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We examined two sisters who had an ischaemic stroke at 32 and 41 years respectively. One had the prothrombin 20210 G to A variant1 and mild hyperhomocysteinaemia. The other had two prothrombotic mutations: the factor V Leiden mutation2 and the prothrombin 20210 G to A variant.1 We argue that these abnormalities may have caused the strokes.
Patient III-36 (pedigree, figure) was admitted at the age of 41 years with a left sided paresis. Her medical history was unremarkable, including the absence of migraine. Neurological examination showed a mild left sided paresis. Blood pressure was normal. She had no livedo reticularis. Brain CT showed a right sided cerebral infarct. Cardiological investigation, carotid angiography, and laboratory testing were normal, including investigation of antiphospholipid antibodies, lipid profile, fasting and post-methionine loading homocysteine concentrations, antithrombin III, protein C, and protein S. The patient was treated with aspirin and did not have arterial ischaemic disease (or venous thrombosis) until now. Resistance to activated protein C (APC) was measured as described2 and the n-APC-SR was 0.66 (normal>0.84). As expected from this value, the patient was found to be a carrier of the factor V Leiden mutation.2 Subsequently, she was also shown to be a carrier of the prothrombin 20210 G to A variant1.
Patient III-37 was admitted at the age of 33 years because of an acute left sided paresis. One year before, she had experienced a transient weakness of the right leg. Otherwise, her medical history was unremarkable (no migraine). She smoked 20 cigarettes a day, did not drink alcohol, and did not take oral contraceptives. She had a left facial palsy, hemianopia, and hemiparesis. Blood pressure was normal. She had no livedo reticularis. Brain CT showed an old left frontoparietal infarct and a recent right frontoparietal infarct. Laboratory investigation, including lipid profile, protein C, protein S, and antithrombin III, cardiological investigation, and carotid angiography were normal. Fasting homocysteine concentration was raised (28.2 μmol/l), without abnormal post-methionine loading concentration. She was treated with aspirin, folate, and pyridoxin and did not have arterial or venous thrombosis until now. APC resistance was normal (n-APC-SR of 1.09), and the factor V Leiden mutation was not present. She was a carrier of the prothrombin 20210 G to A variant.
After informed consent, we prospectively investigated the family members of the probands. DNA testing was not performed in all family members (see pedigree). Medical history of all family members was unremarkable (no ischaemic heart disease, stroke, migraine, or deep venous thrombosis), except for III-39 who had mental retardation, epilepsy, and blindness (she could not be studied). The factor V Leiden and prothrombin variant were investigated in III-34, III-38, III-40, IV-65, IV-66, IV-68, and IV-70. The factor V Leiden mutation was present in III-34 and IV-70, the prothrombin variant in III-40, both variants in IV-65, IV-66, and IV-68, and no mutation in III-38. III-35 (who was not tested) may have both mutations, because her two daughters carry both mutations. III-61 (who is not a relative) probably carries the factor V Leiden mutation, as his wife has the prothrombin mutation, but their daughter has the factor V Leiden mutation. Fasting and post-methionine loading serum homocysteine concentrations were normal in III-34, III-38, III-40, III-41, IV-65, and IV-70.
The occurrence of a stroke in a young person is relatively rare. It is even more rare when two first degree relatives have a stroke at a young age. The second situation strongly suggests a genetic cause, which reduces the list of possible causes considerably.3 On clinical and radiological grounds and after laboratory and cardiac investigations, in the probands many hereditary causes of stroke were excluded (mitral valve prolapse, atrial myxomas, cardiomyopathies, CADASIL, Sneddon’s syndrome, MELAS, and abnormalities of protein C, protein S, and antithrombin III). In homocystinuria thrombotic events are invariably more severe than in our probands, although the occurrence of mental retardation, epilepsy, and blindness in subject III-39 is compatible with homocystinuria (unfortunately, she could not be studied). III-37 had mild hyperhomocysteinaemia, but it is unlikely that this was the (only) cause for her strokes, as hyperhomocystinaemia mostly causes premature atherosclerosis, microangiopathy, and leukoencephalopathy, which were not found. We therefore considered the prothrombotic mutations as the most likely cause.
The factor V Leiden mutation occurs in about 4% of the Dutch population,2 and the prothrombin mutation in 1% to 2%.1 The simultaneous occurrence of both mutations in one subject can therefore be calculated as 0.04% to 0.08%—that is, 6000 to 12 000 persons in The Netherlands (about 15 million inhabitants). Nevertheless, so far only one Dutch family in which both mutations occur has been described.1 All members in this family with both genetic defects experienced venous thromboses.1 The only other published pedigree in which both mutations occur originates from France.4 In this pedigree only one subject carried both mutations, and she had recurrent venous thrombosis, but no arterial ischaemic events.4 The risk for venous thrombosis in patients with both mutations is probably high, as it is known that the factor V Leiden mutation enhances the risk for thrombosis in patients with other prothrombotic states, such as protein S and protein C deficiencies.5
Although the association of prothrombotic mutations, such as the factor V Leiden mutation and the prothrombin variant, with (recurrent) venous thrombosis is now well established, the association with arterial thromboembolism is not clear.5 Population and case-control studies have shown that the factor V Leiden mutation is not a risk factor for myocardial infarction or cerebrovascular disease5. Nevertheless, this mutation has been assiociated with ischaemic stroke.6 The relation between the more recently discovered prothrombin 20210 A to G mutation1 and arterial disease has not yet been intensively studied, but seems unlikely.6 It is, however, possible that the strokes in the probands can be attributed to the co-occurrence of two risk factors (prothrombin mutation and factor V Leiden mutation in one, and prothrombin mutation and hyperhomocysteinaemia in the other), because it is likely that a synergistic interaction occurs between thrombogenic risk factors. To study this further, a case-control study determining the importance of a combination of thrombogenic risk factors in unselected young patients with stroke is necessary.