Gene-Gene Interaction Between Factor-XI and ABO Genes in Cerebral Venous Thrombosis: The BEAST Study.

BACKGROUND AND OBJECTIVES: Gene-gene interactions likely contribute to the etiology of multifactorial diseases such as cerebral venous thrombosis (CVT) and could be one of the main sources of known missing heritability. We explored Factor XI (F11) and ABO gene interactions among patients with CVT. METHODS: Patients with CVT of European ancestry from the large Bio-Repository to Establish the Aetiology of Sinovenous Thrombosis (BEAST) international collaboration were recruited. Codominant modelling was used to determine interactions between genome-wide identified F11 and ABO genes with CVT status. RESULTS: We studied 882 patients with CVT and 1,205 ethnically matched control participants (age: 42 ± 15 vs 43 ± 12 years, p = 0.08: sex: 71% male vs 68% female, p = 0.09, respectively). Individuals heterozygous (AT) for the risk allele (T) at both loci (rs56810541/F11 and rs8176645/ABO) had a 3.9 (95% CI 2.74-5.71, p = 2.75e-13) increase in risk of CVT. Individuals homozygous (TT) for the risk allele at both loci had a 13.9 (95% CI 7.64-26.17, p = 2.0e-15) increase in risk of CVT. The presence of a non-O blood group (A, B, AB) combined with TT/rs56810541/F11 increased CVT risk by OR = 6.8 (95% CI 4.54-10.33, p = 2.00e15), compared with blood group-O combined with AA. DISCUSSION: Interactions between factor XI and ABO genes increase risk of CVT by 4- to 14-fold.

Coma in adult cerebral venous thrombosis: The BEAST study.

BACKGROUND AND PURPOSE: Coma is an independent predictor of poor clinical outcomes in cerebral venous thrombosis (CVT). We aimed to describe the association of age, sex, and radiological characteristics of adult coma patients with CVT. METHODS: We used data from the international, multicentre prospective observational BEAST (Biorepository to Establish the Aetiology of Sinovenous Thrombosis) study. Only positively associated variables with coma with <10% missing data in univariate analysis were considered for the multivariate logistic regression model. RESULTS: Of the 596 adult patients with CVT (75.7% women), 53 (8.9%) patients suffered coma. Despite being a female-predominant disease, the prevalence of coma was higher among men than women (13.1% vs. 7.5%, p = 0.04). Transverse sinus thrombosis was least likely to be associated with coma (23.9% vs. 73.3%, p < 0.001). The prevalence of superior sagittal sinus thrombosis was higher among men than women in the coma sample (73.6% vs. 37.5%, p = 0.01). Men were significantly older than women, with a median (interquartile range) age of 51 (38.5-60) versus 40 (33-47) years in the coma (p = 0.04) and 44.5 (34-58) versus 37 (29-48) years in the non-coma sample (p < 0.001), respectively. Furthermore, an age- and superior sagittal sinus-adjusted multivariate logistic regression model found male sex (odds ratio = 1.8, 95% confidence interval [CI] = 1.0-3.4, p = 0.04) to be an independent predictor of coma in CVT, with an area under the receiver operating characteristic curve of 0.61 (95% CI = 0.52-0.68, p = 0.01). CONCLUSIONS: Although CVT is a female-predominant disease, men were older and nearly twice as likely to suffer from coma than women.

Post-lumbar puncture cerebral vein thrombosis.

Lumbar puncture (LP) is rarely complicated by cerebral vein thrombosis (CVT), especially if other risk factors coexist. We describe the case of a 28-year-old woman who developed CVT after corticosteroid treatment and LP performed for suspected multiple sclerosis. The day after LP, she developed intense headache and on Day 8 generalized tonic-clonic seizures. A brain computed tomography scan showed thrombosis of the superior sagittal sinus and cortical veins. Thrombophilia screening showed heterozygous G20210A prothrombin mutation. Anticoagulant therapy with low molecular weight heparin and then warfarin was administered until Day 16 after LP, when a brain magnetic resonance imaging showed a subdural hematoma. Warfarin was interrupted and dabigatran was started. The patient recovered completely, both from the initial thrombotic event and the hemorrhagic complication. This case highlights the importance to keep in mind CVT in the differential diagnosis of post-LP headache not responsive to standard therapy, and suggests that dabigatran can be considered an effective and safe treatment of CVT.

