrobanBivalirudin (Angiomax)Dabigatran (Pradaxa)Hirudin derivativesDesirudinLepiruden (Refludan)
  • Heparin and LMWH are the most commonly utilized anticoagulants beyond warfarin
  • Routine use of DTIs is being studied

Excretion primarily renal with FXa inhibitors, Dabigatran, and Hirudin derivatives necessitating caution with impaired renal function

Epidemiology

Incidence and Prevalence Estimates

  • Indirect inhibitors of thrombinUp to 1/3 patients develop bleeding complication2-6% of bleeding is major
  • Anti-platelet agents>300 over-the-counter medications contain aspirinConflicting studies regarding increased hematoma expansion and mortality
  • FXa Inhibitors
  • DTIs

Etiology

  • Indirect inhibitors of thrombinCombines with antithrombin III to inactivate activated FXa and also inhibits thrombinLMWH has a reduced ability to inactivate thrombinHalf-life is dose dependent (30-150 min), can be up to 8 hr with LMWH
  • Anti-platelet agentsInactivates cyclooxygenase-1 (COX-1) preventing formation of thromboxane A2, which inactivates plateletsSingle dose suppresses for 1 wkNew platelet production recovers 10%/dayPatients may manifest normal hemostasis with as few as 20% platelets with normal COX1 activityAspirin half-life 15-30 minClopidogrel half-life 8 hr
  • FXa inhibitorsBinds to antithrombin III, catalyzing FXa inhibitionNo direct inhibitory effect on thrombinHalf-life 12-21 hr in normal renal function
  • DTIsCompetitively targets active site of thrombin +/- exosite (substrate binding site)Half-life long with dabigatran (14-17 hr) and short with others (20-45 min)

Diagnosis

  • Patient on anticoagulants with active bleeding
  • Indications for reversalSerious or life-threatening bleedingTraumaGI bleedingIntracerebral hemorrhage (ICH)Procedural

Signs and Symptoms

History

  • Type of anticoagulant
  • Last anticoagulant use
  • Length of anticoagulant
  • Recent injury or trauma
  • Bleeding location
  • Symptoms (fatigue, lightheadedness, headache, abdominal pain)

Physical Exam

  • VS +/- orthostatics
  • Search for hemorrhage locations/signs of trauma
  • Comprehensive neurologic exam
  • Rectal with stool guaiac test

Essential Workup

  • CBC
  • PT/INR
  • PTT
  • Stool guaiac test
  • +/- Fibrinogen/DIC panel

Diagnosis Tests & Interpretation

  • Indirect inhibitors of thrombin
  • Anti-platelet agents
  • FXa inhibitorsAnti-FXaPT, PTT minimally helpfulFondaparinux level (institution specific)
  • DTIsPTT minimally helpfulDabigatran level aka dilute thrombin time (institution specific)

Differential Diagnosis

  • Disseminated intravascular coagulopathy
  • Inherited coagulation disorders
  • Platelet dysfunction:

