Recurrent Cerebral Venous Thrombosis Treated with Direct Oral Anticoagulants in a Japanese Man with Hereditary Protein C Deficiency.

We herein report a case involving a 32-year-old Japanese man with recurrent cerebral venous thrombosis due to hereditary protein C deficiency. He was admitted to our hospital with impaired consciousness. Brain magnetic resonance imaging demonstrated high intensities diffusely along the bilateral sulci and magnetic resonance venography revealed left transverse sinus and superior sagittal sinus stenoses. His father had a history of cerebral infarction and venous thrombosis. The protein C activity level examined by chromogenic synthetic substrate assay was markedly reduced. He was diagnosed with protein C deficiency, and a genetic analysis revealed a heterozygous mutation at exon 3 c.199G>A,p.Glu67Lys on the protein C gene. Four months later, at his second admission, he had transient aphasia, and his protein C activity was under 10%. We switched warfarin to the direct oral anticoagulants edoxaban. He remains fully recovered with no adverse events after the administration of edoxaban for a year. Direct oral anticoagulants may be a new tool for treating cerebral venous thrombosis due to hereditary protein C deficiency.

Ischemic Stroke and Bleeding: Clinical Benefit of Anticoagulation in Atrial Fibrillation After Intracerebral Hemorrhage.

Background and Purpose- Patients with intracerebral hemorrhage (ICH) and atrial fibrillation (AF) are at risk for ischemic events. While risk calculators (CHA2DS2-VASc and HAS-BLED) have been validated to assess risk for ischemic stroke and major bleeding in AF patients, decisions about anticoagulation must consider the net clinical benefit of anticoagulation. Furthermore, stroke and bleeding risk are highly correlated, making decisions more difficult. Methods- We examined patients in the GERFHS III study (Genetic and Environmental Risk Factors for Hemorrhagic Stroke)-a population-based retrospective study of spontaneous ICH patients without a structural or traumatic cause in the Greater Cincinnati/Northern Kentucky region between July 2008 and December 2012. CHA2DS2-VASc and HAS-B(L)ED (minus L because labile international normalized ratio was unavailable) scores were calculated for ICH patients with AF. Using a Markov state transition model, we estimated net clinical benefit of anticoagulation relative to no treatment in quality-adjusted life years (QALYs). We defined minimal clinically relevant benefit as 0.1 QALYs. Results- Among 1186 cases of spontaneous ICH, 95 cases had AF and met our survival criteria. Within 1 year, 8 of 95 (8%) would be expected to have a major bleeding event on anticoagulation, and 5 of 95 (5%) of patients would be expected to have an ischemic stroke off anticoagulation. Sixty-eight of 95 (71%) patients would have higher risk for major bleeding than for ischemic stroke. Anticoagulation with directly acting anticoagulants would result in no clinically significant gain or loss in 73%. Roughly 12% would gain >0.1 QALYs, and 15% would lose >0.1 QALYs. Among patients receiving aspirin, most have no significant net clinical benefit or loss. Overall, anticoagulation of the entire cohort would result in an aggregate loss of 0.92 QALYs. Conclusions- Our analysis suggests that universal anticoagulation after ICH would be associated with a net loss of QALY. Additional factors should be considered before anticoagulating patients with AF after ICH. Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT00930280.

Looking into the next decade of antithrombotic therapy for patients with atrial fibrillation and percutaneous coronary intervention.

Patients with atrial fibrillation who undergo percutaneous coronary intervention are at increased risk for both coronary and cerebral thrombotic events. As a result, antithrombotic therapy for this patient population continues to pose a significant challenge. In this review, we discuss the development of warfarin triple therapy as the standard of care in the last century, the transition to dual therapy with warfarin and a P2Y12 inhibitor, the advent of NOACs, recent clinical trials, and new regimens with a NOAC and a P2Y12 inhibitor. We also discuss our current clinical practice, based on the available data.

Low prevalence of JAK2 V617F mutation in patients with thrombosis and normal blood counts: a retrospective impact study.