Genetic Variants Identified by Whole Exome Sequencing in a Large Italian Family with High Plasma Levels of Factor VIII and Von Willebrand Factor.

High plasma levels of factor VIII (FVIII) and von Willebrand factor (VWF) have been indicated as independent risk factors for venous thromboembolism. However, the genetic factors responsible for their increase remain poorly known. In a large Italian family with high FVIII/VWF levels and thrombotic episodes, whole exome sequencing (WES) was performed on 12 family members to identify variants/genes involved in FVIII/VWF increase. Twenty variants spread over a 8300 Kb region on chromosome 5 were identified in 12 genes, including the low frequency rs13158382, located upstream of the MIR143/145 genes, which might affect miR-143/145 transcription or processing. The expression of miR-143/145 and VWF mRNA were evaluated in the peripheral blood mononuclear cells of six family members. Members with the variant (n = 3) showed lower levels of both miRNAs and higher levels of VWF mRNA compared to members without the variant (n = 3). An analysis of genetic and expression data from a larger cohort of individuals from the 1000 Genomes and GEUVADIS project confirmed a statistically significant reduction (p-value = 0.023) in miR-143 in heterozygous (n = 35) compared to homozygous wild-type individuals (n = 386). This family-based study identified a new genetic variant potentially involved in VWF increase by affecting miR-143/145 expression.

Age of onset of cerebral venous thrombosis: the BEAST study.

Background: Cerebral venous thrombosis (CVT) is an uncommon cause of stroke in young adults. We aimed to determine the impact of age, gender and risk factors (including sex-specific) on CVT onset. Methods: We used data from the BEAST (Biorepository to Establish the Aetiology of Sinovenous Thrombosis), a multicentre multinational prospective observational study on CVT. Composite factors analysis (CFA) was performed to determine the impact on the age of CVT onset in males and females. Results: A total of 1309 CVT patients (75.3% females) aged ⩾18 years were recruited. The overall median (IQR-interquartile range) age for males and females was 46 (35-58) years and 37 (28-47) years (p < 0.001), respectively. However, the presence of antibiotic-requiring sepsis (p = 0.03, 95% CI 27-47 years) among males and gender-specific risk factors like pregnancy (p < 0.001, 95% CI 29-34 years), puerperium (p < 0.001, 95% CI 26-34 years) and oral contraceptive use (p < 0.001, 95% CI 33-36 years) were significantly associated with earlier onset of CVT among females. CFA demonstrated a significantly earlier onset of CVT in females, ~12 years younger, in those with multiple (⩾1) compared to '0' risk factors (p < 0.001, 95% CI 32-35 years). Conclusions: Women suffer CVT 9 years earlier in comparison to men. Female patients with multiple (⩾1) risk factors suffer CVT ~12 years earlier compared to those with no identifiable risk factors.

A retrospective study on the use of low-molecular-weight heparin for prevention of pregnancy-related recurrent venous thromboembolism and obstetrical complications.

BACKGROUND: The risk of venous thromboembolism (VTE) is increased during pregnancy and it is further increased together with pregnancy complications in women with personal history of VTE and thrombophilia abnormalities. It is unclear how the use of low-molecular-weight heparin (LMWH) may prevent such complications. OBJECTIVE: To evaluate the potential benefits and risks of the use of LMWH for prevention of pregnancy-related VTE and obstetrical complications in the first pregnancy after a previous VTE. METHODS: This retrospective cohort study includes fertile women referred to the Thrombosis Center from January 2000 to September 2018 for a thrombophilia work-up, after having had at least one previous VTE and one pregnancy thereafter. Data on pregnancy-related recurrent VTE, pregnancy outcomes and the use of LMWH were collected. RESULTS: Among 208 women, no thrombosis or major bleeding was recorded in 138 pregnancies conducted with LMWH, whereas 10 VTE (14%) were recorded in 70 pregnancies conducted without. Nine women (90%) with recurrent VTE had had a previous hormone-related event. The incidence of miscarriage was lower in pregnancies with LMWH than in those without (11% vs. 26%, relative risk 0.4, 95% confidence interval: 0.2-0.8), whereas late obstetrical complications and terminations were similar in the two groups. The prevalence of terminations was doubled in women with thrombophilia (12%) than in those without (6%). CONCLUSIONS: LMWH prophylaxis during pregnancy appears to be effective and safe for the prevention of recurrent VTE and may reduce the incidence of miscarriage.

