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The circadian system regulates 24-h time-of-day patterns of cardiovascular physiology, with circadian misalignment resulting in adverse cardiovascular risk. Although many proteins in the coagulation-fibrinolysis axis show 24-h time-of-day patterns, it is not understood if these temporal patterns are regulated by circadian or behavioral (e.g., sleep and food intake) cycles, or how circadian misalignment influences these patterns. Thus, we utilized a night shiftwork protocol to analyze circadian versus behavioral cycle regulation of 238 plasma proteins linked to cardiovascular physiology. Six healthy men aged 26.2 ± 5.6 years (mean ± SD) completed the protocol involving two baseline days with 8-h nighttime sleep opportunities (circadian alignment), a transition to shiftwork day, followed by 2 days of simulated night shiftwork with 8-h daytime sleep opportunities (circadian misalignment). Plasma was collected for proteomics every 4 h across 24 h during baseline and during daytime sleep and the second night shift. Cosinor analyses identified proteins with circadian or behavioral cycle-regulated 24-h time-of-day patterns. Five proteins were circadian regulated (plasminogen activator inhibitor-1, angiopoietin-2, insulin-like growth factor binding protein-4, follistatin-related protein-3, and endoplasmic reticulum resident protein-29). No cardiovascular-related proteins showed regulation by behavioral cycles. Within the coagulation pathway, circadian misalignment decreased tissue factor pathway inhibitor, increased tissue factor, and induced a 24-h time-of-day pattern in coagulation factor VII (all FDR < 0.10). Such changes in protein abundance are consistent with changes observed in hypercoagulable states. Our analyses identify circadian regulation of proteins involved in cardiovascular physiology and indicate that acute circadian misalignment could promote a hypercoagulable state, possibly contributing to elevated cardiovascular disease risk among shift workers., (© 2024 The Author(s). European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

The global propagation of SARS-CoV-2 leads to an unprecedented public health emergency. Despite that the lungs are the primary organ targeted by COVID-19, systemic endothelial inflammation and dysfunction is observed particularly in patients with severe COVID-19, manifested by elevated endothelial injury markers, endotheliitis, and coagulopathy. Here, we review the clinical characteristics of COVID-19 associated endothelial dysfunction; and the likely pathological mechanisms underlying the disease including direct cell entry or indirect immune overreactions after SARS-CoV-2 infection. In addition, we discuss potential biomarkers that might indicate the disease severity, particularly related to the abnormal development of thrombosis that is a fatal vascular complication of severe COVID-19. Furthermore, we summarize clinical trials targeting the direct and indirect pathological pathways after SARS-CoV-2 infection to prevent or inhibit the virus induced endothelial disorders., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Evidence suggests severe coronavirus disease-19 (COVID-19) infection is characterised by pulmonary and systemic microvasculature dysfunction, specifically, acute endothelial injury, hypercoagulation and increased capillary permeability. Diabetes, which is also characterised by vascular injury in itself, confers an increased risk of adverse COVID-19 outcomes. It has been suggested that pre-existing endothelial dysfunction and microvascular disease in diabetes will exacerbate the vascular insults associated with COVID-19 and thus lead to increased severity of COVID-19 infection. In this article, we evaluate the current evidence exploring the impact of microvascular complications, in the form of diabetic retinopathy and nephropathy, in individuals with COVID-19 and diabetes. Future insights gained from exploring the microvascular injury patterns and clinical outcomes may come to influence care delivery algorithms for either of these conditions., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Current cytoreductive and antithrombotic strategies in MPNs are mostly based on cell counts and on patient's demographic and clinical history. Despite the numerous studies conducted on platelet function and on the role of plasma factors, an accurate and reliable method to dynamically quantify the hypercoagulability states of these conditions is not yet part of clinical practice. Starting from our experience, and after having sifted through the literature, we propose an in-depth narrative report on the contribution of the clonal platelets of MPNs-rich in tissue factor (TF)-in promoting a perpetual procoagulant mechanism. The whole process results in an unbalanced generation of thrombin and is self-maintained by Protease Activated Receptors (PARs). We chose to define this model as a "circulating wound", as it indisputably links the coagulation, inflammation, and fibrotic progression of the disease, in analogy with what happens in some solid tumours. The platelet contribution to thrombin generation results in triggering a vicious circle supported by the PARs/TGF-beta axis. PAR antagonists could therefore be a good option for target therapy, both to contain the risk of vascular events and to slow the progression of the disease towards end-stage forms. Both the new and old strategies, however, will require tools capable of measuring procoagulant or prohaemorrhagic states in a more extensive and dynamic way to favour a less empirical management of MPNs and their potential clinical complications.

Objectives: The spectrum of thrombophilia in women with recurrent pregnancy loss (RPL) is different in Indian ethnicity as reported by few studies. We aimed to study the prevalence of thrombophilia in RPL patients referred to hematology department of a tertiary centre., Material and Methods: This is an observational study of 112 RPL patients with no apparent cause after extensive workup for non-hematological causes. The investigations performed were routine coagulogram, APLA workup, plasma homocysteine, MTHFRC677T polymorphisms, Protein C, free Protein S, Anti-thrombin III levels, test for Activated Protein C resistance (APC-R) ,Factor V Leiden and Prothrombin gene G20210A mutation., Results: Of 112 patients, at least one thrombophilia was identified in 70.5% and combined thrombophilia in 12.5% patients. Hyperhomocysteinemia (30.4%) and APLA (25.9%) were the commonest thrombophilia whereas anticoagulant defects were seen in 12.5% of the population. Protein C deficiency (5.35%) was the commonest anticoagulant defect followed by APCR (3.6%). Mutational analysis revealed MTHFRC677T polymorphism in 20.5% whereas Factor V Leiden heterozygous in 1.8% patients. None of the patients had homozygous Factor V Leiden or Prothrombin gene G20210A mutation. Hyperhomocysteinemia, MTHFRC677T and Protein C deficiency were more associated with early pregnancy losses whereas Protein S deficiency, Factor V Leiden and APLA caused both early and late losses. Patients with greater number of losses were positive for homozygous MTHFRC677T, factor V Leiden and APLA., Conclusion: The approach to investigating Indian women with RPL should be based on the prevalence of thrombophilia which is unique to Indian ethnicity.

