Investigating the Relationship Between Anti-seizure Medications and Bleeding Disorders: A Comprehensive Review of the Current Literature
https://ror.org/01h85hm56grid.412080.f0000 0000 9363 9292Department of Medicine, Dow University of Health Sciences, Karachi, Pakistan
https://ror.org/02ht5pq60grid.442864.80000 0001 1181 4542Kabul University of Medical Sciences, Kabul, Afghanistan
Abstract
Anti-seizure medications (ASMs) are specific types of anticonvulsants used to treat epileptic seizures. However, several studies have shown an association between ASMs and an increased risk of hematological disorders, such as thrombocytopenia, aplastic anemia, and platelet function disorders leading to prolonged bleeding times. This review explores the existing literature on this topic, investigating a wide variety of ASMs, ranging from first-generation medications to newer ones. A comprehensive search was conducted on all the currently approved ASMs using PubMed and Google Scholar: review articles, clinical trials, meta-analysis, observational studies, case reports, and relevant animal studies were identified. We extracted 15 ASMs including valproic acid (VPA), carbamazepine, phenytoin, phenobarbital, diazepam, clonazepam, lamotrigine, levetiracetam, oxcarbazepine, felbamate, topiramate, pregabalin, lacosamide, cannabidiol (CBD), and perampanel that contain considerable literature regarding different coagulopathies. An in-depth review of over 140 studies revealed a robust association between ASM-induced changes and the onset of bleeding disorders via several different mechanisms. Polytherapy, the use of multiple ASMs, also emerged as a significant risk factor for the development of coagulopathies. This review highlights the potential link between ASMs and bleeding disorders, emphasizing the importance of considering this risk during treatment planning. By understanding these associations, healthcare providers can optimize patient outcomes and minimize bleeding risks. Additionally, this review identifies the need for further research to bridge current knowledge gaps in clinical pharmacology related to ASMs and bleeding disorders.
Key Points
| Blood homeostasis is a systemic process involving the liver, bone marrow, plasma proteins, and blood cells, and anti-seizure medications (ASMs) may affect all these systems, inducing different coagulopathies. |
| ASMs can result in various hematological disturbances across both pediatric and adult populations. |
| In this review article, we have highlighted potential mechanisms by which ASMs may lead to bleeding disorders. These mechanisms include myelosuppression, drug-induced peripheral platelet destruction, platelet membrane damage, disruption of platelet adhesion and aggregation, hepatotoxicity due to oxidative stress, and hepatic enzyme inhibition or induction. However, for some ASMs, the exact mechanisms remain unknown, necessitating further research. |
Introduction
Anti-seizure medications (ASMs) are primarily utilized for the treatment of epilepsy and other seizure-related conditions to reduce the frequency of convulsions [1]. These medications can be administered as either monotherapy or polytherapy and are prescribed to both children and adults affected by these disorders [1–4]. ASMs aim to control the occurrence and severity of seizures by modifying ion channel function, inhibiting γ-aminobutyric acid (GABA) transaminase to increase brain levels of GABA, and other mechanisms [5–8].
When administered as monotherapy or polytherapy, ASMs have been reported to induce certain uncommon hematological side effects, including thrombocytopenia, pancytopenia, aplastic anemia, and other blood dyscrasias [9–18].
These hematological disturbances may arise due to various mechanisms, such as myelosuppression, drug-induced peripheral platelet destruction, platelet membrane damage, disruption of platelet adhesion and aggregation, impairment of vitamin K synthesis, hepatotoxicity due to oxidative stress, hepatic enzyme inhibition or induction affecting the synthesis of coagulation factors, and drug–drug interactions when used in polytherapy [15, 19–24].
Therefore, it is crucial to select or develop an ASM that effectively controls seizure-related symptoms while minimizing adverse effects, particularly hematological side effects. In this review, our objectives are threefold: firstly, to identify ASMs associated with bleeding disorders on the basis of previous studies; secondly, to explore the potential mechanisms through which these medications cause hematological adverse effects; and lastly, to identify populations at risk of developing bleeding disorders due to the use of these medications, and to emphasize alternative therapies and strategies to alleviate these hematological disturbances.
Methods
A Boolean search was performed in MEDLINE-PubMed and Google scholar from its inception to March 2024 using a combination of medical subject headings (MeSH) and free search terms. The terms used included “Anti-epileptics,” “Anti-seizure medications,” “Thrombocytopenia,” “Pancytopenia,” “Bleeding Disorders,” “Aplastic anemia”, “Meta-analysis,” “Case report,” “Observational studies,” “Clinical trials,” and “randomized controlled trial.” The full text of all relevant articles in English, along with supplementary appendices, was obtained. Additionally, the full text of pertinent cross-references was also acquired.
The inclusion criteria for the studies were: (1) original studies, which include observational studies, cross-sectional studies, randomized controlled trials, meta-analyses as well as comprehensive review articles, case reports, and animal studies highlighting novel mechanisms and (2) studies that analyzed or described cases of bleeding disorders associated with the administration of specific ASMs, including valproic acid (VPA), carbamazepine, phenytoin, phenobarbital, diazepam, clonazepam, lamotrigine, levetiracetam, oxcarbazepine, felbamate, topiramate, pregabalin, lacosamide, cannabidiol (CBD), and perampanel. Only studies published in peer-reviewed journals were included in this narrative review. Other ASMs lacking substantial literature on bleeding disorders were not included in this review article.
