Protein Z in ischaemic stroke

Many risk factors associated with ischaemic stroke are known, including high levels of fibrinogen or factor VII. Protein Z is a vitamin K-dependent coagulation factor, which was found to promote the assembly of thrombin with phospholipid vesicles that might promote coagulation. Indeed, a low protein Z level may be associated with a varying bleeding tendency. Therefore, we hypothesized that high protein Z levels could induce a hypercoagulable state and performed a case-control study to investigate a potential association between high protein Z plasma levels and ischaemic stroke. We measured protein Z in plasma samples from 157 patients with stroke of unknown aetiology and 192 control subjects. All patients had survived an ischaemic stroke or transient ischaemic attack (TIA) for at least 2 months. We found an increased relative risk of ischaemic stroke with increasing protein Z levels, with an odds ratio of 4.3 [95% confidence interval (CI): 1.7--11] for protein Z plasma levels > or = 160%. Excluding patients with a history of venous thromboembolism from the analysis, the same result was obtained (odds ratio 4.2; 95% CI: 1.6--11.2). Using a logistic regression model, this association also remained significant (P = 0.04) after adjustment for established risk factors. Our data indicated that a high plasma level of protein Z is an independent risk factor for ischaemic stroke.     

Prognostic role of C-reactive protein in very old patients with acute ischaemic stroke

BACKGROUND AND SCOPE: Recent literature has demonstrated that inflammation contributes to all phases of atherosclerosis and brain damage caused by stroke. In acute phase of cerebrovascular diseases biochemical markers of inflammation, such as C-reactive protein (CRP), could represent an indicator of severity of stroke, but few studies have verified this hypothesis, especially in very old patients. The aim of this study was to evaluate the role of CRP on short- and long-term prognosis in 75-year old and over elderly patients with acute ischaemic stroke. MATERIALS AND METHODS: We retrospectively evaluated CRP values (nephelometric method), performed within 12 h from hospital admission, in 196 elderly patients (124 females and 72 males with mean age+/-SD 83.32+/-10.46 years), discharged with diagnosis of acute ischaemic stroke, 68 of them with atherothrombotic large vessel stroke, 38 with lacunar stroke and 90 with cardioembolic stroke. We studied the relationship between CRP values and short-term prognosis [30-day mortality, length of hospitalization (LOS) and physical disability measured by modified Rankin scale and long-term prognosis (12-month mortality and re-hospitalization)]. RESULTS: Mean values of CRP were significantly higher in patients with cardioembolic stroke compared with atherothrombotic large vessel and lacunar stroke, in patients who died in the first 30 days from the acute event compared with survivors. LOS and physical disability score rose with increasing values of CRP for all subtypes of stroke. Higher CRP values were associated with the 12-month re-hospitalization for cerebrovascular events, whereas it did not influence the 12-month cumulative re-hospitalization and 12-month mortality. CONCLUSIONS: Elevation of CRP values at hospital admission could represent a negative prognostic index in elderly patients with ischaemic stroke, in particular, for short-term prognosis.     

Atrial fibrillation characteristics in patients with ischaemic stroke

BACKGROUND: Atrial fibrillation (AF) is a common arrhythmia and an important risk factor for ischaemic stroke (IS). Aim: To assess the frequency of AF, including paroxysmal (pxAF), persistent (psAF) and permanent AF (pmAF), in patients hospitalised due to IS as well as to establish the natural course of AF and IS prognosis. METHODS: A prospective, non-interventional study of consecutive acute stroke patients with AF with a 6-month follow-up. A favourable stroke outcome was defined when a patient survived or had no disabling stroke during follow-up. RESULTS: Within 24 months of recruitment, 838 patients were hospitalised due to IS or transient ischaemic attack. Concomitant AF was diagnosed in 200 (24.4%) of these patients. Permanent AF was observed in 108 (54%), pxAF in 70 (35%), psAF in 9 (4.5%), and AF of unknown duration in 13 (6.5%) patients. Mean age, demographics and concomitant treatment did not differ significantly among groups. The pxAF patients had less often a disabling stroke on admission (81 and 91 vs. 50%, p <0.001) and discharge (55 and 31 vs. 19%, p <0.001) than pmAF and psAF patients, respectively. In-hospital (13 and 9 vs. 3%, p <0.001) and 6-month mortality rates (35 and 40 vs. 14%, p <0.001) were also significantly higher in pmAF and psAF patients than in the pxAF group. Lack of chronic anticoagulation tended to be a risk factor for death (OR 2.1, 95% CI 0.8-5.1, p=0.09). In 20 (66%) patients with pxAF who experienced recurrence of spontaneous AF during hospitalisation, a successful pharmacological cardioversion was performed, whereas in 10 (34%) patients sinus rhythm was not restored. Restoration of sinus rhythm was a risk factor for unfavourable stroke outcome in the 6-month observation period (OR 2.14; 95% CI 1.07-4.29; p=0.03). During the study 29 (40%) patients with pxAF experienced at least one AF recurrence, and 20 (29%) developed psAF. Transformation of psAF to pmAF was observed in 8 (36%) patients. Disabling stroke on admission was a risk factor (OR 4.5, 95% CI 0.9-22.9, p=0.05) for transformation of pxAF to pmAF. CONCLUSION: Atrial fibrillation was present in 24.4% of acute IS patients. Paroxysmal AF was diagnosed in 35%, pmAF in 54% and psAF in 11% of patients. During follow-up 29% of pxAF progressed to psAF and 36% psAF to pmAF. In-hospital and 6-month mortality rates and the number of patients with disabling stroke were significantly lower in pxAF than in pmAF and psAF patients. A trend towards unfavourable outcome was observed among patients not receiving chronic anticoagulation.     