To determine the prevalence of the V617F Janus Kinase 2 (JAK2) mutation in patients with thrombosis without other biological signs of underlying myeloproliferative neoplasm (MPN) and identify associated risk factors for thrombosis. Over a 10-year period, data were collected from patients with thrombotic events and who had also been screened for the V617F JAK2 mutation. Patients with signs of underlying MPN, such as haematocrit levels ≥ 50% and/or platelet counts ≥ 450 × 109/L and/or splanchnic thrombosis were excluded from the study. Of 340 patients fulfilling inclusion criteria, JAK2 mutation was found in 9 (2.65%), the allele burden being at least 2% in 4 (1.1%). Upon follow-up, MPN was diagnosed in the latter 4. Univariate analysis of the whole cohort showed that age (54 ± 15 vs. 64 ± 13, p = 0.027), platelet count (317 ± 111 vs. 255 ± 75, p = 0.017), C-reactive protein level > 5 mg/L (OR 7.29, p = 0.014), and splenomegaly (OR 54.5, p = 0.0002) were significantly associated with JAK2 mutation. There was also a trend for an increased risk of cerebral venous thrombosis (OR 6.54, p = 0.064). Logistic regression confirmed a significant association between splenomegaly and JAK2 mutation (OR 43.15 [95%CI, 3.05-610.95], p = 0.0054). The V617F JAK2 mutation is rarely found in patients with thrombotic events without overt MPN. Splenomegaly, however, is a statistically and clinically relevant indicator of a potential JAK2 mutation in patients with non-splanchnic thrombotic events. Such patients should require further assessment and a close follow-up.

Recombinant Human Milk Fat Globule-Epidermal Growth Factor 8 Attenuates Microthrombosis after Subarachnoid Hemorrhage in Rats.

BACKGROUND: Microthrombosis after subarachnoid hemorrhage has an adverse effect on prognosis. Milk fat globule-epidermal growth factor 8 promotes phagocytosis of phagocytic cells and may reduce microthrombosis. This study investigated the effects of recombinant human milk fat globule-epidermal growth factor 8 on microthrombosis and neurological function after subarachnoid hemorrhage. METHODS: Rats subarachnoid hemorrhage model was induced by intravascular puncture method. Western blot was performed to measure the expression of endogenous milk fat globule-epidermal growth factor 8 after subarachnoid hemorrhage. Microthrombosis was quantified by microthrombi count using immunohistochemistry and immunofluorescence. The neuroprotective effect of recombinant human milk fat globule-epidermal growth factor 8 administration was evaluated by modified Garcia score, beam balance, Rotarod test, and Morris water maze. RESULTS: Endogenous milk fat globule-epidermal growth factor 8 protein level increased after subarachnoid hemorrhage. Microthrombosis was significantly increased in subarachnoid hemorrhage rats brain, while recombinant human milk fat globule-epidermal growth factor 8 dramatically reduced microthrombosis as well as improve short- and long- term neurobehavior after subarachnoid hemorrhage. CONCLUSIONS: Recombinant human milk fat globule-epidermal growth factor 8 reduces microthrombosis and improves neurological function after subarachnoid hemorrhage, which may be an effective strategy for treating subarachnoid hemorrhage.

Thrombosis and systemic and cardiac oxidative stress and DNA damage induced by pulmonary exposure to diesel exhaust particles and the effect of nootkatone thereon.

