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Reversal of anticoagulation

Anticoagulants, also known as ‘blood thinners’, are drugs effective in the prevention and treatment of thromboembolic disorders. The decision to prescribe anticoagulation is governed by individual patient factors.

With the advent of heparin in the 1903s, anticoagulation therapy began. By the 1950s, oral anticoagulation was available in the form of warfarin. Unfractionated heparin (UFH) and warfarin were the mainstay of treatment of thromboembolic disorders until fractionated heparin (ie, low molecular weight heparins (LMWH)), were licensed in 1990, followed by parenteral direct thrombin (FIIa) inhibitors (lepirudin, argatroban, bivalirudin).

In 2008, the first of the direct oral anticoagulants (DOACs) were approved. Randomised trials have proven these novel agents to be safe and effective without monitoring, and these are increasingly used.

‘Each class of anticoagulant medication has a different target and therefore mechanism of action. It is not possible to have a ‘one-for-all’ reversal agent’

How then should one proceed should a patient on anticoagulation bleed? What is the best way to manage the patient who requires an emergency procedure while on anticoagulation? These questions often challenge physicians and generate much uncertainty in everyday practice. We have compiled this article to as a guide for clinicians.

General measures to stop bleeding

In cases of a minor bleed in the setting of over-anticoagulation, non-pharmacological measures are generally sufficient to treat or prevent bleeding. The following measures should be taken in all patients who have a bleeding event on anticoagulant therapy.

  1. Stop antithrombotic medication.
  2. Document the dose and the time the medication was last taken.
  3. Check for presence of pre-existing renal or hepatic impairment.
  4. Document the half-life of the medication taken.
  5. Access the source of bleeding.
  6. Request full blood count (FBC), prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen level, and serum creatinine level (Cr).
  7. If available, request a specific laboratory test to measure the antithrombotic effect of the drug (discuss with your haematology laboratory or the haematologist on-call).
  8. Apply mechanical pressure if possible.
  9. Correct haemodynamic compromise with intravenous fluids and red cell transfusion.
  10. Use endoscopic, radiological and surgical measures.

Specific measures for each anticoagulant medication

Each class of anticoagulant medication has a different target and therefore mechanism of action. It is not possible to have a ‘one-for-all’ reversal agent.

The following are the reversal options for the anticoagulants most commonly prescribed.

  • UFH: The half-life of UFH is one-to-two hours, therefore this anticoagulant can be reversed rapidly by protamine. This makes UFH still the anticoagulant of choice in situations requiring rapid reversal of the drug. UFH consists of a molecular chain of varying lengths and molecular weight (MW), from 5,000 to >40,000 daltons.
  • Mechanism of action: Heparin binds to antithrombin, which will produce its major anticoagulant effect by inactivating thrombin (FII) and factor X (FX). Thus, activity of UFH can be measured by APTT.
  • LMWH:  The most commonly-used LMWHs in Ireland are tinzaparin (half-life three-to-four hours) and enoxaparin (half-life two-to-eight hours). LMWHs consist of short-chain polysaccharides, average MW <8,000 daltons. These are obtained by various methods of fractionation or depolymerisation of polymeric heparin.
  • Mechanism of action: Similar to the action of UFH, LMWH also activates antithrombin and accelerates inactivity of FII and FX.  The binding of LMWH to antithrombin causes less inactivation of FII when compared with that of UFH. Thus the APTT, a measure of antithrombin activity, is not used to measure the activity of LMWH, which requires instead a specific anti-Xa assay. This can usually be arranged, if necessary, to determine the anticoagulant effect of a LMWH, on discussion with your haematology laboratory.
  • Warfarin: The half-life of warfarin is 36 hours, making the washout period of warfarin approximately five days. Warfarin has been the best-known anticoagulant for the last 50 years. Despite its effectiveness as an anticoagulant, treatment with warfarin has several disadvantages, mainly interaction with a larger number of medications, food and alcohol. Therefore, its anticoagulant effects need to be monitored by a blood test (PT/INR) regularly.
  • Mechanism of action: Warfarin inhibits the synthesis of the vitamin K-dependent clotting factors II, VII, IX and X and the anticoagulant proteins C and S. An anticoagulation effect generally begins within 24 hours after warfarin administration. However, peak anticoagulant effect may take up to 72-to-96 hours to be achieved. The duration of action of a single dose of warfarin is two-to-five days. This is consistent with the half-lives of the vitamin K-dependent clotting factors and anticoagulant proteins: FII -60 hours, FVII -four-six hours, FIX -24 hours, FX -48-72 hours, and proteins C and S are approximately eight hours and 30 hours, respectively. Warfarin is monitored by measurement of the PT/INR and in the majority of the cases, the target INR recommended is two-three.