Results
Our search strategy identified studies examining bleeding disorders linked to the use of various ASMs across different generations. First-generation ASMs included VPA, phenobarbital, phenytoin, carbamazepine, diazepam, and clonazepam. Second-generation ASMs included lamotrigine, levetiracetam, oxcarbazepine, felbamate, pregabalin, and topiramate. Third-generation ASMs included lacosamide, perampanel, and CBD.
First-Generation ASMs
Valproic Acid
VPA is one of the most prescribed ASMs worldwide due to its wide spectrum of effectiveness against all types of seizure and epileptic syndromes, both in pediatric and adult patients [25]. VPA has both been tested and proved effective against generalized, tonic–clonic, absence, myoclonic, and focal seizures [26].
VPA therapy, although versatile, can lead to significant hematological complications. These include thrombocytopenia, pancytopenia, myelosuppression, aplastic anemia, and bleeding tendencies evidenced by petechiae and ecchymosis [27, 28].
VPA therapy has been reported to cause hematological disturbances and coagulopathies, affecting both pediatric and adult populations. In a comprehensive pediatric study by Delgado et al., among 306 children, 64 (21%) developed thrombocytopenia, and 21 (10.5%) experienced clinically significant thrombocytopenia (defined as a platelet count less than 100,000/mm) [2]. In adults, VPA monotherapy has been linked to notably reduced platelet counts and prolonged bleeding times [3, 29].
When comparing adult and pediatric responses to VPA therapy, children demonstrate a higher susceptibility to VPA-induced coagulopathies compared with adults. Demi PS et al. found a greater occurrence of coagulopathy diagnoses in children than in adults through a retrospective cross-sectional analysis. Platelet function disorders were twice as common in children (57.1%) than in adults (24.2%), highlighting children’s increased vulnerability to hematological adverse effects triggered by VPA [10]. Moreover, children receiving VPA therapy have been documented to develop Von Willebrand’s disease type 1 due to VPA’s ability to reduce platelet counts and fibrinogen concentrations [11]. In the prospective trial conducted by Koenig et al., significant decreases were observed in the levels of von Willebrand factor antigen and von Willebrand factor ristocetin cofactor in 35% of patients [12]. These findings highlight the increased vulnerability of children to adverse hematological side effects triggered by VPA.
The exact cause of VPA-induced hematological adverse effects remains unknown, but several potential mechanisms have been proposed.
Firstly, VPA has been proposed to block the differentiation and maturation of megakaryocytes, the precursors of platelets. Studies examining bone marrow consistently show normal or elevated megakaryocyte counts, indicating increased peripheral platelet destruction [19]. Additionally, trephine biopsies reveal the presence of small, underdeveloped megakaryocytes, suggesting a VPA-induced hematologic disorder [30]. This observed dysmegakaryopoiesis leads to reduced platelet formation and subsequently causes thrombocytopenia [21, 31].
Secondly, studies have also suggested that VPA can cause damage to the platelet membrane by decreasing the production of platelet malondialdehyde, a marker of oxidative stress [20]. The drug disrupts platelet adhesion and aggregation, thereby contributing to a decline in platelet count and function. P-selectin (CD62P) expression, responsible for leukocyte adherence to activated platelets and endothelium, increases with VPA dosage, while fibrinogen binding significantly decreases. These changes decrease platelet aggregation, raising the risk of hematologic adverse effects associated with VPA therapy [32].
Lastly, due to VPA primarily undergoing metabolism in the liver, prolonged usage might lead to hepatotoxicity in certain individuals via oxidative stress. This could impede the synthesis and secretion of proteins such as fibrinogen and coagulation factors, particularly F-XIII, synthesized within the liver. Hence, VPA-induced hepatic dysfunction could reduce fibrinogen production, subsequently impacting platelet function [12, 21].
Co-administration of VPA and warfarin can potentially increase the risk of bleeding complications because a loading dose of VPA may displace warfarin from its binding sites [33]. Reduced dosage of VPA with constant hematologic monitoring can also help to improve symptoms [2]. Additionally, carnitine supplementation, melatonin, and the introduction of antioxidants such as vitamin E alongside VPA treatment can help to ameliorate VPA-induced hepatotoxicity by decreasing oxidative stress [34, 35]. Alternative therapies can also be given in the case of VPA-induced hematological side effects that include gabapentin, levetiracetam, tiagabine, topiramate, and zonisamide [36].
Phenytoin
Phenytoin is primarily used to treat tonic–clonic and partial seizures; it is administered orally and intravenously. Since its discovery, phenytoin has been evaluated as a treatment for multiple disorders such as multiple sclerosis, ulcers, bipolar disorders, and wound healing [36].
Phenytoin prolongs the neural refractory period by deactivating voltage-gated sodium channels at abnormal high-frequency nerve impulses without affecting low-frequency discharges. It also inhibits Ca+2 influx at synapses and regulates neurotransmitters such as acetylcholine, serotonin, norepinephrine, dopamine, GABA, and endorphins. Reduction in Na+ and Ca+2 influx promotes GABA release, preventing transmission of abnormal impulses [29].