Adverse cardiovascular effects of particulate air pollution persist even at lower concentrations than those of the current air quality limit. Therefore, identification of safe and effective measures against particle-induced cardiovascular toxicity is needed. Nootkatone is a sesquiterpenoid in grapefruit with diverse bioactivities including anti-inflammatory and antioxidant effects. However, its protective effect on the cardiovascular injury induced by diesel exhaust particles (DEPs) has not been studied before. We assessed the possible protective effect of nootkatone (90 mg/kg) administered by gavage 1 h before intratracheal instillation of DEPs (30 µg/mouse). Twenty-four hours after the intratracheal administration of DEPs, various thrombotic and cardiac parameters were assessed. Nootkatone inhibited the prothrombotic effect induced by DEPs in pial arterioles and venules in vivo and platelet aggregation in whole blood in vitro. Also, nootkatone prevented the shortening of activated partial thromboplastin time and prothrombin time induced by DEPs. Nootkatone inhibited the increase of plasma concentration of fibrinogen, plasminogen activator inhibitor-1, interleukin-6, and lipid peroxidation induced by DEPs. Immunohistochemically, hearts showed an analogous increase in glutathione and nuclear factor erythroid-derived 2-like 2 expression by cardiac myocytes and endothelial cells after DEP exposure, and these effects were enhanced in mice treated with nootkatone + DEPs. Likewise, heme oxygenase-1 was increased in mice treated with nootkatone + DEPs compared with those treated with DEPs or nootkatone + saline. The DNA damage caused by DEPs was prevented by nootkatoone pretreatment. In conclusion, nootkatoone alleviates DEP-induced thrombogenicity and systemic and cardiac oxidative stress and DNA damage, at least partly, through nuclear factor erythroid-derived 2-like 2 and heme oxygenase-1 activation. NEW & NOTEWORTHY Nootkatoone, a sesquiterpenoid found in grapefruit, alleviates the thrombogenicity and systemic and cardiac oxidative stress and DNA damage in mice exposed to diesel exhaust particles. Nootkatone-induced boosting of nuclear factor erythroid-derived 2-like 2 and heme oxygenase-1 levels in the heart of mice exposed to diesel exhaust particles suggests that its protective effect is, at least partly, mediated through nuclear factor erythroid-derived 2-like 2 and heme oxygenase-1 activation.

Symptomatic Cerebral Sinovenous Thrombosis Associated With L-Asparaginase In Children With Acute Lymphoblastic Leukemia: A Single Institution Experience Over 17 Years.

BACKGROUND: Cerebral sinovenous thrombosis (CSVT) is a rare, yet important complication of acute lymphoblastic leukemia (ALL) therapy, associated with significant morbidity and mortality. Paucity of data from India prompted us to report our experience with CSVT over a period of 17 years. MATERIALS AND METHODS: This is a retrospective analysis of 500 consecutive ALL patients, below 18 year of age, treated between January 1998 and December 2014, who developed symptomatic CVST. RESULTS: Seven of the 467 eligible patients developed symptomatic CVST with an incidence of 1.5% (7/467). Six of the CVST events, occurred during induction and 1 during reinduction. Median time to symptoms was 21 days (range, 2 to 27 d) from first exposure to L-asparaginase therapy. Management included low-molecular-weight heparin (enoxaparin sodium) at a dose of 1 mg/kg twice a day for at least 3 months along with supportive care. There were 2 thrombosis-attributable deaths. The remaining patients tolerated rechallenge with L-asparaginase uneventfully during reinduction, under cover of heparin prophylaxis. Complete neurological recovery was observed in all surviving patients. CONCLUSIONS: Incidence of symptomatic L-asparaginase associated CSVT during ALL treatment was 1.5% with high case fatality rate (28%). It is noteworthy that full neurological recovery is likely in surviving patients, and rechallenge with L-asparaginase is safe with heparin prophylaxis. Currently available screening methods are not practically implementable in resource-limited settings.

Safety of Pregnancy After Cerebral Venous Thrombosis: Results of the ISCVT (International Study on Cerebral Vein and Dural Sinus Thrombosis)-2 PREGNANCY Study.

BACKGROUND AND PURPOSE: Pregnancy is associated with increased risk of venous thrombotic events, including cerebral venous thrombosis. We aimed to study the complications and outcome of subsequent pregnancies in women with previous cerebral venous thrombosis. METHODS: Follow-up study of women with acute cerebral venous thrombosis at childbearing age included in a previously described cohort (International Study of Cerebral Vein and Dural Sinus Thrombosis). Patients were interviewed by local neurologists to assess rate of venous thrombotic events, pregnancy outcomes, and antithrombotic prophylaxis during subsequent pregnancies. RESULTS: A total of 119 women were included, with a median follow-up of 14 years. Eighty-two new pregnancies occurred in 47 women. In 83% (68 of 82), some form of antithrombotic prophylaxis was given during at least 1 trimester of pregnancy or puerperium. Venous thrombotic events occurred in 3 pregnancies, including 1 recurrent cerebral venous thrombosis. Two of the 3 women were on prophylactic low-molecular-weight heparin at the time of the event. Outcomes of pregnancies were 51 full-term newborns, 9 preterm births, 2 stillbirths, and 20 abortions (14 spontaneous). CONCLUSIONS: In women with prior cerebral venous thrombosis, recurrent venous thrombotic events during subsequent pregnancies are infrequent.