Treatment

Pre-Hospital

  • Pressure to hemorrhage (if possible)
  • 2 large-bore IVs
  • IV fluids

Initial Stabilization/Therapy

  • Same as pre-hospital
  • Hold anticoagulants

Ed Treatment/Procedures

  • Indirect inhibitors of thrombinLevel bleedingMinor: Observe PTT, anti-FXaMajor: Protamine (Class II for UFH and Class III for LMWH)Protamine1 mg IV neutralizes 100 U UFH administered in prior 3-4 hrIf <30 min since UFH, use 1 mg/100 U UFHIf 30-120 min, use 0.5 mg/100 U UFHIf >120 min, use 0.25 mg/100 U UFHGive slowly IV over 1-3 min not to exceed 50 mg in any 10-min periodShort half-life, may need to re-doseProtamine reversal effectiveness is compound specific for LMWH (does not reverse enoxaparin completely)1 mg for each 1 mg/100 IU LMWH given in last 8 hrIf 8-12 hr since LMWH, use 0.5 mg for each 1 mg/100 IU LMWHIf >12 hr since LMWH, no protamine suggestedFor LMWH, if PTT remains prolonged, may repeat with half of the 1st doseHigh or excessive dosing can have a paradoxical anticoagulant effectRapid administration can cause hypotension, bradycardia, and anaphylaxisAnaphylaxis is more likely with a fish allergy or prior exposure to protamine and if concerned, can premedicate with corticosteroids and antihistamines
  • Anti-platelet agentsLevel bleedingMinor: Observe bleedingMajor: DDAVP +/- platelet transfusion(s) (class III)Desmopressin (DDAVP)Induces the release of von Willebrand factor and factor VIII0.3 μg/kg IV over 15 minEffect is immediateMultiple doses associated with tachyphylaxis, hyponatremia, and seizuresPlateletsTransfuse to increase count by 50,000/μL (on average, 1 U increases platelet count by 10k)May need to repeat transfusions dailyRisks include infection transmission, acute lung injury, and allergic reactions
  • FXa inhibitorsLevel bleedingMinor: Observe bleedingMajor: PCC or rFVIIa (Class III), consider hemodialysis (HD) for fondaparinux, consider charcoal if rivaroxaban and ingested in previous 2 hrProthrombin complex concentrates (PCCs)3 factor: Contains factors II, IX, X and low concentrations of nonactivated factor VII + anticoagulant protein C, protein S, antithrombin III4 factor: Contains II, IX, X, activated VIIFactor 4 is now available widely in the USFDA approved for bleeding episodes in patients with hemophilia BDose 25-50 U/kg not to exceed 2 mL/minGive 1-2 U FFP for factor VIIa componentEffect in <30 minLimited data to support use in traumaVary widely in compositionLong-term safety has not been assessedAssociated with risk of thrombosisAllergic reactions may occurRecombinant activated factor VII (rFVIIa)FDA approved for bleeding episodes in patients with hemophilia A and BOff-label use for life-threatening bleedingDose 15-90 μg/kg (suggested 40 μg/kg) IV over 3-5 minEffect in <30 minMay repeat in 2 hr if continued bleedingAssociated with risk of thrombosisUltrafiltration/HDFor fondaparinux, may remove 20%Activated charcoalIf ingestion within 1-2 hr of rivaroxaban
  • DTIsLevel bleedingMinor: Observe bleeding (DTIs have short half-life except dabigatran, which is 14-17 hr), IV fluids to improve renal clearanceMajor: PCC or rFVIIa (no strong evidence for either), consider DDAVP, activated charcoal if within 1-2 hr ingestion, consider HD (especially if dabigatran)PCCDose 25-50 U/kg not to exceed 2 mL/minGive 1-2 U FFP if using 3 factorrFVIIaDose 100 μg/kg IV over 3-5 minMay repeat in 2 hr if continued bleedingDDAVPDose 0.3 μg/kg IV over 15 minDemonstrated effectiveness with hirudinUltrafiltration/HDConsider early in course for dabigatran and major bleedingActivated charcoalIf ingestion within 1-2 hr

Follow-Up

Disposition

Admission Criteria

  • Clinically significant bleeding
  • Utilization of reversal agents

Discharge Criteria

  • Insignificant bleeding that is controlled without the use of anticoagulant reversal
  • Discussion with outpatient hematologist or primary care physician (PCP) is ideal for follow-up

Issues for Referral

  • Blood bank reversal medication availability
  • Surgical/Interventional Radiology specialty availability to control hemorrhage

Followup Recommendations

Close follow-up and monitoring is paramount

Pearls and Pitfalls

  • Prophylactic heparin dosing does not typically confer an increased risk of major bleeding
  • LMWH is not always reversed with protamine-it is compound specific
  • If >12 hr have elapsed since LMWH administration, protamine may not be necessary
  • Single-dose aspirin suppresses COX1 for 1 wk
  • Caution is needed with renal impairment if utilizing FXa inhibitors, dabigatran, or hirudin derivatives
  • FFP as 1st-line replacement has to be weighed against extensive volume expansion

Additional Reading

  • Ageno W, Gallus AS, Wittkowsky A, et al. Oral anticoagulant therapy: Antithrombotic therapy and prevention of thrombosis. Chest. 2012;141:e44S-e88S.
  • Tawil I, Seder D, Duprey J. Emergency management of coagulopathy in acute intracranial hemorrhage. EB Medicine. EM Crit Car. 2012;2:2.
  • van Ryn J, Stangier J, Haertter S, et al. Dabigatran etexilate-a novel, reversible, oral direct thrombin inhibitor: Interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost. 2010;103:1116-1127.

Codes

ICD9

  • 286.6 Defibrination syndrome
  • 286.9 Other and unspecified coagulation defects
  • V58.61 Long-term (current) use of anticoagulants
  • 287.1 Qualitative platelet defects

ICD10

  • D65 Disseminated intravascular coagulation
  • D68.9 Coagulation defect, unspecified
  • Z79.01 Long term (current) use of anticoagulants
  • D69.1 Qualitative platelet defects
  • D68.8 Other specified coagulation defects

SNOMED

  • 64779008 Blood coagulation disorder (disorder)
  • 161647008 History of - anticoagulant therapy (situation)
  • 67406007 Disseminated intravascular coagulation (disorder)