Reversal, decided by the bleed — not by the number.

• Rapidly reverse anticoagulation in patients who have major trauma with haemorrhage.
• Hospital trusts that admit patients with major trauma should have a protocol for the rapid identification of patients who are taking anticoagulants and the reversal of anticoagulation agents.
• Use prothrombin complex concentrate immediately in adults (16 or over) with major trauma who have active bleeding and need emergency reversal of a vitamin K antagonist.
• Do not use plasma to reverse a vitamin K antagonist in patients with major trauma.
• Consult a haematologist immediately for advice on adults (16 or over) who have active bleeding and need reversal of any anticoagulant agent other than a vitamin K antagonist.
• Consult a haematologist immediately for advice on children (under 16s) with major trauma who have active bleeding and may need reversal of any anticoagulant agent.
• Do not reverse anticoagulation in patients who do not have active or suspected bleeding.

NG39 also directs the reader to the MHRA safety advice on DOACs for a list of reversal agents.

• Use intravenous tranexamic acid as soon as possible in patients with major trauma and active or suspected active bleeding.
• Do not use intravenous tranexamic acid more than 3 hours after injury in patients with major trauma unless there is evidence of hyperfibrinolysis.
• For patients with active bleeding use a restrictive approach to volume resuscitation until definitive early control of bleeding has been achieved.
• In hospital settings do not use crystalloids for patients with active bleeding.
• For adults (16 or over) use a ratio of 1 unit of plasma to 1 unit of red blood cells to replace fluid volume. For children (under 16s) use a ratio of 1 part plasma to 1 part red blood cells, and base the volume on the child's weight.
• For patients with active bleeding, start with a fixed-ratio protocol for blood components and change to a protocol guided by laboratory coagulation results at the earliest opportunity.

NICE noted in February 2016 that this was an off-label use of tranexamic acid.

• Offer immediate prothrombin complex concentrate transfusions for the emergency reversal of warfarin anticoagulation in people with either: severe bleeding, or head injury with suspected intracerebral haemorrhage.
• Consider immediate prothrombin complex concentrate transfusions to reverse warfarin anticoagulation in people having emergency surgery, depending on the level of anticoagulation and the bleeding risk.
• Monitor the international normalised ratio (INR) to confirm that warfarin anticoagulation has been adequately reversed, and consider further prothrombin complex concentrate.

NG24 cross-refers to NICE's stroke guideline for reversal in primary intracerebral haemorrhage, and to the MHRA safety advice on DOACs for reversing direct-acting oral anticoagulants.

• All hospitals managing patients on warfarin should stock a licensed four-factor PCC (1C).
• Emergency anticoagulation reversal in major bleeding should be with 25–50 U/kg four-factor PCC and 5 mg intravenous vitamin K (1B).
• Recombinant factor VIIa is not recommended for emergency anticoagulation reversal (1B).
• Fresh frozen plasma produces suboptimal anticoagulation reversal and should only be used if PCC is not available (1C).
• Anticoagulation reversal for non-major bleeding should be with 1–3 mg intravenous vitamin K (1B).
• Patients with an INR > 5.0 but who are not bleeding should have 1–2 doses of warfarin withheld and their maintenance dose reduced (1B). The cause of the elevated INR should be investigated (1C).
• Asymptomatic patients with an INR of ≥ 8.0 should receive 1–5 mg of oral vitamin K (1B). The INR should be rechecked the following day in case an additional dose of vitamin K is required.
• For surgery that requires reversal of warfarin and that can be delayed 6–12 h, the INR can be corrected by giving intravenous vitamin K. For surgery that cannot be delayed, the INR can be corrected by giving PCC and intravenous vitamin K. PCC should not be used to enable elective or non-urgent surgery (2C).

For acenocoumarol, phenindione and phenprocoumon the principles are the same, but further vitamin K should be considered for the agents with longer half-lives.

Both UK four-factor PCCs use the same dose bands, expressed as IU of factor IX per kg:

Beriplex P/N: "The correction of the vitamin K antagonist-induced impairment of haemostasis is commonly reached approximately 30 minutes after the injection." And: "Repeated dosing with Beriplex for patients requiring urgent reversal of vitamin K antagonist treatment is not supported by clinical data and therefore not recommended."

Octaplex: correction persists approximately 6–8 hours, while co-administered vitamin K takes effect within 4–6 hours, "thus, repeated treatment with human prothrombin complex is not usually required when vitamin K has been administered". Octaplex is given at 0.12 mL/kg/min (~3 units/kg/min), to a maximum of 8 mL/min.