Anticoagulant Therapy in Patients with Antiphospholipid Syndrome.

Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by the persistent positivity of antiphospholipid antibodies (aPLA) together with thrombosis or obstetrical complications. Despite their recognized predominant role, aPLA are not sufficient to induce the development of thrombosis and a second hit has been proposed to be necessary. The mainstay of treatment of APS is anticoagulant therapy. However, its optimal intensity in different presentations of the disease remains undefined. Moreover, decision on which patients with aPLA would benefit from an antithrombotic prophylaxis and its optimal intensity are challenging because of the lack of stratification tools for the risk of thrombosis. Finally, decision on the optimal type of anticoagulant drug is also complex because the central pathway responsible for the development of thrombosis is so far unknown and should be carried out on an individual basis after a careful evaluation of the clinical and laboratory features of the patient. This review addresses the epidemiology, physiopathology, diagnosis and management of thrombosis and obstetrical complications in APS, with a special focus on the role of direct oral anticoagulants.

D-dimer and reduced-dose apixaban for extended treatment after unprovoked venous thromboembolism: the Apidulcis study.

D-dimer assay is used to stratify patients with unprovoked venous thromboembolism (VTE) for the risk of recurrence. However, this approach was never evaluated since direct oral anticoagulants are available. With this multicenter, prospective cohort study, we aimed to assess the value of an algorithm incorporating serial D-dimer testing and administration of reduced-dose apixaban (2.5 mg twice daily) only to patients with a positive test. A total of 732 outpatients aged 18 to 74 years, anticoagulated for ≥12 months after a first unprovoked VTE, were included. Patients underwent D-dimer testing with commercial assays and preestablished cutoffs. If the baseline D-dimer during anticoagulation was negative, anticoagulation was stopped and testing repeated after 15, 30, and 60 days. Patients with serially negative results (286 [39.1%]) were left without anticoagulation. At the first positive result, the remaining 446 patients (60.9%) were given apixaban for 18 months. All patients underwent follow-up planned for 18 months. The study was interrupted after a planned interim analysis for the high rate of primary outcomes (7.3%; 95% confidence interval [CI], 4.5-11.2), including symptomatic proximal deep vein thrombosis (DVT) or pulmonary embolism (PE) recurrence, death for VTE, and major bleeding occurring in patients off anticoagulation vs that in those receiving apixaban (1.1%; 95% CI, 0.4-2.6; adjusted hazard ratio [HR], 8.2; 95% CI, 3.2-25.3). In conclusion, in patients anticoagulated for ≥1 year after a first unprovoked VTE, the decision to further extend anticoagulation should not be based on D-dimer testing. The results confirmed the high efficacy and safety of reduced-dose apixaban against recurrences. This trial was registered at www.clinicaltrials.gov as #NCT03678506.

The usefulness of D-dimer as a predictive marker for mortality in patients with COVID-19 hospitalized during the first wave in Italy.

