A multi-constituent model for assessing the effect of impeller shroud on the thrombosis potential of a centrifugal blood pump.

Centrifugal blood pumps can be used for treating heart failure patients. However, pump thrombosis has remained one of the complications that trouble clinical treatment. This study analyzed the effect of impeller shroud on the thrombosis risk of the blood pump, and predicted areas prone to thrombosis. Multi-constituent transport equations were presented, considering mechanical activation and biochemical activation. It was found that activated platelets concentration can increase with shear stress and adenosine diphosphate(ADP) concentration increasing, and the highest risk of thrombosis inside the blood pump was under extracorporeal membrane oxygenation (ECMO) mode. Under the same condition, ADP concentration and thrombosis index of semi-shroud impeller can increase by 7.3% and 7.2% compared to the closed-shroud impeller. The main reason for the increase in thrombosis risk was owing to elevated scalar shear stress and more coagulation promoting factor-ADP released. The regions with higher thrombosis potential were in the center hole, top and bottom clearance. As a novelty, the findings revealed that impeller shroud can influence mechanical and biochemical activation factors. It is useful for identifying potential risk regions of thrombus formation based on relative comparisons.

Quantifying Shear-induced Margination and Adhesion of Platelets in Microvascular Blood Flow.

Platelet margination and adhesion are two critical and closely related steps in thrombus formation. Using dissipative particle dynamics (DPD) method that seamlessly models blood cells, blood plasma, and vessel walls with functionalized surfaces, we quantify the shear-induced margination and adhesion of platelets in microvascular blood flow. The results show that the occurrence of shear-induced RBC-platelet collisions has a remarkable influence on the degree of platelet margination. We characterize the lateral motion of individual platelets by a mean square displacement analysis of platelet trajectories, and find that the wall-induced lift force and the shear-induced displacement in wall-bounded flow cause the variation in near-wall platelet distribution. We then investigate the platelet adhesive dynamics under different flow conditions, by conducting DPD simulations of blood flow in a microtube with fibrinogen-coated wall surfaces. We find that the platelet adhesion is enhanced with the increase of fibrinogen concentration level but decreased with the increase of shear rate. These results are consistent with available experimental results. In addition, we demonstrate that the adherent platelets have a negative impact on the margination dynamics of the circulating platelets, which is mainly due to the climbing effect induced by the adherent ones. Taken together, these findings provide useful insights into the platelet margination and adhesion dynamics, which may facilitate the understanding of the predominant processes governing the initial stage of thrombus formation.

Multiphysics and multiscale modeling of microthrombosis in COVID-19.

Emerging clinical evidence suggests that thrombosis in the microvasculature of patients with Coronavirus disease 2019 (COVID-19) plays an essential role in dictating the disease progression. Because of the infectious nature of SARS-CoV-2, patients' fresh blood samples are limited to access for in vitro experimental investigations. Herein, we employ a novel multiscale and multiphysics computational framework to perform predictive modeling of the pathological thrombus formation in the microvasculature using data from patients with COVID-19. This framework seamlessly integrates the key components in the process of blood clotting, including hemodynamics, transport of coagulation factors and coagulation kinetics, blood cell mechanics and adhesive dynamics, and thus allows us to quantify the contributions of many prothrombotic factors reported in the literature, such as stasis, the derangement in blood coagulation factor levels and activities, inflammatory responses of endothelial cells and leukocytes to the microthrombus formation in COVID-19. Our simulation results show that among the coagulation factors considered, antithrombin and factor V play more prominent roles in promoting thrombosis. Our simulations also suggest that recruitment of WBCs to the endothelial cells exacerbates thrombogenesis and contributes to the blockage of the blood flow. Additionally, we show that the recent identification of flowing blood cell clusters could be a result of detachment of WBCs from thrombogenic sites, which may serve as a nidus for new clot formation. These findings point to potential targets that should be further evaluated, and prioritized in the anti-thrombotic treatment of patients with COVID-19. Altogether, our computational framework provides a powerful tool for quantitative understanding of the mechanism of pathological thrombus formation and offers insights into new therapeutic approaches for treating COVID-19 associated thrombosis.