The maximum single doses in both SmPCs are framed around patients over 100 kg. Note the mismatch worth knowing about: the SmPC tables start at INR 2.0 and cap the dose, whereas BSH quotes a flat 25–50 U/kg range — many trust protocols use a fixed 30 U/kg or a fixed 500/1000 IU-vial regimen instead. Use your trust's protocol and the SmPC for the product your trust actually stocks.

• Transfuse patients with massive bleeding with blood, platelets and clotting factors in line with local protocols for managing massive bleeding.
• Base decisions on blood transfusion on the full clinical picture, recognising that over-transfusion may be as damaging as under-transfusion.
• Do not offer platelet transfusion to patients who are not actively bleeding and are haemodynamically stable.
• Offer platelet transfusion to patients who are actively bleeding and have a platelet count of less than 50 × 10⁹/litre. Offer fresh frozen plasma to patients who are actively bleeding and have a prothrombin time (or INR) or APTT greater than 1.5 times normal. If fibrinogen remains less than 1.5 g/litre despite FFP, offer cryoprecipitate as well.
• Offer prothrombin complex concentrate to patients who are taking warfarin and actively bleeding.
• Treat patients who are taking warfarin and whose upper gastrointestinal bleeding has stopped in line with local warfarin protocols.
• Do not use recombinant factor VIIa except when all other methods have failed.

Also: Blatchford score at first assessment and full Rockall after endoscopy; consider early discharge if the pre-endoscopy Blatchford score is 0; endoscopy immediately after resuscitation in unstable patients with severe bleeding, and within 24 hours for everyone else. Do not offer acid suppression before endoscopy in suspected non-variceal bleeding; offer PPIs after endoscopy where there are stigmata of recent haemorrhage. For suspected variceal bleeding, offer terlipressin and prophylactic antibiotics at presentation. Continue low-dose aspirin for secondary prevention once haemostasis is achieved.

"Andexanet alfa is recommended as an option for reversing anticoagulation from apixaban or rivaroxaban in adults with life-threatening or uncontrolled bleeding, only if: the bleed is in the gastrointestinal tract, and the company provides andexanet alfa according to the commercial arrangement."

The committee's reasoning is worth carrying in your head: there is no trial directly comparing andexanet alfa with PCC. An indirect comparison suggested improved survival in gastrointestinal bleeding or ICH, but lower survival for bleeds elsewhere, and the comparison is uncertain. The cost-effectiveness estimates were within NICE's acceptable range for gastrointestinal bleeding but not for ICH or other sites — hence a recommendation that stops at the GI tract.

For intracranial haemorrhage there is no NICE recommendation to rely on: TA697 records that this part has been "updated and replaced by NICE's technology appraisal guidance on andexanet alfa for reversing anticoagulation in people with intracranial haemorrhage (terminated appraisal)".

Andexanet alfa is for apixaban and rivaroxaban. It is not the answer for edoxaban, dabigatran, or a vitamin K antagonist. The licensed indication is "adult patients".

Dosing (Ondexxya SmPC 4.2)

Choose by the drug, its dose and the time since the last dose: apixaban 5 mg or less, or rivaroxaban 10 mg or less — low dose regardless of timing. Above those doses — high dose if the last dose was less than 8 hours ago, low dose at 8 hours or more.

Anticoagulant activity from a factor Xa inhibitor or LMWH is anticipated to return within 4 hours of the end of the infusion; antithrombotic therapy can be re-initiated as soon as medically indicated once the patient is stable and haemostasis is adequate.

"The recommended dose is 5 g idarucizumab (2 vials of 2.5 g/50 mL)", "administered intravenously as two consecutive infusions over 5 to 10 minutes each or as a bolus injection."

A second 5 g dose may be considered in patients with recurrent bleeding and prolonged clotting times, those at risk of life-threatening re-bleeding with prolonged clotting markers, or those needing a second emergency procedure with prolonged coagulation parameters.

"Dabigatran etexilate treatment can be re-initiated 24 hours after administration of idarucizumab, if the patient is clinically stable and adequate haemostasis has been achieved." Other antithrombotic therapy such as LMWH can be started at any time once the patient is stable and haemostasis is adequate.

Praxbind is restricted to hospital use.

