Homozygous prothrombin gene mutation and ischemic cerebrovascular disease: A case report and review of literature

Mohammed AlSheef; Mohammed S Almohaya; Arshad M Mian; Saad Mohammed Aljuhayyim

doi:10.4103/joah.joah_17_19

CASE REPORT

Year : 2019 | Volume : 10 | Issue : 2 | Page : 70-72

Homozygous prothrombin gene mutation and ischemic cerebrovascular disease: A case report and review of literature

Mohammed AlSheef, Mohammed S Almohaya, Arshad M Mian, Saad Mohammed Aljuhayyim
Department of Internal Medicine, King Fahad Medical City, Riyadh, Saudi Arabia

Date of Web Publication

10-Jul-2019

Correspondence Address:
Dr. Mohammed AlSheef
Department of Internal Medicine, King Fahad Medical City, Riyadh
Saudi Arabia

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/joah.joah_17_19

Abstract

This report describes a 32-year-old Saudi nonsmoker man who presented to the emergency department with a history of left-sided hemiparesis and no risk factors for cerebral stroke being reported, except type II diabetes mellitus. Magnetic resonance imaging (MRI) showed an ischemic stroke involving the right putamen and the posterior limb of the right internal capsule. During the hospitalization, he developed new weakness bilaterally, and repeat MRI showed infarctions involving both basal ganglia with a new acute infarct in the left putamen. The patient had normal laboratory hematological investigations; however, he was found to be homozygous for the G20210A mutation in the 3'-untranslated region of the prothrombin gene. In the absence of multiple risk factors that are usually related with cerebral stroke, the association between homozygous prothrombin gene mutation and cerebral stroke was suggested.

Keywords: Gene, homozygous, mutation, novel, prothrombin

How to cite this article:
AlSheef M, Almohaya MS, Mian AM, Aljuhayyim SM. Homozygous prothrombin gene mutation and ischemic cerebrovascular disease: A case report and review of literature. J Appl Hematol 2019;10:70-2

How to cite this URL:
AlSheef M, Almohaya MS, Mian AM, Aljuhayyim SM. Homozygous prothrombin gene mutation and ischemic cerebrovascular disease: A case report and review of literature. J Appl Hematol [serial online] 2019 [cited 2023 May 29];10:70-2. Available from: https://www.jahjournal.org/text.asp?2019/10/2/70/262539

Introduction

Homozygous mutations of the anticoagulant system, more commonly in prothrombin gene G20210A and factor V Leiden, often have severe clinical presentations.^[1] The homozygous prothrombin gene 20210A is a single-point mutation that occurs in the 3'-untranslated region of the prothrombin gene (G–A at position 20210) which is associated with a high prothrombin titer.^[2]

Studies showed that the prevalence of prothrombin gene mutation ranged from 5% to 19% in patients with thromboembolisms.^[2],[3],[4] It is four to five times higher in those patients than in the general population, where it was found to be between 1% and 5% among the general Caucasian population.^[4] The pioneer studies suggested that there is an association between prothrombin gene mutation and each of venous thrombosis;^[2],[3],[4] however, the association with cerebral ischemia is still doubtful.^[5],[6]

The mutation in prothrombin gene (G–A at position 20210) was found to be significantly related to the elevated levels of plasma prothrombin. It has been identified as a predisposing factor that increases the incidence of venous thrombosis three to five times.^[2],[7] The homozygous prothrombin gene mutation was found as a high-risk factor for cerebral ischemia in the absence of hypertension and other risk factors.^[6] Thus, genotyping for homozygous prothrombin gene mutation could be included in the investigations of cerebral ischemia, especially in young patients who are free of other risk factors.

This report describes a case of homozygous prothrombin gene mutation, G20210A, presented with multiple cerebral infarctions in a young adult.

Clinical Presentation

A 32-year-old Saudi man with a history of type II diabetes mellitus and primary infertility related to oligospermia presented to the emergency department with a history of left-sided hemiparesis. He had no history of previous stroke, venous thromboembolism, smoking, hypertension, and illicit drugs or alcohol use. There was no family history of arterial or venous thromboembolism. His medical history revealed no signs or symptoms suggestive of connective tissue disease, neither endocarditis nor malignancy.