Role of protein Z in stroke

Opinion statement Protein Z (PZ) is a vitamin K-dependent plasma glycoprotein that acts as a cofactor for PZ-dependent protease inhibitor to inhibit coagulation factor X_a. Studies in mice suggest that that decreased blood PZ levels lead to reduced inhibition of blood coagulation, thereby predisposing to thrombosis; however, clinical studies in humans have yielded conflicting results. Among patients with stroke, some epidemiologic studies have reported that reduced PZ levels increase the risk of stroke, whereas others have reported no association between PZ levels and stroke, or that elevated PZ levels increase stroke risk. Polymorphisms involving the gene for PZ can influence the PZ concentration and some polymorphisms (eg, intron G79A AA allele) may be protective against stroke, particularly among younger individuals. Although the association between PZ levels and stroke appears to be stronger in younger patients and in patients who do not have conventional vascular risk factors, it remains unclear whether the link between PZ levels and stroke is confounded or causal or whether blood levels of PZ are altered as a consequence of the acute stroke event.     

High frequency of protein Z deficiency in patients with unexplained early fetal loss

The protein Z-protein Z-dependent inhibitor complex is a factor Xa inhibitor. Protein Z deficiencies have recently been described in patients with ischemic stroke. As placenta infarction leads to poor pregnancy outcome, we studied protein Z plasma concentrations in nonthrombotic, nonthrombophilic consecutive patients with unexplained pregnancy wastage. A significant amount of protein Z deficiencies was only found in the early fetal loss group (< 1 mg/L; 44 of 200, P < 10(-4)) and mainly in the case of fetal demise between the beginning of the 10th and the end of the 15th week of gestation (odds ratio, 6.7 [3.1-14.8], P < 10(-3)). These deficiencies were not due to partial vitamin K1 deficiency, and at least some of them were constitutional ones. In women, protein Z deficiency may induce an enhanced risk of severe placental insufficiency soon after the connection of maternal and fetal circulations.     

Management of acute ischaemic stroke in patients with dementia

An estimated 10% of stroke patients have an underlying dementia. As a consequence, health professionals often face the challenge of managing patients with dementia presenting with an acute stroke. Patients with dementia are less likely to receive thrombolysis (0.56–10% vs. 1–16% thrombolysis rates in the general population), be admitted to a stroke unit or receive some types of care. Anticoagulation for secondary stroke prevention is sometimes withheld, despite dementia not being listed as an exclusion criterion in current guidelines. Studies in this population are scarce, and results have been contradictory. Three observational studies have examined intravenous thrombolysis for treatment of acute ischaemic stroke in patients with dementia. In the two largest matched case–control studies, there were no significant differences between patients with and without dementia in the risks of intracerebral haemorrhage or mortality. The risk of intracerebral haemorrhage ranged between 14% and 19% for patients with dementia. Studies of other interventions for stroke are lacking for this population. Patients with dementia are less likely to be discharged home compared with controls (19% vs. 41%) and more likely to be disabled (64% vs. 59%) or die during hospitalization (22% vs. 11%). The aim of this review was to summarize current knowledge about the management of ischaemic stroke in patients with pre‐existing dementia, including organizational aspects of stroke care, intravenous thrombolysis, access to stroke unit care and use of supportive treatment. Evidence to support anticoagulation for secondary prevention of stroke in patients with atrial fibrillation and antiplatelet therapy in nonembolic stroke will be discussed, as well as rehabilitation and how these factors influence patient outcomes. Finally, ethical issues, knowledge gaps and pathways for future research will be considered.     

