Showing papers in "Seminars in Thrombosis and Hemostasis in 2018"

Risk of Venous Thrombosis in Antithrombin Deficiency: A Systematic Review and Bayesian Meta-analysis.

Abstract: Antithrombin deficiency is a strong risk factor for venous thromboembolism (VTE), but the absolute risk of the first and recurrent VTE is unclear. The objective of this paper is to establish the absolute risks of the first and recurrent VTE and mortality in individuals with antithrombin deficiency. The databases Embase, Medline Ovid, Web of Science, the Cochrane Library, and Google Scholar were systematically searched for case-control and cohort studies. Bayesian random-effects meta-analysis was used to calculate odds ratios (ORs), absolute risks, and probabilities of ORs being above thresholds. Thirty-five publications were included in the systematic review and meta-analysis. Based on 19 studies, OR estimates for the first VTE showed a strongly increased risk for antithrombin deficient individuals, OR 14.0; 95% credible interval (CrI), 5.5 to 29.0. Based on 10 studies, meta-analysis showed that the annual VTE risk was significantly higher in antithrombin-deficient than in non-antithrombin-deficient individuals: 1.2% (95% CrI, 0.8-1.7) versus 0.07% (95% CrI, 0.01-0.14). In prospective studies, the annual VTE risk in antithrombin deficient individuals was as high as 2.3%; 95% CrI, 0.2-6.5%. Data on antithrombin deficiency subtypes are very limited for reliable risk-differentiation. The OR for recurrent VTE based on 10 studies was 2.1; 95% CrI, 0.2 to 4.0. The annual recurrence risk without long-term anticoagulant therapy based on 4 studies was 8.8% (95% CrI, 4.6-14.1) for antithrombin-deficient and 4.3% (95% CrI, 1.5-7.9) for non-antithrombin-deficient VTE patients. The probability of the recurrence risk being higher in antithrombin-deficient patients was 95%. The authors conclude that antithrombin deficient individuals have a high annual VTE risk, and a high annual recurrence risk. Antithrombin deficient patients with VTE require long-term anticoagulant therapy.

Thromboinflammatory Functions of Platelets in Ischemia-Reperfusion Injury and Its Dysregulation in Diabetes.

Abstract: Ischemia-reperfusion (IR) injury is a common complication of a variety of cardiovascular diseases, including ischemic stroke and myocardial infarction (MI). While timely re-establishment of blood flow in a thrombosed artery is the primary goal of acute therapy in these diseases, paradoxically, reperfusion of ischemic tissue can cause widespread microvascular dysfunction that significantly exacerbates organ damage. Reperfusion injury is associated with activation of the humoral and cellular components of the hemostatic and innate immune systems and also with excessive reactive oxygen species production, endothelial dysfunction, thrombosis, and inflammation. Platelets are critical mediators of thromboinflammation during reperfusion injury and a hyperactive platelet phenotype may contribute to an exaggerated IR injury response. This is particularly relevant to diabetes which is characteristically associated with hyperactive platelets, significantly worse IR injury, increased organ damage, and increased risk of death. However, the mechanisms underlying vulnerability to IR injury in diabetic individuals is not well defined, nor the role of "diabetic platelets" in this process. This review summarizes recent progress in understanding the role of platelets in promoting microvascular dysfunction and inflammation in the context of IR injury. Furthermore, the authors discuss aspects of the thromboinflammatory function of platelets that are dysregulated in diabetes. They conclude that diabetes likely enhances the capacity of platelets to mediate microvascular thrombosis and inflammation during IR injury, which has potentially important implications for the future design of antiplatelet agents that can reduce microvascular dysfunction and inflammation.

Inhibitors in Hemophilia B.

Abstract: Hemophilia B (HB) is an X-linked bleeding disorder caused by deficiency of factor IX (FIX). Patients with the severe form (FIX <1%) account approximately for 30 to 45% of persons with HB and usually suffer from recurrent joint, soft-tissue, and muscle bleeds. The availability of safe plasma-derived and recombinant products has virtually abolished the risk of viral infections and the adoption of prophylactic regimens has attenuated the impact of hemophilic arthropathy. Therefore, the development of an inhibitor against FIX is currently the most serious complication that can still occur in the new generations of HB patients. The development of an inhibitor in HB is a rare event (1.5-3% of all patients) but is associated with a significant morbidity, related not only to the bleeding risk but also to the frequent occurrence of allergic/anaphylactic reactions and nephrotic syndrome. Due to the relative rarity of this event, few data exist about risk factors, pathophysiology, and clinical aspects of inhibitors in HB. The induction of immune tolerance is often unsuccessful and can be otherwise affected by many complications in patients with history of allergy or anaphylaxis. Therefore, alternative therapeutic strategies and new approaches are developing. The aim of this narrative review is to discuss current knowledge about risk factors, pathophysiology, and clinical aspects of this rare but serious complication.

