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Warfarin Complications, Emergency Medicine

Basics

Description

- Contraindications include any condition in which the risk of hemorrhage or adverse reaction outweighs clinical benefit - Prior hypersensitivity - Skin reactions - Recent surgeries - Active or potential GI, intracerebral, or genitourinary bleeding - Fall risk

- Risk factors for nontherapeutic INR: - Age >75 yr - Hypertension, cerebrovascular disease, severe heart disease - Diabetes, renal insufficiency - Alcoholism or liver disease - Hypermetabolic states, fever - Hyperthyroidism - Cancer - Collagen vascular disease - Hereditary warfarin resistance - Cytochrome P450 polymorphism

- Subtherapeutic/low INR: Breakthrough thrombosis - Therapeutic and supratherapeutic: GI, CNS, retroperitoneal bleeding - Skin necrosis and limb gangrene: - Classic lesions of warfarin skin necrosis and limb gangrene begin on the 3rd " 8th day of therapy - Capillary thrombosis in subcutaneous fat (skin necrosis) and obstruction of venous circulation of the limb (limb gangrene) - Often associated with protein C deficiency - Eschar in center differentiates lesions from ecchymosis

- Intentional overdose - May be asymptomatic - Superwarfarin (rat poison) can result in prolonged bleeding risk (months) - Follow serial INR - Do not start vitamin K empirically, may mask late development of INR elevation - Consider activated charcoal

- Thorough history: - Many chief complaints are complicated by anticoagulation. - Reason for anticoagulation, recent dose changes, compliance, recent INR testing, other prescriptions, over the counter, and alternative medicines - Subtle changes in mental status, recent "minor falls, " or bleeding

- PT/PTT/INR: - Significant bleeding may occur even in INR therapeutic range. - PTT also elevated with toxicity - Elevations will be delayed in overdose

- Abdominal CT: - Blunt abdominal trauma without significant tenderness - Retroperitoneal hemorrhage - Solid organ or visceral injury

- Establish central IV access for hypotension not responsive to initial fluid bolus: - Replace lost blood as soon as possible - Initiate with O-negative blood until type-specific blood available. - 10 mL/kg bolus in children

- FFP: - Traditionally 3 " 4 U of FFP (1 L) are given to control continued bleeding in the short term without excessive risk of thromboembolism. - Additional units may be necessary - Follow serial INR closely - Patient response is variable and may not correlate with correction of the INR. - Side effects: - Fluid overload - Virus transmission-rare - Transfusion-related acute lung injury (TRALI) " rare

- Multiple studies show more rapid reversal of INR, reduction bleeding compared to FFP - Relationship to patient outcome has not been demonstrated - 4-factor PCC (Kcentra) is a fractionation product of FFP containing equal amounts of factors II, VII, IX, and X: - FDA approved in 2013, not widely available - For patients with an INR of 2 " 3.9, administer 25 U/kg, 4 " 5.9, 35 U/kg, and >6, 50 U/kg

- 3-factor PCC (Bebulin-VH, Profilnide-SD) contains very little factor VIIa: - Some use in combination with VIIa or VIIa alone depending on availability - 50 U/kg PCC and 1 " 2 mg FVIIa has been suggested - Consider FFP supplementation of FVIIa unavailable - More widely available in US - Warfarin reversal is off label use

- Active GI, retroperitoneal, or CNS bleeding - Anticoagulated trauma patient with evidence of active bleeding requires: - Reversal of anticoagulation and blood replacement - Early surgical consultation for operative intervention - Transport to a level 1 " trauma center after initial stabilization for definitive care.

  • Most commonly prescribed oral anticoagulant
  • Inhibits vitamin K metabolism required for activation of factors II, VII, IX, and X
  • Blocks the coagulation cascades extrinsic system and common pathway
  • Commonly used for venous thromboembolism and prevention of embolism with prosthetic heart valves or atrial fibrillation
  • Adjustments based on the international normalization ratio (INR)Typical therapeutic range 2 " 32.5 " 3.5 for mechanical valves and antiphospholipid syndromes
  • Contraindications include any condition in which the risk of hemorrhage or adverse reaction outweighs clinical benefitPrior hypersensitivitySkin reactionsRecent surgeriesActive or potential GI, intracerebral, or genitourinary bleedingFall risk

Etiology

  • Bleeding complications:15% of patients/yr4.9% major bleeding eventsUp to 0.8% fatal, most commonly intracranial hemorrhage (ICH)Bleeding risk is directly related to INRIncreases dramatically above 4
  • Risk factors for nontherapeutic INR:Age >75 yrHypertension, cerebrovascular disease, severe heart diseaseDiabetes, renal insufficiencyAlcoholism or liver diseaseHypermetabolic states, feverHyperthyroidismCancerCollagen vascular diseaseHereditary warfarin resistanceCytochrome P450 polymorphism