Effect of Therapeutically Related Drugs on Coagulation-Anticoagulation Balance in Acute Promyelocytic Leukemia.

Acute promyelocytic leukemia (APL) usually presents with a series of coagulation-anticoagulation disturbance. Early administration of All-trans retinoic acid (ATRA) can reduce the risk of bleeding, but the potential for thrombosis needs to be addressed in some cases. The role of arsenic agent in correcting coagulation disorder remains to be studied, but oral arsenic agent shows potential advantages in coagulation recovery compared with intravenous agent, and chemotherapy can aggravate the progress of coagulation disease. In addition to early application of ATRA, avoiding invasive procedures and transfusion support can reduce the risk of bleeding. Whether the administration of heparin, thrombomodulin, recombinant factor VIIa or antifibrinolytics reduces the risk of bleeding and thrombosis associated with APL remains to be further explored, and their routine use outside of clinical trials is not recommended. This article reviews the effects of related drugs on coagulation-anticoagulation balance in APL patients.

Computational investigation of blood cell transport in retinal microaneurysms.

Microaneurysms (MAs) are one of the earliest clinically visible signs of diabetic retinopathy (DR). MA leakage or rupture may precipitate local pathology in the surrounding neural retina that impacts visual function. Thrombosis in MAs may affect their turnover time, an indicator associated with visual and anatomic outcomes in the diabetic eyes. In this work, we perform computational modeling of blood flow in microchannels containing various MAs to investigate the pathologies of MAs in DR. The particle-based model employed in this study can explicitly represent red blood cells (RBCs) and platelets as well as their interaction in the blood flow, a process that is very difficult to observe in vivo. Our simulations illustrate that while the main blood flow from the parent vessels can perfuse the entire lumen of MAs with small body-to-neck ratio (BNR), it can only perfuse part of the lumen in MAs with large BNR, particularly at a low hematocrit level, leading to possible hypoxic conditions inside MAs. We also quantify the impacts of the size of MAs, blood flow velocity, hematocrit and RBC stiffness and adhesion on the likelihood of platelets entering MAs as well as their residence time inside, two factors that are thought to be associated with thrombus formation in MAs. Our results show that enlarged MA size, increased blood velocity and hematocrit in the parent vessel of MAs as well as the RBC-RBC adhesion promote the migration of platelets into MAs and also prolong their residence time, thereby increasing the propensity of thrombosis within MAs. Overall, our work suggests that computational simulations using particle-based models can help to understand the microvascular pathology pertaining to MAs in DR and provide insights to stimulate and steer new experimental and computational studies in this area.

Segmental partial thrombosis of the corpora cavernosa: Case report and diagnostic/therapeutic algorithm / Trombosis parcial segmentaria del cuerpo cavernoso: reporte de caso y presentación de un algoritmo diagnóstico/terapéutico

Cavernous body thrombosis is a rare condition. The etiology and pathophysiology of this entity is still poorly understood and there is no clear diagnostic and treatment algorithm. The objective of this article is to publish a clinical case of a partial segmental thrombosis of the corpus cavernosum and present a flow chart for diagnosis and treatment based on the review of the published literature on this disease. (AU)

La trombosis del cuerpo cavernoso es una afección rara. La etiología y la fisiopatología de esta entidad todavía son poco entendidas y no existe un algoritmo de diagnóstico y tratamiento claro. El objetivo de este artículo es publicar el caso clínico de una trombosis parcial segmentaria del cuerpo cavernoso y presentar un flujograma para el diagnóstico y el tratamiento basados en la revisión de la literatura. (AU)

Covid-19 and Liver Injury: Role of Inflammatory Endotheliopathy, Platelet Dysfunction, and Thrombosis.

Liver injury, characterized predominantly by elevated aspartate aminotransferase and alanine aminotransferase, is a common feature of coronavirus disease 2019 (COVID-19) symptoms caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). Additionally, SARS-CoV-2 infection is associated with acute-on-chronic liver failure in patients with cirrhosis and has a notably elevated mortality in patients with alcohol-related liver disease compared to other etiologies. Direct viral infection of the liver with SARS-CoV-2 remains controversial, and alternative pathophysiologic explanations for its hepatic effects are an area of active investigation. In this review, we discuss the effects of SARS-CoV-2 and the inflammatory environment it creates on endothelial cells and platelets more generally and then with a hepatic focus. In doing this, we present vascular inflammation and thrombosis as a potential mechanism of liver injury and liver-related complications in COVID-19.

