Management

The general principles for the management of haemorrhage in the anticoagulated patient detailed using the mnemonic:

HASHTI [5]

1. Hold further doses of the anticoagulant
2. Consider using an Antidote
3. Supportive treatment – volume resuscitation and inotropic support
4. Local or surgical Haemostatic measures – also agents like tranexamic acid
5. Transfusion – packed red cells, platelets, etc
6. Investigate for the bleeding source

The use of novel anticoagulants is complicated by a lack of easily available laboratory tests to measure their levels and thereby optimize their clinical benefit and safety. Whereas UFH, LMWH, and warfarin therapy all can be monitored using either indirect or more specific quantitative assays, many of the novel anticoagulants are either not routinely monitored (e.g. Apixaban and fondaparinux) or are usually monitored using indirect tests (Dabigatran) [5-7].

Parenteral Anticoagulants – Heparins/Fondaparinux

Heparin and its derivatives are the most widely used parenteral anticoagulants in the UK, for the treatment and prophylaxis of thrombo-embolic disease. It produces its major anticoagulant effect by inactivating thrombin and activated factor X (factor Xa). By inactivating thrombin, heparin not only prevents fibrin formation but also inhibits thrombin-induced activation of platelets.

The main difference between UFH and LMWH is that the latter has relatively lower binding properties to plasma proteins, and a significantly reduced ability to inactivate thrombin. This reduced ability to bind plasma proteins is responsible for its predictable dose-response relationship, longer plasma half-life, and lower risk of heparin-induced thrombocytopenia and osteopenia. It is worth noting that LMWHs are cleared principally by the kidneys so should be avoided or dose reduced in patients with renal impairment were UFH is preferable [8,9].

Fondaparinux is a parenteral Factor Xa inhibitor like LMWH and similarly has no anti-thrombin activity, facilitating a more subtle regulation of coagulation with a safer therapeutic window [9,10].

Agent	Laboratory test and monitoring	Half-life	Reversing agent	Dose management
UFH	APTT/APTTr	45-90 mins	Protamine	1 mg/100iu
LMWH	Anti-factor Xa assay	3-6 hours	Protamine	1 mg/100iu (1 mg enoxaparin = 100 iu)
Fondaparinux	Anti-factor Xa assay	17 hours	Recombinant factor VIIa	90 µg/kg

Parenteral Anticoagulants – Reversal

The following approach describes the specific management of patients with bleeding when taking parenteral anticoagulants. It is worth noting patients given treatment dose UFH are routinely monitored (with APTT) and the dose adjusted to achieve the desired therapeutic range unlike LMWH and Factor Xa inhibitors which are not [3,5-10].

UFH is reliably and rapidly reversed with protamine sulphate, which binds to heparin to form a stable salt. Given heparin‘s half-life only that given during the preceding 4hrs needs to be considered; a patient receiving a continuous IV infusion of heparin at 1000iu/hr requires approximately 40 mg of protamine to neutralise heparin given in the past 4hrs.

Neutralisation of subcutaneously administered heparin may require a prolonged infusion of protamine as it has a half-life of approximately 7 minutes [11,12].

LMWH has no specific antidote for its reversal but protamine will neutralise approximately 60% of its anticoagulant effect. The dose is calculated for the LMWH given in the last 8 hours. A second dose of protamine 0.5mg/100iu is given if the bleeding persists. Smaller doses of protamine can be given if the time since LMWH exceeds 8 hours.

The effects of LMWHs cannot be acceptably measured using the APTT or activated clotting time tests; instead it can be monitored by the anti-factor Xa assay [11].

Fondaparinux does not bind to protamine. If major bleeding occurs, recombinant factor VIIa is used (despite no good evidence). Haemodialysis is an option in patients were bleeding does not settle as it reduces fondaparinux by 20%. Antifibrinolytic agents are another option in patients with life-threatening haemorrhage in the form of transexamic acid 1g IV. Anti-Xa activity can be used to indirectly monitor fondaparinux [6,10,11]. Figure 1 shows the management of over-coagulation in patients on parenteral anticoagulant.

Parenteral Anticoagulants – Overdose Management

After accidental or intentional overdose, bleeding is the most common feature. This may present as major or minor bleeding. Other features can include hypotension and cardiovascular collapse.

If bleeding is present the patient is managed as described in figure 1.

In asymptomatic patients observe for 6 hours for UFH and 24 hours for LMWH and Fondaparinux. Monitor heart rate, blood pressure and urine output and observe for features suggesting overt or occult bleeding.

Measure the APTT, FBC, U&Es, LFTs, and if LMWH or Fondaparinux is taken discuss with a haematologist for anti-Xa levels.

