Thrombosis Update最新文献

Introduction

Treatment of congenital thrombotic thrombocytopenic purpura (cTTP), a disease characterized by the congenital deficiency of ADAMTS13, remains a challenge as there are no specific treatments available yet, other than therapy based on the use of fresh frozen plasma (FFP). Since cTTP is caused by low levels of ADAMTS13 protein, commercially available coagulation factor concentrates have been considered as potential ADAMTS13 source in place of FFP. The study aimed to validate the therapeutic potential of a plasma-derived factor VIII (FVIII) product as a source of ADAMTS13.

Methods

The quantitation of ADAMTS13 activity levels in eight lots of a plasma-derived FVIII product, (Koāte®) was carried out with three different methodologies: a Fluorescence Resonance Energy Transfer (FRET) assay, a chemiluminescence assay, and a chromogenic ELISA. ADAMTS13 protein antigen levels were measured by the FRET technique as well. In addition, von Willebrand factor (VWF) activity (VWF ristocetin cofactor, VWF:RCo, and VWF collagen binding, VWF:CB) and antigen (VWF:Ag) were measured using chemiluminescence assays. Qualification protocols were applied to the methods used.

Results

The results showed high levels of ADAMTS13 in all eight Koāte® lots analyzed, with antigen and activity levels respectively of 10.72 IU/ml ± 3.94 and 5.62 IU/ml ± 1.39. Despite the significant content of ADAMTS13, VWF integrity seems not to be affected (0.81 ± 0.15 VWF:RCo/VWF:Ag and 0.75 ± 0.15 VWF:CB/VWF:Ag ratios).

Conclusions

These findings suggest that Koāte® could be a potential candidate for the treatment of cTTP, warranting evaluation in a clinical trial.

Background

The risk of adults with a congenital heart defect (ACHD) developing heart failure, stroke, arrhythmias, and the need for valve replacement is increased compared to healthy peers. Evidence for the use of novel oral anticoagulants (NOAC) in this patient group is still lacking and vitamin K antagonists (VKA) are the primary choice for patients with a mechanical valve. The present aim was to determine the rate of thromboembolic and major bleeding events in ACHD patients on VKA therapy.

Methods

This was a retrospective study on ACHD patients on VKA treatment registered in the National Quality Registry for Congenital Heart Disease, SWEDCON, and Atrial fibrillation and Anticoagulation, AuriculA, from Southern Sweden.

Results

213 patients were included with a mean age of 50 years (±18) years and a mean follow-up of 6.6 years (±3.3 years), 16% had complex defects and 41% had valvular VKA therapy indication. In total, 34 complications were registered, of which 14 were thromboembolic events and 20 were major bleeding events. The rate of thromboembolism and major bleeding events was 1.0 (95% CI: 0.6–1.6) and 1.4 (95% CI: 0.9–2.2) per 100 patient-years, respectively. Forty-three patients died during the study period. The mortality rate was 3.1 per 100 patient-years (95% CI: 2.2–4.1).

Conclusion

We found a low rate of thromboembolic events and major bleeding events for low-moderate risk ACHD patients with good quality of VKA anticoagulation. The target of TTR>65% for ACHD patients is recommended.

Background

SARS-COV-2, in most cases, only generates a mild acute respiratory disease. However, patients with severe disease show an exaggerated response of the immune system, creating a pro-inflammatory state, which could cause abnormalities in the coagulation system that increases mortality. Latin American countries, specially those with limited resources, have few studies about clinical features, coagulation and inflammatory biomarkers that could be useful at admission to assess poor outcomes.

Objective

The objective of this study is to describe the clinical features, coagulation, and inflammatory biomarkers, and identify risk factors at admission that are associated poor outcomes in Honduran population.

Methods

A cohort study was conducted. 210 patients were included, which 105 died during hospitalization due to COVID-19 and 105 were discharged alive, between September 2020 and January 2021. Clinical and laboratorial data was retrospectively collected.

Results

57,6% of the population were male. The median age was 58 years. The median time between symptom onset and hospital admission was 6 days. D-dimer median was higher in the dead group compared with the alive group. Poor prognosis factors in the Cox multivariable model were male gender, age, symptom's duration, obesity and an elevated d dimer at admission.

Conclusion

In low-middle income countries, the assessment of these clinical and laboratory tools, especially in those with risk factors for prothrombotic states, could help clinicians to correctly stratify disease prognosis, establish a baseline to evaluate further evolution, and also predict outcomes, thus improving patient management.

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.

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.

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.

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.