Low protein Z levels but not the protein Z gene G79A polymorphism are a risk factor for ischemic stroke.

BACKGROUND: Protein Z (PZ) is a vitamin K-dependent plasma protein that plays a role in both pro-and anticoagulant pathways, but its exact physiological function remains unclear. The aim of this study was to determine the association between the G79A PZ gene polymorphism in intron F, PZ levels and the occurrence of ischemic stroke. METHODS: We performed a case-control study in 118 Caucasian patients with first ever ischemic stroke or TIA confirmed by CT, and 113 age-and sex-matched population controls. Venous blood samples for PZ levels were collected 7 to 14 days and 3 months after stroke onset. Estimates of relative risk (odds ratios) were adjusted for vascular risk factors. RESULTS: The adjusted relative risk of ischemic stroke associated with PZ levels in the lowest quartile versus the highest quartile was 3.0 (95% CI: 1.1-8.7) at 7-14 days, and 5.1 (95% CI: 1.2-21.9) at 3 months after the stroke. PZ levels in the convalescent sample were significantly lower than in the acute sample. In the convalescent sample, odds ratios increased with lower quartiles of protein Z level (test for trend p=0.02). Thirty-nine patients (33%) and 32 (28%) controls were heterozygous for the G79A PZ gene polymorphism and 4 (3%) patients and 4 (4%) controls had the AA-genotype. The PZ levels were significantly lower in subjects with the AA-genotype and intermediate in heterozygote subjects. The odds ratio of ischemic stroke associated with A-allele carriers versus GG-homozygotes was 1.2 (95% CI: 0.7-2.1). CONCLUSION: No association between the G79A PZ gene polymorphism and the occurrence of stroke was observed. However, low PZ levels are independently associated with an increased risk of ischemic stroke.

High functional levels of thrombin-activatable fibrinolysis inhibitor are associated with an increased risk of first ischemic stroke.

BACKGROUND AND OBJECTIVE: Several studies have suggested that thrombin-activatable fibrinolysis inhibitor (TAFI) levels are associated with the risk of arterial thrombosis, but results have been contradictory. We studied functional TAFI levels and TAFI gene polymorphisms in 124 patients with a recent ischemic stroke and 125 age- and sex-matched controls to establish the role of TAFI in ischemic stroke. METHODS AND RESULTS: Functional TAFI levels, defined as TAFI-related retardation (RT), the difference in clot lysis time (LT) in the absence or presence of a specific activated TAFI inhibitor (potato carboxypeptidase inhibitor [PCI]), were higher in patients than controls (19.5 +/- 4.2 vs. 17.7 +/- 3.7 min, P < 0.005). Clot LTs in the presence of PCI, which were independent of TAFI, were also increased in ischemic stroke patients. This indicates that in these patients fibrinolysis is impaired not only by high TAFI levels, but also by other mechanisms. Individuals with functional TAFI levels in the highest quartile had an increased risk of ischemic stroke compared with the lowest quartile [odds ratio (OR) 4.0, 95% confidence interval (CI): 1.6-9.8]. In an unselected group of 36 of the 125 stroke patients functional TAFI levels were also measured at 3 months, and were persistently high. This indicates that increased functional TAFI levels after stroke are not caused by an acute phase reaction. No difference was found between patients and controls with respect to TAFI genotype distribution. CONCLUSIONS: Increased functional TAFI levels, resulting in decreased fibrinolysis, are associated with an increased risk of ischemic stroke.

The -148 C/T fibrinogen gene polymorphism and fibrinogen levels in ischaemic stroke: a case-control study.

BACKGROUND: To determine whether -148 C/T fibrinogen gene promoter polymorphism increases stroke risk by modifying the fibrinogen level. DESIGN: A case-control study of patients with first ever ischaemic stroke, confirmed by computed tomography. METHODS: Venous blood samples were collected for fibrinogen and routine coagulation tests one week after the stroke, and after three months in about half the patients. Population controls were age and sex matched. -148 C/T fibrinogen polymorphism was determined by polymerase chain reaction followed by digestion with restriction enzymes HindIII/AluI. RESULTS: There were 124 patients and 125 controls, mean age 56 years (range 18 to 75); 34 patients (27%) and 41 controls (33%) were heterozygous for -148 C/T fibrinogen polymorphism; six patients (5%) and five controls (4%) had the T/T genotype. The odds ratio of ischaemic stroke associated with CC homozygotes v T carriers was 0.8 (95% confidence interval, 0.5 to 1.4). Relative risk for ischaemic stroke associated with fibrinogen levels in the highest quartile was 3.9 (1.9 to 8.4) at one week, decreasing to 1.4 (0.6 to 3.3) at three months. CONCLUSIONS: -148 C/T fibrinogen gene polymorphism was not a strong risk factor for ischaemic stroke. High fibrinogen levels early after acute stroke probably represent an acute phase response.

Do antiphospholipid antibodies increase the long-term risk of thrombotic complications in young patients with a recent TIA or ischemic stroke?

BACKGROUND: The purpose of our study was to determine the relative risk of thrombotic events in young patients with a recent TIA or ischemic stroke and positive antiphospholipid antibodies (aPL). METHODS: We included 128 consecutive patients aged 18-45 years with a recent TIA or ischemic stroke. All patients underwent computed tomography scanning and were screened for cardiovascular risk factors, cardiac disorders and large vessel disease. Lupus anticoagulant (LA) was screened for by an APTT-based assay and a diluted PT-assay. Anticardiolipin antibodies (aCL) were tested by enzyme-linked immunosorbent assay, using cardiolipin and anti-human IgG and IgM. Thrombotic events could be TIA, stroke, myocardial infarction, deep venous thrombosis or pulmonary embolism. Product limit estimates of the time free of TIA or stroke and of the time free of any thrombotic event were made. The relative risk was estimated by means of a Cox proportional hazards regression model. RESULTS: Of the 128 patients, 22 (17.2%) had aPL. The mean follow-up was 3 years and 3 months (range 41 days to 6 yrs). The incidence of any thrombotic event per 100 patient years of follow-up was 9.0, and the incidence of recurrent stroke or TIA was 7.9. The relative risk of any thrombotic event in patients with aPL was 0.9 (95% CI: 0.3-2.4) and for recurrent ischemic stroke or TIA 0.7 (95% CI: 0.3-2.2). CONCLUSION: In young patients with a recent TIA or ischemic stroke, aPL do not seem to be a strong risk factor for recurrent stroke or TIA, nor for other thrombotic complications.

Elevated prothrombin is a risk factor for cerebral arterial ischemia in young adults.

The prevalence of elevated prothrombin (PT) in the absence of the G20210A mutation has not been studied in patients with cerebral ischemia. We carried out a case-control study of PT G20210A and PT activity in 49 adult patients aged 45 years or less, with TIA or ischemic stroke without cardiac embolism or large vessel disease, and 87 controls from a group of blood donors. Five patients were heterozygous for PT 20210A (OR=2.3, 95% CI: 0.6-8.0). Even after exclusion of individuals with the PT gene variant, the PT activity was significantly higher in patients than in controls (1.11 vs. 0.97, P=0.0003). The relative risk of cerebral ischemia in patients within the fourth quartile of PT activity (1.10 U/ml or higher), was 3.2 fold (95% CI: 1.03-9.96), than in patients whose level of PT activity was in the second or third quartile. We conclude that, although PT 20210A may be a weak risk factor for TIA and ischemic stroke in young patients, increased PT activity, which is more frequent than the mutation, appears to be more strongly related to cerebral ischemia.