Thrombosis and bleeding after COVID-19 vaccination: do differences in sex matter?

Gender medicine deals with differences in approach to diagnostic work-up and management according to gender. Although the issue is relevant in every field of medicine, it is often neglected. However, the recent SARS-CoV-2 pandemic has made consideration of gender even more urgent. In fact, available literature has suggested a higher number of deaths among infected men than in women and more side effects in women than in male recipients of certain anti-COVID-19 vaccines. This review examines sex-disaggregated data on thrombotic and bleeding events associated with vaccination against COVID-19. Thrombotic complications are by far more frequently reported than bleeding events after vaccination and are mostly observed in young women receiving viral-vectored vaccines. However, detailed data that could help better stratify the risk according to sex/gender are generally lacking. Likewise, overall bleeding complications and those associated with a specific vaccine are mainly reported as aggregated data, including thrombocytopenia that is reported to occur in the presence or absence of thrombotic complications. Such information is important as it underlines the need to differentiate between thrombocytopenia with and without thrombosis because management and prognosis differ according to the association of thrombotic events. Here, we highlight how the lack of disaggregated data has led to the publication of conflicting information about adverse events by sex in recipients of viral-vectored vaccines. Lastly, we examine the possible mechanisms underlying vaccine-associated thrombotic and bleeding complications according to sex/gender.

Obstetric outcomes in pregnant COVID-19 women: the imbalance of von Willebrand factor and ADAMTS13 axis.

BACKGROUND: Thrombotic microangiopathy has been invoked as one of the most important mechanisms of damage in COVID-19 patients. Protease ADAMTS13 is a marker of microangiopathy responsible for controlling von Willebrand multimers size. Von Willebrand factor/ADAMTS13 ratio has been found impaired in COVID-19 patients outside pregnancy. METHODS: We prospectively investigated 90 pregnant women admitted to two tertiary academic hospitals in Italy with a laboratory-confirmed diagnosis of SARS-CoV-2 infection. Demographic, clinical information and routine laboratory data were collected at the hospital admission and until discharge. We investigated whether vonWillebrand /ADAMTS13 axis imbalance is a predictor of adverse outcomes. Logistic regression analysis, which controlled for potential confounders, was performed to evaluate the association between laboratory parameters and clinical outcomes. RESULTS: Most women (55.6%) were parae, with median gestational age at admission of 39 weeks. At hospital admission, 63.3% were asymptomatic for COVID-19 and 24.4% showed more than one sign or symptom of infection. Nulliparae with group O showed Willebrand / ADA MTS-13 ratios significantly lower than non-O, whereas in multiparae this difference was not observed. Logistic regression showed that ratio von Willebrand to ADAMTS13 was significantly and independently associated with preterm delivery (OR 1.9, 95%CI 1.1-3.5). CONCLUSION: This study shows an imbalance of vonWillebrand /ADAMTS13 axis in pregnant women with COVID-19, leading to a significantly higher and independent risk of preterm delivery. Monitoring these biomarkers might support decision making process to manage and follow-up pregnancies in this setting.

Blood supply, transfusion demand and mortality in Italian patients hospitalised during nine months of COVID-19 pandemic.

BACKGROUND: We describe blood supply and usage from March to December 2020 in two research medical hospitals in the Apulia region of Italy: Research Hospital "Casa Sollievo della Sofferenza" (Centre 1) and University Hospital of Bari (Centre 2). MATERIALS AND METHODS: We performed a retrospective observational study of blood component transfusions in the first eight months of the pandemic: 1st March-31st December 2020. We assessed the number of hospitalised patients who were transfused, the number and type of blood components donated and the number and type of blood components transfused in different care settings. RESULTS: Blood donations were lower in 2020 than in 2019, with a significant reduction in red blood cells (RBC) transfused (-29% in 2020 vs 2019) and fewer transfusions in 2020 in the Internal Medicine departments (-67% and -44% in Centres 1 and 2, respectively) and Intensive Care Units (ICUs) (-53% and -54% in Centres 1 and 2, respectively). The overall number of fatalities was significantly lower in 2020 than in 2019; the proportion of fatalities in men was significantly higher in 2020 than in 2019 (53.9% and 41.5%, respectively; p=0.000). Among COVID-19 patients (n=645), 427 (66.2%) were transfused in Infectious Disease departments and the remaining in ICUs. The fatality rate was 14.3% in COVID patients transfused in Infectious Disease departments and 22.5% in those transfused in ICUs. Kaplan-Meier analysis showed 30- and 60-day mortality was significantly higher in patients transfused in 2020 compared to those transfused in 2019. Fatalities were mostly observed in COVID-19 patients. DISCUSSION: Present data may be helpful in understanding the trend of collection and use of blood supplies during periods of pandemic. The implementation of a Patient Blood Management programme is essential to maintain sufficient blood supplies and to keep track of clinical outcomes that represent the most important goal of transfusion.

Approach to the Evaluation and Treatment of Venous Thromboembolism in Pregnancy.