BACKGROUND: The coronavirus disease 2019 (COVID-19) presents an urgent threat to global health. Identification of predictors of poor outcomes will assist medical staff in treatment and allocating limited healthcare resources. AIMS: The primary aim was to study the value of D-dimer as a predictive marker for in-hospital mortality. METHODS: This was a cohort study. The study population consisted of hospitalized patients (age >18 years), who were diagnosed with COVID-19 based on real-time PCR at 9 hospitals during the first COVID-19 wave in Lombardy, Italy (Feb-May 2020). The primary endpoint was in-hospital mortality. Information was obtained from patient records. Statistical analyses were performed using a Fine-Gray competing risk survival model. Model discrimination was assessed using Harrell's C-index and model calibration was assessed using a calibration plot. RESULTS: Out of 1049 patients, 507 patients (46%) had evaluable data. Of these 507 patients, 96 died within 30 days. The cumulative incidence of in-hospital mortality within 30 days was 19% (95CI: 16%-23%), and the majority of deaths occurred within the first 10 days. A prediction model containing D-dimer as the only predictor had a C-index of 0.66 (95%CI: 0.61-0.71). Overall calibration of the model was very poor. The addition of D-dimer to a model containing age, sex and co-morbidities as predictors did not lead to any meaningful improvement in either the C-index or the calibration plot. CONCLUSION: The predictive value of D-dimer alone was moderate, and the addition of D-dimer to a simple model containing basic clinical characteristics did not lead to any improvement in model performance.

External validation of risk scores to predict in-hospital mortality in patients hospitalized due to coronavirus disease 2019.

BACKGROUND: The coronavirus disease 2019 (COVID-19) presents an urgent threat to global health. Prediction models that accurately estimate mortality risk in hospitalized patients could assist medical staff in treatment and allocating limited resources. AIMS: To externally validate two promising previously published risk scores that predict in-hospital mortality among hospitalized COVID-19 patients. METHODS: Two prospective cohorts were available; a cohort of 1028 patients admitted to one of nine hospitals in Lombardy, Italy (the Lombardy cohort) and a cohort of 432 patients admitted to a hospital in Leiden, the Netherlands (the Leiden cohort). The endpoint was in-hospital mortality. All patients were adult and tested COVID-19 PCR-positive. Model discrimination and calibration were assessed. RESULTS: The C-statistic of the 4C mortality score was good in the Lombardy cohort (0.85, 95CI: 0.82-0.89) and in the Leiden cohort (0.87, 95CI: 0.80-0.94). Model calibration was acceptable in the Lombardy cohort but poor in the Leiden cohort due to the model systematically overpredicting the mortality risk for all patients. The C-statistic of the CURB-65 score was good in the Lombardy cohort (0.80, 95CI: 0.75-0.85) and in the Leiden cohort (0.82, 95CI: 0.76-0.88). The mortality rate in the CURB-65 development cohort was much lower than the mortality rate in the Lombardy cohort. A similar but less pronounced trend was found for patients in the Leiden cohort. CONCLUSION: Although performances did not differ greatly, the 4C mortality score showed the best performance. However, because of quickly changing circumstances, model recalibration may be necessary before using the 4C mortality score.

Rivaroxaban for the treatment of noncirrhotic splanchnic vein thrombosis: an interventional prospective cohort study.

Heparins and vitamin K antagonists are the mainstay of treatment of splanchnic vein thrombosis (SVT). Rivaroxaban is a potential alternative, but data to support its use are limited. We aimed to evaluate the safety and efficacy of rivaroxaban for the treatment of acute SVT. In an international, single-arm clinical trial, adult patients with a first episode of noncirrhotic, symptomatic, objectively diagnosed SVT received rivaroxaban 15 mg twice daily for 3 weeks, followed by 20 mg daily for an intended duration of 3 months. Patients with Budd-Chiari syndrome and those receiving full-dose anticoagulation for >7 days prior to enrollment were excluded. Primary outcome was major bleeding; secondary outcomes included death, recurrent SVT, and complete vein recanalization within 3 months. Patients were followed for a total of 6 months. A total of 103 patients were enrolled; 100 were eligible for the analysis. Mean age was 54.4 years; 64% were men. SVT risk factors included abdominal inflammation/infection (28%), solid cancer (9%), myeloproliferative neoplasms (9%), and hormonal therapy (9%); 43% of cases were unprovoked. JAK2 V617F mutation was detected in 26% of 50 tested patients. At 3 months, 2 patients (2.1%; 95% confidence interval, 0.6-7.2) had major bleeding events (both gastrointestinal). One (1.0%) patient died due to a non-SVT-related cause, 2 had recurrent SVT (2.1%). Complete recanalization was documented in 47.3% of patients. One additional major bleeding event and 1 recurrent SVT occurred at 6 months. Rivaroxaban appears as a potential alternative to standard anticoagulation for the treatment of SVT in non-cirrhotic patients. This trial was registered at www.clinicaltrials.gov as #NCT02627053 and at eudract.ema.europa.eu as #2014-005162-29-36.