Phenytoin toxicity can lead to ataxia, enzyme-induced hepatotoxicity, and purple glove syndrome, which can necessitate amputations [37]. In plasma, phenytoin binds to albumin, and with no antidote available, phenytoin toxicity is hard to treat [41].
Phenytoin is known to cause a vitamin K deficiency in neonates exposed to phenytoin during fetal life, leading to a decrease in coagulation factors 2, 7, 9, and 10 and increased prothrombin time (PT). The decreased levels of vitamin K-dependent proteins may lead to hemorrhagic diseases in newborns [15].
Combination therapy of VPA and phenytoin can increase high serum levels of phenytoin, which can result in increased bleeding during birth and neonatal hemorrhaging. Phenytoin is also associated with reduced plasma fibrinogen levels [23].
There are multiple proposed mechanisms of phenytoin antagonism, with the most promising one being the disruption of vitamin K metabolism by liver microbial enzymes [16]. Phenytoin can also cause hypocoagulation in septic patients characterized by elevated prothrombin time and partial prothrombin time [42]. Phenytoin also affects P-glycoprotein (P-gp) induction and competition, increasing the risk of bleeding and thromboembolism in patients taking non-vitamin K antagonist oral anticoagulants (NOACs) [43, 44]. To prevent fatal effects of phenytoin antagonism, intramuscular administration in neonates and oral administration in pregnant mothers is advised. It is highly advised to closely monitor the PT, partial prothrombin time (PTT), and coagulation factor levels in patients taking phenytoin.
Phenytoin decreases the serum concentration of therapeutic agents, as it is a CYP450 enzyme inducer [44]. It elevates serum concentrations of topiramate and phenobarbital, which is another enzyme-inducing drug, but serum concentrations of phenytoin can be increased by felbamate and oxcarbazepine [45, 46]. Phenytoin can be paired with drugs such as levetiracetam, gabapentin, pregabalin, and vigabatrin, which are not affected by enzyme induction to any clinically relevant extent [46].
Carbamazepine
Carbamazepine is used as the initial treatment for focal epilepsy; it can also be considered for generalized tonic–clonic seizures [47]. It is also used for multiple other disorders such as alcohol withdrawal syndrome, trigeminal neuralgia neuropathic pain, and multiple psychiatric disorders [48, 49].
Carbamazepine works by blocking abnormal high-frequency nerve impulses by inhibiting Na voltage-gated channels. Despite being a reliable ASM, carbamazepine is known to cause hematological disorders such as aplastic anemia, red cell aplasia, and leukopenia [17, 50]. Carbamazepine decreases the effects of anticoagulants such as warfarin by inducing hepatic microsomal enzymes, increasing degradation [51]. Carbamazepine also decreases prothrombin in neonatal blood by interfering with vitamin K metabolism [52]. There have been multiple cases of carbamazepine-induced thrombocytopenic purpura in children as well as adults, which resolved after discontinuing the drug [53–55]. There have been many cases of carbamazepine-induced immune thrombocytopenia, which occurs due to platelet apoptosis by platelet antibodies through protein kinase A inhibition, highlighting a potential therapeutic target [56]. Strict monitoring of platelet counts and PT is recommended for patients undergoing carbamazepine therapy, and under critical conditions, carbamazepine use should be discontinued.
Carbamazepine is an enzyme inducer; thus, its concentrations are decreased in the presence of other enzyme-inducing antiepileptic drugs (AEDs). Carbamazepine also lowers the efficacy of NOACs by enhancing their elimination by cytochrome P450 3A4 (CYP3A4) and P-gp induction [57]. Carbamazepine is also an autoinducer, which means that it decreases its own serum concentrations, inhibition of epoxide hydrolase by VPA increases serum concentrations of carbamazepine, and sudden discontinuation of enzyme-inducers can lead to serum elevations [24]. These serum concentrations are significant in treating coagulopathies because in most cases drug discontinuation leads to recovery, a hidden pretext could be active metabolite toxicity.
Benzodiazepines
Diazepam and clonazepam are benzodiazepines that are primarily used to treat anxiety. Diazepam was approved by the Food and Drug Administration (FDA) for the treatment and management of anxiety, and muscular spasms, as the first-line treatment of status epilepticus and refractory epilepsy [58, 59]. Diazepam is also used as a sedative before surgeries, endoscopic procedures, and cardioversion [60].
Diazepam targets the allosteric site on the GABA-A receptor chloride channel and thus facilitates the activity of GABA by increasing the frequency at which the chloride channel opens into the neuron. The neuronal membrane becomes hyperpolarized and therefore decreases epileptic activity [61].
Common side effects of diazepam include drowsiness, confusion, and dysarthria [62, 63]. However, it also exhibits uncommon hematological effects such as acute granulocytopenia, acute thrombocytopenic purpura, and active antiplatelet antibodies. Additionally, it can also induce rare hepatic side effects, including elevated serum alanine aminotransferase (ALT) levels and drug-induced liver injury [62, 64–69].