Stress Analysis in AAA does not Predict Rupture Location Correctly in Patients with Intraluminal Thrombus.

BACKGROUND: A biomechanical approach to the rupture risk of an abdominal aortic aneurysm could be a solution to ensure a personalized estimate of this risk. It is still difficult to know in what conditions, the assumptions made by biomechanics, are valid. The objective of this work was to determine the individual biomechanical rupture threshold and to assess the correlation between their rupture sites and the locations of their maximum stress comparing two computed tomography scan (CT) before and at time of rupture. METHODS: We included 5 patients who had undergone two CT; one within the last 6 months period before rupture and a second CT scan just before the surgical procedure for the rupture. All DICOM data, both pre- and rupture, were processed following the same following steps: generation of a 3D geometry of the abdominal aortic aneurysm, meshing and computational stress analysis using the finite element method. We used two different modelling scenarios to study the distribution of the stresses, a "wall" model without intraluminal thrombus (ILT) and a "thrombus" model with ILT. RESULTS: The average time between the pre-rupture and rupture CT scans was 44 days (22-97). The median of the maximum stresses applied to the wall between the pre-rupture and rupture states were 0.817 MPa (0.555-1.295) and 1.160 MPa (0.633-1.625) for the "wall" model; and 0.365 MPa (0.291-0.753) and 0.390 MPa (0.343-0.819) for the "thrombus" model. There was an agreement between the site of rupture and the location of maximum stress for only 1 patient, who was the only patient without ILT. CONCLUSIONS: We observed a large variability of stress values at rupture sites between patients. The rupture threshold strongly varied between individuals depending on the intraluminal thrombus. The site of rupture did not correlate with the maximum stress except for 1 patient.

Soluble thrombomodulin ameliorates aberrant hemostasis after rewarming in a rat accidental hypothermia model.

BACKGROUND: Accidental hypothermia (AH) sometimes leads to coagulation disorder, especially in severe AH. We previously demonstrated that intrasplenic platelet activation caused aberrant hemostasis and thrombus formation after rewarming in a murine AH model. However, no study has focused on the appropriate management of platelets causing coagulation activation after rewarming of AH. We investigated whether or not recombinant soluble thrombomodulin (rTM) can suppress thrombosis formation after rewarming using a rat AH model. METHODS: Wistar rats were exposed to an ambient temperature of -20 °C under general anesthesia until their rectal temperature decreased to 26 °C. The Hypo group rats (n = 5) were immediately euthanized, while the Hypo/Re group (n = 5) and rTM group rats (n = 5), which were administered rTM (1 mg/kg) via the tail vein, were rewarmed until the rectal temperature returned to 34 °C and then euthanized 6 h later. Tissue and blood samples were collected from all rats for histopathological and coagulation analyses at euthanasia. RESULTS: There was no significant change in the D-dimer level in the Hypo group rats, while the D-dimer level was significantly elevated at 6 h after rewarming in the Hypo/Re group rats (P = 0.015), and histopathology detected both fibrin and platelets in the renal glomerulus. However, the rTM group rats did not show any elevation of the D-dimer levels at 6 h after rewarming, and no fibrin was noted on histopathology. CONCLUSIONS: rTM may be useful as an appropriate anticoagulant in cases of aberrant hemostasis after rewarming of AH.

Influence of lipoproteins and antiplatelet agents on vein graft patency 1 year after coronary artery bypass grafting.