Rivaroxaban Versus Dabigatran or Warfarin in Real-World Studies of Stroke Prevention in Atrial Fibrillation: Systematic Review and Meta-Analysis.

BACKGROUND AND PURPOSE: This study was designed to evaluate the effectiveness and safety of rivaroxaban in real-world practice compared with effectiveness and safety of dabigatran or warfarin for stroke prevention in atrial fibrillation through meta-analyzing observational studies. METHODS: Seventeen studies were included after searching in PubMed for studies reporting the comparative effectiveness and safety of rivaroxaban versus dabigatran (n=3), rivaroxaban versus Warfarin (n=11), or both (n=3) for stroke prevention in atrial fibrillation. RESULTS: Overall, the risks of stroke/systematic thromboembolism with rivaroxaban were similar when compared with those with dabigatran (stroke/thromboembolism: hazard ratio, 1.02; 95% confidence interval, 0.91-1.13; I2=70.2%, N=5), but were significantly reduced when compared with those with warfarin (hazard ratio, 0.75; 95% confidence interval, 0.64-0.85; I2=45.1%, N=9). Major bleeding risk was significantly higher with rivaroxaban than with dabigatran (hazard ratio, 1.38; 95% confidence interval, 1.27-1.49; I2=26.1%, N=5), but similar to that with warfarin (hazard ratio, 0.99; 95% confidence interval, 0.91-1.07; I2=0.0%, N=6). Rivaroxaban was associated with increased all-cause mortality and gastrointestinal bleeding, but similar risk of acute myocardial infarction and intracranial hemorrhage when compared with dabigatran. When compared with warfarin, rivaroxaban was associated with similar risk of any bleeding, mortality, and acute myocardial infarction, but a higher risk of gastrointestinal bleeding and lower risk of intracranial hemorrhage. CONCLUSIONS: In this systematic review and meta-analysis, rivaroxaban was as effective as dabigatran, but was more effective than warfarin for the prevention of stroke/thromboembolism in atrial fibrillation patients. Major bleeding risk was significantly higher with rivaroxaban than with dabigatran, as was all-cause mortality and gastrointestinal bleeding. Rivaroxaban was comparable to warfarin for major bleeding, with an increased risk in gastrointestinal bleeding and decreased risk of intracranial hemorrhage.

Use of Platelet Function Testing Before Pipeline Embolization Device Placement: A Multicenter Cohort Study.

BACKGROUND AND PURPOSE: Thromboembolic complications constitute a significant source of morbidity after neurointerventional procedures. Flow diversion using the pipeline embolization device for the treatment of intracranial aneurysms necessitates the use of dual antiplatelet therapy to reduce this risk. The use of platelet function testing before pipeline embolization device placement remains controversial. METHODS: A retrospective review of prospectively maintained databases at 3 academic institutions was performed from the years 2009 to 2016 to identify patients with intracranial aneurysms treated with pipeline embolization device placement. Clinical and radiographic data were analyzed with emphasis on thromboembolic complications and clopidogrel responsiveness. RESULTS: A total of 402 patients underwent 414 pipeline embolization device procedures for the treatment of 465 intracranial aneurysms. Thromboembolic complications were encountered in 9.2% of procedures and were symptomatic in 5.6%. Clopidogrel nonresponders experienced a significantly higher rate of thromboembolic complications compared with clopidogrel responders (17.4% versus 5.6%). This risk was significantly lower in nonresponders who were switched to ticagrelor when compared with patients who remained on clopidogrel (2.7% versus 24.4%). In patients who remained on clopidogrel, the rate of thromboembolic complications was significantly lower in those who received a clopidogrel boost within 24 hours pre-procedure when compared with those who did not (9.8% versus 51.9%). There was no significant difference in the rate of hemorrhagic complications between groups. CONCLUSIONS: Clopidogrel nonresponders experienced a significantly higher rate of thromboembolic complications when compared with clopidogrel responders. However, this risk seems to be mitigated in nonresponders who were switched to ticagrelor or received a clopidogrel boost within 24 hours pre-procedure.