Diazepam can inhibit platelet activation by a few mechanisms. It has been shown to decrease calcium influx into intestinal smooth muscle cells, and calcium ions play a significant role in the platelet aggregation and secretion reaction [70, 71]. Diazepam also inhibits serotonin secretion, malondialdehyde (MDA) production by adenosine-5′-diphosphate (ADP), epinephrine, and arachidonic acid. These findings indicate that diazepam may be blocking platelet activation by preventing prostaglandin synthesis [72].
When prescribing diazepam to the elderly population, clinicians should be careful since elderly people typically have impaired renal function, and accumulation of diazepam and its metabolites can occur [73].
Diazepam users should undergo regular complete blood count (CBC) assessments to detect clinically significant thrombocytopenia. If such adverse events arise, diazepam should be discontinued and replaced with other suitable ASMs.
Clonazepam acts as a positive allosteric modulator of GABA-A receptors, thereby controlling epilepsy through the enhancement of GABA’s inhibitory effects and regulation of neuronal excitability [74].
Clonazepam therapy has been associated with hematological side effects, including pancytopenia and thrombocytopenia [75].
These hematological side effects mainly occur due to the presence of benzodiazepine-dependent antibodies, which lead to platelet destruction [75]. Users of clonazepam should undergo periodic CBC assessments to monitor the potential emergence of clinically relevant pancytopenia or thrombocytopenia. Serological tests may be necessary to detect benzodiazepine-dependent antibodies targeting platelets. Clonazepam therapy should be discontinued if hematological side effects are observed [75].
Second-Generation ASMs
Lamotrigine
Lamotrigine, a widely used broad-spectrum ASM, is a valuable therapeutic option for several neurological disorders. It is mainly used for partial seizure disorders and is known to be one of the most effective and ideal drugs for pregnant women with epilepsy. Lamotrigine was initially developed as an antifolate when folate was thought to have an epileptogenic action [76]. Lamotrigine’s antiepileptic properties branch off from its multiple pharmacological effects, which include its role as a selective inhibitor in the release of glutamate by blockage of voltage-gated sodium channels; as a channel blocker for neuronal alpha-4, beta-2 nicotinic acetylcholine receptors, blocking voltage-gated calcium channels, hence reducing the vesicular release of excitatory neurotransmitters; and as a modulator for transient potassium outward current [77–80].
Lamotrigine is now labeled with a warning that the drug can cause a rare immune disorder, hemophagocytic lymphohistiocytosis (HLH). The immune system overreacts uncontrollably in HLH, which can lead to severe problems with the lungs, liver, kidneys, or blood cells [81]. Hematological side effects are rare with lamotrigine treatment; however, some cases of combined leukopenia and thrombocytopenia were reported in adults, which disappeared on discontinuation of the drug [82]. It should be noted that the mechanism underlying lamotrigine-induced thrombocytopenia is not understood and is a subject of ongoing research. Drug-induced thrombocytopenic purpura (DITP) involves multiple mechanisms and can be caused by various medications, leading to severe bleeding symptoms [83].
Life-threatening multiorgan failure and disseminated intravascular coagulation (DIC) were first reported in the case of two children who were administered lamotrigine as an add-on therapy to VPA [84]. These cases were synonymous with AHS with rhabdomyolysis as a distinct feature in lamotrigine therapy. This life-threatening adverse reaction was also reported in the case of an 11-year-old girl who was transitioned to lamotrigine from sodium valproate [85]. Localized purpura has also been reported in a 10-year-old patient after months of lamotrigine therapy who did not present with other features of AHS [86].
VPA inhibits the metabolism of lamotrigine; it can result in a twofold increase in serum levels of the drug. This increase in serum levels can increase the risk of lamotrigine-induced skin rashes, which are dependent on the rate of increase in serum lamotrigine concentration. To mitigate this risk, patients who are taking both VPA and lamotrigine should initiate lamotrigine at reduced dosages and move more slowly to target dosages. Overall, it is important to be aware of these drug interactions and adjust dosages accordingly to avoid the adverse effects of these combinative therapies [87].
Levetiracetam
In individuals with epilepsy, levetiracetam, a broad-spectrum ASM, has demonstrated efficacy as an adjunctive treatment for refractory partial-onset seizures and myoclonic seizures in clinical trials [92–94]. Its mechanism of action involves the modulation of synaptic neurotransmitter release by binding to the synaptic vesicle protein SV2A within the brain [88].
Levetiracetam has certain common side effects, but it can also exhibit significant, though rare, hematological side effects, including thrombocytopenia and pancytopenia [89, 90].
Thrombocytopenia, an uncommon side effect observed in both pediatric and adult patients using levetiracetam, is linked to an immune-triggered reaction destroying peripheral platelets. This adverse effect has been documented multiple times in medical literature [91–93].
Firstly, it has been suggested that thrombocytopenia may arise due to bone marrow toxicity induced by levetiracetam resulting in bone marrow suppression and subsequently reducing platelet production. Bone marrow analysis frequently shows significantly reduced cellularity and mild reduction in megakaryocytes, alongside granulocytic hypoplasia with sufficient megakaryocytes, indicating the possibility of levetiracetam-induced bone marrow toxicity [94]. Secondly, it has been reported that levetiracetam may cause platelet dysfunction by inhibiting thromboxane-dependent platelet activation, potentially leading to thrombocytopenia [90].