OBJECTIVE: It remains unclear whether aggressive low-density lipoprotein cholesterol (LDL-C) management (<1.8 mmol/L) can slow the process of vein graft stenosis. This study aimed to explore the impact of baseline LDL-C levels on vein graft patency in patients on ticagrelor with or without aspirin 1 year after coronary artery bypass grafting (CABG). METHODS: This was a post hoc analysis of the DACAB (Different Antiplatelet Therapy Strategy After Coronary Artery Bypass Graft Surgery) trial (NCT02201771), a randomized controlled trial (ticagrelor + aspirin or ticagrelor vs aspirin) of patients undergoing CABG in China. The study subjects were stratified as LDL-low (baseline LDL-C <1.8 mmol/L, 148 patients with 430 vein grafts) versus LDL-high (baseline LDL-C ≥1.8 mmol/L, 352 patients with 1030 vein grafts). The primary outcome was the 1-year vein graft patency (Fitzgibbon grade A) assessed by coronary computed tomographic angiography or coronary angiography. RESULTS: Baseline/1-year LDL-C were 1.4/1.6 and 2.6/2.4 mmol/L in the LDL-low and LDL-high subgroups, respectively. Regardless of antiplatelet regimen, no significant inter-subgroup difference was observed for 1-year graft patency (LDL-low: 83.8% [359/430 grafts]; LDL-high: 82.3% [848/1030 grafts]; adjusted OR for non-patency [ORadj], 0.96; 95% confidence interval [CI], 0.62-1.50, P = .857). For both subgroups, the 1-year graft patency rates were greater with ticagrelor + aspirin versus aspirin (LDL-low: ORadj, 0.41; 95% CI, 0.17-0.97; LDL-high: ORadj, 0.38; 95% CI, 0.20-0.71; inter P = .679). CONCLUSIONS: In general, baseline LDL-C is not associated with 1-year vein graft patency after CABG. Regardless of the baseline LDL-C levels, ticagrelor + aspirin was superior to aspirin alone in maintaining vein graft patency. The primary factor causing early vein graft disease might not be atherosclerosis but thrombosis.

Lifestyle Influences Changes in Fibrin Clot Properties Over a 10-Year Period on a Population Level.

Case-control and observational studies have provided a plausible mechanistic link between clot structure and thrombosis. We aimed to identify lifestyle, demographic, biochemical, and genetic factors that influence changes in total fibrinogen concentration and clot properties over a 10-year period in 2,010 black South Africans. Clot properties were assessed with turbidimetry and included lag time, slope, maximum absorbance, and clot lysis time. Linear mixed models with restricted maximum likelihood were used to determine whether (1) outcome variables changed over the 10-year period; (2) demographic and lifestyle variables, biochemical variables, and fibrinogen single-nucleotide polymorphisms influenced the change in outcome variables over the 10-year period; and (3) there was an interaction between the exposures and time in predicting the outcomes. A procoagulant risk score was furthermore created, and multinomial logistic regression was used to determine the exposures that were associated with the different risk score categories. In this population setting, female gender, obesity, poor glycemic control, increased low-density lipoprotein cholesterol, and decreased high-density lipoprotein cholesterol contributed to the enhanced progression to prothrombotic clot properties with increasing age. Alcohol consumption on the other hand, offered a protective effect. The above evidence suggest that the appropriate lifestyle changes can improve fibrin clot properties on a population level, decreasing cardiovascular disease risk and thus alleviate the strain on the medical health care system.

Iron-Driven Alterations on Red Blood Cell-Derived Microvesicles Amplify Coagulation during Hemolysis via the Intrinsic Tenase Complex.

Hemolytic disorders characterized by complement-mediated intravascular hemolysis, such as autoimmune hemolytic anemia and paroxysmal nocturnal hemoglobinuria, are often complicated by life-threatening thromboembolic complications. Severe hemolytic episodes result in the release of red blood cell (RBC)-derived proinflammatory and oxidatively reactive mediators (e.g., extracellular hemoglobin, heme, and iron) into plasma. Here, we studied the role of these hemolytic mediators in coagulation activation by measuring factor Xa (FXa) and thrombin generation in the presence of RBC lysates. Our results show that hemolytic microvesicles (HMVs) formed during hemolysis stimulate thrombin generation through a mechanism involving FVIII and FIX, the so-called intrinsic tenase complex. Iron scavenging during hemolysis using deferoxamine decreased the ability of the HMVs to enhance thrombin generation. Furthermore, the addition of ferric chloride (FeCl3) to plasma propagated thrombin generation in a FVIII- and FIX-dependent manner suggesting that iron positively affects blood coagulation. Phosphatidylserine (PS) blockade using lactadherin and iron chelation using deferoxamine reduced intrinsic tenase activity in a purified system containing HMVs as source of phospholipids confirming that both PS and iron ions contribute to the procoagulant effect of the HMVs. Finally, the effects of FeCl3 and HMVs decreased in the presence of ascorbate and glutathione indicating that oxidative stress plays a role in hypercoagulability. Overall, our results provide evidence for the contribution of iron ions derived from hemolytic RBCs to thrombin generation. These findings add to our understanding of the pathogenesis of thrombosis in hemolytic diseases.

