Thrombosis Update最新文献

Background

Cancer-associated thrombosis (CAT) is caused, at least in part, by procoagulant factors produced by the tumour itself. Although MUC1 is an established biomarker for the diagnosis, immunotherapy, and prognosis of cancer, it is unclear whether it contributes to the procoagulant phenotype of cancer cells.

Methods

MUC1 knockdown breast cancer MCF-7 cells were used to investigate the influence of overexpression of MUC1 on procoagulant parameters. In addition, the effect of treating normal human epithelial cells with extracellular vesicles from several human breast and pancreatic cancer cell lines, which overexpress MUC1, was determined. The impact of a pharmacological anti-MUC1 antibody on cancer cells was also analysed.

Results

The level of a range of procoagulant proteins was observed to correlate with the MUC1 level of human breast and pancreatic cancer cell lines. MUC1 downregulation in MCF-7 cells led to a reduction in the procoagulant parameters particularly thrombin activity. The levels of selected tumorigenic markers, procoagulant proteins and miRNAs associated with tumorigenicity and thromboembolism were also modulated by treatment of normal cells with tumour cell derived extracellular vesicles in correlation with that of the extracellular vesicles donor cells. Moreover, the procoagulant properties were also reduced by an anti-MUC1 antibody in these cancer cells.

Conclusions

A range of procoagulant proteins found in human breast and pancreatic cancer cells were shown to exhibit a positive correlation with the level of MUC1 and thereby potentially contribute to the pathogenesis of CAT. The reduction of the procoagulant activity by MUC1 antibody could be an additional beneficial effect of its therapeutic efficacy. These findings also suggest that the level of tumour associated MUC1 could be of use as a risk factor for CAT.

Purpose

We aimed to evaluate the risk of recurrent venous thromboembolism (VTE) among patients receiving direct oral anticoagulant (DOAC) therapy (extended and non-extended) using claims data.

Methods

Patients treated with DOACs at the first VTE event were identified using Japanese claims data; Cox proportional hazard models were used to evaluate the risk of recurrence. Unadjusted, adjusted, and stabilized inverse probability treatment weighting (s-IPTW) analyses were used to assess the differences between patients treated for more than 90 days after the index date (extended treatment group) and those treated within 90 days (nonextended treatment group). Bleeding was assessed separately from recurrent VTE evaluation during the observation period.

Results

We included 4,010 patients (mean age, 69 years; 57.9% females; extended: 2,684, nonextended: 1,326). After IPTW, all patient characteristics were well balanced. When the follow-up was censored at 18 months, the hazard ratio (extended/nonextended) for unadjusted, adjusted, and two s-IPTW analyses were 1.31 (P = 0.2762), 1.25 (P = 0.372), 1.32 (P = 0.2579), and 1.33 (P = 0.2498), respectively. The proportions of those who experienced intracranial, gastrointestinal, respiratory, and renal/urinary tract bleeding during the observation period in both groups were 2.9% vs. 3.8%, 2.1% vs. 2.3%, 1.0% vs. 0.5%, and 1.4% vs. 0.7% (extended vs. nonextended), respectively.

Conclusions

There were no differences in VTE recurrence between the two groups. In clinical practice and with a risk-benefit evaluation, both VTE treatment types were well controlled. Further evaluation is required, considering patient background within the observation period of 90 days and safety of treatment for bleeding events.

Thrombotic Thrombocytopenic Purpura (TTP) is a rare form of thrombotic microangiopathy (TMA) typically characterized by microangiopathic hemolytic anemia, severe thrombocytopenia, and end-organ ischemia secondary to microvascular dissemination of platelet-rich thrombi. Systemic Lupus Erythematosus (SLE) is a chronic autoimmune condition characterized by multi-organ system inflammation with the generation of autoantibodies. The specific cause of SLE is unknown but multiple factors seem to be associated with the development of the disease including: genetic, epigenetic, ethnic, hormonal, and environmental factors. In SLE, patients may present with a wide assortment of clinical variations, but diagnosis is based generally on clinical and laboratory findings after excluding alternative diagnoses. Very rarely do SLE and TTP present simultaneously. Both disease processes have overlapping clinical features which makes diagnosis and management challenging. The following case report describes a forty-year-old female with no prior history of SLE or TTP who presented with clinical findings and features of TTP as the initial clinical manifestation of her underlying SLE, as well as serologic criteria, requiring treatment with plasma exchange, high dose steroids, and eventual outpatient infusion with Rituximab.

It is now well established that infection with SARS-CoV-2 resulting in COVID-19 disease includes a severely symptomatic subset of patients in whom an aggressive and/or dysregulated host immune response leads to cytokine storm syndrome (CSS) that may be further complicated by thrombotic events, contributing to the severe morbidity and mortality observed in COVID-19. This review provides a brief overview of cytokine storm in COVID-19, and then presents a mechanistic discussion of how cytokine storm affects integrated pathways in thrombosis involving the endothelium, platelets, the coagulation cascade, eicosanoids, auto-antibody mediated thrombosis, and the fibrinolytic system.