Radiological and laboratory manifestations

Magnetic resonance imaging (MRI) showed an ischemic stroke involving the right putamen and the posterior limb of the right internal capsule. During the hospitalization, he developed new weakness bilaterally, and a repeat MRI showed infarctions in different stages of evolution involving both basal ganglia with a new acute infarct in the left putamen [Figure 1].

Figure 1: Magnetic resonance imaging of the brain. Axial view showing an ischemic stroke involving the right putamen and the posterior limb of the right internal capsule

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Transesophageal echocardiogram showed insignificant patent foramen ovale with a negative bubble study. A vascular ultrasound of the lower limbs' veins was negative for deep vein thrombosis bilaterally. Cerebral angiogram demonstrated multiple areas of stenosis. Frontal cortex and dural biopsies revealed no evidence of vasculitis.

Laboratory investigations, including complete blood count, renal profile, liver function tests, lipid profile, and coagulation profile, were normal. Antinuclear Antibody (ANA) and Anti-neutrophil cytoplasmic antibody (ANCA) were negative; rheumatoid factor and complement levels were normal. Protein C, protein S, antithrombin, homocysteine, factor V Leiden, methylenetetrahydrofolate reductase, and antiphospholipid antibodies were unremarkable. On genetic testing, the patient was found to be homozygous for G20210A mutation in the 3'-untranslated region of the prothrombin gene. Both parents were found to be positive for G20210A heterozygous prothrombin mutation.

Discussion

Prothrombin is an important precursor of the thrombin and a key enzyme in fibrin formation.^[8] In literature, several studies have examined the association between the G20210A homozygous prothrombin mutation and venous thrombosis.^[2],[3],[4] They found a higher prevalence of prothrombin gene mutation in patients with venous thrombosis, while the relationship between this mutation and cerebral stroke was less evident.^[6],[9]

The prothrombin gene mutation was found not only as a risk factor for thrombosis, but it was also associated with high plasma prothrombin levels.^[2] The mechanisms of how gene mutation leads to increase in prothrombin levels are not fully understood. Most likely, the elevated levels of plasma prothrombin could lead to a higher occurrence of thrombin formation and subsequently more incidence of fibrin clotting.^[10]

Patients with homozygous prothrombin mutations were associated with more severe thrombosis manifestation than their heterozygous relatives.^[8] However, it was less severe than homozygous mutations of protein S or C deficiencies.^[11]

In this report, a case presented with cerebral ischemic lesions was found to be homozygous for G20210A mutation in the 3'-untranslated region of the prothrombin gene. Similar findings were reported by Giordano et al.,^[9] where a 31-year-old woman experienced an ischemic stroke associated with hemiparesis. Their radiological manifestations showed a wide hypodense ischemic lesion in the right Sylvian area. Unlike our case, she had a familial history of ischemic strokes and myocardial infarction that affected her father and mother at the age of 54 and 48 years, respectively. These findings were consistent with the results of a retrospective study conducted by Martinelli et al.,^[12] where the incidence of the prothrombin gene mutation was higher in subjects with cerebral venous thrombosis than in normal controls. This is consistent with findings of a study conducted by De Stefano et al.,^[6] who found two young cases with homozygous prothrombin gene mutation. The first case was affected by two cerebral strokes at the age of 24 and 26 years, which involved left thalamic area and left cortex, respectively. The second case was also a 26-year-old young patient who experienced ischemic stroke affected basilar artery. Both cases were young, nonsmokers without any apparent risk factor for cerebral stroke. These findings were consistent with our case, except for diabetes mellitus, where no risk factors for cerebral stroke were reported.

Different findings were reported by a large-scale prospective study conducted by Ridker et al.,^[13] among US men, which found no association between the prothrombin gene mutation and incidence of cerebral stroke. In the study of Ridker et al., the prevalence of prothrombin gene mutation in the control group was greater than that found in the literature, which could indicate a possible bias in control selection. Thus, further prospective studies with robust methodology are required to prove or disprove this association between cerebral ischemic diseases and prothrombin gene mutation.

Conclusion

Homozygous prothrombin gene mutation, G20210A, may cause ischemic cerebrovascular diseases in the absence of other prothrombotic abnormalities. Hence, it could be included in the investigations of cerebral ischemia, especially in young patients with no apparent risk factors. Further prospective studies are recommended to confirm this observation.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

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