Frequency and effect of optimal anticoagulation before onset of ischaemic stroke in patients with known atrial fibrillation

BACKGROUND: The aims of the study were (i) to examine which antithrombotic therapy patients with known atrial fibrillation use at the point of time when they suffer an ischaemic stroke, (ii) to evaluate the effects of optimal antithrombotic treatment on outcome and severity of the stroke. METHODS: Patients with known atrial fibrillation before onset of acute ischaemic stroke, and age >60 years were included. Antithrombotic therapy on admission was classified into four groups: no antithrombotic therapy, aspirin, sub-optimal anticoagulation (warfarin and international normalized ratio, INR<2.0) and optimal anticoagulation (warfarin and INR>or=2.0). Primary outcome: modified Rankin Scale (mRS) 5 or 6 at day 7 poststroke. Secondary outcomes: (i) death or discharge to a nursing home, (ii) death, (iii) stroke severity on admission assessed by Scandinavian Stroke Scale. RESULTS: A total of 394 patients were included. On admission 109 (28%) patients used no antithrombotic therapy, 169 (43%) aspirin, 52 (13%) warfarin and had an INR<2.0, and 64 (16%) used warfarin and had an INR>or=2.0. The proportion of patients with an mRS 5 or 6 and the corresponding odds ratios were: in the warfarin group with INR<2.0, 16 (31%), OR 3.1 (CI: 1.2-8.0), (P=0.019), in the group with no antithrombotic therapy 29 (27%), 2.5 (1.1-5.9), (P=0.034), and in the aspirin group 41(24%), 2.2 (1.0-5.1) (P=0.054), compared with the warfarin group with INR>or=2.0, where eight (13%) patients had a poor outcome. A significantly higher proportion of patients died or were discharged to a nursing home in the warfarin group with an INR<2.0 (P=0.014), in the aspirin group (P=0.018) and in the no-treatment group (P=0.035), compared with the warfarin group with an INR>or=2.0. No significant differences were found regarding death alone and stroke severity on admission. DISCUSSION: Few patients with known atrial fibrillation who suffer an ischaemic stroke receive optimal antithrombotic therapy prior to the onset of stroke. Optimal anticoagulation does not only reduce the risk of ischaemic stroke, but also appears to reduce death and severe dependency as well as the need for nursing home care, if an ischaemic stroke occurs.     

Medication compliance in ischaemic stroke patients

Aim: This study aimed to assess the degree of patient compliance with medications prescribed at hospital discharge following ischaemic stroke, and concordance between self‐reported medication use and general practitioner (GP) records. Methods: The Auckland City Hospital Stroke database was used to identify consecutive patients with ischaemic stroke over a three‐month period. Participants were contacted and invited to participate in a telephone questionnaire that asked about current medications. GPs were also asked to list the medications their patients were taking. Results: Fifty‐one patients were approached to participate of whom 48 consented to be interviewed at 6 weeks and 47 at 6 months. At 6 weeks, 36 of 38 (95%) were compliant with aspirin, 12 of 13 (92%) dipyridamole, 8 of 9 (88%) warfarin, 36 of 41 (88%) statins, 33 of 38 (87%) antihypertensive medications, and 7 of 7 (100%) diabetes medications. At 6 months, 97% were compliant with aspirin, 100% dipyridamole, 100% warfarin, 94% statins, 91% antihypertensive medications, and 100% diabetes medications. Natural or herbal remedy use was reported by 10 of 48 (21%) at 6 weeks and 11 of 47 (23%) at 6 months. Blister packs were used by 8 of 48 (17%) at 6 weeks and 5 of 47 (11%) at 6 months. Conclusion: Adherence to secondary stroke prevention medication was between 87% and 100% at 6 weeks with similar findings at 6 months after discharge. We speculate that these high compliance rates may be due to one‐on‐one stroke nurse counselling and the use of stroke information packs, which include information about the importance of adherence to secondary prevention medication.     