Levetiracetam therapy has also been reported to cause type 1 von Willebrand disease, due to reduced activity of the ristocetin cofactor, hence increasing the likelihood of thrombocytopenia [32].
Hematological adverse effects triggered by levetiracetam can be managed by discontinuing the treatment and regularly monitoring the patient’s blood counts to prevent or control any potential complications. An alternative option to levetiracetam is lamotrigine, which inhibits thromboxane-dependent platelet activation and function, thus offering an alternative approach [95].
Oxcarbazepine
Oxcarbazepine is used to treat tonic–clonic and focal epilepsy, especially in children. It is also prescribed to patients with bipolar disorder, neuropathic pain, and trigeminal neuralgia [96].
Oxcarbazepine is a sodium voltage-gate inhibitor that also inhibits the release of glutamate. The occurrence of adverse reactions is rarer in oxcarbazepine as compared with carbamazepine; clinically, oxcarbazepine is better tolerated [97]. Oxcarbazepine is structurally similar to carbamazepine; therefore, people who have experienced adverse reactions to carbamazepine are more likely to be sensitive to oxcarbazepine [98].
Adverse hematopoietic effects are rarely reported in patients on oxcarbazepine therapy, but there have been a considerable number of cases of leukopenia and thrombocytopenia, mostly in adults. Similarly, pancytopenia upon initiation of oxcarbazepine therapy and in combination with leukopenia is also a likely adverse effect [99]. Delayed-onset oxcarbazepine-related thrombotic thrombocytopenic purpura (TTP) in children, thrombocytopenia, and leukopenia were also reported, the former of which was treated using intravenous immunoglobulin, and the latter was relieved on the discontinuation of the drug [100].
These cases highlight the importance of routine monitoring for blood dyscrasias; if symptoms appear, it must be discontinued immediately. Moreover, oxcarbazepine should not be prescribed to patients who have previously displayed hypersensitivity reactions to aromatic ASMs [101]. Oxcarbazepine does not affect warfarin metabolism and can be prescribed to patients undergoing warfarin therapy [102].
Oxcarbazepine is a weak cytochrome P450 2C19 (CYP2C19) inhibitor and may increase serum levels of phenytoin and phenobarbital, leading to increased risks of bleeding disorders associated with phenytoin serum concentration [103].
Felbamate
Felbamate is a dicarbamate that is chemically similar to meprobamate, but it lacks the tranquilizing effect. Several mechanisms mediate its activity: potentiation of GABA transmission, decrease of glutamatergic transmission via regulation of N-methyl-D-aspartate receptor (NMDA) receptors, and inhibition of voltage-sensitive sodium and calcium channels. It is an effective drug for refractory seizure types such as seizures due to Lennox Gastaut syndrome (LGS) [104]. However, post-marketing administration unveils the adverse effects not observed during clinical experiments. This broad-spectrum ASM was approved by the FDA in 1993 as monotherapy and adjunctive therapy for partial and generalized seizures. Despite promising outcomes, the administration of felbamate to patients brings up several cases of aplastic anemia [18].
The risk of aplastic anemia in patients taking felbamate is 100 times greater than it is in the general population [18].
Aplastic anemia may initiate after several months since the treatment started, and patients may remain at risk for some time even if the drug is discontinued [18]. Patients taking felbamate should remain alert for signs of infection, bleeding, fatigue, ecchymotic skin lesions, easy bruising, or symptoms of anemia such as fatigue or weakness [18].
The cases of aplastic anemia take 2–6 months to be evident after administering felbamate [105]. Aplastic crisis occurs due to the failure of erythropoiesis because of the absence of erythroid precursors in the bone marrow with the relative preservation of other hematopoietic cells, reticulocytopenia, and an abrupt worsening of anemia, which is a result of sudden stop of erythropoiesis [105]. Aplastic crisis tends to be resolved with the support of blood transfusions. Unfortunately, immunocompromised patients can also be diagnosed with transient parvovirus infection [105]. It remains unclear whether felbamate is primarily responsible for causing aplastic crisis, whether it renders the patient’s bone marrow unusually susceptible to B19 parvovirus, or whether the coincidence of aplastic crisis and felbamate administration is incidental [105].
Nevertheless, the high association rate leads to the immediate withdrawal of the drug on the recommendation of the FDA and the manufacturers unless there is absolute necessity [105].
Pregabalin
Pregabalin has proven to be an effective adjunctive treatment to treat drug-resistant partial-onset seizures [106]. Pregabalin regulates neuronal excitability by binding to the α(2)δ subunit of P/Q-type voltage-gated calcium channels, thereby reducing the presynaptic calcium influx and regulating neurotransmitter release, which helps to control the frequency of seizures [107].
Pregabalin has some common side effects; however, it also exhibits certain hematological side effects such as neutropenia and a decrease in platelet count that are uncommon but significant [108–110].