Severe acute respiratory syndrome coronavirus (SARS-COV-2) is the culprit of the Coronavirus Disease (COVID-19), which has infected approximately 173 million people and killed more than 3.73 million. At risk groups including diabetic and obese patients are more vulnerable to COVID-19-related complications and poor outcomes. Substantial evidence points to hypovitaminosis D as a risk factor for severe disease, the need for ICU, and mortality. 1,25(OH)D, a key regulator of calcium homeostasis, is believed to have various immune-regulatory roles including; promoting anti-inflammatory cytokines, down regulating pro-inflammatory cytokines, dampening entry and replication of SARS-COV-2, and the production of antimicrobial peptides. In addition, there are strong connections which suggest that dysregulated 1,25(OH)D levels play a mechanistic and pathophysiologic role in several disease processes that are shared with COVID-19 including: diabetes, obesity, acute respiratory distress syndrome (ARDS), cytokine storm, and even hypercoagulable states. With evidence continuing to grow for the case that low vitamin D status is a risk factor for COVID-19 disease and poor outcomes, there is a need now to address the public health efforts set in place to minimize infection, such as lock down orders, which may have inadvertently increased hypovitaminosis D in the general population and those already at risk (elderly, obese, and disabled). Moreover, there is a need to address the implications of this evidence and how we may apply the use of cheaply available supplementation, which has yet to overcome the near global concern of hypovitaminosis D. In our review, we exhaustively scope these shared pathophysiologic connections between COVID-19 and hypovitaminosis D., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objective: Vasculopathy is considered central to the pathogenesis of juvenile dermatomyositis (DM) and is associated with severe extramuscular manifestations. We undertook this study to investigate the hypothesis that the vasculopathy of juvenile DM can be noninvasively tracked by examining biomarkers of endothelial injury, subclinical inflammation, hypercoagulability, and vascular arterial stiffness., Methods: The study population was a UK cohort of children with juvenile DM. Circulating endothelial cells (CECs) and microparticles (MPs) were identified using immunomagnetic bead extraction and flow cytometry, respectively. Plasma thrombin generation was determined using a fluorogenic assay. Cytokine and chemokine levels were measured by electrochemiluminescence. Arterial stiffness was assessed using pulse wave velocity (PWV). Results were expressed as the median and interquartile range (IQR), and statistical significance was assessed using nonparametric analyses., Results: Ninety patients with juvenile DM and 79 healthy control subjects were included. The median age of the patients was 10.21 years (IQR 6.68-13.40), and the median disease duration was 1.63 years (IQR 0.28-4.66). CEC counts were higher in all patients with juvenile DM compared to controls (median 96 cells/ml [IQR (40-192] and 12 cells/ml [IQR 8-24], respectively; P < 0.0001). Circulating MP numbers were also significantly higher in patients with active juvenile DM compared to controls (median 204.7 × 10 3 /ml [IQR 87.9-412.6] and 44.3 × 10 3 /ml [IQR 15.0-249.1], respectively; P < 0.0001). MPs were predominantly of platelet and endothelial origin. Enhanced plasma thrombin generation was demonstrated in patients with active juvenile DM compared to those with inactive disease (P = 0.0003) and controls (P < 0.0001). Carotid-radial PWV adjusted for age was increased in patients with juvenile DM compared to controls (P = 0.003)., Conclusion: We observed increased endothelial injury and increased levels of proinflammatory cytokines in patients with active juvenile DM. MP profiles reflected distinct disease activity status in juvenile DM and are markers of vascular pathology, platelet activation, and thrombotic propensity. Ongoing long-term vascular injury may result in increased arterial stiffness in patients with juvenile DM., (© 2021 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

The severe acute respiratory syndrome coronavirus 2 or coronavirus disease 2019 (COVID-19) pandemic has raised concerns about the correlation with this viral illness and increased risk of stroke. Although it is too early in the pandemic to know the strength of the association between COVID-19 and stroke, it is an opportune time to review the relationship between acute viral illnesses and stroke. Here, we summarize pathophysiological principles and available literature to guide understanding of how viruses may contribute to ischemic stroke. After a review of inflammatory mechanisms, we summarize relevant pathophysiological principles of vasculopathy, hypercoagulability, and hemodynamic instability. We will end by discussing mechanisms by which several well-known viruses may cause stroke in an effort to inform our understanding of the relationship between COVID-19 and stroke.

Aim. The disease caused by the 2019 novel coronavirus is known predominantly for its respiratory outcomes; a subset of critically ill patients demonstrates clinically remarkable hypercoagulability in which thrombotic events range from acute pulmonary embolism in patients with COVID-19 pneumonia to extremity ischemia. Our observational study aimed to describe the incidence and characteristics, as well as clinical outcomes, of patients presenting and treated for mesenteric ischemia during the COVID-19 pandemic. Material and Methods. Between March 13 and May 13, 2020, 60 patients operated for emergency reasons were analyzed, and it was noticed that 5 of the 6 COVID-positive patients were operated due to mesenteric ischemia. Results. Five of sixty patients (83.3%) applied to our emergency clinic with COVID-19 positive and acute abdomen. Two of them (40%) did not have any comorbidities. All of them (%100) were male. There were no complications and only 1 death (20%). Mean leukocyte, neutrophil, and platelet levels were within the normal range, while the lymphocyte level was near the lower limit. C-Reactive Protein was above the limit in all patients. The mean levels of International Normalized Ratio, Platelet, and Activated Partial Thromboplastin Time were above the limits. While D-dimer levels were close to the upper limit; fibrinogen levels were above the normal limit for each patient. Conclusion. The presence of hypercoagulation status in critical COVID-19 patients should be observed closely, and anticoagulation therapy can be considered in selected patients. More clinical data are needed to examine the role of anticoagulation in COVID-19 treatment.

Objective: The defective interplay between coagulation and inflammation may be the leading cause of intravascular coagulation and organ dysfunction in coronavirus disease-19 (COVID-19) patients. Abnormal coagulation profiles were reported to be associated with poor outcomes. In this study, we assessed the prognostic values of antithrombin (AT) activity levels and the impact of fresh frozen plasma (FFP) treatment on outcome., Materials and Methods: Conventional coagulation parameters as well as AT activity levels and outcomes of 104 consecutive critically ill acute respiratory distress syndrome (ARDS) patients with laboratory-confirmed COVID-19 disease were retrospectively analyzed. Patients with AT activity below 75% were treated with FFP. Maximum AT activity levels achieved in those patients were recorded., Results: AT activity levels at admission were significantly lower in nonsurvivors than survivors (73% vs. 81%). The cutoff level for admission AT activity was 79% and 58% was the lowest AT for survival. The outcome in those patients who had AT activity levels above 75% after FFP treatment was better than that of the nonresponding group. As well as AT, admission values of D-dimer, C-reactive protein, and procalcitonin were coagulation and inflammatory parameters among the mortality risk factors., Conclusion: AT activity could be used as a prognostic marker for survival and organ failure in COVID-19-associated ARDS patients. AT supplementation therapy with FFP in patients with COVID-19-induced hypercoagulopathy may improve thrombosis prophylaxis and thus have an impact on survival.