Prothrombotic phenotype of protein Z deficiency

Protein Z (PZ) is a vitamin K-dependent plasma protein whose function has been uncertain. The structure of PZ is very similar to that of the coagulation-related factors VII, IX, and X and PC, but PZ differs from these other proteins in that it is not the zymogen of a serine protease. We have shown recently that PZ forms a calcium ion-dependent complex with activated factor X at phospholipid surfaces and that this interaction leads to the inhibition of activated factor X activity through, in part, the action of a previously unidentified plasma protein named PZ-dependent protease inhibitor. Herein, we report that the presence of PZ dampens the coagulation response in human plasma and that concomitant PZ deficiency dramatically increases the severity of the prothrombotic phenotype of factor V(Leiden) mice. The results indicate that PZ plays a physiologically important role in the regulation of coagulation.     

Specific cardiac disorders in 402 consecutive patients with ischaemic cardioembolic stroke

BACKGROUND: To determine the cardiological substrate in acute stroke patients presenting with a cardioembolic stroke subtype. METHODS: Data of 402 consecutive patients with cardioembolic stroke (cerebral infarction, n=347; transient ischaemic attack, n=55) were collected from a prospective hospital-based stroke registry in which data on 2000 stroke patients over a 10-year period were included. In all patients, specific cardiac disorders were identified by physical examination and results of electrocardiography and transthoracic echocardiography. Holter monitoring and more sensitive techniques of cardiac imaging were used in selected cases. RESULTS: Cardioembolic cerebral ischaemia accounted for 20% of all acute strokes (25% of ischaemic cerebrovascular events). Cardiac sources of embolism included the following: (a) structural cardiac disorders associated with arrhythmia (n=232), the most frequent being left ventricular hypertrophic hypertensive disease (n=120) and rheumatic mitral valve disease (n=49); (b) structural cardiac disease with sustained sinus rhythm (n=81), the most frequent being systolic left ventricular dysfunction of both ischaemic (n=35) or non-ischaemic (n=24) aetiology; and (c) isolated atrial dysrhythmia (atrial fibrillation, n=88 and atrial flutter, n=1). CONCLUSIONS: Hypertrophic hypertensive cardiac disease complicated with atrial fibrillation was the most frequent cardiac source of emboli in cardioembolic stroke. Other important cardiac sources were isolated atrial fibrillation, rheumatic mitral valve disease, and systolic left ventricular dysfunction of ischaemic and non-ischaemic cause. The incidence of traditional emboligenous-prone cardiac disorders, such as mitral valve prolapse and mitral annular calcification was low.     

Protein C deficiency manifesting as an acute myocardial infarction and ischaemic stroke

Protein C deficiency is a disorder in the coagulation cascade that results in predominantly venous thromboembolism. However, recent studies have implicated this disorder as a possible contributor to arterial thrombosis, especially myocardial infarction. There are six reported cases of myocardial infarction secondary to protein C deficiency in the literature. This is the first report of myocardial infarction and ischaemic stroke in the same patient as a manifestation of protein C deficiency. The investigation of hypercoagulable state is an essential component of the investigation of young patients with myocardial infarction.     

High prevalence of undiagnosed diabetes among Chinese patients with ischaemic stroke.

We reviewed the prevalence of diabetes mellitus, hypertension and cigarette smoking in 176 Chinese patients with acute stroke, classified, on computed tomographic findings, as intracerebral haemorrhage or cerebral infarction. In all patients with no known history of diabetes, a 75 g OGTT was done 3-6 months after ictus and interpreted using WHO criteria. The overall prevalence of diabetes and impaired glucose tolerance (IGT) was 33.5% and 21.0%, respectively, with a higher prevalence being found in patients with cerebral infarction (P less than 0.05). Forty percent of those with diabetes were previously undiagnosed - all but 2 had ischaemic stroke. Compared to reported findings in the general population, an increased prevalence of hypertension, and possibly also cigarette smoking was found in patients with both stroke categories. On the other hand, significant hypercholesterolaemia was not found in patients of either category. In view of the high prevalence of undiagnosed diabetes among these stroke patients and the increased morbidity and mortality associated with diabetes mellitus, screening for diabetes is recommended especially in those with ischaemic stroke. If a fasting plasma glucose of greater than or equal to 6 mmol/l was used for the initial screening of undiagnosed diabetes in this group of patients, the sensitivity and specificity values would have been 78% and 94%, respectively. Whether this cut-off value can be cost-effectively employed for mass screening remains to be confirmed by studies involving larger numbers of stroke patients.