Antithrombotic treatment after stroke due to intracerebral haemorrhage.

BACKGROUND: Survivors of stroke due to intracerebral haemorrhage (ICH) are at risk of thromboembolism. Antithrombotic (antiplatelet or anticoagulant) treatments may lower the risk of thromboembolism after ICH, but they may increase the risks of bleeding. OBJECTIVES: To determine the overall effectiveness and safety of antithrombotic drugs for people with ICH. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (24 March 2017). We also searched the Cochrane Central Register of Controlled Trials (CENTRAL: the Cochrane Library 2017, Issue 3), MEDLINE Ovid (from 1948 to March 2017), Embase Ovid (from 1980 to March 2017), and online registries of clinical trials (8 March 2017). We also screened the reference lists of included trials for additional, potentially relevant studies. SELECTION CRITERIA: We selected all randomised controlled trials (RCTs) of any antithrombotic treatment after ICH. DATA COLLECTION AND ANALYSIS: Three review authors independently extracted data. We converted categorical estimates of effect to the risk ratio (RR) or odds ratio (OR), as appropriate. We divided our analyses into short- and long-term treatment, and used fixed-effect modelling for meta-analyses. Three review authors independently assessed the included RCTs for risks of bias and we created a 'Summary of findings' table using GRADE. MAIN RESULTS: We included two RCTs with a total of 121 participants. Both RCTs were of short-term parenteral anticoagulation early after ICH: one tested heparin and the other enoxaparin. The risk of bias in the included RCTs was generally unclear or low, with the exception of blinding of participants and personnel, which was not done. The included RCTs did not report our chosen primary outcome (a composite outcome of all serious vascular events including ischaemic stroke, myocardial infarction, other major ischaemic event, ICH, major extracerebral haemorrhage, and vascular death). Parenteral anticoagulation did not cause a statistically significant difference in case fatality (RR 1.25, 95% confidence interval (CI) 0.38 to 4.07 in one RCT involving 46 participants, low-quality evidence), ICH, or major extracerebral haemorrhage (no detected events in one RCT involving 75 participants, low-quality evidence), growth of ICH (RR 1.64, 95% CI 0.51 to 5.29 in two RCTs involving 121 participants, low-quality evidence), deep vein thrombosis (RR 0.99, 95% CI 0.49 to 1.96 in two RCTs involving 121 participants, low quality evidence), or major ischaemic events (RR 0.54, 95% CI 0.23 to 1.28 in two RCTs involving 121 participants, low quality evidence). AUTHORS' CONCLUSIONS: There is insufficient evidence from RCTs to support or discourage the use of antithrombotic treatment after ICH. RCTs comparing starting versus avoiding antiplatelet or anticoagulant drugs after ICH appear justified and are needed in clinical practice.

Effects on bone metabolism markers and arterial stiffness by switching to rivaroxaban from warfarin in patients with atrial fibrillation.