Introduction: COVID-19 has similarities to the Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS) outbreaks, as severe patients and non-survivors have frequently shown abnormal coagulation profiles. Immune-mediated pathology is a key player in this disease; hence, the role of the complement system needs assessment. The complement system and the coagulation cascade share an intricate network, where multiple mediators maintain a balance between both pathways. Coagulopathy in COVID-19, showing mixed features of complement-mediated and consumption coagulopathy, creates a dilemma in diagnosis and management., Areas Covered: Pathophysiology of coagulopathy in COVID-19 patients, with a particular focus on D-dimer and its role in predicting the severity of COVID-19 has been discussed. A comprehensive search of the medical literature on PubMed was done till May 30th, 2020 with the keywords 'COVID-19', 'SARS-CoV-2', 'Coronavirus', 'Coagulopathy', and 'D-dimer'. Twenty-two studies were taken for weighted pooled analysis of D-dimer., Expert Opinion: A tailored anticoagulant regimen, including intensification of standard prophylactic regimens with low-molecular-weight heparin is advisable for COVID-19 patients. Atypical manifestations and varying D-dimer levels seen in different populations bring forth the futility of uniform recommendations for anticoagulant therapy. Further, direct thrombin inhibitors and platelet inhibitors in a patient-specific manner should also be considered.

The pathology of coronavirus disease 2019 (COVID-19) is exacerbated by the progression of thrombosis, and disseminated intravascular coagulation (DIC), and cytokine storms. The most frequently reported coagulation/fibrinolytic abnormality in COVID-19 is the increase in D-dimer, and its relationship with prognosis has been discussed. However, limits exist to the utility of evaluation by D-dimer alone. In addition, since the coagulation/fibrinolytic condition sometimes fluctuates within a short period of time, regular examinations in recognition of the significance of the examination are desirable. The pathophysiology of disseminated intravascular coagulation (DIC) associated with COVID-19 is very different from that of septic DIC, and both thrombotic and hemorrhagic pathologies should be noted. COVID-19 thrombosis includes macro- and microthrombosis, with diagnosis of the latter depending on markers of coagulation and fibrinolysis. Treatment of COVID-19 is classified into antiviral treatment, cytokine storm treatment, and thrombosis treatment. Rather than providing uniform treatment, the treatment method most suitable for the severity and stage should be selected. Combination therapy with heparin and nafamostat is expected to develop in the future. Fibrinolytic therapy and adsorption therapy require further study.

Coronavirus disease 2019 (COVID-19), due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in Wuhan city, China in December 2019 and rapidly spread to other countries. The most common reported symptoms are fever, dry cough, myalgia and fatigue, headache, anorexia, and breathlessness. Anosmia and dysgeusia as well as gastrointestinal symptoms including nausea and diarrhea are other notable symptoms. This virus also can exhibit neurotropic properties and may also cause neurological diseases, including epileptic seizures, cerebrovascular accident, Guillian barre syndrome, acute transverse myelitis, and acute encephalitis. In this study, we discuss stroke as a complication of the new coronavirus and its possible mechanisms of damage., (© 2020 Walter de Gruyter GmbH, Berlin/Boston.)

Three leading infectious disease experts in China were invited to share their bedside observations in the management of COVID-19 patients. Professor Taisheng Li was sent to Wuhan to provide frontline medical care. He depicts the clinical course of SARS-CoV-2 infection. Furthermore, he observes the significant abnormality of coagulation function and proposes that the early intravenous immunoglobulin and low molecular weight heparin anticoagulation therapy are very important. Professor Hongzhou Lu, a leader in China to try various anti-viral drugs, expresses concern on the quality of the ongoing clinical trials as most trials are small in scale and repetitive in nature, and emphasizes the importance of the quick publication of clinical trial results. Regarding the traditional Chinese medicine, Professor Lu suggests to develop a creative evaluation system because of the complicated chemical compositions. Professor Wenhong Zhang is responsible for Shanghai's overall clinical management of the COVID-19 cases. He introduces the team approach to manage COVID-19 patients. For severe or critically ill patients, in addition to the respiratory supportive treatment, timely multiorgan evaluation and treatment is very crucial. The medical decisions and interventions are carefully tailored to the unique characteristics of each patient.

Background: Postinjury hypercoagulability occurs in >25% of injured patients, increasing risk of thromboembolic complications despite chemoprophylaxis. However, few clinically relevant animal models of posttraumatic hypercoagulability exist. We aimed to evaluate a rodent model of bilateral hindlimb injury as a preclinical model of postinjury hypercoagulability., Methods: Forty Wistar rats were anesthetized with isoflurane: 20 underwent bilateral hindlimb fibula fracture, soft tissue and muscular crush injury, and bone homogenate injection intended to mimic the physiological severity of bilateral femur fracture. Twenty sham rats underwent anesthesia only. Terminal citrated blood samples were drawn at 0, 6, 12, and 24 hours (n = 5 per timed group) for analysis by native thromboelastography in the presence and absence of taurocholic acid to augment fibrinolysis. Plasminogen activator inhibitor 1 and α-2 antiplasmin levels in plasma were assessed via enzyme-linked immunosorbent assay., Results: Injured rats became hypercoagulable relative to baseline by 6 hours based on thromboelastography maximal amplitude (MA) and G (p < 0.005); sham rats became hypercoagulable to a lesser degree by 24 hours (p < 0.005). Compared with sham animals, injured rats were hypercoagulable by MA and G within 6 hours of injury, remained hypercoagulable by MA and G through at least 24 hours (all p < 0.01), and showed impaired fibrinolysis by taurocholic acid LY30 at 12 hours (p = 0.019) and native LY30 at 24 hours (p = 0.045). In terms of antifibrinolytic mediators, α-2 antiplasmin was elevated in trauma animals at 24 hours (p = 0.009), and plasminogen activator inhibitor 1 was elevated in trauma animals at 6 hours (p = 0.004) and 12 hours (p < 0.001) when compared with sham., Conclusions: Orthopedic injury in rodents induced platelet and overall hypercoagulability within 6 hours and fibrinolytic impairment by 12 to 24 hours, mimicking postinjury hypercoagulability in injured patients. This rodent model of orthopedic injury may serve as a preclinical testing ground for potential therapies to mitigate hypercoagulability, maintain normal fibrinolysis, and prevent thromboembolic complications.