Intracranial Hemorrhage and Early Mortality in Patients Receiving Extracorporeal Membrane Oxygenation for Severe Respiratory Failure.

Abstract: Intracranial hemorrhage (ICH) is a serious complication in patients receiving veno-venous extracorporeal membrane oxygenation (VV-ECMO) and is associated with high mortality. It is unknown whether ICH may be a consequence of the ECMO or of an underlying disease. The authors first aimed to assess the incidence of ICH at initiation and during the course of VV-ECMO and its associated mortality. The second aim was to identify clinical and laboratory measures that could predict the development of ICH in severe respiratory failure. Data were collected from a total number of 165 patients receiving VV-ECMO from January, 2012 to December, 2016 in a single tertiary center and treated according to a single protocol. Only patients who had a brain computed tomography within 24 hours of initiation of ECMO ( n = 149) were included for analysis. The prevalence and incidence of ICH at initiation and during the course of VV-ECMO (at median 9 days) were 10.7% (16/149) and 5.2% (7/133), respectively. Thrombocytopenia and reduced creatinine clearance (CrCL) were independently associated with increased risk of ICH on admission; odds ratio (95% confidence interval): 22.6 (2.6–99.5), and 10.8 (5.6–16.2). Only 30-day (not 180-day) mortality was significantly higher in patients with ICH on admission versus those without (37.5% [6/16] vs 16.4% [22/133]; p = 0.03 and 43.7% [7/16] vs 26.3% [35/133]; p = 0.15, respectively). Reduced CrCL and thrombocytopenia were associated with ICH at initiation of VV-ECMO. The higher incidence of ICH at initiation suggests it is more closely related to the severity of the underlying lung injury than to the VV-ECMO itself. ICH at VV-ECMO initiation was associated with early mortality.

Nonvitamin K Antagonist Oral Anticoagulants Use in Patients with Atrial Fibrillation and Bioprosthetic Heart Valves/Prior Surgical Valve Repair: A Multicenter Clinical Practice Experience

Abstract: This is an observational study to investigate the efficacy and safety of nonvitamin K antagonist oral anticoagulants (NOACs) in atrial fibrillation (AF) patients with bioprosthetic valves or prior surgical valve repair in clinical practice. A total of 122 patients (mean age: 74.1 ± 13.2; 54 females) with bioprosthetic heart valve or surgical valve repair and AF treated with NOACs were included in the analysis. The mean CHA2DS2-VASc (Congestive heart failure, Hypertension, Age >75 years, Diabetes mellitus, prior Stroke or transient ischemic attack, Vascular disease) and HAS-BLED (Hypertension, Abnormal renal and liver function, Stroke, Bleeding, Labile INR [international normalized ratio], Elderly, Drugs or alcohol) score values were 3.6 ± 1.2 and 2.6 ± 1.4, respectively. Of the total study population, 28.6% was taking apixaban 5 mg twice daily (BID), 24.5% apixaban 2.5 mg BID, 18% dabigatran 150 mg BID, 13% dabigatran 110 mg BID, 9.8% rivaroxaban 20 mg daily (QD), and 5.7% rivaroxaban 15 mg QD. Also, 92% of the study population previously had warfarin replaced with NOACs due to lack compliance and labile INR control (time in therapeutic range

Hemostasis at Extremes of Body Weight.

Abstract: Extremes of body weight are not uncommon in the modern world and include anorexia nervosa (AN) and obesity. Both conditions are associated with increased morbidity and mortality: AN has the highest mortality rate of all mental illnesses and unfortunately obesity has reached epidemic proportions and is a well-recognized risk factor for cardiovascular disease including venous thromboembolism (VTE). This article summarizes the current understanding of hemostatic changes of these extremes of body weight. The hemostatic changes of AN have not been well described. Severe AN is associated with pancytopenia with decreased bone marrow cellularity, which causes a mild thrombocytopenia. Platelet hyperaggregability has been recognized in AN and has been attributed at least in part to increased adrenoceptor density. Obesity and the metabolic syndrome are associated with prothrombotic changes, which have been well characterized and related to complex adipocyte-induced inflammatory changes, including increased levels of plasminogen activator inhibitor type 1, von Willebrand factor, fibrinogen, and other evidence of increased coagulation and platelet activation. Accumulating evidence suggests a significant role for increased tissue factor expression and signaling in this relationship, with increased tissue factor expression present in adipose and possibly systemic tissues, induced by adipose-generated cytokines. Intriguingly, the hemostatic changes do not seem to increase with increasing BMI, although the risk of VTE increases with BMI, suggesting that decreased venous flow due to venous enlargement may play the most important role in increased VTE risk with obesity.