Unfractionated heparin has a plasma half-life of 45–90 minutes at therapeutic intravenous doses, so stopping it plus general measures is often enough. Where it is not, protamine sulphate forms a stable, inactive salt with heparin.

Unfractionated heparin

Dose from the quantity of UFH given in the preceding 2 hours, assuming 1 mg protamine neutralises 80–100 units of UFH. BSH's own worked examples: bleeding during an infusion of 1250 units/h requires 25 mg protamine; bleeding soon after a 5000-unit bolus requires 50 mg. Monitor the reversal effect with the APTT.

Low molecular weight heparin

Protamine reverses approximately 60% of LMWH. The BSH recommendations:

• LMWH given within 8 hours of the time reversal is needed: protamine sulphate 1 mg per 100 anti-Xa units of LMWH. If ineffective, consider a further 0.5 mg per 100 anti-Xa units (2C).
• LMWH given more than 8 hours before: consider smaller doses of protamine (2C).
• Consider rFVIIa only if life-threatening bleeding continues despite protamine and the timing suggests residual LMWH effect (2C).

Give protamine slower than 5 mg/min to minimise adverse reactions. Its half-life is about 7 minutes — shorter than UFH — so prolonged administration may be needed after subcutaneous heparin, where entry into the circulation is delayed. Severe allergic reactions including anaphylaxis, hypotension, bronchospasm and skin reactions occur in up to 10% of patients.

The APTT may be prolonged by LMWH but should not be used to assess the extent of its effect — that is the anti-Xa test.

"For people with a head injury and a GCS score of 12 or less who are not thought to have active extracranial bleeding, consider:

• a 2 g intravenous bolus injection of tranexamic acid for people 16 and over
• a 15 mg/kg to 30 mg/kg (up to a maximum of 2 g) intravenous bolus injection of tranexamic acid for people under 16.

Give the tranexamic acid as soon as possible within 2 hours of the injury, in the pre-hospital or hospital setting and before imaging." NICE noted in March 2023 that these were off-label uses.

Where there is suspected or confirmed extracranial bleeding as well, NG232 hands over to the major trauma guideline instead — which is the 3-hour window, not the 2-hour one.

HALT-IT — tranexamic acid does not belong in GI bleeding

12,009 patients with significant upper or lower gastrointestinal bleeding, randomised to high-dose tranexamic acid (1 g loading dose then 3 g over 24 h) or placebo. Death due to bleeding within 5 days: 222/5956 (4%) with tranexamic acid versus 226/5981 (4%) with placebo, RR 0.99 (95% CI 0.82–1.18). Venous thromboembolic events were higher with tranexamic acid: 48/5952 (0.8%) versus 26/5977 (0.4%), RR 1.85 (95% CI 1.15–2.98). The authors' conclusion: "tranexamic acid should not be used for the treatment of gastrointestinal bleeding outside the context of a randomised trial."

This is the single most transferable error in this tool's subject area: the trauma reflex of early tranexamic acid is not just unhelpful in GI bleeding, it carries a thrombotic cost.

PATCH — platelets are not the answer for antiplatelet-associated ICH

190 participants with spontaneous intracerebral haemorrhage while on antiplatelet therapy, randomised to platelet transfusion or standard care. The odds of death or dependence at 3 months were higher with platelet transfusion (adjusted common odds ratio 2.05, 95% CI 1.18–3.56; p=0.0114). The authors: "Platelet transfusion cannot be recommended for this indication in clinical practice."

PATCH studied spontaneous ICH, not traumatic ICH or surgical bleeding, so it does not settle every case — but it removes any assumption that platelets are the obvious antidote to an antiplatelet.

From the BSH guideline's table of non-pharmacological measures:

• Stop the antithrombotic drug.
• Document the timing and amount of the last drug dose, and any pre-existing renal or hepatic impairment.
• Estimate the half-life and the length of the functional defect the drug has caused.
• Assess the source of bleeding.
• Request full blood count, prothrombin time, APTT, thrombin time, fibrinogen concentration, creatinine concentration — and, if available, a specific assay for the drug's effect.
• Correct haemodynamic compromise with intravenous fluids and red cell transfusion.
• Apply mechanical pressure if possible; use endoscopic, radiological or surgical measures.

Renal function matters more than it feels like it should: dabigatran is about 80% renally eliminated, with a half-life of roughly 13 hours normally and 22–35 hours when creatinine clearance is under 30 mL/min. In renal impairment, "wait for it to wear off" is a much longer plan than you think.