Prothrombin Complex Concentrate Versus Plasma for Reversal of Anticoagulation

Prothrombin complex concentrate is a plasma derived concentrate of vitamin K dependent clotting factors, given for rapid reversal of vitamin K antagonists and, when specific agents are unavailable, for bleeding on factor Xa inhibitors. It corrects the international normalised ratio within minutes in a small volume, whereas plasma needs large volumes and time.

Composition. Four factor concentrate contains factors II, VII, IX and X with proteins C and S, and some products contain heparin. Three factor concentrate contains little factor VII. Doses are expressed in international units of factor IX.

Plasma comparison. Plasma contains all clotting factors at normal concentration, but its low concentration means that reversal needs about 10 to 15 mL/kg, takes hours to organise and infuse, and carries risks of overload, lung injury and allergy.

Time course. Concentrate acts within about 10 minutes, but factor VII has a half-life of about 6 hours, so vitamin K must be given at the same time to give lasting reversal, with its effect beginning in about 6 to 12 hours.

Special groups. Older adults, patients with atrial fibrillation or mechanical valves (thrombosis balance), pregnancy (warfarin is avoided, so this is rare), and renal impairment (direct oral anticoagulant accumulation). In East Africa, warfarin remains widely used, direct oral anticoagulants are increasing, and concentrate and specific reversal agents are often unavailable, so plasma with vitamin K is frequently the only option.

Indications for concentrate.

• Major bleeding (intracranial, gastrointestinal with instability, retroperitoneal, major trauma) in a patient on a vitamin K antagonist with an elevated international normalised ratio.

• Emergency surgery or procedure within about 6 to 8 hours in a patient on a vitamin K antagonist.

• Life-threatening bleeding on a factor Xa inhibitor (rivaroxaban, apixaban, edoxaban) when the specific reversal agent is unavailable.

Indications for plasma. Only when concentrate is not available, and in massive haemorrhage as part of balanced resuscitation.

Non-indications. Minor bleeding, elevated international normalised ratio without bleeding (use vitamin K orally in selected cases, with warfarin held), and routine pre-procedure correction in patients stable on warfarin.

Specific reversal agents. Dabigatran: idarucizumab 5 g intravenously (two 2.5 g doses). Factor Xa inhibitors: andexanet alfa where available, dosed by the product's scheme, or concentrate 25 to 50 units/kg when it is not. Unfractionated heparin: protamine about 1 mg for each 100 units given in the previous 2 to 3 hours, maximum single dose 50 mg. Low molecular weight heparin: protamine about 1 mg for each 1 mg of enoxaparin given in the previous 8 hours, with partial effect only.

Contraindications and cautions. Recent thromboembolism or high thrombotic risk (accept the risk in life-threatening bleeding), disseminated intravascular coagulation, heparin induced thrombocytopenia (if the product contains heparin), and previous hypersensitivity.

Dose of prothrombin complex concentrate. Two approaches are used. The most widely used is international normalised ratio based dosing:

• International normalised ratio 2 to under 4: 25 units/kg (maximum about 2500 units).

• International normalised ratio 4 to 6: 35 units/kg (maximum about 3500 units).

• International normalised ratio over 6: 50 units/kg (maximum about 5000 units).

The main alternative is a fixed dose, usually 1000 to 2000 units (about 25 units/kg) in adults, with a repeat dose as the response directs. For factor Xa inhibitor bleeding without specific agents, 25 to 50 units/kg is used. Follow the product specification.

Vitamin K. 5 to 10 mg intravenously by slow infusion over about 20 to 30 minutes, given with concentrate in all vitamin K antagonist reversal. In children, 0.3 mg/kg is a usual dose, up to 10 mg.

Dose of plasma. 10 to 15 mL/kg (about 3 to 4 units in a 70 kg adult), with a repeat dose as the international normalised ratio and bleeding direct, over 1 to 2 hours, slower if there is a risk of overload.

Rate. Concentrate is infused at the rate stated by the product, usually up to about 3 mL/minute (about 100 units/minute), and over several minutes. Weight-based doses are calculated on actual weight, up to a ceiling weight stated by the product (often 100 kg).

Monitoring. International normalised ratio 15 to 60 minutes after concentrate or plasma, bleeding control and neurological observations in intracranial bleeding. Repeat the international normalised ratio at 6 to 8 hours to detect rebound, and repeat vitamin K if needed.

Special groups.

• Renal impairment: direct oral anticoagulant effect lasts longer, so repeated reversal may be needed.

• Pregnancy: warfarin avoidance, with low molecular weight heparin as the usual agent, reversed with protamine.

• Mechanical heart valves: reverse in life-threatening bleeding, and restart anticoagulation as early as bleeding control allows.

• Older adults: lower weight based doses are not routinely required, but watch for overload with plasma.

Adverse effects. Thromboembolic events (in a few of every hundred patients in the days after reversal), allergic reactions, rarely heparin induced thrombocytopenia from heparin containing products, and for plasma, transfusion associated circulatory overload, transfusion related acute lung injury and allergy.

Failure of reversal. Causes include insufficient dose, severe liver disease, disseminated intravascular coagulation and ongoing bleeding from a surgical source.

Follow up. Restart anticoagulation once bleeding is controlled and the thrombotic risk justifies it, usually after several days, with the decision made with the specialist. Start thromboprophylaxis with a mechanical method early where needed. Review the indication for anticoagulation and the intensity of monitoring.

Referral and escalation. Haematology and the stroke, neurosurgical or surgical teams in life-threatening bleeding, cardiology for patients with mechanical valves, and the blood bank for concentrate supply.