Figure 1: Suggested Risk Stratification for Perioperative Thromboembolism

Adapted, with permission, from Douketis and collegues.111 Severe thrombophilia includes protein C, protein S, or antithrombin deficiency; antiphospholipid antibodies, or multiple abnormalities. Non-severe thrombophilia includes heterozygosity for factor V Leiden or prothrombin G20210A mutation. High risk patients also include those with a previous stroke or transient ischemic attack more than three months before the planned surgery and a CHADS2 score < 5, those with previous thromboembolism during temporary interruption of vitamin K antagonists, and those undergoing certain types of surgery associated with an increased risk for stroke or other thromboembolism (such as cardiac valve replacement, carotid endarterectomy, major vascular surgery). AF=atrial fibrillation; CHADS2 score=one point for each of the following: congestive heart failure, hypertension, age ≥ 75 years, and diabetes mellitus, and two points for a history of stroke or TIA; MVH=mechanical heart valve; TIA=transient ischemic attack; VTE=venous thromboembolism

Figure 2: Suggested Approach to Elective Pre-Procedure Management of Vitamin K Antagonists

Adapted from Daniels112. ACCP=American College of Chest Physicians; BT=bridging therapy; INR=international normalized ratio; LMWH=low molecular weight heparin;
UFH=unfractionated heparin21

Figure 3. Resuming Anticoagulation after Surgery

Procedure bleeding risk¹¹³ (Douketis et al):

High risk (2-day risk of major bleed 2% to 4% or higher)

• Heart valve replacement
• CABG
• AAA repair
• Neurosurgical, urologic, head and neck, abdominal, or breast cancer surgery
• Bilateral knee replacement
• Laminectomy
• Transurethral resection of the prostate
• Kidney biopsy
• Polypectomy, variceal treatment, biliary sphincterotomy, pneumatic dilatation
• Percutaneous endoscopic gastrostomy tube placement
• Endoscopically guided fine needle aspiration
• Multiple tooth extractions
• Vascular and general surgery
• Any major operation (duration >45 minutes)

Low risk (2-day risk of major bleed 0% to 2%)

• Cholecystectomy
• Abdominal hysterectomy
• GI endoscopy with or without biopsy, enteroscopy, biliary/pancreatic stent without sphincterotomy, endoscopic ultrasound without fine needle aspiration
• Permanent placement or cardiac defibrillator insertion with electrophysiologic testing
• Simple dental extractions
• Carpel tunnel repair
• Knee or hip replacement and shoulder, foot, or hand surgery
• Arthroscopy
• Dilatation and curettage
• Skin cancer excision
• Abdominal hernia repair
• Hemorrhoidal surgery
• Axillary node dissection
• Hydrocele repair
• Cataract and non-cataract eye surgery
• Non-coronary angiography
• Bronchoscopy with or without biopsy
• Removal of a central venous catheter
• Skin, bladder, prostate, thyroid, breast, and lymph node biopsies

Warfarin Considerations

• If INR ≤1.5, no reversal is necessary for minor surgical interventions (refer to Section 1 for the list)
• For ophthalmologic surgery, excluding cataract surgery, and neurosurgery, including lumbar puncture, complete reversal is required

Bridging Therapy

• Patients at high risk of thromboembolism such as patients with antiphospholipid antibody syndrome, recent/recurrent PE or DVTs, patients with mechanical valves, and atrial fibrillation based upon CHAD score: consider bridging anticoagulation with UFH or LMWH
  • Discontinue warfarin 5 days before procedure
  • Start therapeutic dose of LMWH when INR is below lower limit of targeted therapeutic range
  • If patient is maintained on LMWH, stop LMWH 24 hours prior to procedure.Last dose of LMWH should be reduced to 50% of the regular dose
  • If patient is maintained on UFH, hold UFH 4 hours prior to surgical procedure.Check APTT 1 hour prior to surgery to ensure adequate clearance of UFH
  • Check INR within 24 hours and morning of surgery. INR should be <1.5 prior to going to surgery
  • Resume anticoagulation (UFH or LMWH) within 24-72 hrs after surgery depending on the risk of bleeding
  • Note: If risk of immediate post-operative bleeding is minimal due to the surgery, then consideration should be given to initiating prophylactic dosing of LMWH  (0.5 mg/kg/dose q 12 hours for children and 40 mg, S.C. daily for adults)
• Reassess patient every 6-8 hours for clinical bleeding and decide about continuation of heparin (UFH or LMWH)
• Transition to warfarin may be initiated 24 hours after the surgery or any subsequent post-operative day depending on the bleeding risk and ability for oral intake and GI absorption
• Dose of warfarin: patient can resume regular maintenance dose depending on the risk of bleeding
  • Reduced dosing may be required if risk of bleeding persists
• UFH or LMWH should be continued until INR reaches therapeutic range. Two consecutive INRs performed 24 hours apart should be in the target INR range. It may take 2-5 days for INR  to increase if patient is resumed on his/her routine dose
• Refer to standard warfarin dosing guidelines

Figure 4: Chronic Warfarin Dose Adjustment in Non-Bleeding Patients

Reproduced from ASH Clinical Practice Guide on Antithrombotic Drug Dosing and Management of Antithrombotic Drug-Associated Bleeding in Adults (February 2014). This nomogram is suggested for nonbleeding patients with a target INR 2.0-3.0 who are out of range and who are not at high risk of bleeding.