Sudden Cardiac and Noncardiac Death in Sports: Epidemiology, Causes, Pathogenesis, and Prevention.

Abstract: Although few doubts remain that physical exercise should be widely promoted for maintenance of health and fitness, the risk of adverse events such as sudden death (especially due to cardiac causes, i.e., sudden cardiac death [SCD]) during exercise remains tangible. The overall risk of sudden death in athletes is relatively low (i.e., usually comprised between 0.1 and 38/100,000 person-years), and globally comparable to that of the general population. However, up to 20% of all sudden death cases are still recorded while exercising. The most frequent underlying disorders encountered in SCD are hypertrophic cardiomyopathy and coronary artery disease (CAD), representing three quarters of all conditions. The risk related to CAD increases with aging (>35 years old), while that attributable to cardiomyopathies or fatal arrhythmias is especially frequent among young people (

Anabolic Androgenic Steroid Abuse: The Effects on Thrombosis Risk, Coagulation, and Fibrinolysis

Abstract: Anabolic androgenic steroid (AAS) abuse surged during the 1980s and is seen in approximately 1 in 20 of all males today. A wide spectrum of AAS compounds and abuse regimens are applied and AAS abuse has been associated with an unfavorable cardiovascular profile. The aim of this review is to critique the collected data concerning effects of AAS abuse on thrombosis risk through presentation of condensed evidence from studies investigating AAS-induced changes in coagulation, fibrinolysis, and cardiovascular risk markers. AAS abuse inflicts a procoagulant distribution of cardiovascular risk markers including dyslipidemia and atherosclerosis proneness. AAS abuse overall stimulates synthesis of coagulation factors, inhibitors, and fibrinolytic proteins resulting in both increased global coagulation and stimulation of fibrinolysis. Overall, supported by many case reports and some epidemiological studies, AAS abuse is associated with an increased risk of thrombosis. However, to provide clear evidence for a causal relationship between AAS abuse and thrombosis risk, future studies need to address a range of potential biases, insufficient methodology, and other shortcomings of the current literature as highlighted in this review.

Toward Flow Cytometry Based Platelet Function Diagnostics.

Abstract: The laboratory diagnostics of (inherited) platelet function disorders mainly comprises aggregation and secretion assays, which may be suitable for diagnosing some specific severe platelet function disorders, but are not reliable enough for diagnosing mild platelet function disorders or disorders associated with low platelet count. Flow cytometric assessment of platelet reactivity will expectedly provide additional value during the diagnostic work-up of platelet function disorders because it only requires a small volume of whole blood and allows the measurement of platelet function in thrombocytopenic samples. Flow cytometry has frequently been used to evaluate platelet function in the research setting, and therefore, these assays will require clinical validation before they can be used as routine diagnostic tools. The main challenge in the validation of innovative platelet function diagnostic tests is the lack of a gold standard test for mild platelet function disorders. This review aims to address the many applications of flow cytometry in the current diagnostic work-up of platelet function testing and to discuss the challenges in introducing new tools for diagnosing platelet function disorders.

Hemostasis and Thrombosis in the Oldest Old.

Abstract: There is a growing proportion of the elderly population in the Western world, and these individuals require special considerations regarding a broad variety of aspects, including treatment approaches to illnesses that affect all age groups. The hemostatic system in individuals changes considerably with aging. Specifically, changes in levels of procoagulant and natural anticoagulant factors along with thrombopathy simultaneously create a hypercoagulable state and hemostatic difficulties. Underlying morbidities, such as congestive heart failure, chronic obstructive pulmonary disease, diabetes mellitus, and cancer, increase the risk for venous and arterial thrombosis. This population is also increasingly affected by acquired bleeding disorders, including acquired hemophilia and acquired von Willebrand syndrome, as well as mild congenital bleeding disorders. Real-life data demonstrate that recurrent and fatal venous thromboembolism is the major hemostatic concern in the elderly. The fact that treatment of thrombotic complications increases the bleeding risk also has to be taken into consideration, particularly in the older age group. This remains true in the era of direct oral anticoagulants. In conclusion, maintaining a delicate balance between thrombosis and bleeding risks is the key issue in providing qualified treatment to elderly patients.

Antithrombotic Treatment after Transcatheter Heart Valves Implant

Abstract: Transcatheter heart valve replacement technology was introduced as alternative to surgery for the growing high-risk profile population. Developed first, aortic valve replacement (TAVR) became a standard of care for patients with severe aortic stenosis at high operative risk, with a potential future use also for low-risk subjects. In the last decade, a multitude of transcatheter mitral valve replacement (TMVR) devices have been developed for the treatment of severe mitral regurgitation, with encouraging results coming from first-in-man and feasibility studies. As for biological surgical-type valves, transcatheter implanted valves still preserve the risk of thrombosis and embolic events and anticoagulation- or antiplatelet-based strategies are the most widely used options. Unfortunately, these last remain recommended on the basis of empirical or not widely validated evidence. Therefore, given the exponential rise of TAVR and TMVR procedures, it is important to identify the optimal antithrombotic strategies that best fit the risk of thromboembolic and bleeding events. Hereafter, this review evaluates the current guidelines, trials, and observational data discussing antithrombotic strategy after transcatheter aortic or mitral valve replacement.