COVID-19 severity appears to lie in its propensity to cause a hyperinflammatory response, attributed to the cytokine release syndrome (CRS) or 'cytokine storm', although the exact role of the CRS remains to be fully elucidated. Hyperinflammation triggers a hypercoagulable state, also thought to play a key role in COVID-19 pathogenesis. Disease severity is linked to age, sex and comorbid conditions, which in turn may be linked to oxidative stress and pre-existing depletion of nicotinamide adenine dinucleotide (NAD+). There is increasing evidence that the host genome may determine disease outcome. Since most information pertaining to COVID-19 has thus far been extrapolated from the 'global North', similar studies in African populations are warranted. Many studies are aimed at finding a therapeutic strategy based on scientific rationale. Some promising results have emerged, e.g. the use of corticosteroids in severe acute respiratory distress syndrome (ARDS).

In this paper, a model is proposed of the pathophysiological processes of COVID-19 starting from the infection of human type II alveolar epithelial cells (pneumocytes) by SARS-CoV-2 and culminating in the development of ARDS. The innate immune response to infection of type II alveolar epithelial cells leads both to their death by apoptosis and pyroptosis and to alveolar macrophage activation. Activated macrophages secrete proinflammatory cytokines and chemokines and tend to polarise into the inflammatory M1 phenotype. These changes are associated with activation of vascular endothelial cells and thence the recruitment of highly toxic neutrophils and inflammatory activated platelets into the alveolar space. Activated vascular endothelial cells become a source of proinflammatory cytokines and reactive oxygen species (ROS) and contribute to the development of coagulopathy, systemic sepsis, a cytokine storm and ARDS. Pulmonary activated platelets are also an important source of proinflammatory cytokines and ROS, as well as exacerbating pulmonary neutrophil-mediated inflammatory responses and contributing to systemic sepsis by binding to neutrophils to form platelet-neutrophil complexes (PNCs). PNC formation increases neutrophil recruitment, activation priming and extraversion of these immune cells into inflamed pulmonary tissue, thereby contributing to ARDS. Sequestered PNCs cause the development of a procoagulant and proinflammatory environment. The contribution to ARDS of increased extracellular histone levels, circulating mitochondrial DNA, the chromatin protein HMGB1, decreased neutrophil apoptosis, impaired macrophage efferocytosis, the cytokine storm, the toll-like receptor radical cycle, pyroptosis, necroinflammation, lymphopenia and a high Th17 to regulatory T lymphocyte ratio are detailed., Competing Interests: Declaration of competing interest MB is supported by a NHMRC Senior Principal Research Fellowship (1059660 and 1156072). MB has received Grant/Research Support from the NIH, Cooperative Research Centre, Simons Autism Foundation, Cancer Council of Victoria, Stanley Medical Research Foundation, Medical Benefits Fund, National Health and Medical Research Council, Medical Research Futures Fund, Beyond Blue, Rotary Health, A2 milk company, Meat and Livestock Board, Woolworths, Avant and the Harry Windsor Foundation, has been a speaker for Astra Zeneca, Lundbeck, Merck, Pfizer, and served as a consultant to Allergan, Astra Zeneca, Bioadvantex, Bionomics, Collaborative Medicinal Development, Lundbeck Merck, Pfizer and Servier – all unrelated to this work. LO is supported by a NHMRC Early Career Fellowship (1158487). WM is currently funded by an Alfred Deakin Postdoctoral Research Fellowship and a Multiple Sclerosis Research Australia early-career fellowship. WM has previously received funding from the Cancer Council Queensland and university grants/fellowships from La Trobe University, Deakin University, University of Queensland, and Bond University. WM has received industry funding and has attended events funded by Cobram Estate Pty. Ltd. WM has received travel funding from Nutrition Society of Australia. WM has received consultancy funding from Nutrition Research Australia. WM has received speaker honoraria from The Cancer Council Queensland and the Princess Alexandra Research Foundation. The Food & Mood Centre has received Grant/Research support from Fernwood Foundation, Wilson Foundation, the A2 Milk Company, and Be Fit Foods. AO is supported by a Future Leader Fellowship (#101160) from the Heart Foundation Australia and Wilson Foundation. She has received research funding from National Health & Medical Research Council, Australian Research Council, University of Melbourne, Deakin University, Sanofi, Meat and Livestock Australia and Woolworths Limited and Honoraria from Novartis., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Competing Interests: None.

The 2019 coronavirus disease (COVID-19) presents with a large variety of clinical manifestations ranging from asymptomatic carrier state to severe respiratory distress, multiple organ dysfunction and death. While it was initially considered primarily a respiratory illness, rapidly accumulating data suggests that COVID-19 results in a unique, profoundly prothrombotic milieu leading to both arterial and venous thrombosis. Consistently, elevated D-dimer level has emerged as an independent risk factor for poor outcomes, including death. Several other laboratory markers and blood counts have also been associated with poor prognosis, possibly due to their connection to thrombosis. At present, the pathophysiology underlying the hypercoagulable state is poorly understood. However, a growing body of data suggests that the initial events occur in the lung. A severe inflammatory response, originating in the alveoli, triggers a dysfunctional cascade of inflammatory thrombosis in the pulmonary vasculature, leading to a state of local coagulopathy. This is followed, in patients with more severe disease, by a generalized hypercoagulable state that results in macro- and microvascular thrombosis. Of concern, is the observation that anticoagulation may be inadequate in many circumstances, highlighting the need for alternative or additional therapies. Numerous ongoing studies investigating the pathophysiology of the COVID-19 associated coagulopathy may provide mechanistic insights that can direct appropriate interventional strategies., (Copyright © 2020. Published by Elsevier Ltd.)

Early clinical evidence suggests that severe cases of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are frequently characterized by hyperinflammation, imbalance of renin-angiotensin-aldosterone system, and a particular form of vasculopathy, thrombotic microangiopathy, and intravascular coagulopathy. In this paper, we present an immunothrombosis model of COVID-19. We discuss the underlying pathogenesis and the interaction between multiple systems, resulting in propagation of immunothrombosis, which through investigation in the coming weeks, may lead to both an improved understanding of COVID-19 pathophysiology and identification of innovative and efficient therapeutic targets to reverse the otherwise unfavorable clinical outcome of many of these patients., (Copyright © 2020 Elsevier B.V. All rights reserved.)

