Phenytoin-Induced Severe Thrombocytopenia: A Case Report

Phenytoin is a commonly prescribed antiepileptic medication for the prevention and treatment of tonic-clonic or partial seizures. Thrombocytopenia is a rare and serious adverse effect of phenytoin. This case report presents the case of a patient with severe thrombocytopenia induced by phenytoin for the treatment of tonic-clonic seizures. A 63-year-old male received 300 mg/day of phenytoin for the treatment of tonic-clonic seizures. Seven days after receiving the first dose of phenytoin, he was diagnosed with severe thrombocytopenia (platelet count 44 x 109/L) without hemorrhage. Phenytoin was discontinued, and seizures were controlled with levetiracetam. Seven days after stopping phenytoin, his daily platelet count improved from 44 to 177 x 109/L. The Naranjo algorithm score of 7 was at a probable level for phenytoin-induced thrombocytopenia. Thrombocytopenia is a serious adverse drug reaction that can result in life-threatening bleeding. Phenytoin-induced thrombocytopenia commonly begins 1-90 days after administration, and the recovery time is 3-21 days. The potential mechanism of phenytoin-induced thrombocytopenia is drug-induced immune thrombocytopenia. Drugs that enhance the concentration of phenytoin epoxide may be a contributing factor in phenytoin-induced thrombocytopenia. Phenytoin-induced thrombocytopenia is a rare but serious hematological complication. It should be recognized early, particularly in patients with a high risk of hemorrhage or concurrently with medications that increase phenytoin epoxide. Regularly consecutive complete blood count tests may be essential in order to detect an early decrease in platelet count in these patients.


Introduction
Drug-induced thrombocytopenia (DIT) is a relatively rare but severe adverse drug reaction [1].
Thrombocytopenia is defined as a platelet count of less than 150 x 10 9 /L [2].Patients with severe thrombocytopenia (platelet count of less than 50 x 10 9 /L) can experience spontaneous bleeding such as ecchymoses, petechiae, mucosal bleeding, or life-threatening spontaneous intracranial hemorrhage [1].The incidence rates of major and fatal hemorrhages in patients with severe thrombocytopenia were 9 and 0.8%, respectively [3].
In general, the platelet count decreases within seven days or more after beginning a new drug or 2-3 days after consuming a previously consumed drug.Within 1-10 days of stopping the drug, the platelet count rises to the normal range [1,3].
The incidence rates of the medications responsible for DIT vary [4].The incidence of DIT among critically ailing patients is approximately 25%, whereas the overall incidence rate is approximately 10 cases per million persons per year [4].Anticonvulsants, such as carbamazepine, phenytoin, and valproic acid, are among the drugs most frequently associated with DIT [5].
Phenytoin is a commonly prescribed antiepileptic medication for the prevention and treatment of tonicclonic or partial seizures [4].Thrombocytopenia is a rare and serious adverse effect of phenytoin [4].In this article, we present a case of phenytoin-induced thrombocytopenia in a patient with a generalized tonicclonic seizure.