Common Interactions

View LargeIncrease INRDecrease INRMultiple antibioticsCarbamazepineNSAIDsBarbituatesAmiodoroneRifampinPropranololHaloperidolPrednisoneSt. John wortCimetidineHigh vitamin K foodsGrapefruit, garlicGinko biloba

  • Pregnancy class X
  • Crosses the placenta causing spontaneous abortion and birth defects

Diagnosis

Signs and Symptoms

  • Presentation may be occult or dramatic:High index of suspicion required to detect potentially life-threatening complications
  • Subtherapeutic/low INR: Breakthrough thrombosis
  • Therapeutic and supratherapeutic: GI, CNS, retroperitoneal bleeding
  • Skin necrosis and limb gangrene:Classic lesions of warfarin skin necrosis and limb gangrene begin on the 3rd " 8th day of therapyCapillary thrombosis in subcutaneous fat (skin necrosis) and obstruction of venous circulation of the limb (limb gangrene)Often associated with protein C deficiencyEschar in center differentiates lesions from ecchymosis
  • Intentional overdoseMay be asymptomaticSuperwarfarin (rat poison) can result in prolonged bleeding risk (months)Follow serial INRDo not start vitamin K empirically, may mask late development of INR elevationConsider activated charcoal

Essential Workup

  • Thorough history:Many chief complaints are complicated by anticoagulation.Reason for anticoagulation, recent dose changes, compliance, recent INR testing, other prescriptions, over the counter, and alternative medicinesSubtle changes in mental status, recent "minor falls, " or bleeding
  • Check for vital sign abnormalities:Early hemorrhagic shockHypertension and bradycardia may be secondary to Cushing response in ICH.Cardiac meds often mask important changes in vital signs.
  • Examine carefully for:Pallor, contusions, abrasions, ecchymosis, palpable pulses in affected extremity and skin lesionsCheck stool for blood.

Diagnosis Tests & Interpretation

Lab

  • PT/PTT/INR:Significant bleeding may occur even in INR therapeutic range.PTT also elevated with toxicityElevations will be delayed in overdose
  • CBC:Initial HCT inaccurate measure of acute rapid bleedingPlatelets:Aspirin and ADP inhibitors/Plavix result in normal platelet levels but qualitative deficits.
  • Electrolytes, BUN, creatinine, LFTs, and glucose:Elevated BUN may indicate blood in GI tract.Coingestants if intentional ingestion
  • Type and cross-match

Imaging

  • Low threshold for CT imaging to detect occult but life-threatening bleeding:
  • Head CT:Minor mechanisms of blunt head trauma without loss of consciousnessDetect ICH prior to symptom onset
  • Abdominal CT:Blunt abdominal trauma without significant tendernessRetroperitoneal hemorrhageSolid organ or visceral injury

Differential Diagnosis

  • All causes of bleeding:GI, retroperitoneal, CNS, and traumatic
  • Skin lesions " hemorrhagic skin disorders:Hemostatic deficits such as platelet disordersVascular purpuras including glucocorticoid use, vitamin C deficiency, purpura fulimnans, disseminated intravascular coagulation, Henoch " Sch Άnlein purpura, protein C deficiency

Treatment

Pre-Hospital

  • ABCs
  • Treat hypotension with 2 large-bore IV lines and 0.9% NS infusion.
  • Cardiac and pulse oximetry monitoring

Initial Stabilization/Therapy

  • Establish central IV access for hypotension not responsive to initial fluid bolus:
  • Replace lost blood as soon as possibleInitiate with O-negative blood until type-specific blood available.10 mL/kg bolus in children

Ed Treatment/Procedures

  • Specific management depends on the INR, presence of bleeding, reason for anticoagulation, and reliability of patient:INR <5 without bleeding:Lower or omit next dose.Recheck INR in 24 hr.INR ≥5 " <9 without bleeding:Omit next 1 or 2 doses or omit 1 dose and give 1 " 2.5 mg PO vitamin K.If at increased risk for bleeding or pre-op, then administer vitamin K 1 " 5 mg PO, INR will be lowered in 24 hr.Recheck INR in 24 hr.INR ≥9 without significant bleeding:Hold warfarin and give vitamin K 2.5 " 5 mg PO; INR will be substantially lowered in 24 " 48 hrINR >20 with minor bleeding or life-threatening bleeding regardless of INR:Hold WarfarinVitamin K 10 mg by slow IV infusionFresh frozen plasma (FFP) or prothrombin complex concentrate (PCC) depending on volume status and availabilityPCC shows faster INR reversal and hemostasis; however, no clear benefit has been shown in patient outcomePCC preferred in cases of ICH, volume overload, or massive bleeding.
  • In the setting of controlled bleeding, maintain the INR at the lower level of therapeutic efficacy:1.5 " 2 for atrial fibrillation2 " 2.5 with mechanical heart valves
  • Starting reversal agents before transferring patient leads to better outcomes