European stroke organization interim expert opinion on cerebral venous thrombosis occurring after SARS-CoV-2 vaccination.

Severe cases of cerebral venous thrombosis (CVT) with thrombocytopenia and anti-platelet factor 4 (PF4) antibodies occurring after adenoviral vector anti-SARS-CoV-2 vaccines have been recently reported. We aim to present a guidance document on the diagnosis and treatment of patients presenting with CVT after vaccination against SARS-CoV-2 infection. We reviewed the available evidence which consists on case reports, small case series, expert opinion and analogy with heparin-induced thrombocytopenia (HIT) management. Because of the low level of evidence, this is an interim document, based only on expert opinion consensus. In patients presenting with CVT after being vaccinated against SARS-CoV-2 infection, if there is thrombocytopenia a reliable HIT PF4 Antibody ELISA test should be performed, to confirm vaccine-induced immune thrombotic thrombocytopenia (VITT). In patients with CVT and thrombocytopenia, in whom VITT is suspected or confirmed, heparin (unfractionated or low molecular weight) should be avoided and non-heparin anticoagulants are preferred. If possible, platelet transfusions should be avoided. If the diagnosis of VITT is confirmed or suspected, early intravenous immunoglobulins are indicated. This expert opinion is supported by low quality evidence. It should be periodically updated, or changed to a formal guideline, as new and higher quality evidence is eventually produced. Because of their potential unfavourable clinical course, patients developing symptoms and signs suggestive of CVT after being vaccinated against SARS-CoV-2 virus should undergo urgent clinical and neuroimaging evaluation. In cases of suspected or confirmed VITT, non-heparin anticoagulants should be used, platelet transfusions avoided and intravenous immunoglobulin started early.

Role of ADAMTS13, VWF and F8 genes in deep vein thrombosis.

BACKGROUND: We previously described the association between rare ADAMTS13 single nucleotide variants (SNVs) and deep vein thrombosis (DVT). Moreover, DVT patients with at least one rare ADAMTS13 SNV had a lower ADAMTS13 activity than non-carriers. AIMS: To confirm ADAMTS13 variants association with DVT and reduced plasma ADAMTS13 activity levels in a larger population. To investigate the role of VWF and F8 variants. METHODS: ADAMTS13, VWF and F8 were sequenced using next-generation sequencing in 594 Italian DVT patients and 571 controls. Genetic association testing was performed using logistic regression and gene-based tests. The association between rare ADAMTS13 variants and the respective plasmatic activity, available for 365 cases and 292 controls, was determined using linear regression. All analyses were age-, sex- adjusted. RESULTS: We identified 48 low-frequency/common and 272 rare variants. Nine low-frequency/common variants had a P<0.05, but a false discovery rate between 0.06 and 0.24. Of them, 7 were found in ADAMTS13 (rs28641026, rs28503257, rs685523, rs3124768, rs3118667, rs739469, rs3124767; all protective) and 2 in VWF (rs1800382 [risk], rs7962217 [protective]). Rare ADAMTS13 variants were significantly associated with DVT using the burden, variable threshold (VT) and UNIQ (P<0.05), but not with C-ALPHA, SKAT and SKAT-O tests. Rare VWF and F8 variants were not associated with DVT. Carriers of rare ADAMTS13 variants had lower ADAMTS13 activity than non-carriers (ß -6.2, 95%CI -11,-1.5). This association was stronger for DVT patients than controls (ß -7.5, 95%CI -13.5,-1.5 vs. ß -2.9, 95%CI -10.4,4.5). CONCLUSIONS: ADAMTS13 and VWF low-frequency/common variants mainly showed a protective effect, although their association with DVT was not confirmed. DVT patients carrying a rare ADAMTS13 variants had slightly reduced ADAMTS13 activity levels, but a higher DVT risk. Rare VWF and FVIII variants were not associated with DVT suggesting that other mechanisms are responsible for the high VWF and FVIII levels measured in DVT patients.