• If INR >3.0 confirm no bleeding
• Consider noncompliance, illness, drug interaction, or dietary change as reason for out of range INR
• Clinical judgment should supersede this nomogram

Vitamin K Dosing for Warfarin Reversal

• Vitamin K half-life: 1.5-3.0 hours
• I.V. route recommended for emergent reversal. Full effect of I.V. vitamin K is achieved within 6 hours, P.O. effect in 24 hours. Subcutaneous or intramuscular administration NOT recommended for emergent reversal due to unpredictable absorption and risk of intramuscular bleeding
• Large doses can cause warfarin resistance on resumption of therapy
• May not be effective in the face of significant hepatic dysfunction/failure due to poor liver synthetic function of coagulation factors
• Vitamin K preparations available in USA:
  • Intravenous preparation: Brand name: Mephyton^® (Pharmaceutical company: Merck)
    • Concentration: 10 mg/mL and 2 mg/mL
    • Small risk of anaphylaxis with rapid infusion, possibly due to polyoxyethylated castor oil (preservative)
    • Administration precaution: slow administration over 20-30 minutes 
  • Oral preparation: Brand name: Mephyton^® (Pharmaceutical company: Merck)
    • Tablet: 5 mg tablets
    • Please note, I.V. preparation can be used as oral preparation

Table 4A: Recommended Adult Dosing of Vitamin K as an Antidote for Warfarin(Vitamin K Antagonists) Reversal

Prothrombin Complex Concentrates (PCC) for Warfarin (VKA) Reversal:

• The concentration of coagulation factors is 25 times higher in PCC than in plasma. Hence, the dose of PCC is 1/25th of plasma dose. Dose of PCC is dependent upon patient’s body weight, desired reduction of INR, and presence or absence of active bleeding. PCC unit label is in factor IX activity units
• Kcentra is the only PCC FDA approved for urgent warfarin reversal during acute major bleeding or need for urgent surgery. Use of all other PCC concentrates for this indication is off-label
• If 4-factor PCC is not available, 3-factor PCC supplemented with FFP is appropriate

Note: 3-factor PCC preparations in U.S. contain negligible quantity of FVII, hence concurrent infusion of FFP at 10-15 mL/kg is required for effective warfarin reversal

Table 5: Recommended Dosing of Prothrombin Complex Concentrates for Warfarin Reversal Available in the U.S. (Grade 2C)

Repeat dosing of PCC may be required for persistent bleeding

Kcentra: FIX:FII:FVII:FX = 1:1:1:1

• Vial Sizes: 500, 1000 IU
• Plasma-derived, contains heparin

Profilnine: FIX:FII:FX = 1:1.5:1

• Vial sizes: 500, 1000, 1500 IU
• Plasma-derived, does not contain heparin

Bebulin: FIX:FII:FX = 1:1:1

• Vial Sizes: 200-1200 IU
• Plasma-derived, contains heparin

FEIBA:

• Activated PCC that contains factors II, VII, IX and X, factor VII in mostly activated form. Given its potential increased prothrombotic risk, it is generally not used for reversing warfarin anticoagulation.

Recombinant Factor VIIa (rVIIa, NovoSeven RT) for Warfarin (VKA) Reversal:

• In the U.S., NovoSeven RT is FDA approved for treatment of FVII deficiency as well as a bypassing agent for acquired hemophilia and congenital hemophilia A or B with inhibitors. Its use for antithrombotic reversal is off-label and carries a significant risk of thrombosis (5-10%)
• Mechanism of action of rVIIa: Generation of thrombin burst either via tissue factor pathway or independent of tissue factor in association with phospholipids on cell  membrane
• Off-label experience, absence of high quality data: Warfarin-associated bleeding, reversal of direct thrombin inhibitors, reversal of factor Xa inhibitors, coagulopathy of liver dysfunction, acute intracerebral hemorrhage, post-traumatic hemorrhage, reversal of GPIIb/IIIa antagonists, inherited disorders of platelet dysfunction
• Given paucity of high-quality data, thrombosis risk and cost: off-label rVIIa should be considered only for bleeding conditions for which no other therapy is available or when hemorrhage has not responded to conventional therapy
• Dosing: 15-90 mcg/kg depending on coagulopathy and bleeding severity
  • If the degree of hemostatic impairment is severe: initial dose of 90 mcg/kg
  • rVIIa has a short t1/2 of 4-6 hrs, repeat dosing may be required
  • Vial size: 1, 2, 5, and 8 mg

rVIIa for VKA reversal

• It is preferable to use Kcentra (4-factor PCC) for VKA reversal. If Kcentra is not available, we would recommend using 3-factor PCC + FFP
• NovoSeven RT corrects the INR as the INR is especially sensitive to FVII activity; this may not equate to hemostasis in vivo as it does not replace other coagulation factors (II, IX, X)
• Various dosing strategies have been reported for INR reversal with NovoSeven RT. Several reports suggest that a lower dosing strategy of 10-20 mcg/kg may be just as effective as a higher dosing strategy of 80-90 mcg/kg. The use of rVIIa for VKA reversal is off-label. If used, the appropriate dosing strategy is at the clinician’s discretion. The severity of clinical bleeding, potential morbidity, and the degree of INR elevation should be considered when choosing the appropriate rVIIa dose. For life-threatening VKA-related bleeding (i.e., intracranial bleeding), a higher dose of 90 mcg/kg should be considered. For non-life-threatening bleeding, a lower initial dose of 15-30 mcg/kg may be considered.