In UFH overdose, if the APTT is prolonged and there is no sign of bleeding, no further treatment is required. If high, the APTT should be monitored 6 hourly until it is within the therapeutic range and heparin restarted if clinically indicated [16].

The National Poisons Information Service (NPIS) can be contacted for further advice and it is always good practice to consult toxbase – the web-based poisons advice website.

Figure 1, Management of haemorrhage in parentral anticoagulation.

Click on the image to enlarge.

In asymptomatic patients observe for 6hrs for UFH and 24hrs for LMWH and Fondaparinux, monitor Hr, BP and urine output and observe for features suggesting overt or occult bleeding.

Measure the APTT, FBC, U&Es, LFTs, and if LMWH or Fondaparinux is taken discuss with a haematologist for anti-Xa levels.

In UFH overdose, if the APTT is prolonged and there is no sign of bleeding, no further treatment is required. If high the APTT should be monitored 6hrly until it is within the therapeutic range and heparin restarted if clinically indicated [16].

The National Poisons Information Service (NPIS) can be contacted for further advice and it is always good practice to consult the web-based poisons advice website. Refer to the Web Resources page for contact details.

Oral Anticoagulants – Vitamin K antagonists

Warfarin is the commonest VKA and anticoagulant in use worldwide, as it is well understood pharmacologically, cheap, and has effective reversal. It is highly water soluble so is rapidly absorbed in the GI system. It is used in the treatment of thrombo-embolic conditions, and the prevention of systemic embolism in patients with artificial heart valves and atrial fibrillation (AF).

Most patients on warfarin will have a target international normalised ratio (INR) of 2-3. It has a narrow therapeutic window with significant variability in dose responses in patients, and its therapeutic effects take 48-72 hours to develop with a half-life of 36-48 hours. Another important feature is the large number of commonly used drugs and foods that enhance and inhibit its effects. These key features increase the likelihood of over-coagulation and haemorrhage.

A prolonged INR without clinically evident bleeding necessitates cessation of warfarin, observation, serial INR measurements, cause for elevation investigated and maintenance dose reduced. There is an exponential rise in the risk of bleeding with increasing INR >5. However the exact risk for the individual is dependent on patient characteristics, including; older age, uncontrolled hypertension, diabetes, renal or liver failure, previous gastrointestinal or cerebral bleed and concurrent use of anti-platelets [13-15].

Vitamin K antagonists – Reversal

Patients who experience clinically significant bleeding should have their anticoagulation reversed with the following three approaches:

1. Omit warfarin and/or
2. Vitamin K (Vit K) and/or
3. Fresh frozen plasma (FFP) or prothrombin complex concentrates (PCCs) Beriplex or Octaplex. It is recommended that all hospitals managing patients on warfarin should stock PCC as it is more effective and has fewer complications than plasma [9,13-15]

The following Figure 2 gives a pathway suggested by the SIGN and the British committee for standards in haematology [2,13-15]:

Modality	Time to reverse an INR of 6-10 to <4.0	Pros/cons	Dose
Omit Wafarin	2-3 days	Slow reversal
Omit + oral Vit K	1-2 days	Cheap, action dependant on the Liver function	1-10mg
Low dose IV Vit K High dose IV Vit K	1-2 days Total reversal within 24hrs	Cheap, dependant on the Liver function	1-10mg 10-20mg
PCC + Vit K	Fast within 10 mins	Expensive, small infusion volume, easy to prepare and give, no infection risk	30-50 U/kg
FFP + Vit K	Fast but only given if PCC not available	Infection risk, volume overload, needs X-match, time to thaw, Risk of TRALI, cheaper than PCC	15 ml/kg

Vitamin K antagonists Overdose management

For major bleeding manage as described in figure 2 with the addition of activated charcoal if taken within 1 hour.

• Dose of vitamin K is 10-20 mg orally (250 mcg/kg for a child). Delay oral vitamin K for at least 4 hours after any activated charcoal has been given. Repeat INR at 24 hours and consider further vitamin K
• Measure INR (and clotting profile) at presentation then at 12 hourlyfor a minimum of 48 hours after ingestion

Figure 2  management of haemorrhage in the warfarinised patient

Click on the image to enlarge.

For those with minor or no bleeding, management is dependent on whether they are on long-term therapy or not [16].