Effects of Repeated Bouts of Exercise on the Hemostatic System

Abstract: Physical activity is beneficial for health, for example, by lowering the risk of cardiovascular events. However, vigorous exercise is associated with the occurrence of thromboembolic events and sudden cardiac death, in particular in untrained individuals. Whereas acute exercise is known to cause a hypercoagulable state, repeated exposure to (strenuous) exercise by means of training may actually condition the hemostatic response to exercise. To date, the effects of exercise training on blood coagulability and the underlying mechanisms have yet to be fully discerned. In this review, the authors provide an overview of existing literature on how training programs and training status influence hemostasis in healthy individuals. Furthermore, they present data of a pilot study in which we studied the effects of repetitive submaximal intensity cycling on procoagulant and anticoagulant processes. It is known that factor VIII (FVIII) and von Willebrand factor (VWF) increase after exercise, but we found that this increase in FVIII and VWF (antigen, propeptide, and VWF in active conformation) was smaller on each of three subsequent days, suggesting either adaptation of endothelial activation or exhaustion of endothelial VWF supplies. With respect to thrombin generation, elevated FVIII significantly increased the thrombin generation peak but not the endogenous thrombin potential. In contrast, platelet activation in terms of P-selectin expression after stimulation with protease-activated receptor-1 and glycoprotein VI agonists decreased after exercise and did not recover, indicating exhaustion of the platelet response to repetitive exercise.

Hemostasis and Thrombosis in Extreme Temperatures (Hypo- and Hyperthermia).

Abstract: The delicate biochemistry of coagulation and anticoagulation is greatly affected by deviations from the optimal temperature required for the interactions between various coagulation enzymes, cellular receptors, and intracellular mechanisms. Hyperthermia will lead to a prothrombotic state and, if sufficiently severe such as in heatstroke, a consumption coagulopathy, which will clinically manifest with the simultaneous appearance of intravascular thrombotic obstruction and an increased bleeding tendency. Hypothermia slows down the coagulation process, but as this seems to be adequately balanced by impairment of anticoagulant and fibrinolytic processes, its clinical effects are modest; however, hypothermia may be modestly linked to a somewhat higher risk of localized thrombosis. Restoration of a normal body temperature in patients affected by hyper- or hypothermia is the cornerstone for the management of associated coagulation derangements.

Anticancer Drug-Related Nonvalvular Atrial Fibrillation: Challenges in Management and Antithrombotic Strategies.

Abstract: Cancer patients may experience nonvalvular atrial fibrillation (AF) as a manifestation of cardiotoxicity. AF may be a direct effect of a neoplasm or, more often, appear as a postsurgical complication, especially after thoracic surgery. AF may also develop as a consequence of anticancer therapy (chemotherapy or radiotherapy), a condition probably underestimated. Cancer patients with AF require a multidisciplinary approach involving oncologists/hematologists, cardiologists, and coagulation experts. An echocardiogram should be performed to detect possible abnormalities of left ventricular systolic and diastolic function, as well as left atrial dilation and the existence of valvular heart disease, to determine pretest probability of sinus rhythm restoration, and identify the best treatment. The choice of antiarrhythmic treatment in cancer patients may be difficult because scanty information is available on the interactions between anticancer agents and antiarrhythmic drugs. A careful evaluation of the antithrombotic strategy with the best efficacy/safety ratio is always needed. The use of vitamin K antagonists (VKAs) may be problematic because of the unpredictable therapeutic response and high bleeding risk in patients with active cancer who are undergoing chemotherapy and who may experience thrombocytopenia and changes in renal or hepatic function. Low molecular weight heparins (in particular for short and intermediate periods) and non-VKA oral anticoagulants (NOACs) should be preferred. However, the possible pharmacological interactions of NOACs with both anticancer and antiarrhythmic drugs should be considered. Based on all these considerations, antiarrhythmic and anticoagulant therapy for AF should be tailored individually for each patient.

Toxins Are an Excellent Source of Therapeutic Agents against Cardiovascular Diseases.