COVID-19, caused by SARS-CoV-2, is characterized by pneumonia, lymphopenia, exhausted lymphocytes and a cytokine storm. Several reports from around the world have identified obesity and severe obesity as one of the strongest risk factors for COVID-19 hospitalization and mechanical ventilation. Moreover, countries with greater obesity prevalence have a higher morbidity and mortality risk of developing serious outcomes from COVID-19. The understanding of how this increased susceptibility of the people with obesity to develop severe forms of the SARS-CoV-2 infection occurs is crucial for implementing appropriate public health and therapeutic strategies to avoid COVID-19 severe symptoms and complications in people living with obesity. We hypothesize here that increased ACE2 expression in adipose tissue displayed by people with obesity may increase SARS-CoV-2 infection and accessibility to this tissue. Individuals with obesity have increased white adipose tissue, which may act as a reservoir for a more extensive viral spread with increased shedding, immune activation and pro-inflammatory cytokine amplification. Here we discuss how obesity is related to a pro-inflammatory and metabolic dysregulation, increased SARS-CoV-2 host cell entry in adipose tissue and induction of hypercoagulopathy, leading people with obesity to develop severe forms of COVID-19 and also death. Taken together, it may be crucial to better explore the role of visceral adipose tissue in the inflammatory response to SARS-CoV-2 infection and investigate the potential therapeutic effect of using specific target anti-inflammatories (canakinumab or anakinra for IL-1β inhibition; anti-IL-6 antibodies for IL-6 inhibition), anticoagulant or anti-diabetic drugs in COVID-19 treatment of people with obesity. Defining the immunopathological changes in COVID-19 patients with obesity can provide prominent targets for drug discovery and clinical management improvement., (Copyright © 2020 Pasquarelli-do-Nascimento, Braz-de-Melo, Faria, Santos, Kobinger and Magalhães.)

A comprehensive review of the neurological disorders reported during the current COVID-19 pandemic demonstrates that infection with SARS-CoV-2 affects the central nervous system (CNS), the peripheral nervous system (PNS) and the muscle. CNS manifestations include: headache and decreased responsiveness considered initial indicators of potential neurological involvement; anosmia, hyposmia, hypogeusia, and dysgeusia are frequent early symptoms of coronavirus infection. Respiratory failure, the lethal manifestation of COVID-19, responsible for 264,679 deaths worldwide, is probably neurogenic in origin and may result from the viral invasion of cranial nerve I, progressing into rhinencephalon and brainstem respiratory centers. Cerebrovascular disease, in particular large-vessel ischemic strokes, and less frequently cerebral venous thrombosis, intracerebral hemorrhage and subarachnoid hemorrhage, usually occur as part of a thrombotic state induced by viral attachment to ACE2 receptors in endothelium causing widespread endotheliitis, coagulopathy, arterial and venous thromboses. Acute hemorrhagic necrotizing encephalopathy is associated to the cytokine storm. A frontal hypoperfusion syndrome has been identified. There are isolated reports of seizures, encephalopathy, meningitis, encephalitis, and myelitis. The neurological diseases affecting the PNS and muscle in COVID-19 are less frequent and include Guillain-Barré syndrome; Miller Fisher syndrome; polyneuritis cranialis; and rare instances of viral myopathy with rhabdomyolysis. The main conclusion of this review is the pressing need to define the neurology of COVID-19, its frequency, manifestations, neuropathology and pathogenesis. On behalf of the World Federation of Neurology we invite national and regional neurological associations to create local databases to report cases with neurological manifestations observed during the on-going pandemic. International neuroepidemiological collaboration may help define the natural history of this worldwide problem., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

In less than 6 months, the severe acute respiratory syndrome-coronavirus type 2 (SARS-CoV-2) has spread worldwide infecting nearly 6 million people and killing over 350,000. Initially thought to be restricted to the respiratory system, we now understand that coronavirus disease 2019 (COVID-19) also involves multiple other organs, including the central and peripheral nervous system. The number of recognized neurologic manifestations of SARS-CoV-2 infection is rapidly accumulating. These may result from a variety of mechanisms, including virus-induced hyperinflammatory and hypercoagulable states, direct virus infection of the central nervous system (CNS), and postinfectious immune mediated processes. Example of COVID-19 CNS disease include encephalopathy, encephalitis, acute disseminated encephalomyelitis, meningitis, ischemic and hemorrhagic stroke, venous sinus thrombosis, and endothelialitis. In the peripheral nervous system, COVID-19 is associated with dysfunction of smell and taste, muscle injury, the Guillain-Barre syndrome, and its variants. Due to its worldwide distribution and multifactorial pathogenic mechanisms, COVID-19 poses a global threat to the entire nervous system. Although our understanding of SARS-CoV-2 neuropathogenesis is still incomplete and our knowledge is evolving rapidly, we hope that this review will provide a useful framework and help neurologists in understanding the many neurologic facets of COVID-19. ANN NEUROL 2020;88:1-11 ANN NEUROL 2020;88:1-11., (© 2020 American Neurological Association.)

Advanced interatrial block (A-IAB) has been associated to atrial fibrillation (AF) and ischemic stroke, raising the question as to whether such patients, even when still in sinus rhythm without documented AF, could benefit from oral anticoagulation. AF and A-IAB are both markers of stroke. The anatomical substrate in both is fibrotic atrial cardiomyopathy, resulting in atrial electromechanical dyssynchrony, dysfunction, and left atrial remodelling, that favour blood stasis and hypercoagulation. Under these conditions thrombogenic cascade may be triggered, resulting in systemic embolization. Before proposing oral anticoagulation in the management of selected patients with A-IAB, as is currently recommended in patients with AF and high CHA 2 DS 2 -Vasc score, a randomized clinical trial will have to demonstrate efficacy and safety of anticoagulation in this setting. In the meantime, an individualized approach may be considered based on the recognition of those patients at a higher risk of stroke. These may be elderly patients with A-IAB and several risk factors and, thus, with a high CHA 2 DS 2 -Vasc score and the presence of environmental arrhythmias., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Aim of this study was to compare cardiovascular risk in women with and without inheritable thrombophilia after hypertensive disorders of pregnancy (HDP). Blood pressure, anthropometrics and blood samples were measured 9-13 years after early-onset (<34 weeks) HDP. Amongst the 114 women included, no differences in hypertension (31.1% vs. 33.7%, OR 0.90 95% CI (0.29-2.79)), body mass index > 25 kg/m 2 (43.8% vs. 53.1%, OR 0.69 95% CI (0.24-2.00)) or metabolic syndrome (18.8% vs. 13.3%, OR 1.51 95% CI (0.38-6.02)) were found. These data show similar cardiovascular risk profile in women with and without inheritable thrombophilia.