As far as hematological side effects are concerned, neutropenia and low leukocyte levels are rare (1 in 1000–10,000 patients), whereas a decline in platelet count happens more frequently (1 in 100–1000 patients) [109]. Thrombocytopenia is fairly uncommon but a probable occurrence when being treated with pregabalin. Only a couple of cases of thrombocytopenia have been documented concerning the use of pregabalin so far [109, 110]. Pregabalin is a drug with minimal hepatic metabolism; therefore, it is a safe choice for patients with decreased liver function. However, this also means that thrombocytopenia due to hepatic dysfunction is unlikely [111].
In cases of thrombocytopenia, pregabalin should be discontinued, and the patient’s blood counts should be monitored frequently to check for the development of thrombocytopenia.
Topiramate
Topiramate is usually used to treat partial seizures with adjunctive treatment in adults. The structure of topiramate is acquired from D-fructose, which acts as an inhibitor for voltage-gated sodium channels and improves GABA activity with the blockage of glutamate. Topiramate is also a carbonic anhydrase inhibitor [112].
Upon approval, the only contraindication noted was hypersensitivity to the drug. However, there have been reports of hepatotoxicity associated with its administration, which may contribute to coagulopathy given the liver’s crucial role in the clotting process [112]. The hepatotoxicity may result in decreased synthesis of clotting factors, quantitative and qualitative platelet defects, hyperfibrinolysis, and accelerated intravascular coagulation [112].
However, it was noted that the signs of coagulation abnormalities improved as soon as topiramate was discontinued. In addition, it is rarely mentioned whether topiramate causes hepatotoxicity, with the mechanism being unclear as well [113]. Moreover, the simultaneous use of NOACs and ASMs in patients with atrial fibrillation can put them at a higher risk of major bleeding. Topiramate decreases the effect of NOACs by inducing CYP3A4 activity in vitro [57]. However, in cases where administering NOACs is mandatory, then the ASMs that are known to not interfere with CYP3A4 activity should be prescribed, which include gabapentin and zonisamide, because topiramate may weaken the anticoagulant effect of NOACs [57].
Third-Generation ASMs
Lacosamide
Lacosamide (Vimpat; previously known as harkeroside) is commonly used in partial-onset seizures [114]. It is a functionalized amino acid that exerts its anti-epileptic effects by selectively enhancing slow inactivation of voltage-gated sodium channels, maintaining hyperexcitable neuron membranes, and reducing repetitive firing of nerve impulses. Additionally, it exhibits a dual mode of action through interaction with collapsin response mediator protein 2 (CRMP2) and has been found to act on GABA receptors, contributing to its efficacy in preventing status epilepticus [115, 116].
Hematological disorders in response to lacosamide treatment are rarely reported; however, a case of TTP with microangiopathic activity raises serious concerns and requires further research on the adverse effect profile of lacosamide with regards to TTP [83]. The persistence of anti-ADAMTS13 antibodies until after the discontinuation of lacosamide shows a causal relationship between this ASM and TTP; however, the underlying mechanism was not well understood, and this emphasizes the need for further research [117].
Lacosamide was also discontinued in one of the patients who developed normochromic anemia, thrombocytopenia, and granulocytopenia in a study by Gavatha et al. [117]. Similarly, Jones et al. also reported a child who developed thrombocytopenia and leukopenia even though the blood counts were completely normal before lacosamide initiation [118].
There has been a case of drug–drug reaction with lacosamide usage when used with VPA [118]. In a trial conducted on healthy males, lacosamide posed no threat to VPA serum concentrations, lamotrigine, and levetiracetam; however, a drug–drug interaction that could be important for the identification and management of coagulopathies linked to these medications was exhibited [119].
Overall, even though the use of lacosamide is effective and safe, medical practitioners must be aware of these hematological side effects associated with lacosamide use as an add-on drug before prescribing it to patients, as it may result in severe complications. They must carefully monitor and evaluate patients for TTP. Complete blood counts and platelet levels must be closely monitored. If TTP is suspected, lacosamide must be discontinued immediately, and appropriate treatments must be followed [83].
Perampanel
Perampanel received approval to be used as an adjunct in the treatment of generalized tonic–clonic seizures associated with idiopathic generalized epilepsy in patients aged ≥ 12 years and refractory focal onset seizures in patients with ages ≥ 4 years [120]. In 2018 perampanel was also approved for monotherapy. Perampanel is administered orally and is a very strong, noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist. Glutamate, the primary excitatory neurotransmitter in the central nervous system (CNS) released from glutamatergic nerve terminals, is responsible for activating the AMPA receptors which are ligand-gated ion channels [121].
Glutamate is known for having a significant role in the onset of seizures. Even though the CNS has other glutamate receptors such as N-methyl-D-aspartate, AMPA receptors are the main neurotransmission mediator and play a fundamental role in the propagation of epileptic activity [122]. Perampanel is the first approved ASM that targets AMPA receptors. Since it attaches to AMPA receptors at an allosteric site, it is considered a non-competitive antagonist [123].
Clinical studies indicate that perampanel is generally safe and effective; however, common side effects include migraines, drowsiness, and blurred vision [124]. Additionally, it is associated with rare hematological side effects such as thrombocytopenia [125–127].
The exact mechanism through which perampanel induced thrombocytopenia is not yet understood; it may occur due to increased platelet eradication, development of autoantibodies that target platelets, or a reduction in the production of platelets [126]. Future research studies should focus on highlighting the various mechanisms through which perampanel can induce thrombocytopenia. A CBC check in patients is recommended after using perampanel to immediately detect any negative effects.