Abstract: Venomous and hematophagous animals use their venom or saliva for survival, to obtain food, and for self-defense. Venom and saliva from these animals are cocktails of bioactive molecules primarily composed of proteins and peptides. These molecules are called toxins because they cause unwanted consequences on prey. They exhibit unique, diverse, and specific biological activities that perturb normal physiological processes of their prey and host. However, the potential of toxins as inspirations for the development of therapeutic agents or pharmacological tools has also long been recognized. In addition to their small size, the exquisite selectivity and structural stability of toxins make them attractive as starting molecule in the development of therapeutic and diagnostic agents. Drug discovery and development from venomous and hematophagous animals against cardiovascular diseases have been particularly successful. Some of the notable success include antihypertensive (captopril and enalapril) and antiplatelet agents (tirofiban and eptifibatide), as well as anticoagulants (lepirudin and bivalirudin). Highlighted in this review are many venom or saliva-derived cardiovascular-active proteins and peptides of therapeutic interest, including those that are currently in preclinical stages and those that have been approved by FDA and currently in the market. The authors attempt to summarize their structure, function, mechanism of action, and development with respect to cardiovascular diseases.

Hemostasis in the Very Young.

Abstract: Hemostasis is a dynamic process that starts in utero. The coagulation system evolves with age, as evidenced by marked physiological differences in the concentration of the majority of hemostatic proteins in early life compared with adulthood. This concept, known as "developmental hemostasis," has important biological and clinical implications. Overall, impaired platelet function, along with physiologically reduced levels of vitamin K-dependent and contact coagulation factors, may cause poorer clot firmness even in healthy neonates. However, increased activity of von Willebrand factor and low levels of coagulation inhibitors that promote hemostasis counterbalance the delicate and immature hemostatic system. Since this hemostatic system has little reserve capacity, preterm neonates or sick infants are extremely vulnerable and predisposed to either hemorrhagic or thrombotic complications. This review will address the concept and manifestations of developmental hemostasis with respect to clinical disease phenotypes. It will discuss bleeding diagnosis in neonates, dealing especially with the devastating complications of intracerebral and pulmonary hemorrhage in preterm infants. Neonates, especially the sickest preterm ones, are also extremely susceptible to thrombotic complications; thus, thrombosis in neonates will be reviewed, with special focus on arterial ischemic perinatal stroke. Based on the concept of developmental hemostasis, the phenotypes of clinically relevant bleeding or thrombotic disorders among neonates may differ from those of older infants and children. Treatment options for these conditions will be suggested and reviewed.

Alloimmunization in Congenital Deficiencies of Platelet Surface Glycoproteins: Focus on Glanzmann's Thrombasthenia and Bernard-Soulier's Syndrome.

Abstract: Glanzmann's thrombasthenia (GT) and Bernard–Soulier's syndrome (BSS) are well-understood congenital bleeding disorders, showing defect/deficiency of platelet glycoprotein (GP) IIb/IIIa (integrin αIIbβ3) and GPIb-IX-V complexes respectively, with relevant clinical, laboratory, biochemical, and genetic features. Following platelet transfusion, affected patients may develop antiplatelet antibodies (to human leukocyte antigen [HLA], and/or αIIbβ3 in GT or GPIb-IX in BSS), which may render future platelet transfusion ineffective. Anti-αIIbβ3 and anti-GPIb-IX may also cross the placenta during pregnancy to cause thrombocytopenia and bleeding in the fetus/neonate. This review will focus particularly on the better studied GT to illustrate the natural history and complications of platelet alloimmunization. BSS will be more briefly discussed. Platelet transfusion, if unavoidable, should be given judiciously with good indications. Patients following platelet transfusion, and women during and after pregnancy, should be monitored for the development of platelet antibodies. There is now a collection of data suggesting the safety and effectiveness of recombinant activated factor VII in the management of affected patients with platelet antibodies.

Regular Physical Activity and Risk of Venous Thromboembolism.

Abstract: Venous thromboembolism (VTE) is a complex multifactorial disease that represents a growing public health concern. Identification of modifiable risk factors at the population level may provide a measure to reduce the burden of VTE. In this review, we summarize current knowledge of the role of physical activity on the risk of VTE and VTE-related complications. We also discuss methodological challenges related to research on physical activity, and put forward plausible mechanisms for an association between physical activity and VTE. Up to now, published studies have reported diverging results on the relationship between physical activity and VTE, and a complex picture has emerged. However, the available evidence appears to be balanced toward a small beneficial effect of physical activity on the risk of incident VTE, but not in a dose-dependent manner. Still, the lack of an operational definition and standardized assessment method for physical activity, as well as several sources of bias, impairs the interpretation of the available literature. Additional work is necessary to understand the role and how to apply physical activity in the VTE setting. Future research should utilize objective assessment strategies of physical activity and physical fitness, account for the fluctuating nature in habitual activity levels, and explore the role of physical activity in the areas of secondary prevention and VTE-related complications.