Hypercoagulability can occur after severe tissue injury, that is likely related to tissue factor exposure and impaired endothelial release of tissue plasminogen activator (tPA). In contrast, when shock and hypoperfusion occur, activation of the protein C pathway and endothelial tPA release induce a shift from a procoagulant to a hypocoagulable and hyperfibrinolytic state with a high risk of bleeding. Both thrombotic and bleeding phenotypes are associated with increased mortality and are influenced by the extent and severity of tissue injury and degree of hemorrhagic shock. Response to trauma is a complex, dynamic process in which risk can shift from bleeding to thrombosis depending on the injury pattern, hemostatic treatment, individual responses, genetic predisposition, and comorbidities. Based on this body of knowledge, we will review and consider future directions for the management of severely injured trauma patients.

We have explored the relationship between possible hemostatic changes and clinical manifestation of the systemic lupus erythematosus (SLE) as a function of greater or lesser disease activity according to Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) criteria. Endothelial injury and hypercoagulability were investigated in patients with SLE by measuring thrombomodulin (TM), D-dimer (DDi) and thrombin generation (TG) potential. A total of 90 participants were distributed into three groups: 1) women with SLE presenting with low disease activity (laSLE) (SLEDAI-2K ≤ 4), 2) women with SLE presenting with moderate to high disease activity (mhaSLE) (SLEDAI-2K > 4), and 3) a control group comprising healthy women. Levels of TM and DDi were higher both in the laSLE and mhaSLE groups compared to controls and in mhaSLE compared to the laSLE group. With respect to TG assay, lagtime and endogen thrombin potential, low concentrations of tissue factor provided the best results for discrimination among groups. Analysis of these data allow us to conclude that TM, DDi and TG are potentially useful markers for discriminating patients with very active from those with lower active disease. Higher SLE activity may cause endothelial injury, resulting in higher TG and consequently a hypercoagulability state underlying the picture of thrombosis common in this inflammatory disease.

COVID-19 has proven to be particularly challenging given the complex pathogenesis of SARS-CoV-2. Early data have demonstrated how the host response to this novel coronavirus leads to the proliferation of pro-inflammatory cytokines, massive endothelial damage, and generalized vascular manifestations. While SARS-CoV-2 primarily targets the upper and lower respiratory tract, other organ systems are also affected. SARS-CoV-2 relies on 2 host cell receptors for successful attachment: angiotensin-converting enzyme 2 and transmembrane protease serine 2. Clinicopathologic reports have demonstrated associations between severe COVID-19 and viral coagulopathy, resulting in pulmonary embolism; venous, arterial, and microvascular thrombosis; lung endothelial injury; and associated thrombotic complications leading to acute respiratory distress syndrome. Viral coagulopathy is not novel given similar observations with SARS classic, including the consumption of platelets, generation of thrombin, and increased fibrin degradation product exhibiting overt disseminated intravascular coagulation-like syndrome. The specific mechanism(s) behind the thrombotic complications in COVID-19 patients has yet to be fully understood. Parenteral anticoagulants, such as heparin and low-molecular-weights heparins, are widely used in the management of COVID-19 patients. Beyond the primary (anticoagulant) effects of these agents, they may exhibit antiviral, anti-inflammatory, and cytoprotective effects. Direct oral anticoagulants and antiplatelet agents are also useful in the management of these patients. Tissue plasminogen activator and other fibrinolytic modalities may also be helpful in the overall management. Catheter-directed thrombolysis can be used in patients developing pulmonary embolism. Further investigations are required to understand the molecular and cellular mechanisms involved in the pathogenesis of COVID-19-associated thrombotic complications.

High-fat diet (HFD) feeding is known to induce metabolic dysregulation, however, less is known on its impact in promoting the hypercoagulable state. This current study aimed to evaluate platelet-monocyte aggregate (PMA) formation following short-term HFD feeding. This is particularly important for understanding the link between inflammation and the hypercoagulable state during the early onset of metabolic dysregulation. To explore such a hypothesis, mice were fed a HFD for 8 weeks, with body weights as well as insulin and blood glucose levels monitored on a weekly basis during this period. Basal hematological measurements were determined and the levels of spontaneous peripheral blood PMAs were assessed using whole blood flow cytometry. The results showed that although there were no significant differences in body weights, mice on HFD displayed impaired glucose tolerance and markedly raised insulin levels. These metabolic abnormalities were accompanied by elevated baseline PMA levels as an indication of hypercoagulation. Importantly, it was evident that baseline levels of monocytes, measured using the CD14 monocyte marker, were significantly decreased in HFD-fed mice when compared to controls. In summary, the current evidence shows that in addition to causing glucose intolerance, such as that identified in a prediabetic state, HFD-feeding can promote undesirable hypercoagulation, the major consequence implicated in the development of cardiovascular complications.

Background: Microvascular invasion (MVI) predicts poor prognosis in patients with hepatocellular carcinoma (HCC). HCC patients with hypercoagulability are prone to develop thrombosis; however, the relationship between preoperative coagulability state, as reflected by the international normalized ratio (INR) level, and MVI remains unclear., Methods: From January 2009 to December 2012, HCC patients who underwent R0 liver resection (LR) from four cancer centers entered into this study. The overall survival (OS) and recurrence-free survival (RFS) rates were compared using the Kaplan-Meier method and Cox regression analysis., Results: Of the 2509 HCC patients who were included into this study, 1104 were found to have MVI in the resected specimens. These patients were divided into the low (n = 151), normal (n = 796), and high (n = 157) INR subgroups based on the preoperative INR levels. The low INR subgroup had a significantly higher incidence of MVI than the normal or high INR subgroups (61.6% vs. 41.6% vs. 44.6%; p < 0.001). HCC patients with MVI were significantly more likely to have a low preoperative INR level (p < 0.001); the INR level (p < 0.001) was an independent risk factor of OS and RFS. HCC patients with MVI in the low INR subgroup had significantly worse RFS and OS than the normal or high INR subgroups (median RFS 13.5 vs. 20.2 vs. 21.6 months, p < 0.001; median OS 35.5 vs. 59.5 vs. 57.0 months, p < 0.001)., Conclusions: Preoperative hypercoagulability was associated with poor long-term prognosis in HCC patients with MVI after R0 LR.

Protein C (PC) deficiency is a heritable or acquired risk factor for thrombophilia, with presentations varying from asymptomatic to venous thromboembolism to neonatal purpura fulminans, a life-threatening disorder. Hereditary PC deficiency is caused by mutation in the PC ( PROC ) gene located on chromosome 2q14.3. Heterozygous and acquired PC deficiencies are more common than homozygous deficiency. The recommended initial laboratory test measures PC activity using either clot-based or chromogenic methods. There are numerous potential interferences in PC activity testing that may result in either false-positive (falsely low activity) or false-negative (falsely normal or elevated activity) results. In the present review, we discuss common clinical presentations; laboratory testing, with a focus on potential assay interferences; treatment options; and prognosis in patients with PC deficiency.