In recent years, direct oral anticoagulants (DOACs) of dabigatran, rivaroxaban, apixaban, edoxaban, which are all alternatives to warfarin, have been released. The use of DOACs is becoming more widespread in the clinical management of thrombotic stroke risk in patients with atrial fibrillation (AF). In large-scale clinical trials of each drug, DOACs were reported to inhibit intracranial hemorrhage, stroke, and death compared to warfarin. Warfarin is an endogenous vitamin K antagonist; therefore, patients who are taking warfarin must be prohibited from taking vitamin K. Vitamin K is an essential cofactor required for the ɤ-carboxylation of vitamin K-dependent proteins including coagulation factors, osteocalcin (OC), matrix Gla protein (MGP), and the growth arrest-specific 6 (GAS6). OC is a key factor for bone matrix formation. MGP is a local inhibitor of soft tissue calcification in the vessel wall. GAS6 prevents the apoptosis of vascular smooth muscle cells. Therefore, decrease of blood vitamin K levels may cause osteoporosis, vascular calcification, and the inhibition of vessels angiogenesis. This study aimed to evaluate the effects of changing from warfarin to rivaroxaban on bone mineral metabolism, vascular calcification, and vascular endothelial dysfunction. We studied 21 consecutive patients with persistent or chronic AF, who were treated with warfarin at least for 12 months. Warfarin administration was changed to rivaroxaban (10 or 15 mg/day) in all patients. Osteopontin (OPN), bone alkaline phosphatase (BAP), and under-carboxylated osteocalcin (ucOC) were measured. Pulse wave velocity (PWV) and augmentation index (AI) were also measured as atherosclerosis assessments. All measurements were done before and six months after the rivaroxaban treatment. There was a significant increase in serum level of BAP compared to baseline (12.5 ± 4.6 to 13.4 ± 4.1 U/L, P < 0.01). In contrast, there was a significant decrease in the serum level of ucOC (9.5 ± 5.0 to 2.7 ± 1.3 ng/ml, P < 0.01). Also, in the ucOC levels, there was a significant negative correlation between baseline values and baseline to 6-months changes in high ucOC group (r = -0.97, P < 0.01). The atherosclerosis- and osteoporosis-related biomarker, serum level of OPN were significantly decreased compared to baseline (268.3 ± 46.8 to 253.4 ± 47.1 ng/ml, P < 0.01). AI and PWV were significantly decreased after 6 months of treatment with rivaroxaban (33.9 ± 18.4 to 24.7 ± 18.4%, P = 0.04; 1638.8 ± 223.0 to 1613.0 ± 250.1 m/s, P = 0.03, respectively). Switching to rivaroxaban from warfarin in patients with atrial fibrillation was associated with an increase of bone formation markers and a decrease of bone resorption markers, and also improvements of PWV and AI.

Cerebral Thrombosis: A Neurogenetic Approach.

Cerebral venous thrombosis (CVT) is a severe multifactorial condition with various clinical manifestations that may include headache, papilledema, seizures, focal deficits, coma and death. The mortality rate of untreated CVT is up to 50%, but it drops to 10% when CVT is properly treated. Prevention of CVT is feasible through healthy lifestyle, genetic counseling, molecular genetic analysis for common thrombophilia-related mutations, and prophylactic anticoagulative medication.

Apixaban versus Warfarin for the Prevention of Periprocedural Cerebral Thromboembolism in Atrial Fibrillation Ablation: Multicenter Prospective Randomized Study.

INTRODUCTION: Stroke can be a life-threatening complication of atrial fibrillation (AF) catheter ablation. Uninterrupted warfarin treatment contributes to minimizing the risk of stroke complications. METHODS AND RESULTS: This was a prospective, open-label, randomized, multicenter study assessing the safety and efficacy of apixaban for the prevention of cerebral thromboembolism complicating AF catheter ablation. Two hundred patients with drug-resistant AF were equally assigned to take either apixaban (5 mg or 2.5 mg twice daily) or warfarin (target international normalized ratio, 2-3) for at least 1 month before AF ablation. Neither drug regimen was interrupted throughout the operative period. Diffusion-weighted magnetic resonance imaging was performed for all patients to detect silent cerebral infarction (SCI) after the ablation. Primary outcomes were defined as the occurrence of stroke, transient ischemic attack, SCI, or major bleeding that required intervention. The secondary outcome was minor bleeding. The groups did not statistically differ in patients' backgrounds or procedural parameters. During AF ablation, the apixaban group required administration of more heparin to maintain an activated clotting time > 300 seconds than the warfarin group (apixaban, 14,000 ± 4,000 units; warfarin, 9,000 ± 3,000 units). Three primary outcome events occurred in each group (apixaban, 2 SCI and 1 major bleed; warfarin, 3 SCI, P = 1.00), and 3 and 4 secondary outcome events occurred in the apixaban and warfarin groups (P = 0.70), respectively. CONCLUSION: Apixaban has similar safety and effectiveness to warfarin for the prevention of cerebral thromboembolism during the periprocedural period of AF ablation.

Alteplase Reduces Downstream Microvascular Thrombosis and Improves the Benefit of Large Artery Recanalization in Stroke.

