The aim of this updated guideline is to provide comprehensive and timely evidence-based recommendations on the prevention of future stroke among survivors of ischemic stroke or transient ischemic attack. The guideline is addressed to all clinicians who manage secondary prevention for these patients. Evidence-based recommendations are provided for control of risk factors, intervention for vascular obstruction, antithrombotic therapy for cardioembolism, and antiplatelet therapy for noncardioembolic stroke. Recommendations are also provided for the prevention of recurrent stroke in a variety of specific circumstances, including aortic arch atherosclerosis, arterial dissection, patent foramen ovale, hyperhomocysteinemia, hypercoagulable states, antiphospholipid antibody syndrome, sickle cell disease, cerebral venous sinus thrombosis, and pregnancy. Special sections address use of antithrombotic and anticoagulation therapy after an intracranial hemorrhage and implementation of guidelines.

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Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association

Activated protein C (APC) is a serine protease with potent anticoagulant properties, which is formed in blood on the endothelium from an inactive precursor During normal haemostasis, APC limits clot formation by proteolytic inactivation of factors Va and VIIIa (ref 2) To do this efficiently the enzyme needs a nonenzymatic cofactor, protein S (ref 3) Recently it was found that the anticoagulant response to APC (APC resistance) was very weak in the plasma of 21% of unselected consecutive patients with thrombosis and about 50% of selected patients with a personal or family history of thrombosis; moreover, 5% of healthy individuals show APC resistance, which is associated with a sevenfold increase in the risk for deep vein thrombosis Here we demonstrate that the phenotype of APC resistance is associated with heterozygosity or homozygosity for a single point mutation in the factor V gene (at nucleotide position 1,691, G-->A substitution) which predicts the synthesis of a factor V molecule (FV Q506, or FV Leiden) that is not properly inactivated by APC The allelic frequency of the mutation in the Dutch population is approximately 2% and is at least tenfold higher than that of all other known genetic risk factors for thrombosis (protein C (ref 8), protein S (ref 9), antithrombin10 deficiency) together

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Mutation in blood coagulation factor V associated with resistance to activated protein C

https://scholarlypublications.universiteitleiden.nl/access/item%3A3138188/view

A common genetic variation in the 3'-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis.

The aim of this new statement is to provide comprehensive and timely evidence-based recommendations on the prevention of ischemic stroke among survivors of ischemic stroke or transient ischemic attack Evidence-based recommendations are included for the control of risk factors, interventional approaches for atherosclerotic disease, antithrombotic treatments for cardioembolism, and the use of antiplatelet agents for noncardioembolic stroke Further recommendations are provided for the prevention of recurrent stroke in a variety of other specific circumstances, including arterial dissections; patent foramen ovale; hyperhomocysteinemia; hypercoagulable states; sickle cell disease; cerebral venous sinus thrombosis; stroke among women, particularly with regard to pregnancy and the use of postmenopausal hormones; the use of anticoagulation after cerebral hemorrhage; and special approaches for the implementation of guidelines and their use in high-risk populations

https://www.ahajournals.org/doi/pdf/10.1161/01.str.0000199147.30016.74?ijkey=567b368d4e69985fc2c1c99723b3d8de8e39c28a

Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic Attack : A statement for healthcare professionals from the American Heart Association/American Stroke Association Council on Stroke : Co-sponsored by the Council on Cardiovascular Radiology and Intervention : The American Academy of Neurology affirms the value of this guideline

Context Venous thrombosis is a common complication in patients with cancer, leading to additional morbidity and compromising quality of life. 

Objective To identify individuals with cancer with an increased thrombotic risk, evaluating different tumor sites, the presence of distant metastases, and carrier status of prothrombotic mutations. 

