Anticoagulants: indications, overdoses and complications

Overdoses and complications of anticoagulant treatments are common in outpatient practice and even more so in inpatient settings. Generally easy to correct, they must be recognized quickly to avoid hemorrhagic consequences.

General Information and Indications

Unfractionated Heparin

Administered only IV via syringe pumps, it has three advantages:

• Rapidly effective and quickly reversible action
• Effective antidote (protamine)
• Easy monitoring (aPTT). Disadvantage: monitoring is required 1 to 6 times/day depending on the situation.

For these reasons, it is frequently used in hospital settings for the following indications:

• Initial treatment of many acute conditions requiring anticoagulation, especially those at high hemorrhagic risk
• As a bridge for other types of anticoagulants when monitoring of activity and/or rapid interruption and resumption of treatment are necessary

Low-Molecular-Weight Heparins (LMWH)

Administered SC 1 to 2 times/day depending on the type of LMWH.

They have the following disadvantages: monitoring (anti-Xa activity) is less available in clinical practice (but usually not necessary), antidote (protamine) is less effective than for unfractionated heparin, and onset/cessation of action is slower than unfractionated heparin.

They are commonly used both in outpatient and inpatient settings:

• At reduced doses: antithrombotic prophylaxis for bedridden patients
• Initial treatment of many acute conditions before switching to oral anticoagulants
• As a bridge for oral anticoagulants when planning situations where the treatment needs to be temporarily interrupted

Vitamin K Antagonists (VKA)

VKAs (acenocoumarol, warfarin) are "old-generation" oral anticoagulants still widely used in outpatient practice for any situation requiring long-term anticoagulation. Regular monitoring is possible and necessary (INR), and an antidote (vitamin K) exists. Anticoagulant activity is subject to numerous drug interactions, intercurrent illnesses, and dietary changes (→ temporarily increase monitoring frequency as needed, patient education).

Main indications:

• Treatment of DVT and pulmonary embolisms: as an early bridge from LMWH. Target: INR 2-3
• Cardiac valve prostheses:
  • Bioprostheses: coverage for 3 months
  • Mechanical valves: permanent coverage, target: INR 3-4.5
• AF: indication according to CHADS2, target: INR 2-3
• Congenital deficiencies in antithrombin, protein C or S + recurrent thromboembolic events

New Oral Anticoagulants (NOACs)

These include factor Xa inhibitors (rivaroxaban, apixaban, edoxaban) and thrombin inhibitors (dabigatran). Their main advantage over VKAs is that they do not require monitoring and are prescribed at fixed doses 1 to 2 times/day... their main disadvantage being that there is no way to monitor their activity. Renal elimination. Less sensitive to drug interactions and dietary variations than VKAs.

There is an antidote (idarucizumab) for dabigatran but no antidote for the other NOACs.

More recent, their indications are rapidly expanding but remain more limited than those of VKAs. They are currently approved for:

• Prevention and treatment of DVT and PE
• Thromboembolic prevention for non-valvular AF

Overdoses of Vitamin K Antagonists (VKA)

Clinical and Biological Situation	Management
INR < 5 and no bleeding	Skip 1 dose → resume at reduced dose under INR control
INR 5 to 9 and/or minor bleeding	Stop VKA + 2 mg vit K PO/SC → INR 1x/day → resume VKA at reduced dose when INR approaches therapeutic range → adjust dose under INR control
INR > 9 and no bleeding and compliance	Stop VKA + 5mg vit K PO/SC → INR at 6 hours → vit K PO as needed → resume VKA at reduced dose when INR approaches therapeutic range → adjust dose under INR control
INR > 9 and minor bleeding or doubtful compliance	Same as above + hospitalization
INR > 20 and/or major bleeding	Stop VKA + hospitalization + 10 mg vit K slow IV + FFP 10-15ml/kg IV or PPSB 25U/kg → INR at 6 hours → vit K IV as needed ± FFP/PPSB → resume VKA at reduced dose when INR approaches therapeutic range → adjust dose under INR control

Additionally, investigate and correct any potential cause of the overdose as needed.

Oral Anticoagulants and Surgery

Except for minor procedures (dental extraction, superficial biopsy, etc.) where coverage with an INR = 2-3 can be maintained, VKAs must be stopped 4 days before surgery. The patient will be placed on SC LMWH 36 hours after stopping VKAs and until 12-18 hours before the surgery.

For mechanical valve patients: heparin starting 24 hours after stopping VKAs at a curative dose, suspension on the morning of surgery, resumption of heparin, bridging from heparin to VKAs.

In case of emergency surgery, a PPSB infusion can be used to restore coagulation.

Less documented but similar approach for NOACs.

Hemorrhagic Complications with New Oral Anticoagulants

There is no specific antidote for these anticoagulants except for dabigatran. In case of:

• Minor bleeding: interrupt treatment / postpone next dose by 24h
• Moderate bleeding: same + supportive measures, fluid replacement and transfusions as needed + idarucizumab 5 g IV if dabigatran
• Major bleeding: same + consider activated recombinant factor VII / prothrombin concentrates + consider hemodialysis

Hemorrhagic Complications with Heparin

The most frequent hemorrhagic complications under heparin are: retroperitoneal, cutaneous, gastrointestinal, hematuria, cerebral hemorrhages.

In case of:

• Overdose without hemorrhagic complications: simple dose adjustment or interruption of treatment for 4 hours before resuming after aPTT / anti-Xa activity control
• Hemorrhagic complication: administration of protamine sulfate, 1 mg IV neutralizes 100 IU of heparin. Neutralize 50% of the last dose (max dose 50mg/10min).
  • Note: protamine is less effective on LMWH than on unfractionated heparin

Heparin-Induced Thrombocytopenia

A classic complication of heparin therapy (more frequent with unfractionated heparin but can occur with LMWH). Suspected if platelets drop below 100,000/mm³ from the 5th day of treatment. Rare after day 21. Often associated with the occurrence of arterial or venous thrombosis or consumption coagulopathy.

→ immediate discontinuation of heparin and switch to another type of anticoagulant.

Bibliography

EMC, traité de médecine AKOS, Elsevier, 2018

Haute Autorité de Santé, Anticoagulants oraux, recommandations, 2018