Case Presentation
A 63-year-old male was admitted to the internal medicine ward for treatment of generalized tonic-clonic seizures.Four months prior to admission, he had an accident resulting in an epidural hematoma and cervical spondylosis cord compression.The craniotomy with clot removal was employed to manage an epidural hematoma.Long-term gabapentin and nortriptyline were prescribed for the treatment of cervical spondylosis and cord compression.Subsequently, he received a diagnosis of a syndrome of inappropriate antidiuretic hormone secretion and received a sodium chloride tablet for treatment of this condition.Three days before admission, he had watery diarrhea and confusion.Moreover, he overused sodium chloride tablets because of a misunderstanding.
On the first day of admission, his serum sodium was 257.2 mmol/L, and his complete blood count, liver function, and renal function were normal.He received a diagnosis of symptomatic hypernatremia and presented with generalized tonic-clonic seizures.The etiology of hypernatremia was suspected to be dehydration and overuse of sodium chloride tablets.Phenytoin, 100 mg IV every 8 hours, was prescribed to control seizures for one day.After that, phenytoin was changed from intravenous to phenytoin 50 mg tablet administration via nasogastric tube, two tablets every 8 hours (total daily dose: 300 mg/day).
Four days later, his serum sodium decreased into the normal range, but he still had a generalized tonicclonic seizure.Therefore, phenytoin was continued, and levetiracetam 1000 mg IV every 12 hours was added to control seizures.Furthermore, he was diagnosed with ventilator-associated pneumonia.He received ceftazidime for treatment of this condition.
Seven days after receiving the first dose of phenytoin, his platelet count decreased from 539 to 44 x 10 9 /L.He had no signs or symptoms of bleeding.The peripheral blood smear showed thrombocytopenia without platelet aggregation and normal red blood cell morphology.Consequently, a multidisciplinary team worked together to find the cause of this patient's thrombocytopenia, such as hypersplenism due to chronic liver disease, chronic alcohol abuse, nutrient deficiencies (folate and vitamin B12), autoimmune disorders (systemic lupus erythematosus and rheumatoid arthritis), and lymphoproliferative diseases (non-Hodgkin lymphoma).
This patient had sepsis due to ventilator-associated pneumonia during the period of thrombocytopenia.However, it was found that platelets tended to decrease before this condition.In addition, the activated partial thromboplastin time (aPTT), prothrombin time (PT), and international normalized ratio (INR) were 22.2 seconds, 12.6 seconds, and 1.13, respectively.These results were within the normal range.Therefore, it could exclude disseminated intravascular coagulation.
When exploring other potential causes of thrombocytopenia in this patient, it was determined that the results of the anti-HIV and anti-HCV tests were negative.Additionally, the patient reported no history of chronic drinking.Analysis of the peripheral blood smear test revealed normochromic and normocytic red blood cells, indicating the absence of folate or vitamin B12 deficiency.Furthermore, his physical examination and medical history revealed no signs or symptoms of autoimmune disorders or lymphoproliferative diseases.
After considering all potential factors, it was determined that the patient's thrombocytopenia was druginduced.Possible culprit medications include phenytoin and ceftazidime.The patient did not receive medication that had a potential drug interaction with phenytoin.The concentration of phenytoin in his serum was 8.8 mg/L.Liver function was still within the normal range.The multidisciplinary team decided to discontinue phenytoin and continue ceftazidime because the platelet count had decreased prior to the initiation of ceftazidime.
After discontinuing phenytoin, the patient was gradually recovering, although he continued to receive ceftazidime.Seven days after stopping phenytoin, his daily platelet count improved from 44 to 50, 82, 116, 117, 124, and 177 x 10 9 /L, respectively.He was transferred to the medical-respiratory care unit for observation.His seizure was controlled with levetiracetam 2000 mg/day.Over time, his platelet count rose to 337 x 10 9 /L by day 15 after stopping phenytoin (Figure 1).The Naranjo algorithm score of 7 was at a probable level for phenytoin-induced thrombocytopenia.

FIGURE 1: Relationship between platelet count and drug administration Discussion
Thrombocytopenia can be caused by several factors, such as infectious illnesses, hypersplenism due to chronic liver disease, chronic alcohol abuse, nutrient deficiencies, autoimmune disorders, lymphoproliferative diseases, pregnancy, and DIT [2].Drugs are one of the most common causes of thrombocytopenia, particularly in critically ill patients.DIT has been reported in approximately 19-25% of all patients.Several medications are associated with this condition, such as acetaminophen, ampicillin, cimetidine, carbamazepine, heparin, ibuprofen, naproxen, phenytoin, piperacillin, quinine, sulfonamides, valproic acid, and vancomycin [1][2][3].In this case report, we present a case of thrombocytopenia induced by phenytoin in a patient with tonic-clonic seizures.
Treatment of DIT involves discontinuation of the offending drug.Typically, the platelet count begins to recover after four or five half-lives of the causative drug or drug metabolite.Patients with severe thrombocytopenia and hemorrhage can receive large doses of intravenous immunoglobulin [4].
Our patient presented with severe thrombocytopenia (platelet level was 44 x 10 9 /L) seven days after receiving phenytoin.This patient was treated by discontinuing phenytoin and controlling his seizures with levetiracetam.Because there was no hemorrhaging, intravenous immunoglobulin and platelet transfusions were unnecessary for the patient.His platelet count increased to over 150 x 10 9 /L seven days after phenytoin was discontinued.This is similar to the previous case report.Previous case reports are summarized in Table 1.

TABLE 1: Summary of case reports of phenytoin-induced thrombocytopenia in the literature
DIT can be separated into two types by pathophysiology.The first type is non-immune DIT.It is defined as a direct cytotoxic effect of the drug molecules on platelets, which leads to either dysfunctional thrombopoiesis in the bone marrow or increased platelet destruction in the bloodstream [1].These drugs include chemotherapy drugs, ganciclovir, and thiazide diuretics [4].Another type is drug-induced immune