Thrombosis in pregnancy is a major cause of maternal and fetal morbidity and mortality. Risk stratification of venous thromboembolism (VTE) during pregnancy is complex. The hypercoagulability observed in pregnant women can reduce bleeding during childbirth, but may cause thrombosis especially in the presence of additional prothrombotic risk factors such as antiphospholipid antibodies or genetic thrombophilic defects. The availability of large datasets allows for the identification of additional independent risk factors, including assisted reproductive technologies (ARTs), endometriosis, and recurrent pregnancy loss. Data on the risk of VTE linked to COVID-19 in pregnant women are very limited, but suggest that infected pregnant women have an increased risk of VTE. Current guidelines on the prevention and treatment of VTE in pregnancy are based on available, albeit limited, data and mainly present expert opinion. Low-molecular-weight heparins (LMWHs) are the mainstay of anticoagulation to be employed during pregnancy. Administration of LMWH for VTE treatment in pregnancy should be based on the personalized approach, taking into account a weight-based adjusted scheme. During gestation, due to physiological changes, in women at high risk of VTE, monitoring of anti-Xa activity is performed to ensure adequate LMWH dosing. As for the treatment duration for pregnant women with acute VTE, guidelines suggest that anticoagulation should be continued for at least 6 weeks postpartum for a minimum total duration of therapy of 3 months.

The Prognostic Value of ADAMTS-13 and von Willebrand Factor in COVID-19 Patients: Prospective Evaluation by Care Setting.

BACKGROUND: Endothelial dysfunction, coupled with inflammation, induces thrombo-inflammation. In COVID-19, this process is believed to be associated with clinical severity. Von Willebrand factor (VWF), and a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS-13), are strong markers of endothelial dysfunction. We evaluated the impact of the VWF/ADAMTS-13 fraction on COVID-19 severity and prognosis. MATERIALS AND METHODS: A cohort study including 74 COVID-19 patients, with 22 admitted to the intensive care unit (ICU) and 52 to the medical ward (MW), was carried out. We also evaluated, in a group of 54 patients who were prospectively observed, whether variations in VWF/ADAMTS-13 correlated with the degree of severity and routine blood parameters. RESULTS: A VWF:RCo/ADAMTS-13 fraction above 6.5 predicted in-hospital mortality in the entire cohort. At admission, a VWF:RCo/ADAMTS-13 fraction above 5.7 predicted admission to the ICU. Furthermore, the VWF:RCo/ADAMTS-13 fraction directly correlated with C-reactive protein (CRP) (Spearman r: 0.51, p < 0.0001) and D-dimer (Spearman r: 0.26, p = 0.03). In the prospective cohort, dynamic changes in VWF:RCo/ADAMTS-13 and the CRP concentration were directly correlated (Spearman r, p = 0.0014). This relationship was significant in both groups (ICU: p = 0.006; MW: p = 0.02). CONCLUSIONS: The present findings show that in COVID-19, the VWF/ADAMTS-13 fraction predicts in-hospital mortality. The VWF/ADAMTS-13 fraction may be a helpful tool to monitor COVID-19 patients throughout hospitalization.

Use of low-molecular weight heparin, transfusion and mortality in COVID-19 patients not requiring ventilation.

It is still debated whether prophylactic doses of low-molecular- weight heparin (LMWH) are always effective in preventing Venous Thromboembolism (VTE) and mortality in COVID-19. Furthermore, there is paucity of data for those patients not requiring ventilation. We explored mortality and the safety/efficacy profile of LMWH in a cohort of Italian patients with COVID-19 who did not undergo ventilation. From the initial cohort of 422 patients, 264 were enrolled. Most (n = 156, 87.7%) received standard LMWH prophylaxis during hospitalization, with no significant difference between medical wards and Intensive Care Unit (ICU). Major or not major but clinically relevant hemorrhages were recorded in 13 (4.9%) patients: twelve in those taking prophylactic LMWH and one in a patient taking oral anticoagulants (p: n.s.). Thirty-nine patients (14.8%) with median age 75 years. were transfused. Hemoglobin (Hb) at admission was significantly lower in transfused patients and Hb at admission inversely correlated with the number of red blood cells units transfused (p < 0.001). In-hospital mortality occurred in 76 (28.8%) patients, 46 (24.3%) of whom admitted to medical wards. Furthermore, Hb levels at admittance were significantly lower in fatalities (g/dl 12.3; IQR 2.4 vs. 13.3; IQR 2.8; Mann-Whitney U-test; p = 0.001). After the exclusion of patients treated by LMWH intermediate or therapeutic doses (n = 32), the logistic regression showed that prophylaxis significantly and independently reduced mortality (OR 0.31, 95% CI 0.13-0.85). Present data show that COVID-19 patients who do not require ventilation benefit from prophylactic doses of LMWH.

Heparin in COVID-19 Patients Is Associated with Reduced In-Hospital Mortality: The Multicenter Italian CORIST Study.