• Look for any signs or symptoms that may suggest bleeding and ascertain when the overdose was taken
• Give activated charcoal 50 g for adults and 1 g/kg for children if presents within 1 hour and has taken more than 0.25 mg/kg or more than double there therapeutic dose
• Refer for psychiatric assessment before discharge

Not on long-term warfarin:

• Measure INR (and clotting profile)  at presentation then at 24 hours and 48 hours after ingestion depending on the dose taken
• If the INR remains normal for 24-48 hours and there is no evidence of bleeding, there should be no further monitoring necessary.
• Give vitamin K if:
• The patient has ingested more than 0.25 mg/kg
• The INR is >4.0
• Dose of vitamin K is 10-20 mg orally (250 mcg/kg for a child). Delay oral vitamin K1 at least 4 hours after any activated charcoal has been given. Repeat INR at 24 hours and consider further vitamin K1

On long-term warfarin

• Measure INR (and clotting profile)  at presentation then at 12hrly for a minimum of 48hrs after ingestion
• If there is no active bleeding but the INR is INR >= 8.0, give vitamin K slow IV: 0.5-1 mg for adults, 15-30 mcg/kg for children. Further doses may be given as necessary, titrated to INR. Large doses of Vitamin K may completely reverse the effects of warfarin and make it difficult to re-establish anticoagulation

Direct Oral Anticoagulants

These newer anticoagulants directly inhibit thrombin (Dabigatran) or factor Xa (Rivaroxaban, Apixaban etc) and have been recommended for use in the UK for thrombo-embolic prophylaxis. They have been shown to be more effective than and as safe as LMWH and warfarin, with more predictable pharmacokinetics, rapid onset of action, fixed dose regime and no requirement of monitoring. However there is still a potential for major life-threatening bleeds whether spontaneous or trauma-related.

Unlike warfarin coagulation assays have limitations. Dabigatran prolongs the APTT and PT but does not accurately quantify the amount of Dabigatran present; they will however determine the relative intensity of anticoagulation. For factor Xa inhibitors the PT is the most useful test to determine the relative intensity of anticoagulation, but cannot determine the drug levels.

For non-urgent assessment of anticoagulation there are specific tests available in reference labs that are sensitive and specific for the anticoagulant effect and plasma concentrations; namely the ecarin clotting time (ECT) and the hemoclot direct thrombin inhibitor assay (HDTI) for Dabigatran and chromogenic anti-factor Xa assays (CAX) for factor Xa inhibitors.

Dabigatran has a specific antidote in patients with severe haemorrhage – Idarucizumab5gram IV which completely reverses the effects of Dabigatran  It’s use is detailed in figure 3. Factor Xa inhibitors do not have a specific antidote.

Figures 3 and 4 are a summary of the available evidence for the reversal of over-coagulation related to the direct oral anticoagulants Dabigatran and factor Xa inhibits respectively

Fig 3

Click on the image to enlarge.

Fig 4

Click on the image to enlarge.

Direct Oral Anticoagulants Overdose management

There is little evidence on the management of factor Xa inhibitor and Dabigatran overdose. Common adverse effects following therapeutic use include an increased risk of bleeding, particularly epistaxis, haematuria and gastrointestinal bleeding. Other features include nausea, abdominal pain, abnormal LFTs and rash [16].

As with any emergency, maintain a clear airway and ensure adequate ventilation.

Assess the bleeding risk, looking for occult bleeding like haematuria or melaena. If major bleeding is present manage as described in figures 3 and 4.

The benefit of gastric decontamination is uncertain. Consider activated charcoal if the patient presents within 1 hour (charcoal dose: 50 g for adults; 1 g/kg for children) and have ingested:

• >10 mg/kg of Dabigatran
• Twice their daily dose or more of Dabigatran
• > 0.5 mg/kg of factor Xa inhibitor

Observe all patients for at least 6 hours after ingestion and monitor blood pressure and pulse, and check their FBC, U&Es, creatinine, LFTs and coagulation screen:

• APTT and thrombin time after ingestion of Dabigatran
• APTT and PT after ingestion of factor Xa inhibitors
• Consider repeating the coagulation screen at 6 hours after ingestion if initial screen is normal
• Continue monitoring until coagulation returns to normal
• It is worth noting that APTT and PT may be normal despite increased bleeding risk as they are not very sensitive to factor Xa activity [17]

In Dabigatran or factors Xa inhibitor overdose if the coagulation screen remains normal and there is no evidence of bleeding after 12-24 hours, further monitoring is not required.

There is some evidence that Dabigatran can be partly removed from plasma by haemodialysis, its effectiveness in overdose is unknown [21]. Consider the use of Idarucizumab 5 grams IV in severe haemorrhage associated with Dabigatran.

Check Toxbase and discuss the case with your local haematologist and the UK NPIS. Refer to the Web Resources page for contact details.

Discharge of all overdose cases

Patients should be seen by the psychiatric team if they have taken an intentional overdose prior to discharge. They should be advised to seek medical attention if symptoms subsequently develop.