What is the effect of antiepileptic (anti-seizure) medication on coagulation?

From the Guidelines

Anti-seizure medications can significantly interact with anticoagulants, and their use requires careful consideration and monitoring to prevent adverse effects on coagulation. When considering the interaction between anti-seizure medications and coagulation, it's crucial to understand the mechanisms by which these medications affect anticoagulant efficacy and safety. Enzyme-inducing anti-seizure drugs, such as phenytoin, carbamazepine, phenobarbital, and primidone, can increase the metabolism of warfarin and direct oral anticoagulants (DOACs), potentially reducing their effectiveness and requiring higher doses or more frequent monitoring 1.

On the other hand, valproic acid may increase the risk of bleeding when used with anticoagulants by inhibiting their metabolism and displacing them from protein binding sites. In contrast, newer anti-seizure medications like levetiracetam, lamotrigine, gabapentin, and pregabalin have minimal interactions with anticoagulants, making them preferable when both treatments are necessary. The management of patients on both anti-seizure medications and anticoagulants involves regular monitoring of anticoagulation levels, such as INR for warfarin, dose adjustments as needed, and vigilance for signs of bleeding or thrombotic complications.

Key considerations in managing these interactions include:

• Monitoring anticoagulation levels closely, especially when initiating, changing, or discontinuing anti-seizure medications.
• Being aware of the potential for increased bleeding risk with certain combinations, such as valproic acid and anticoagulants.
• Preferentially using anti-seizure medications with minimal interactions with anticoagulants, such as levetiracetam or lamotrigine, when possible.
• Understanding the pharmacokinetic and pharmacodynamic interactions between anti-seizure drugs and anticoagulants, including the role of cytochrome P450 enzymes in metabolizing these medications 1.

Given the complexity of these interactions and the potential for significant morbidity and mortality associated with bleeding or thrombotic complications, a careful and individualized approach to managing patients on anti-seizure medications and anticoagulants is essential, prioritizing regular monitoring, dose adjustments, and patient education to minimize risks and optimize outcomes.

From the FDA Drug Label

Minor, but statistically significant, decreases compared to placebo in total mean RBC count (0.03 × 10^6/mm^3), mean hemoglobin (0.09 g/dL), and mean hematocrit (0.38%), were seen in levetiracetam-treated patients in controlled trials. A total of 3.2% of treated and 1.8% of placebo patients had at least one possibly significant (≤2.8 × 10^9/L) decreased WBC, and 2.4% of treated and 1.4% of placebo patients had at least one possibly significant (≤1.0 × 10^9/L) decreased neutrophil count. Carbamazepine tablets may cause rare but serious blood problems. Symptoms may include: fever, sore throat, or other infections that come and go or do not go away easy bruising red or purple spots on your body bleeding gums or nose bleeds severe fatigue or weakness

Anti-seizure medication and coagulation:

• Levetiracetam may cause minor but statistically significant decreases in RBC count, hemoglobin, and hematocrit.
• Levetiracetam may also cause decreases in WBC and neutrophil counts.
• Carbamazepine may cause rare but serious blood problems, including easy bruising, bleeding gums or nose bleeds, and severe fatigue or weakness. Based on the information provided, both levetiracetam and carbamazepine may affect coagulation, but the effects are different and may vary in severity 2 3.

From the Research

Anti-Seizure Medication and Coagulation

• There is no direct evidence in the provided studies that discusses the relationship between anti-seizure medication and coagulation.
• However, the studies provide information on the management of epilepsy, including the selection of anti-seizure drugs (ASDs) and their potential effects on patients 4, 5, 6, 7, 8.
• The decision to initiate an ASD should be individualized, considering factors such as the type of seizures, epilepsy syndrome, and adverse effects associated with the drug 4.
• Some ASDs, such as carbamazepine and phenytoin, have cytochrome P450 enzyme-inducing properties, which may worsen comorbid coronary and cerebrovascular disease by causing hyperlipidemia and accelerating the metabolism of concomitant drugs used for their treatment 4.
• The selection of ASDs should also consider the patient's age, sex, comorbidities, and potential drug interactions 4, 8.
• There is no mention of coagulation disorders or bleeding risks associated with anti-seizure medications in the provided studies.

Management of Epilepsy

• The primary goal of epilepsy treatment is to eliminate seizures while minimizing adverse effects of ASDs 4.
• The decision to start ASD treatment should be informed by the results of randomized controlled trials, and patients with a low risk of seizure recurrence may not require ASD treatment 6, 7.
• Therapeutic drug monitoring may be useful in confirming ASD toxicity or non-adherence, but routine monitoring of serum levels is not recommended 7.
• The decision to discontinue ASD treatment should follow a full discussion with the patient of risks and benefits, and patients should be followed up by a specialist for at least two years after discontinuation 7.