Uterine radial artery resistance index (URa-RI) by Doppler ultrasound may reflect the changes in the uteroplacental circulation and be associated with adverse events in early pregnancy. Recurrent pregnancy losses (RPL) are associated with thrombophilia, and anticoagulation treatment with low molecular weight heparin improves pregnancy outcome in women with RPL and thrombophilia. A retrospective cohort study was conducted in 139 pregnant women with 3 or more RPL and thrombophilia. The relationship between pregnancy outcome and dynamic changes of URa-RI was analyzed in 116 women who delivered a liveborn infant and 23 who miscarried the index pregnancy. Patients were on preconception low molecular weight heparin, low-dose aspirin (81mg per day), and prednisone treatment. URa-RI was measured during periovulation time, at the time of positive pregnancy test, and then repeated every two weeks until 32-week gestation or the time of miscarriage. The URa-RI at 8-week gestation was significantly higher in women who miscarried the index pregnancy than those who delivered alive born infant (0.51±0.08 vs. 0.42±0.03, P<0.001). Receiver operating characteristic curve analysis demonstrated that URa-RI of 8 wk gestation effectively distinguished women who miscarried from those who had a live birth with an area under the curve of 82.6% (95% CI 69.01-97.17). After adjusting for covariates including age, BMI, and number of miscarriages, multiple logistic regression models showed that each 0.1 unit increase of URa-RI of 8 wk gestation was associated with 18.70-point increase in the risk of miscarriage (OR19.70, 95%CI 4.26-91.1, P<0.001), and women with an URa-RI≥0.45 had an OR of 49.48 (95% CI 8.01-307.95; P<0.001) for miscarriage compared to those who had URa-RI<0.45. In women with RPL and inherited thrombophilia, increased URa-RI at 8-week gestation was associated with spontaneous abortion independent of other risk factors while they were on anticoagulation treatment., Competing Interests: Authors have no conflicts of interest to declare.

Background:  No consensus exists regarding the optimal strategy for perioperative thromboprophylaxis in high-risk microsurgical populations. We present our experience with lower extremity free tissue transfer (FTT) in thrombophilic patients and compare outcomes between non-stratified and risk-stratified anticoagulation protocols., Methods:  Between January 2013 and December 2017, 57 patients with documented thrombophilia underwent FTT for non-traumatic, lower extremity reconstruction by a single surgeon. Patients were divided into two cohorts based on the introduction of a novel, risk-stratified algorithm for perioperative anticoagulation in July 2015. Demographic data, chemoprophylaxis profiles, flap outcomes, and complications were retrospectively compared across time periods., Results:  Fifty-seven free flaps were performed in hypercoagulable patients treated with non-stratified ( n  = 27) or risk-stratified ( n  = 30) thromboprophylaxis. Patients in the risk-stratified cohort received intravenous heparin more often than non-stratified controls (73 vs. 15%, p  < 0.001). Lower rates of total (3 vs. 19%, p  = 0.06) and partial (10 vs. 37%, p  = 0.025) flap loss were observed among risk-stratified patients, paralleling a significant reduction in the prevalence of postoperative thrombotic events (1.2 vs. 12.3%, p  = 0.004). While therapeutic versus low-dose heparin infusion was associated with improved flap survival following intraoperative microvascular compromise (86 vs. 25%, p  = 0.04), salvage rates in the setting of postoperative thrombosis remained 0%, regardless of protocol. On multivariate analysis, recipient-vessel calcification (odds ratio [OR]: 16.7, p  = 0.02) and anastomotic revision (OR, 3.3; p  = 0.04) were independently associated with total flap failure., Conclusion:  Selective therapeutic anticoagulation may improve microsurgical outcomes in high-risk patients with thrombophilia. Our findings highlight the importance of meticulous technique and recipient-vessel selection as critical determinants of flap success in this population., Competing Interests: None declared., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Pregnancy can be seen as a positive time for women migraineurs because the elevated estrogen and endogenous opioid levels raise the pain threshold and the stable hormone levels, which no longer fluctuate, eliminate a major trigger factor for the attacks. In a great majority of cases, indeed, migraine symptoms spontaneously improve throughout pregnancy. Generally, migraine without aura (MO) improves better than migraine with aura (MA), which can occur ex novo in pregnancy more frequently than MO. After childbirth, the recurrence rate of migraine attacks increases, especially during the first month; breastfeeding exerts a protective effect against the reappearance of attacks. Migraine and pregnancy share a condition of hypercoagulability; therefore, attention must be paid to the risk of cardiovascular disorders, like venous thromboembolism and ischemic or hemorrhagic strokes. Some of these diseases can be linked to preeclampsia (PE), a serious complication of pregnancy, characterized by hypertension, proteinuria, or other findings of organ failure. This condition is more common in migraineurs compared with non-migraineurs; furthermore, women whose migraines worsen during pregnancy had a 13-fold higher risk of hypertensive disorders than those in which migraine remitted or improved. Pregnancy is generally recognized to exert a beneficial effect on migraine; nonetheless, clinicians should be on the alert for possible cardiovascular complications that appear to be more frequent in this patient population.

Purpose: The role of genetic polymorphisms in the pathogenesis of recurrent pregnancy loss (RPL) has been studied intensively. Complex diseases, including miscarriage, are believed to have a polygenic basis, and gene-gene interactions can play a significant role in the etiology of the disease. This study was conducted to investigate the association of gene-gene interactions with angiogenesis, endothelial dysfunction-related gene polymorphisms, and RPL., Methods: A case-control study was conducted with 253 unrelated RPL patients with 2 or more spontaneous pregnancy losses and 339 healthy women with no history of pregnancy complications. Genotyping of single-nucleotide polymorphisms (SNPs) was performed using real-time polymerase chain reaction (real-time PCR), restriction fragment length polymorphism (RFLP), or allele-specific polymerase chain reaction methods., Results: The genotypes 677TT of the MTHFR gene, 936TT, 936CT, and 634CC, 634GC of the VEGF gene, and allele 894T of the NOS3 gene were associated with a predisposition to RPL in the Russian population. A significant role of additive and epistatic effects in the gene-gene interactions of the SNPs of SERPINE-1, ACE, NOS3, MTHFR, and VEGF genes in RPL was demonstrated., Conclusions: The results showed that gene-gene interactions are important for RPL susceptibility. Additionally, analysis of the genotype combinations of several allelic variants provides more information on RPL risk than analysis of independent polymorphic markers.