Venous thromboembolism (VTE) is a major cause of morbidity and mortality in pregnancy. Multiple physiologic changes in pregnancy contribute to the increased risk of VTE. VTE in this setting presents unique challenges for diagnosis and management. Evidence-based diagnostic practices include limiting D-dimer testing, reliance on ultrasound and V/Q scan when possible, and counseling patients and their families on the safe use of CT imaging of the chest when needed. Anticoagulation primarily relies on low molecular weight heparin, but unfractionated heparin and fondaparinux may also be used when needed. Warfarin is a known teratogen and induces an anticoagulant effect in the fetus. Safety data for other anticoagulants is lacking. Thrombolysis should be limited to patients with significant hemodynamic compromise due to the high risk of bleeding with this intervention. For individuals with prior VTE who are no longer on anticoagulation, prophylactic anticoagulation is usually reserved for those with prior estrogen-associated or unprovoked VTE. Future prophylaxis can be limited to additional pregnancies in most individuals. Future exposure to exogenous estrogen should be avoided. Prophylactic anticoagulation on the basis of heritable thrombophilias without a personal history of VTEs is not usually indicated, as risks of bleeding and interference with the use of neuraxial anesthesia outweigh benefits in most instances. Therefore, primary prophylaxis should be limited to only the high risk genotypes.

While vaccination is the single most effective intervention to prevent spread of COVID-19, rare thromboembolic events have been reported following vaccination with COVID-19 vaccines ChAdOx1 nCOV-19 (AstraZeneca) and Ad26.COV2·S (Johnson & Johnson/Janssen). We present here a case of one such patient who received Ad26.COV2–S (recombinant) JanssenCOVID_19 vaccine.

A 55-year-old male presented with a two week history of abdominal pain, nausea, vomiting, and distention. He received the Ad26.COV2–S (recombinant) JanssenCOVID_19 vaccine, one month before onset of symptoms. On presentation, lab results revealed hyponatremia, lactic acidosis, and leukocytosis. CT abdomen and pelvis with contrast revealed moderate circumferential bowel wall thickening, prominent mesenteric vessels present, and a portal vein thrombus extending to the superior mesenteric and splenic veins. An extensive hypercoagulable workup was negative. Patient's history revealed he was a frequent airline passenger but was otherwise negative. Additional etiologies were examined before associating the COVID-19 vaccine with thrombosis and the penultimate diagnosis was only reached by exclusion of other causes after initial evaluation and further outpatient follow up.

Introduction

Plasma factor X (FX) levels may affect the therapeutic effects of bypass hemostatic therapy among patients with hemophilia with inhibitors. This study aimed to reproduce low and high FX level conditions in vitro and analyze changes in coagulation capacity.

Materials and methods

To achieve low FX concentrations, FX-deficient plasma was preincubated with anti-factor VIII (FVIII) or anti-factor IX (FIX) antibody. Following this, it was incubated with activated factor VII (FVIIa) or FVIIa/FX mixture in the presence of FX (0.13–0.64 IU/mL). To achieve high FX concentrations, FVIII- or FIX-deficient plasma was preincubated with anti-FVIII or anti-FIX antibody. Next, FX (4–20 IU/mL) was added in the presence of FVIIa (140 IU/mL). Under both conditions, changes in coagulation capacity were assessed by evaluating thrombin generation (TG) and activated partial thromboplastin time (aPTT).

Results

FX at low concentrations induced concentration-dependent changes in TG. In the presence of FX (0.13 IU/mL), adding FVIIa inadequately restored TG. Further, TG in the plasma was normalized after adding FVIIa/FX (62.5/2 IU/mL), and the FVIIa/FX-added group had a stable TG and aPTT, regardless of FX concentrations (0.13–0.64 IU/mL). The FVIIa-added group exhibited a FX concentration-dependent increase in TG and a decrease in aPTT. Furthermore, TG increased with FX concentrations under high FX concentrations (up to 10 IU/mL).

Conclusions

Simultaneous FX supplementation in addition to FVIIa may be effective in promoting hemostasis under low plasma FX levels. Moreover, the risk of overcoagulation might be low even under high plasma FX levels.

HELLP syndrome consists of the triad hemolysis, elevated liver enzymes and low platelets count. It is usually developed in pregnant women with preeclampsia. Intrahepatic liver hematoma is an extremely rare complication of HELLP syndrome. Pulmonary embolism (PE) is not a typical complication of HELLP syndrome but it may appear in the setting of prothrombotic status associated to pregnancy. We report a case of HELLP syndrome complicated with subcapsular and parenchymal liver hematoma and pulmonary embolism, which represents a therapeutic challenge because it faces the need to anticoagulate with the risk of bleeding.

Coronavirus disease 2019 (COVID-19), caused by a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can cause life-threatening pathology characterized by a dysregulated immune response and coagulopathy. While respiratory failure induced by inflammation is the most common cause of death, micro-and macrovascular thrombosis leading to multiple organ failure are also causes of mortality. Dysregulation of systemic inflammation observed in severe COVID-19 patients is manifested by cytokine release syndrome (CRS) - the aberrant release of high levels of proinflammatory cytokines, such as IL-6, IL-1, TNFα, MP-1, as well as complement. CRS is often accompanied by activation of endothelial cells and platelets, coupled with perturbation of the balance between the pro-and antithrombotic mechanisms, resulting in thrombosis. Inflammation and thrombosis form a vicious circle, contributing to morbidity and mortality. Treatment of hyperinflammation has been shown to decrease thrombosis, while anti-thrombotic treatment also downregulates cytokine release. This review highlights the relationship between COVID-19-mediated systemic inflammation and thrombosis, the molecular pathways involved, the therapies targeting these processes, and the challenges currently encountered.