BACKGROUND AND PURPOSE: Downstream microvascular thrombosis (DMT) is known to be a contributing factor to incomplete reperfusion in acute ischemic stroke. The aim of this study was to determine the timing of DMT with intravital imaging and to test the hypothesis that intravenous alteplase infusion could reduce DMT in a transient middle cerebral artery occlusion (MCAO) rat stroke model. METHODS: Rats were subjected to 60-minute transient MCAO. Alteplase (10 mg/kg) was administered 30 minutes after the beginning of MCAO. Real-time intravital fluorescence microscopy through a dura-sparing craniotomy was used to visualize circulating blood cells and fibrinogen. Cerebral microvessel patency was quantitatively evaluated by fluorescein isothiocyanate-dextran perfusion. RESULTS: Immediately after MCAO, platelet and leukocyte accumulation were observed mostly in the venous compartment. Within 30 minutes after MCAO, microthrombi and parietal fibrin deposits were detected in postcapillary microvessels. Alteplase treatment significantly (P=0.006) reduced infarct volume and increased the percentage of perfused vessels during MCAO (P=0.02) compared with saline. Plasma levels of fibrinogen from alteplase-treated rats showed a rapid and profound hypofibrinogenemia. In vitro platelet aggregation demonstrated that alteplase reduced platelet aggregation (P=0.0001) and facilitated platelet disaggregation (P=0.001). These effects were reversible in the presence of exogenous fibrinogen. CONCLUSIONS: Our data demonstrate that DMT is an early phenomenon initiated before recanalization. We further show that alteplase-dependent maintenance of downstream perfusion during MCAO improves acute ischemic stroke outcome through a fibrinogen-dependent platelet aggregation reduction. Our results indicate that early targeting of DMT represents a therapeutic strategy to improve the benefit of large artery recanalization in acute ischemic stroke.

Evidence for the prevention and treatment of stroke in dialysis patients.

The risks of both ischemic and hemorrhagic stroke are particularly high in dialysis patients of any age and outcomes are poor. It is therefore important to identify strategies that safely minimize stroke risk in this population. Observational studies have been unable to clarify the relative importance of traditional stroke risk factors such as blood pressure and cholesterol in those on dialysis, and are affected by biases that usually make them an inappropriate source of data on which to base therapeutic decisions. Well-conducted randomized trials are not susceptible to such biases and can reliably investigate the causal nature of the association between a potential risk factor and the outcome of interest. However, dialysis patients have been under-represented in the cardiovascular trials which have proven net benefit of commonly used preventative treatments (e.g., antihypertensive treatments, low-dose aspirin, carotid revascularization, and thromboprophylaxis for atrial fibrillation), and there remains uncertainty about safety and efficacy of many of these treatments in this high-risk population. Moreover, the efficacy of renal-specific therapies that might reduce cardiovascular risk, such as modulators of mineral and bone disorder, online hemodiafiltration, and daily (nocturnal) hemodialysis, have not been tested in adequately powered trials. Recent trials have also demonstrated how widespread current practices could be causing stroke. Therefore, it is important that reliable information on the prevention and treatment of stroke (and other cardiovascular disease) in dialysis patients is generated by performing large-scale randomized trials of many current and future treatments.

[Interaction of the Humoral Agonist During the Platelets Activation in Patients with Chronic Cerebral Ischemia].

OBJECTIVE: The aim of the study was to determine the effect of the standard drug therapy of 95 patients with chronic cerebral ischemia (CCI) on the functional status of platelets as possible participants of microcirculation of the brain. METHODS: Platelets were isolated from peripheral blood by centrifugation and examined at 24 hours after initiation of standard medical therapy including aspirin (100 mg). The cells were stimulated in vitro using adenosine diphosphate (ADP), epinephrine, platelet activating factor (PAF) and serotonin in an effective concentration (EC50) inducing in healthy individuals platelet aggregation in the range of 50 ± 5%. A study of platelet aggregation was carried out on aggregometer Chrono-Log (USA). RESULTS: Research included 95 patients with CCI 1-2 Stage--82 patients taking antiplatelet and antihypertensive drugs before hospitalization (main group), 13--did not receive these drugs during 7 days prior to hospitalization (comparison group). After start conservative treatment, only ADP induced platelet aggregation, which was similar (p > 0.05) with values in healthy individuals. The pharmacological inhibition of the functional activity of platelets other investigated agonists reproduced hyporesponsiveness of platelets. Against this background, in 34 (41.5%) patients at 24 hours after initiation of therapy occurred potentiation effects of PAF and epinephrine in the test in vitro; whereas the summation of the effects of serotonin and epinephrine on platelets was detected in 12 (14.6%) patients. The basis of this phenomenon may be strengthening effect of ADP secreted from dense-granules, additional stimulation by Gi-protein signaling system by epinephrine and Gq-protein by the action of PAF and serotonin. CONCLUSION: Response to the combined action of platelet agonists may be predictor of the risk of thrombogenesis at CCI.