Numerous types of cancer have been shown to be associated with either ischemic or hemorrhagic stroke. In this review, the epidemiology and pathophysiology of stroke in cancer patients is discussed, while providing vital information on the diagnosis and management of patients with cancer and stroke. Cancer may mediate stroke pathophysiology either directly or via coagulation disorders that establish a state of hypercoagulation, as well as via infections. Cancer treatment options, such as chemotherapy, radiotherapy and surgery have all been shown to aggravate the risk of stroke as well. The clinical manifestation varies greatly depending upon the underlying cause; however, in general, cancer‑associated strokes tend to appear as multifocal in neuroimaging. Furthermore, several serum markers have been identified, such as high D‑Dimer levels and fibrin degradation products. Managing cancer patients with stroke is a delicate matter. The cancer should not be considered a contraindication in applying thrombolysis and recombinant tissue plasminogen activator (rTPA) administration, since the risk of hemorrhage in cancer patients has not been reported to be higher than that in the general population. Anticoagulation, on the contrary, should be carefully examined. Clinicians should weigh the benefits and risks of anticoagulation treatment for each patient individually; the new oral anticoagulants appear promising; however, low‑molecular‑weight heparin remains the first choice. On the whole, stroke is a serious and not a rare complication of malignancy. Clinicians should be adequately trained to handle these patients efficiently.

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 (i.e., 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., Competing Interests: None., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Atrial fibrillation (AF) is numerically the most important risk factor for stroke. It is well established that patients with AF have a 5-fold increased risk of stroke relative to those without and that anticoagulation reduces the risk of stroke by approximately two-thirds. Definitively attributing the mechanism of an individual stroke to AF is more problematic, however. In fact, there is no way to reliably establish the etiology of any ischemic infarction. This necessitates screening for all potential stroke risk factors and treating accordingly. The pattern of infarction is often used to classify the presumed mechanism of infarction as thrombotic or embolic, although even this is approach is based on association and increasingly is recognized as not completely reliable. Furthermore, it should not dictate management-patients with perforating arterial territory infarcts with AF also require and benefit from anticoagulation. Likewise, if other potential embolic sources beyond AF are identified, anticoagulation remains the standard of care. The traditional conceptual model of the mechanistic link between AF and cardioembolic infarction is likely oversimplified. Long-term cardiac rhythm recording studies indicate an inconsistent temporal relationship between AF and infarction. This suggests that cardioembolic stroke in patients with AF may result from the underlying atrial cardiopathy, rather than the rhythm disturbance leading to atrial stasis and thromboembolism. We reviewed traditional and current concepts, as well as evidence for the role of AF in ischemic stroke., (Copyright © 2018 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: None., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Diabetes mellitus (DM), a growing health problem itself, is accompanied by an increased risk of cardiovascular and thrombotic complications. The imbalance between coagulation and fibrinolysis processes observed in patients with diabetes may be defined as diabetic thrombophilia. Several mechanisms are involved in the hypercoagulability state in diabetics, including endothelial cell damage, altered platelet structure and function, increased microparticle formation, different structure of fibrin clots, disturbances in the activity of coagulation factors, fluctuations in the concentrations of fibrinolysis activators and inhibitors, and qualitative changes of proteins due to glycation and oxidation processes. These all are the reasons why DM is the most common cause of acquired thrombophilia. Moreover, diabetes changes the efficacy of certain medications. Results of various trials seem to suggest that thrombolytic drugs are less effective in patients suffering from this disease. The impact of DM on the effectiveness of treatment with acetylsalicylic acid (ASA) remains unclear. Awareness of thrombotic complications in diabetic patients may enable earlier diagnosis and proper therapy.

Pancreatic cancer (PC) is a devastating malignancy with an overall 5-year survival of 8% for all stages combined. Most of the PC patients diagnosed have an advanced disease (40%) or metastatic stage (40%), which eliminates surgery as a potentially curative treatment. The disease course is often complicated by venous thromboembolism (VTE) events, which per se account for significant morbidity and mortality, with significantly worsen survival. PC is associated with the highest risk of VTE among all cancer patients. We review the literature data to address the incidence and clinical outcomes of VTE in PC patients. VTE incidence varies from 5 to 41% according to epidemiological studies and is as high as 57% in postmortem series. Since 2013, international clinical practice guidelines recommend primary thromboprophylaxis with a grade 1B level of evidence as an adjuvant therapy in advanced PC. A recent meta-analysis of randomized controlled trials investigating the benefit and risk of low-molecular-weight heparins (LMWH) in ambulatory advanced PC patients under chemotherapy showed that the incidence of VTE was 2.1% in patients treated with LMWH and 11.2% in controls (risk ratio, 0.18; 95% CI, 0.083-0.39; P<0.0001). In conclusion, improved earlier diagnosis and effective management of VTE, a frequent and life-threatening complication in PC, is warranted to improve PC patient outcomes., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Background: Calciphylaxis is a devastating multifactorial disorder of the subcutaneous fat that is known to be associated with hypercoagulability. Recent literature has proposed subclassifying patients with calciphylaxis as having warfarin-associated or warfarin-unassociated disease., Aim: We aimed to determine whether patients with warfarin-associated calciphylaxis differ clinically from patients with warfarin-unassociated calciphylaxis., Materials and Methods: We performed a subgroup analysis of patients with nonuremic calciphylaxis from a previously studied cohort and compared clinical and outcomes features of patients who were taking warfarin at the time of disease onset to those of patients who were not., Results: Nineteen patients with nonuremic calciphylaxis were identified, including 10 (53%) who had been on warfarin at the time of disease onset and 9 (47%) who had not. Of all clinical and outcomes parameters tested, no significant differences were detected between the two groups., Discussion and Conclusions: Though this study is limited by its retrospective nature and the relatively small number of patients studied, available data do not support subclassifying patients with nonuremic calciphylaxis as having warfarin-associated or warfarin-unassociated disease. Rather, the body of literature would suggest that identification and correction of underlying disorders of hypercoagulability should be prioritized., (© 2018 The International Society of Dermatology.)

A 24-year-old man presented with acute abdominal pain upon ascent to moderate altitude (3500 m). An immediate evaluation revealed a splenic infarct, and he was evacuated to sea level. Upon recovery, he was sent back to 3500 m without detailed etiological evaluation, whereupon he experienced recurrent episodes of left-side subcostal pain. Imaging suggested autosplenectomy, and workup revealed a negative thrombophilia profile but was positive for sickle cell trait (SCT). Individuals with SCT can be asymptomatic until exposure to severe hypoxia, upon which they can manifest clinically as sickle cell syndrome. We discuss the rare presentation of autosplenectomy in a patient with previously undiagnosed SCT on exposure to high altitude., (Copyright © 2017 Wilderness Medical Society. Published by Elsevier Inc. All rights reserved.)