Thyroid Disorders and Hemostasis

Abstract: Lower levels of free thyroxine (whether this is endogenous or exogenous) lead to a hypocoagulable state, and higher levels of free thyroxine lead to a hypercoagulable state. In this narrative review, the effects of different levels of thyroid hormones on clinical end points are described. Hypothyroidism is associated with an increased bleeding risk, whereas hyperthyroidism leads to an increased risk of venous thrombosis. Besides, effects of thyroid hormone on the heart may indirectly influence hemostasis. Hyperthyroidism leads to a higher incidence of atrial fibrillation and atrial flutter, and, at least partly by that mechanism, a higher risk of cerebral arterial thrombosis. In addition, compression effects of goiter on developing venous thrombosis are described. This is caused by local stasis of blood due to tumor expansion.

Direct Oral Anticoagulants in End-Stage Renal Disease

Abstract: Patients with end-stage renal disease (ESRD) were excluded from pivotal clinical trials with oral anticoagulants. While such patients are at an increased risk of venous and arterial thromboembolism, their risk of bleeding is also elevated. It is thus of little surprise that stroke prevention with vitamin K antagonists (VKAs) in ESRD patients with atrial fibrillation is controversial, with observational evidence ranging from beneficial to harmful. This uncertainty extends to the less studied use of VKAs for venous thromboembolism in ESRD. The direct oral anticoagulants (DOACs) apixaban and rivaroxaban have now permissive labeling in the United States for atrial fibrillation in patients with ESRD; this expanded labeling has not yet occurred either in Europe or for venous thromboembolism. This review summarizes the current evidence for the pharmacology of DOACs in ESRD as well as their utilization and safety in patients with ESRD and atrial fibrillation.

Influence of Exercise on Platelet Function in Patients with Cardiovascular Disease.

Abstract: Regular exercise may reduce the risk of major cardiovascular thrombotic events. However, previous studies suggest that the risk of myocardial infarction or primary cardiac arrest is transiently increased during exercise. Thus, on the one hand, exercise seems to be able to protect against cardiovascular disease, but on the other hand, it seems to provoke sudden cardiac death. As platelets play a key role in arterial thromboembolic disease, the effect of exercise on platelet function is of special interest. This systematic review summarizes the evidence of the influence of exercise on platelet function in patients with coronary artery disease, angina pectoris, hypertension, or peripheral arterial disease. We specifically investigated, (1) if platelet function was increased in patients prior to exercise compared with healthy controls, (2) if exercise influenced platelet function differently in patients compared with healthy controls, and finally (3) if exercise reduced the effect of aspirin (acetylsalicylic acid). We performed a literature search in PubMed, Embase, Scopus, and Cochrane Library. In total, 18 articles were included and grouped into studies including patients with coronary artery disease (n = 7), angina pectoris (n = 5), hypertension (n = 5), and patients with peripheral arterial disease (n = 2). One study included both patients with coronary artery disease and patients with hypertension, and this study was therefore included in both groups. All studies performed short-term exercise either using treadmill (n = 12), primarily following the Bruce protocol, or bicycle ergometer test (n = 6). Overall, patients did not differ from healthy controls in platelet aggregation or activation prior to exercise. After exercise, conflicting results were reported with some studies reporting intensified platelet aggregation and/or platelet activation, some studies found no difference, whereas a few studies reported a reduction in platelet aggregation after exercise when compared with controls. Exercise seemed to impair the effect of aspirin during or shortly after exercise. In conclusion, the studies reported contradictive results. However, this review indicates that strenuous short-term exercise induces increased platelet activation also implying a reduced effect of aspirin during short-term exercise. Controlled studies on the effect of regular long-term low-intensity exercise are needed to further clarify the influence of long-term exercise on platelet function.

Inhibitors in Nonsevere Hemophilia A: What Is Known and Searching for the Unknown.

Abstract: Nonsevere hemophilia A (NSHA) is an inherited X-linked bleeding disorder, caused by mutations of the F8 gene, leading to decreases of clotting factor VIII (FVIII) levels to 1 to 40 IU/dL Desmopressin is the first therapeutic option for NSHA, but 40 to 50% of patients fail to attain adequate postinfusion FVIII levels Thus, in these cases, FVIII concentrates remain the mainstay of treatment The development of neutralizing FVIII antibodies (inhibitors) is a major challenge with replacement therapy In contrast to severe disease, NSHA patients have a lifelong risk of inhibitor development Recent data indicate that inhibitors are associated with a deterioration of clinical outcome, illustrated by an increase in bleeding and mortality rate F8 genotype is an important risk factor for inhibitor occurrence together with surgical interventions and a high dose of FVIII concentrate Adequate prevention and treatment of inhibitors in NSHA patients is limited by a lack of understanding of the underlying immunological mechanisms Elucidation of the immunology driving inhibitor development is required to identify high-risk patients, to understand the association between clinical risk factors and inhibitor occurrence, and to provide the opportunity to develop new preventive and therapeutic strategies