Cannabidiol
Clinical trials and open-label studies have proven CBD to be an effective treatment against refractory epilepsy such as LGS and Dravet syndrome, as well as tuberous sclerosis complex (TSC) [128, 129].
The mechanism of action of cannabidiol remains unclear as of yet, but the antagonism of G protein-coupled receptor 55 (GPR55), reduced sensitization of transient receptor potential of vanilloid type 1 (TRPV1) channels, and inhibition of adenosine reuptake have been suggested as possible mechanisms [130].
Recently, CBD treatment in mice with pentetrazol (PTZ)-induced (pentylenetetrazol) epilepsy led to significant alterations in gene expression, particularly impacting NPTX2, Gprc5c, Lipg, and Stc2, suggesting their involvement in CBD’s efficacy against seizures [131].
The use of CBD for epilepsy treatment has been associated with adverse effects, including liver dysfunction marked by increased liver enzymes such as aspartate transferase (AST) and ALT, particularly when used concurrently with VPA and clonazepam [97]. Additionally, hematological side effects, such as thrombocytopenia in children, have been documented when CBD is used alongside VPA [132].
In cases of drug-induced thrombocytopenia following concomitant administration of VPA and CBD, patients should be monitored closely since this combination can give rise to a clinically significant form of thrombocytopenia [132].
Discussion
Although ASMs play a significant role in the management of epilepsy and other neurological disorders, their prolonged use raises serious concerns about the safety, efficacy and potential drug interactions [133]. This article aims to explore the rational use of ASMs, planning for patients who rely on these drugs and particular challenges when administering these drugs to patients on other medications such as anticoagulants after surgery. There are multiple drug interactions associated with ASMs, and hence, the selection of ASMs with minimal or no interactions with other drugs is required [134]. When making treatment decisions for epileptic patients on additional drugs such as postoperative anti-coagulants, certain factors such as the patient’s medical history, the specific type of ASMs and anticoagulants, their dosages, and the risk–benefit ratio must be considered. Prophylactic ASMs for postoperative seizures are not recommended unless significant risk factors exist [135].
Certain populations, including children, the elderly, and critically ill patients, are at an elevated risk for developing ASM-induced thrombocytopenia [10, 66, 136]. Clinicians must exercise caution when managing these vulnerable groups. Children are more susceptible to ASM-induced thrombocytopenia and hypofibrinogenemia, resulting in a higher incidence of ASM-induced coagulopathies compared with adults [10, 66]. Research has demonstrated that children undergoing surgery when treated with VPA, either as monotherapy or in combination with other ASMs, tend to exhibit lower preoperative platelet counts and an increased need for transfusions [10, 137]. In elderly patients, the age-related decline in liver function and decreased serum albumin levels can lead to a higher free fraction of certain ASMs, such as felbamate, levetiracetam, pregabalin, and lacosamide, which may increase the risk of hematological adverse effects [138]. As such, careful monitoring of liver function is crucial when treating elderly individuals with ASMs. Additionally, this population is often prescribed multiple medications, such as aspirin or anticoagulants, which, when combined with ASMs, can further elevate the risk of thrombocytopenia [66]. Elderly cancer patients face additional risks when antineoplastic agents are used alongside classical ASMs, such as phenytoin, carbamazepine, or phenobarbital, which are potent enzyme inducers [139]. These interactions can lower plasma concentrations of antineoplastic drugs and other common medications, including anticoagulants, antidepressants, and antimicrobials, potentially leading to treatment failure or toxicity [139]. Conversely, the enzyme-inhibiting effects of VPA can increase serum concentrations of these drugs and, in combination with certain antineoplastic agents such as temozolomide, may exacerbate hematological toxicity [140]. Furthermore, the use of ASMs, particularly VPA, should be contraindicated in critically ill neurocritical care (NCU) patients, as these medications can significantly contribute to the development of thrombocytopenia, especially when used concurrently with other antiepileptic drugs, which may further amplify this risk [136].