Design, Setting, and Patients A large population-based, case-control (Multiple Environmental and Genetic Assessment [MEGA] of risk factors for venous thrombosis) study of 3220 consecutive patients aged 18 to 70 years, with a first deep venous thrombosis of the leg or pulmonary embolism, between March 1, 1999, and May 31, 2002, at 6 anticoagulation clinics in the Netherlands, and separate 2131 control participants (partners of the patients) reported via a questionnaire on acquired risk factors for venous thrombosis. Three months after discontinuation of the anticoagulant therapy, all patients and controls were interviewed, a blood sample was taken, and DNA was isolated to ascertain the factor V Leiden and prothrombin 20210A mutations. 

Main Outcome Measure Risk of venous thrombosis. 

Results The overall risk of venous thrombosis was increased 7-fold in patients with a malignancy (odds ratio [OR], 6.7; 95% confidence interval [CI], 5.2-8.6) vs persons without malignancy. Patients with hematological malignancies had the highest risk of venous thrombosis, adjusted for age and sex (adjusted OR, 28.0; 95% CI, 4.0-199.7), followed by lung cancer and gastrointestinal cancer. The risk of venous thrombosis was highest in the first few months after the diagnosis of malignancy (adjusted OR, 53.5; 95% CI, 8.6-334.3). Patients with cancer with distant metastases had a higher risk vs patients without distant metastases (adjusted OR, 19.8; 95% CI, 2.6-149.1). Carriers of the factor V Leiden mutation who also had cancer had a 12-fold increased risk vs individuals without cancer and factor V Leiden (adjusted OR, 12.1; 95% CI, 1.6-88.1). Similar results were indirectly calculated for the prothrombin 20210A mutation in patients with cancer. 

Conclusions Patients with cancer have a highly increased risk of venous thrombosis especially in the first few months after diagnosis and in the presence of distant metastases. Carriers of the factor V Leiden and prothrombin 20210A mutations appear to have an even higher risk.

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Malignancies, Prothrombotic Mutations, and the Risk of Venous Thrombosis

https://scholarlypublications.universiteitleiden.nl/access/item%3A3138516/view

Protein C deficiency in a controlled series of unselected outpatients: an infrequent but clear risk factor for venous thrombosis (Leiden Thrombophilia Study)

https://scholarlypublications.universiteitleiden.nl/access/item%3A3139174/view

Increased risk of venous thrombosis in carriers of hereditary protein C deficiency defect.

Reported prevalence rates for protein C (PC) deficiency in the population at large have varied widely. The differences presumably reflect the existence of an apparently high number of clinically recessive forms of the deficiency. In an attempt to document more precisely the prevalence of PC deficiency in the healthy population we have measured PC activity in just under 10,000 blood donors in the West of Scotland. After repeat testing of donors with low results and then further observation and selection, 32 donors were identified who had individual mean PC activities below the age- and gender-specific study reference range. Assessment of available first degree relatives, and also PC gene analysis in 23 of these donors, allowed identification of at least 14 with an inheritable deficiency (8 by both family study and gene analysis, 3 by family study alone and 3 by gene analysis alone). Two recurring and seven unique point mutations, only one of which has been previously described, were identified. The observed prevalence of inherited PC deficiency was 1.45 per 1000 (95% Cl, 0.79/1000 to 2.43/1000). However after correcting for the possibility of missing some genuine inherited deficiencies we estimated the prevalence to be as high as 1 in 500. All cases of hereditary deficiency were asymptomatic with regard to thrombosis and none had a strong family history of thrombosis. These findings confirm the rather frequent occurrence of asymptomatic individuals with PC deficiency and support the hypothesis that additional defects in the anticoagulant pathways may be required to confer a high-thrombotic-risk phenotype.

S R Poort

Papers

A common genetic variation in the 3'-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis.

Protein C deficiency in a controlled series of unselected outpatients: an infrequent but clear risk factor for venous thrombosis (Leiden Thrombophilia Study)

Increased risk of venous thrombosis in carriers of hereditary protein C deficiency defect.

Prevalence of protein C deficiency in the healthy population.

The spectrum of genetic defects in a panel of 40 Dutch families with symptomatic protein C deficiency type I: heterogeneity and founder effects.