Acquired and genetic thrombotic risk factors in the athlete

Abstract: While athletes are often considered the epitome of health due to their physique and lowered potential for metabolic and cardiovascular diseases, they may also be at risk for the onset and development of venous thromboembolism (VTE) In an attempt to achieve and remain competitive, athletes are frequently exposed to numerous athlete-specific risk factors, which may predispose them to VTE through the disruption of factors associated with Virchow's triad (ie, hypercoagulability, venous stasis, and vessel wall injury) Indeed, hypercoagulability within an athletic population has been well documented to occur due to a combination of multiple factors including exercise, dehydration, and polycythemia Furthermore, venous stasis within an athletic population may occur as a direct result of prolonged periods of immobilization experienced when undertaking long-distance travels for training and competition, recovery from injury, and overdevelopment of musculature While all components of Virchow's triad are disrupted, injury to the vessel wall has emerged as the most important factor contributing to thrombosis formation within an athletic population, due to its ability to influence multiple hemostatic mechanisms Vessel wall injury within an athletic population is often related to repetitive microtrauma to the venous and arterial walls as a direct result of sport-dependent trauma, in addition to high metabolic rates and repetitive blood monitoring Although disturbances to Virchow's triad may not be detrimental to most individuals, approximately 1 in 1,000 athletes will experience a potentially fatal post-exercise thrombotic incidence When acquired factors are considered in conjunction with genetic predispositions to hypercoagulability present in some athletes, an overall increased risk for VTE is present

Prevalence and Risk Factors of Acute Pulmonary Embolism in Patients with Lung Cancer Surgery.

Abstract: Acute pulmonary embolism (PE) is one of the serious complications with high mortality after thoracic surgery. The authors aimed to determine the prevalence of PE events and evaluate additional risk factors for PE in patients with lung cancer surgery. Patients underwent lung cancer resections during January 2012 to July 2015 and had 30-day postoperative follow-up were included. Those with incomplete or miscoded data were excluded. The number of postoperative PE events was recorded retrospectively. Analyses were used to evaluate risk factors of PE during the hospitalization. The authors reviewed 11,474 patients who underwent surgery for lung cancer. The overall 30-day incidence of PE after thoracic surgery at their institution was 0.53%. The 30-day PE incidence without chemical prophylaxis was 0.57% (55/9,726) and the mortality rate was 10%. Multivariate analyses revealed that age over 66 (odds ratio [OR]: 1.09, 95% confidence interval [CI]: 1.05–1.12, p

Direct Oral Anticoagulants and the Paradigm Shift in the Management of Venous Thromboembolism.

Abstract: The advent of direct oral anticoagulants (DOACs) has revolutionized anticoagulation management in both stroke prevention and venous thromboembolism (VTE) treatment/prevention. Clinical trials and secondary real-world data have shown that DOACs have similar efficacy and, in some cases, improved bleeding safety profiles compared with vitamin K antagonists. Together with benefits of patient convenience, this has shifted the risk–benefit ratio toward long-term anticoagulation. However, current VTE risk assessment models are based on vitamin K antagonists and do not take into account the new paradigm of DOACs. Therefore, challenges to the thrombosis community remain to determine patients who would benefit from long-term anticoagulation in the DOAC era. Here, the authors review the current literature on risks and benefits of DOACs and their potential role in long-term VTE thromboprophylaxis as well as in current risk assessment models. The increasing use of DOACs, led by their convenience of use and generally lower bleeding rates, calls for a reevaluation of the current models as the benefits of long-term anticoagulation may begin to outweigh risks and inconvenience associated with their predecessors.

Causes of Death in Patients with Venous Thromboembolism Anticoagulated with Direct Oral Anticoagulants: A Systematic Review and Meta-Analysis

Abstract: Death is more frequent than nonfatal recurrent venous thromboembolism (VTE) and major bleeding after acute VTE. The analysis of the causes of death is fundamental to explore new strategies to reduce mortality rates in these patients. The authors performed a meta-analysis to analyze mortality and independently adjudicated causes of death in anticoagulated patients due to VTE, and to evaluate potential differences between different anticoagulant schemes. They searched MEDLINE and CENTRAL, from January 1, 2000, to January 31, 2017, and performed additional searches in Web sites of regulatory agencies, clinical trial registers, and conference proceedings. Two investigators independently selected studies and extracted the data. Study quality was assessed with the Cochrane Collaboration's tool for assessing the risk of bias in randomized studies. Seven prospective randomized trials in 29,844 patients (22,025 patient-year follow-up) were included, comparing dabigatran, rivaroxaban, apixaban, and edoxaban with the standard anticoagulant treatment of VTE. A total of 718 patients died during the follow-up (3.4% per year; 95% confidence interval [CI]: 2.3-4.8). The most frequent causes of death were cancer (42%), followed by VTE (20%), infections (13%), hemorrhage (6%), heart disease (4%), and stroke (2%). There were no differences in the overall survival and causes of death according to the anticoagulant type. Concomitant active cancer during the study was significantly associated with death (odds ratio: 15.2; 95% CI: 9.2-25.1). Cancer is the leading cause of death in contemporary VTE trials. Interventions beyond anticoagulation, particularly in patients with active cancer, are needed.