Furthermore, the interactions between ASMs and anticoagulants become particularly critical in this context. Patients with comorbidities, such as those affecting blood clotting, and patients on polytherapy with medications such as anticoagulants require particular vigilance due to the increased risk of bleeding disorders. For example, carbamazepine significantly reduces the effectiveness of warfarin by inducing P-gp activity, highlighting the importance of close monitoring in such cases [51]. Certain ASMs such as phenobarbital, phenytoin, and levetiracetam might decrease the effect of oral anticoagulants by inducing P-gp activity, which accelerates the breakdown of anticoagulants, potentially reducing their effectiveness [57]. Furthermore, complex interactions can occur between different ASMs themselves. VPA has an inhibitory effect on CYP450 enzymes, which can lead to increased concentrations of other ASMs metabolized by these enzymes, such as carbamazepine, phenytoin, and phenobarbital. Conversely, enzyme-inducing ASMs such as carbamazepine, phenytoin, phenobarbital, and primidone can reduce the effectiveness of VPA by increasing its metabolism [141–143]. Lamotrigine levels can also be significantly impacted by VPA, potentially leading to toxicity, characterized by symptoms such as dizziness, nausea, and neurotoxicity [144–146]. Effective management of bleeding disorders associated with ASMs requires a comprehensive approach, including alternative therapies, vigilant monitoring of hematological parameters and reducing the dosage of the implicated ASM if necessary. In cases of ASM-induced coagulopathy, alternative strategies to manage bleeding risks include considering medications such as gabapentin, levetiracetam, tiagabine, topiramate, or zonisamide for VPA-induced thrombocytopenia, along with adjunctive supplementation of carnitine, melatonin, and antioxidants such as vitamin E to mitigate VPA-induced hepatotoxicity [34–36]. In the case of potential blood dyscrasias from the administration of a combination of lamotrigine and phenobarbital, switching to a combination of phenobarbital and levetiracetam may be a safer option [22]. To manage hematological side effects from levetiracetam, discontinuing the treatment and closely monitoring blood counts is advised, with lamotrigine being a safer alternative to levetiracetam in this case [95]. For patients on phenytoin, alternatives such as levetiracetam or pregabalin, which are less impacted by CYP450 enzyme induction, are viable options [44, 46]. Careful monitoring of the complete blood count is crucial when administering CBD, particularly in combination with VPA, due to the increased risk of developing thrombocytopenia [97, 132]. Implementing these alternative strategies is vital for enhancing patient safety and achieving better therapeutic outcomes when managing ASM-induced bleeding disorders. Recognizing high-risk populations and understanding the intricate drug interactions involved are key to effective management. This highlights the importance of selecting ASMs with fewer drug interactions and maintaining vigilant monitoring of coagulation function.
Further studies and research are crucial to establish the safety and effectiveness of ASMs in long-term usage. Identifying the “individual therapeutic concentration” can be useful to determine whether the treatment regimen needs to be adjusted [147]. It is defined as the range of concentrations that produce optimal responses according to specific patients [147]. The optimal response in these cases is the best possible balance between seizure suppression and dose-dependent side effects [147]. Future research should also focus on using other resources and explore alternative methods to control seizures, as per recent findings, certain phytochemicals from fruit have anticonvulsant characteristics that may be employed as therapeutic approaches [148].
It is important to note that this review is not without limitations. Firstly, not all ASMs were included in the discussion, which limits the scope of our findings. Additionally, this review specifically addresses the risk of bleeding disorders associated with the included ASMs, other potential long-term side effects of ASMs were not explored, as they were not the focus of this review. Moreover, the review concentrated on established drug interactions, potentially overlooking emerging data on interactions with newer medications. Furthermore, the review is constrained by the quality and availability of existing research on the topic, including insufficient data on the underlying mechanisms of these adverse effects for certain ASMs.
Conclusion
Due to the need for improved patient tolerability, more ASMs are anticipated to develop in the next 10 years. Current ASMs, however, have long-term negative consequences such as hepatotoxicity and blood issues, in addition to neurotoxic, sedative, and cognitive side effects. GABA enhancement and sodium channel blockage are examples of the common mechanisms that could be responsible for these effects. They may also affect platelet activity, bone marrow suppression, and endothelial function, which could result in coagulopathies. Further clinical trials are crucial to elucidate the mechanisms underlying bleeding disorders associated with the administration of ASMs. Effective management depends on the identification of high-risk populations, including children, the elderly, cancer patients, and critically ill individuals, as well as a comprehensive understanding of complex drug interactions and the precise selection of ASMs, all while diligently monitoring coagulation parameters. In instances of ASM-induced coagulopathy, clinicians should prioritize careful monitoring of hematological parameters, consider reducing the dosage of the implicated ASMs, or recommend alternative therapies. A deeper understanding of these mechanisms and their involvement in drug-induced coagulopathies could significantly enhance the future landscape of epilepsy treatment.
Abbreviations
- ASMs
- Anti-seizure medications
- TTP
- Thrombotic thrombocytopenic purpura
- VPA
- Valproic acid
- CBD
- Cannabidiol
- NOACs
- Non-vitamin K antagonist oral anticoagulants
- PT
- Prothrombin time
- DIC
- Disseminated intravascular coagulation
- PTT
- Partial prothrombin time
- CRMP2
- Collapsin response mediator protein 2
- GABA
- Gamma-aminobutyric acid
- AHS
- Acute hypersensitivity syndrome
- WBC
- White blood cell
- MDA
- Malondialdehyde
- ADP
- Adenosine-5′-diphosphate
- HLH
- Hemophagocytic lymphohistiocytosis
- DITP
- Drug-induced thrombocytopenic purpura
- LGS
- Lennox Gastaut syndrome
- AMPA
- Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
- CNS
- Central nervous system
- GPR55
- G protein-coupled receptor 55
- TRPV1
- Transient receptor potential of vanilloid type 1 channels
- TSC
- Tuberous sclerosis complex
- P-gp
- P-glycoprotein
- CYP450
- Cytochrome P450
- CYP3A4
- Cytochrome P450 3A4
- ALT
- Alanine aminotransferase
- AST
- Aspartate transferase
- CYP2C19
- Cytochrome P450 2C19
- NMDA
- N-Methyl-d-aspartate receptor
- NCU
- Neurocritical care
Acknowledgements
None to declare.
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