Pathomechanisms Underlying Hypoxemia in Two COVID-19-Associated Acute Respiratory Distress Syndrome Phenotypes: Insights From Thrombosis and Hemostasis.

BACKGROUND: The pathomechanisms of hypoxemia and treatment strategies for type H and type L acute respiratory distress syndrome (ARDS) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced coronavirus disease 2019 (COVID-19) have not been elucidated. MAIN TEXT: SARS-CoV-2 mainly targets the lungs and blood, leading to ARDS, and systemic thrombosis or bleeding. Angiotensin II-induced coagulopathy, SARS-CoV-2-induced hyperfibrin(ogen)olysis, and pulmonary and/or disseminated intravascular coagulation due to immunothrombosis contribute to COVID-19-associated coagulopathy. Type H ARDS is associated with hypoxemia due to diffuse alveolar damage-induced high right-to-left shunts. Immunothrombosis occurs at the site of infection due to innate immune inflammatory and coagulofibrinolytic responses to SARS-CoV-2, resulting in microvascular occlusion with hypoperfusion of the lungs. Lung immunothrombosis in type L ARDS results from neutrophil extracellular traps containing platelets and fibrin in the lung microvasculature, leading to hypoxemia due to impaired blood flow and a high ventilation/perfusion (VA/Q) ratio. COVID-19-associated ARDS is more vascular centric than the other types of ARDS. D-dimer levels have been monitored for the progression of microvascular thrombosis in COVID-19 patients. Early anticoagulation therapy in critical patients with high D-dimer levels may improve prognosis, including the prevention and/or alleviation of ARDS. CONCLUSIONS: Right-to-left shunts and high VA/Q ratios caused by lung microvascular thrombosis contribute to hypoxemia in type H and L ARDS, respectively. D-dimer monitoring-based anticoagulation therapy may prevent the progression to and/or worsening of ARDS in COVID-19 patients.

Follow-up after acute thrombotic events following COVID-19 infection.

OBJECTIVE: COVID-19 infection results in a hypercoagulable state predisposing patients to thrombotic events. We report the 3- and 6-month follow-up of 27 patients who experienced acute arterial thrombotic events in the setting of COVID-19 infection. METHODS: Data were prospectively collected and maintained for all vascular surgery consultations in the Mount Sinai Health System from patients who presented between March 16 and May 5, 2020. RESULTS: Twenty-seven patients experienced arterial thrombotic events. The average length of stay was 13.3 ± 15.4 days. Fourteen patients were treated with open surgical intervention, six were treated with endovascular intervention, and seven were treated with anticoagulation only. At 3-month follow-up, 11 patients (40.7%) were deceased. Nine patients who expired did so during the initial hospital stay. The 3-month cumulative primary patency rate for all interventions was 72.2%, and the 3-month primary patency rates for open surgical and endovascular interventions were 66.7 and 83.3, respectively. There were 9 (33.3%) readmissions within 3 months. Six-month follow-up was available in 25 (92.6%) patients. At 6-month follow-up, 12 (48.0%) patients were deceased, and the cumulative primary patency rate was 61.9%. The 6-month primary patency rates of open surgical and endovascular interventions were 66.7% and 55.6%, respectively. The limb-salvage rate at both 3 and 6 months was 89.2%. CONCLUSIONS: Patients with COVID-19 infections who experienced thrombotic events saw high complication and mortality rates with relatively low patency rates.