Effects of Acute Stress on Thrombosis.

Abstract: Stress, the nonspecific response to any demand for change, is an adaptive response of the human body to various stimulants. As such, stress-induced hypercoagulation may represent an adaptive response to bleeding. Numerous epidemiological studies have revealed that a correlation exists between stress and thrombotic risk and biochemically, links of the relationship between psychological stress and coagulation pathways have been made. The stress reaction is coupled with neurohormonal changes mediated mainly by the sympathetic neural system and the hypothalamic–pituitary–adrenal axis. Singling out the specific pathways affecting coagulation in this complex response is hampered by many confounders. The mediators of the stress reaction (neurotransmitters and hormones) can directly affect platelets and the coagulation cascade and indirectly affect hemostasis via changes in hemodynamics. In this review, the authors will delineate the distinct neurobiological mechanisms that govern the effects of stress on coagulation, and report their recent findings.

Impact of Thrombus Sidedness on Presentation and Outcomes of Patients with Proximal Lower Extremity Deep Vein Thrombosis.

Abstract: Small studies have suggested differences in demographics and outcomes between left- and right-sided deep vein thrombosis (DVT), and also unilateral versus bilateral DVT. We investigated the clinical presentation and outcomes of patients with DVT based on thrombus sidedness. The authors used the data from the Registro Informatizado Enfermedad TromboEmbolica (RIETE) database (2001–2016) to identify patients with symptomatic proximal lower-extremity DVT. Main outcomes included cumulative 90-day symptomatic pulmonary embolism (PE) and 1-year mortality. Overall, 30,445 patients were included. The majority of DVTs occurred in the left leg (16,421 left-sided, 12,643 right-sided, and 1,390 bilateral; p p p

Car Travel-Related Thrombosis: Fact or Fiction?

Abstract: The condition sometimes referred to as "economy class syndrome," and also known as "traveler's thrombosis," is a distinctive pathological condition characterized by occurrence of venous thromboembolism (VTE) in a patient who has recently experienced a long journey (i.e., ≥ 4 h). Typically, the identified travel is by airplane, but travel with other vehicles, such as trains, trucks, buses, or cars, could potentially qualify as contributing to VTE events. Although the enhanced risk of VTE after long haul flights is now widely acknowledged, albeit potentially overhyped, the risk of venous thrombosis after prolonged travel by other modes of transport, in particular, by cars, is less well appreciated. Current evidence, collected from some epidemiological studies, suggests that if any risk of VTE can be attributed to prolonged and uninterrupted car travels, and we give moderate credibility to such an association, the risk may be similar to that already proven for long haul flights. The risk is especially high in individuals undergoing uninterrupted car journeys lasting 4 hours or longer, in vehicles with a narrow seat-pitch, and in particularly would affect those with pre-existing acquired or inherited prothrombotic conditions. The putative biological mechanisms basically entail venous stasis and edema, which are often compounded by a certain degree of hypercoagulability. When these factors are combined with preexistent prothrombotic conditions, the risk may be substantially magnified. In this perspective, then, 'car thrombosis' may be regarded as a trigger rather than a risk factor for venous thrombosis. Although the current evidence is certainly not solid enough to endorse the use of general chemical prophylaxis for lowering the risk of car-related VTE, a set of possible precautionary measures, with no or very little side effects, may be suggested before planning prolonged car travels, especially for at risk individuals.

Impact of Exercise on Hemophilia.

Abstract: Sports and strenuous exercise have traditionally been discouraged for people with hemophilia (PWH) because of the perceived risk of bleeding. In this review, studies investigating the pros and cons of exercise are presented, and although most studies are of low validity, the randomized trials that do exist tell us that PWH benefit from exercise in terms of improved muscular function, endurance, and quality of life and that increased bleeding does not seem to be an issue. The authors also review the studies that have analyzed the current physical status of PWH compared with the general population in different countries. Finally, they review the current knowledge on the effect of exercise on specific coagulation factors as well as on global coagulation and demonstrate that exercise increases factor VIII levels in healthy persons, all persons with hemophilia B (HB) and in persons with mild and moderate hemophilia A (HA). Further, the authors did not find any evidence that the global coagulation capacity, measured with thrombin generation or thromboelastographic methods, increases after exercise in severe HA or HB.