Basics
Description
- 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 " 3
- 2.5 " 3.5 for mechanical valves and antiphospholipid syndromes
- 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
Etiology
- Bleeding complications:
- 15% of patients/yr
- 4.9% major bleeding events
- Up to 0.8% fatal, most commonly intracranial hemorrhage (ICH)
- Bleeding risk is directly related to INR
- Increases dramatically above 4
- 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
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 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
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 medicines
- Subtle changes in mental status, recent "minor falls, " or bleeding
- Check for vital sign abnormalities:
- Early hemorrhagic shock
- Hypertension 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 lesions
- Check stool for blood.
Diagnosis Tests & Interpretation
Lab
- PT/PTT/INR:
- Significant bleeding may occur even in INR therapeutic range.
- PTT also elevated with toxicity
- Elevations will be delayed in overdose
- CBC:
- Initial HCT inaccurate measure of acute rapid bleeding
- Platelets:
- 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 consciousness
- Detect ICH prior to symptom onset
- Abdominal CT:
- Blunt abdominal trauma without significant tenderness
- Retroperitoneal hemorrhage
- Solid 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 disorders
- Vascular 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 possible
- Initiate 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 hr
- INR >20 with minor bleeding or life-threatening bleeding regardless of INR:
- Hold Warfarin
- Vitamin K 10 mg by slow IV infusion
- Fresh frozen plasma (FFP) or prothrombin complex concentrate (PCC) depending on volume status and availability
- PCC shows faster INR reversal and hemostasis; however, no clear benefit has been shown in patient outcome
- PCC 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 fibrillation
- 2 " 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 PO
- SC absorption unpredictable
- IM administration may result in hematoma formation.
- Breakthrough thromboembolism with complete correction, prolonged risk if high dose vitamin K
- 10 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 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
- 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 overload
- Side effects:
- Thrombosis
- Less virus transmission than FFP
- 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
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 replacement
- Early surgical consultation for operative intervention
- Transport 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 bleeding
- Administer 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)