Coagulopathy Reversal (Nonwarfarin Agents), Emergency Medicine

Basics

Description

Patient on anticoagulant medications with minor, major, or clinically significant bleeding needing close monitoring +/- anticoagulant reversal
Anticoagulant medication
- Indirect inhibitors of thrombin
  - Unfractionated heparin (UFH)
  - Low-molecular-weight heparin (LMWH)
    - Enoxaparin
    - Dalteparin
    - Tinzaparin
- Anti-platelet agents
  - Aspirin
  - Clopidogrel hydrogen sulfate (Plavix)
- Factor Xa inhibitors (FXa inhibitors)
  - Fondaparinux (Arixtra)
  - Rivaroxaban (Xarelto)
- Direct thrombin inhibitors (DTIs)
  - Argatroban
  - Bivalirudin (Angiomax)
  - Dabigatran (Pradaxa)
  - Hirudin derivatives
    - Desirudin
    - Lepiruden (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 thrombin
- Up to 1/3 patients develop bleeding complication
- 2-6% of bleeding is major
Anti-platelet agents
- >300 over-the-counter medications contain aspirin
- Conflicting studies regarding increased hematoma expansion and mortality
FXa Inhibitors
- Unknown
DTIs
- Unknown

Etiology

Indirect inhibitors of thrombin
- Combines with antithrombin III to inactivate activated FXa and also inhibits thrombin
- LMWH has a reduced ability to inactivate thrombin
- Half-life is dose dependent (30-150 min), can be up to 8 hr with LMWH
Anti-platelet agents
- Inactivates cyclooxygenase-1 (COX-1) preventing formation of thromboxane A2, which inactivates platelets
- Single dose suppresses for 1 wk
- New platelet production recovers 10%/day
- Patients may manifest normal hemostasis with as few as 20% platelets with normal COX1 activity
- Aspirin half-life 15-30 min
- Clopidogrel half-life 8 hr
FXa inhibitors
- Binds to antithrombin III, catalyzing FXa inhibition
- No direct inhibitory effect on thrombin
- Half-life 12-21 hr in normal renal function
DTIs
- Competitively 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 reversal
- Serious or life-threatening bleeding
  - Trauma
  - GI bleeding
  - Intracerebral 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
- PTT
- Anti-FXa
  - High is >0.8 U/mL
Anti-platelet agents
- Bleeding time
FXa inhibitors
- Anti-FXa
- PT, PTT minimally helpful
- Fondaparinux level (institution specific)
DTIs
- PTT minimally helpful
- Dabigatran level aka dilute thrombin time (institution specific)

Differential Diagnosis

Disseminated intravascular coagulopathy
Inherited coagulation disorders
Platelet dysfunction:
- TTP/HUS
- HIT
- ITP

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 thrombin
- Level bleeding
  - Minor: Observe PTT, anti-FXa
  - Major: Protamine (Class II for UFH and Class III for LMWH)
- Protamine
  - 1 mg IV neutralizes 100 U UFH administered in prior 3-4 hr
    - If <30 min since UFH, use 1 mg/100 U UFH
    - If 30-120 min, use 0.5 mg/100 U UFH
    - If >120 min, use 0.25 mg/100 U UFH
  - 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
Anti-platelet agents
- Level bleeding
  - Minor: Observe bleeding
  - Major: DDAVP +/- platelet transfusion(s) (class III)
- Desmopressin (DDAVP)
  - Induces the release of von Willebrand factor and factor VIII
  - 0.3 Î¼g/kg IV over 15 min
  - Effect is immediate
  - Multiple doses associated with tachyphylaxis, hyponatremia, and seizures
- Platelets
  - Transfuse to increase count by 50,000/Î¼L (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
FXa inhibitors
- Level bleeding
  - Minor: Observe bleeding
  - Major: PCC or rFVIIa (Class III), consider hemodialysis (HD) for fondaparinux, consider charcoal if rivaroxaban and ingested in previous 2 hr
- Prothrombin complex concentrates (PCCs)
  - 3 factor: Contains factors II, IX, X and low concentrations of nonactivated factor VII + anticoagulant protein C, protein S, antithrombin III
  - 4 factor: Contains II, IX, X, activated VII
    - Factor 4 is now available widely in the US
  - 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
    - Several contain heparin
  - Long-term safety has not been assessed
  - Associated with risk of thrombosis
  - Allergic reactions may occur
- Recombinant activated factor VII (rFVIIa)
  - FDA approved for bleeding episodes in patients with hemophilia A and B
  - Off-label use for life-threatening bleeding
  - Dose 15-90 Î¼g/kg (suggested 40 Î¼g/kg) IV over 3-5 min
  - Effect in <30 min
  - May repeat in 2 hr if continued bleeding
  - Associated with risk of thrombosis
- Ultrafiltration/HD
  - For fondaparinux, may remove 20%
- Activated charcoal
  - If ingestion within 1-2 hr of rivaroxaban
DTIs
- Level bleeding
  - Minor: Observe bleeding (DTIs have short half-life except dabigatran, which is 14-17 hr), IV fluids to improve renal clearance
  - Major: PCC or rFVIIa (no strong evidence for either), consider DDAVP, activated charcoal if within 1-2 hr ingestion, consider HD (especially if dabigatran)
- PCC
  - Dose 25-50 U/kg not to exceed 2 mL/min
  - Give 1-2 U FFP if using 3 factor
- rFVIIa
  - Dose 100 Î¼g/kg IV over 3-5 min
  - May repeat in 2 hr if continued bleeding
- DDAVP
  - Dose 0.3 Î¼g/kg IV over 15 min
  - Demonstrated effectiveness with hirudin
- Ultrafiltration/HD
  - Consider early in course for dabigatran and major bleeding
- Activated charcoal
  - If 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)

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