Medication

  • Vitamin K1phytonadione:Side effects:Anaphylaxis with IV >> IM or POSC absorption unpredictableIM administration may result in hematoma formation.Breakthrough thromboembolism with complete correction, prolonged risk if high dose vitamin K10 mg IV infusion over 10 " 30 min is recommended for life-threatening active bleeding with effects beginning in 1 " 2 hr
  • FFP:Traditionally 3 " 4 U of FFP (1 L) are given to control continued bleeding in the short term without excessive risk of thromboembolism.Additional units may be necessaryFollow serial INR closelyPatient response is variable and may not correlate with correction of the INR.Side effects:Fluid overloadVirus transmission-rareTransfusion-related acute lung injury (TRALI) " rare
  • PCC:Long shelf life and easy reconstitution into a highly concentrated volume (20 mL vs. 1 L of FFP per dose)Rapid reversal without volume overloadSide effects:ThrombosisLess virus transmission than FFPMultiple studies show more rapid reversal of INR, reduction bleeding compared to FFPRelationship to patient outcome has not been demonstrated4-factor PCC (Kcentra) is a fractionation product of FFP containing equal amounts of factors II, VII, IX, and X:FDA approved in 2013, not widely availableFor patients with an INR of 2 " 3.9, administer 25 U/kg, 4 " 5.9, 35 U/kg, and >6, 50 U/kg3-factor PCC (Bebulin-VH, Profilnide-SD) contains very little factor VIIa:Some use in combination with VIIa or VIIa alone depending on availability50 U/kg PCC and 1 " 2 mg FVIIa has been suggestedConsider FFP supplementation of FVIIa unavailableMore widely available in USWarfarin reversal is off label use

Follow-Up

Disposition

Admission Criteria

  • Active GI, retroperitoneal, or CNS bleeding
  • Anticoagulated trauma patient with evidence of active bleeding requires:Reversal of anticoagulation and blood replacementEarly surgical consultation for operative interventionTransport to a level 1 " trauma center after initial stabilization for definitive care.
  • Skin necrosis and limb gangrene requires admission for anticoagulation with alternative agents in consultation with a hematologist.
  • Subtheraputic patient may require adequate anticoagulation with inpatient heparin or low molecular weight heparin to prevent a breakthrough thromboembolism:Outpatient Lovenox therapy followed by increased warfarin with close follow-up prevents unnecessary hospitalization

Discharge Criteria

  • Asymptomatic reliable patient with a supratherapeutic INR after consideration of:Indication for anticoagulation, reason for supratherapeutic level, underlying comorbidities, overall risk of bleeding, fall risk, social situation, reliability, and availability of follow-up
  • Asymptomatic anticoagulated patient with minor trauma, therapeutic INR, stable hemoglobin, normal imaging studies, and reliable caretakers, can be discharged with close follow-up.

Issues for Referral

  • Patient should follow up with primary care physician or specialist within 24 " 48 hr of discharge for INR check and further warfarin adjustments.
  • Psychiatric referral for intentional overdose

Followup Recommendations

Educate patient on monitoring for signs and symptoms of excessive bleeding and/or new thrombotic event.

Pearls and Pitfalls

  • Maintain a low threshold for imaging trauma patients on warfarin
  • No vitamin K for an INR <5 without bleeding
  • Vitamin K1 IV may result in fatal anaphylaxis:Use only in patients with INR >20 with minor bleeding, or patients with life-threatening bleedingAdminister PO for everyone else.
  • For rapid reversal, FFP is still considered a 1st-line agent
  • 4-factor PCC, or 3-factor PCC/FVIIa should be used in patients with ICH, volume overload, or massive bleed

Additional Reading

  • Ansell J, Hirsh J, Hylek E, et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133:160S " 198S.
  • Denas G, Marzot F, Offelli P, et al. Effectiveness and safety of a management protocol to correct over-anticoagulation with oral vitamin K: A retrospective study of 1,043 cases. J Thromb Thrombolysis. 2009;27(3):340 " 347.
  • Garcia, DA, Crowther MA. Reversal of warfarin: Case-based practice recommendations. Circulation. 2012;125:2944 " 2947.
  • Sarode R, Matevosyan K, Bhagat R, et al. Rapid warfarin reversal: A 3-factor prothrombin complex concentrate and recombinant factor VIIa cocktail for intracerebral hemorrhage. J Neurosurg. 2012;116:491 " 497.

Codes

ICD9

  • 286.59 Other hemorrhagic disorder due to intrinsic circulating anticoagulants, antibodies, or inhibitors
  • V58.61 Long-term (current) use of anticoagulants

ICD10

  • D68.318 Oth hemorrhagic disord d/t intrns circ anticoag,antib,inhib
  • T45.515A Adverse effect of anticoagulants, initial encounter
  • Z79.01 Long term (current) use of anticoagulants

SNOMED

  • 191287000 Hemorrhagic disorder due to circulating anticoagulants (disorder)
  • 278365007 Anticoagulant-induced bleeding (disorder)
  • 293344008 Warfarin adverse reaction (disorder)
  • 170917004 Warfarin side effects (finding)
  • 294881007 Warfarin allergy (disorder)