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For reversal of anticoagulant effect of warfarin

1. Phytonadione (vitamin K).

Vitamin K will begin to reverse the effect of warfarin within six hours of administration and 70 per cent of the effect will be reversed within eight hours. The recommended dose is dependent on the INR and clinical situation (see Table 3).

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2. Prothrombin complex concentrate (PCC).

PCC is not routinely administered to reverse excessive anticoagulation in the absence of bleeding but should be administered in life-threatening major haemorrhage or if immediate urgent reversal is required to allow for surgery or an interventional procedure. PCC is more effective than fresh frozen plasma (FFP) for reversal of bleeding associated with excessive anticoagulation; therefore FFP is not indicated or recommended when PCC is available.

PCC contains FII, FVII, FIX, FX and protein C and S.

Dose: See Table 3.

Administration: Given as slow IV push over 10 minutes.

Onset: <30 minutes, repeat INR after 30 minutes of the dose.

Caution: Is advised for patients who are at high risk of thrombosis.

Reversal of DOACs

1) Dabigatran (oral direct thrombin inhibitor)

Dabigatran has a short half-life, 12-to-17 hours, in the setting of normal renal function. Thus the most important initial step for any patient with a bleeding complication is to discontinue the drug. Plasma half-life of dabigatran increases with deranged renal function and dabigatran is contraindicated in cases of severe renal impairment CrCl<30ml/min.

The management of bleeding in cases of dabigatran overdose should be individualised according to patient factors, the location and the severity of the haemorrhage. The initiation of appropriate treatment such as surgical haemostasis or transfusion support should be considered. Support is needed with crystalloids to facilitate rapid renal clearance of the drug. The APTT is currently the only readily-available lab test to qualitatively measure dabigatran. A quantitative test is available in some specialised coagulation laboratories, and should be discussed with haematology if required.

‘Despite its effectiveness as an anticoagulant, treatment with warfarin has several disadvantages, mainly interaction with a larger number of medications, food and alcohol’

Specific reversal agent: Idarucizumab is a new promising antidote for reversing the anticoagulant effects of dabigatran. Two centres in Ireland, Cork University Hospital and St James’s Hospital, Dublin, are participating in clinical trials investigating the safety and efficacy of this antibody. It is expected idarucizumab will be widely available from early 2016.

There is some evidence to support the use of PCC and rFVII for reversal of dabigatran in life-threatening situations when idarucizumab is not available. Use of these agents should always be first discussed with haematology, as they may carry thrombotic risk.

Activated charcoal may be considered in cases where dabigatran has been ingested within two hours. Haemodialysis may be considered as a last resort.

2) Rivaroxaban, apixaban and edoxaban (oral direct FXa inhibitors): The half-lives of these anticoagulants are: Rivaroxaban five-to-nine hours; apixaban eight-to-15 hours; and edoxaban nine-to-11 hours. Renal excretion of these is less than that of dabigatran and thus these are relatively safe in patients with mild renal impairment. However, dose adjustment may be required in some cases and these drugs are contraindicated in severe renal failure CrCl<15ml/min. The PT is currently the only readily-available laboratory test to qualitatively measure rivaroxaban and apixaban. Again, a quantitative test is available in some specialised coagulation laboratories, and should be discussed with haematology if required.

The most important first step for any patient with bleeding is to discontinue the drug.

There is no specific reversal agent yet available, though trials are ongoing. If >24 hours has elapsed since the last dose of an oral direct FXa inhibitor and the PT is within normal range, other causes for bleeding rather than over-medication should be considered.

There is some evidence to support the use of PCC and rFVII for reversal of rivaroxaban, apixaban and edoxaban. In cases of ingestion within two hours or overdose, activated charcoal may be considered, however, these agents are not expected to be dialysable due to their high level of protein binding.

Conclusion

In summary, the advent of heparin was the beginning of the evolution of anticoagulation and since then, many therapeutic drugs have been developed and licensed. Treatment agents continue to evolve and specific reversal agents are in clinical trial. Risk-benefit analysis remains applicable in all cases whether initiating, continuing, holding or stopping anticoagulant therapy. Protocols exist to guide us clinicians when there is a need to reverse anticoagulation.

These do not replace the role of the haematologist, whose advice should be sought where there is uncertainty, complexity or the need for reassurance.

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