Incidence of cerebral thromboembolic events during long-term follow-up in patients treated with transcatheter ablation for atrial fibrillation.

AIMS: Net clinical benefit of long-term oral anticoagulation therapy (OAT) continuation after successful atrial fibrillation (AF) ablation is still controversial. To evaluate long-term thromboembolic (TE) and haemorrhagic events incidence according to OAT strategy used after AF transcatheter ablation. METHODS AND RESULTS: Three months after AF ablation, OAT was discontinued in patients with CHADS2 ≤ 1 if no recurrences were documented, while OAT was maintained in patients with CHADS2 ≥ 2 regardless of AF recurrences. CHA2DS2VASc and HAS-BLED scores have been retrospectively evaluated. Seven hundred and sixty-six patients were followed for a median of 60.5 months. Six (6/267 = 2.2%) and five (5/499 = 1%) TE events occurred in the ON and the OFF-OAT patients, respectively (P = 0.145), all in concomitance with the AF recurrence. CHADS2 and CHA2DS2VASc ≥ 2 were associated with high TE incidence (P = 0.047 and P = 0.020). Among patients with a CHADS2 score of 0 or 1, a CHA2DS2VASc score ≥ 2 was predictive of TE events (P = 0.014). Overall, the incidence of the TE events in patients with CHA2DS2VASc ≥ 2 was 0.6 per 100 patient-years whereas seven haemorrhagic events occurred, all of them in the ON-OAT patients (7/267 = 2.6%). CONCLUSION: Patients with AF undergoing transcatheter ablation have a lower incidence of TE events as compared with the general AF population, regardless of OAT maintenance. The unpredictable risk of AF recurrence, mandate the routine use of the CHADS2, CHA2DS2VASc, and HAS-BLED scores to guide clinical decision regarding OAT management in this peculiar setting of patients. The potential protective role of rhythm control strategy in the TE events needs to be confirmed by future large randomized trials.

Cerebral thrombosis and myeloproliferative neoplasms.

Myeloproliferative neoplasms (MPN) are acquired clonal disorders characterized by the proliferation of bone marrow myeloid cells. Different somatic mutations have been recently associated with MPN, the most common being JAK-2 V617F. Among MPN, polycythemia vera and essential thrombocythemia are particularly associated with an increased risk to develop thrombotic complications, either arterial or venous. Cerebrovascular events (stroke and transient ischemic attacks) are prevalent, accounting for approximately two-thirds of all events. Also cerebral vein thrombosis can complicate MPN and can be the first manifestation of the disease. Risk factors for thrombosis in patients with MPN are related or unrelated to the disease. Among the former there are cellular risk factors, such as increased white blood cell counts, vascular cell activation, endothelial dysfunction, and plasmatic risk factors, such as increased plasma viscosity, reduced levels of protein S, increased thrombin generation. The latter include increased age and previous thrombotic events. In addition, common cardiovascular risk factors (smoking, hypertension, diabetes, dyslipidemia, obesity) contribute to the pathogenesis of arterial events, whereas circumstantial risk factors (particularly oral contraceptive use and pregnancy/puerperium) to that of venous events. Primary prevention of arterial thrombosis with antiplatelet therapy is warranted in the majority of patients with MPN, whereas primary prevention of venous thrombosis is limited to anticoagulant prophylaxis during high-risk situations. Secondary prevention includes long-term antiplatelet therapy for arterial and short- or long-term anticoagulant therapy for venous thrombosis, depending on the risk factors present at the first event.