INTRODUCTION: A hypercoagulable condition was described in patients with coronavirus disease 2019 (COVID-19) and proposed as a possible pathogenic mechanism contributing to disease progression and lethality. AIM: We evaluated if in-hospital administration of heparin improved survival in a large cohort of Italian COVID-19 patients. METHODS: In a retrospective observational study, 2,574 unselected patients hospitalized in 30 clinical centers in Italy from February 19, 2020 to June 5, 2020 with laboratory-confirmed severe acute respiratory syndrome coronavirus-2 infection were analyzed. The primary endpoint in a time-to event analysis was in-hospital death, comparing patients who received heparin (low-molecular-weight heparin [LMWH] or unfractionated heparin [UFH]) with patients who did not. We used multivariable Cox proportional-hazards regression models with inverse probability for treatment weighting by propensity scores. RESULTS: Out of 2,574 COVID-19 patients, 70.1% received heparin. LMWH was largely the most used formulation (99.5%). Death rates for patients receiving heparin or not were 7.4 and 14.0 per 1,000 person-days, respectively. After adjustment for propensity scores, we found a 40% lower risk of death in patients receiving heparin (hazard ratio = 0.60; 95% confidence interval: 0.49-0.74; E-value = 2.04). This association was particularly evident in patients with a higher severity of disease or strong coagulation activation. CONCLUSION: In-hospital heparin treatment was associated with a lower mortality, particularly in severely ill COVID-19 patients and in those with strong coagulation activation. The results from randomized clinical trials are eagerly awaited to provide clear-cut recommendations.

Mortality and Transfusion Requirements in COVID-19 Hospitalized Italian Patients According to Severity of the Disease.

There is paucity of data on the transfusion need and its impact on the overall mortality in patients with COVID-19. We explored mortality in hospitalized patients with COVID-19 who required transfusions. Information on clinical variables and in-hospital mortality were obtained from medical records of 422 patients admitted to medical wards or the Intensive Care Unit (ICU). In-hospital mortality occurred in 147 (34.8%) patients, 94 (63.9%) of whom were admitted to the ICU. The median fatalities age was 77 years (IQR 14). Overall, 100 patients (60 males) received transfusion during hospitalization. The overall mortality was significantly and independently associated with age, ICU admission, Chronic Kidney Disease (CKD), and the number of transfused Red Blood Cell (RBC) units. Specifically, CKD was associated with mortality in patients admitted to medical wards, whereas the number of transfused RBC units predicted mortality in those admitted to the ICU. Transfusion strongly interacted with the admission to ICU (OR: 9.9; 95% CI: 2.5-40.0). In patients with COVID-19, age is one of the strongest risk factors in predicting mortality independently of the disease's severity. CKD confers a higher risk of mortality in patients admitted to medical wards. In those admitted to the ICU, the more RBC units are transfused, the more mortality increases.

COVID-19, hemostasis disorders and risk of thrombotic complications

The spread of a new coronavirus infection worldwide since the end of 2019 has becomes a pandemic. Thrombotic complications are the leading cause of death in this disease. After entering the human body, the virus starts a cascade of reactions leading to the development of a cytokine storm, activation of all parts of the hemostasis and complement systems and other changes that result in disturbances in the circulation system with the development of multiple organ failures. Numerous studies have shown that a predictor of a severe course of COVID-19 is a sharp increase of D-dimer concentration in the blood and rise of some other markers of hemostasis activation. Based on the pathogenesis, the developed schemes for the prevention and treatment of COVID-19 severe complications include low molecular weight heparins (LMWH) which are also recommended for an outpatient COVID-19 patient. The prescription of low molecular weight heparin, the duration of their use and doses should be decided on the basis of a risk assessment of factors for each individual patient in combination with laboratory monitoring. Распространение новой коронавирусной инфекции по всему миру с конца 2019 г. превратилось в пандемию. Тромботические осложнения являются ведущей причиной смерти при этом заболевании. После попадания в организм человека вирус запускает каскад реакций, приводящих к развитию цитокинового «шторма», активации всех звеньев системы гемостаза и комплемента, другим изменениям, приводящим к нарушениям в системе кровообращения с развитием полиорганных нарушений. Многочисленные исследования показали, что предиктором тяжелого течения заболевания является резкое повышение концентрации D-димера в крови и некоторых других маркеров активации гемостаза. Исходя из патогенеза, разработанные схемы профилактики и лечения тяжелых осложнений COVID-19 включают низкомолекулярные гепарины, которые также рекомендуют для применения в амбулаторных условиях. Назначение низкомолекулярных гепаринов, длительность их применения и дозы должны определяться на основе оценки факторов риска для каждого отдельного пациента в сочетании с лабораторным мониторингом.

Managing anticoagulation in the COVID-19 era between lockdown and reopening phases.

Patients on anticoagulant treatment are constantly increasing, with an estimated prevalence in Italy of 2% of the total population. The recent spreadout of the COVID-19 pandemic requires a re-organization of Anticoagulation Clinics to prevent person-to-person viral diffusion and continue to offer the highest possible quality of assistance to patients. In this paper, based on the Italian Federation of Anticoagulation Clinics statements, we offer some advice aimed at improving patient care during COVID-19 pandemic, with particular regard to the lockdown and reopening periods. We give practical guidance regarding the following points: (1) re-thinking the AC organization, (2) managing patients on anticoagulants when they become infected by the virus, (3) managing anticoagulation surveillance in non-infected patients during the lockdown period, and (4) organizing the activities during the reopening phases.