Off-Label Use of Thrombopoietin Receptor Agonists: Case Series and Review of the Literature.

Since their license in 2008, studies on thrombopoietin receptor agonists (TPO-RAs) are proceeding at a fast pace. Their favorable efficacy and safety profile makes them good candidates for the management of thrombocytopenia in different settings, even beyond their current indications. In the last 10 years, we faced patients with refractory thrombocytopenia that required treatment with off-label TPO-RA, despite the paucity of data in the literature and the possible risks, particularly that of thrombosis. We hereby report our 10-year real-life single-center experience of TPO-RA used off-label. Fourteen patients were divided into three groups according to the etiology of thrombocytopenia: myelodysplastic syndromes, post-transplantation, and lymphoproliferative diseases. Clinical features and results are reported within each group. Overall, TPO-RA proved effective in all these conditions achieving responses also in heavily pretreated patients. The overall response rate (ORR) was 100% in patients with thrombocytopenia after transplantation and in those with lymphoproliferative diseases and 75% in patients with myelodysplastic syndromes. The median duration of therapy was 285 days (range 93-1,513 days). Four patients (29%) discontinued treatment because of lack of response (n=2) or a sustained response (n=2). No grade 3-4 adverse events occurred, particularly no thrombosis. In our real-life experience, TPO-RAs were effective and safe and proved of value in the challenging management of patients with refractory thrombocytopenia associated with different conditions.

Genome-Wide Association Study Identifies First Locus Associated with Susceptibility to Cerebral Venous Thrombosis.

OBJECTIVE: Cerebral venous thrombosis (CVT) is an uncommon form of stroke affecting mostly young individuals. Although genetic factors are thought to play a role in this cerebrovascular condition, its genetic etiology is not well understood. METHODS: A genome-wide association study was performed to identify genetic variants influencing susceptibility to CVT. A 2-stage genome-wide study was undertaken in 882 Europeans diagnosed with CVT and 1,205 ethnicity-matched control subjects divided into discovery and independent replication datasets. RESULTS: In the overall case-control cohort, we identified highly significant associations with 37 single nucleotide polymorphisms (SNPs) within the 9q34.2 region. The strongest association was with rs8176645 (combined p = 9.15 × 10-24 ; odds ratio [OR] = 2.01, 95% confidence interval [CI] = 1.76-2.31). The discovery set findings were validated across an independent European cohort. Genetic risk score for this 9q34.2 region increases CVT risk by a pooled estimate OR = 2.65 (95% CI = 2.21-3.20, p = 2.00 × 10-16 ). SNPs within this region were in strong linkage disequilibrium (LD) with coding regions of the ABO gene. The ABO blood group was determined using allele combination of SNPs rs8176746 and rs8176645. Blood groups A, B, or AB, were at 2.85 times (95% CI = 2.32-3.52, p = 2.00 × 10-16 ) increased risk of CVT compared with individuals with blood group O. INTERPRETATION: We present the first chromosomal region to robustly associate with a genetic susceptibility to CVT. This region more than doubles the likelihood of CVT, a risk greater than any previously identified thrombophilia genetic risk marker. That the identified variant is in strong LD with the coding region of the ABO gene with differences in blood group prevalence provides important new insights into the pathophysiology of CVT. ANN NEUROL 2021;90:777-788.

Comparison of adverse drug reactions among four COVID-19 vaccines in Europe using the EudraVigilance database: Thrombosis at unusual sites.

BACKGROUND: Real-world experience with adenoviral vector vaccines against COVID-19 raised some safety concerns. Cases of cerebral vein thrombosis (CVT) associated with thrombocytopenia have been observed after the first dose of the adenoviral vector vaccines CHADOX1 NCOV-19 and AD26.COV2.S. OBJECTIVES: To assess the reporting rate of CVT as adverse drug reaction (ADR) for the COVID-19 vaccines authorized in Europe. PATIENTS AND METHODS: This observational study assessed the CVT reporting rate attributed to four COVID-19 vaccines authorized in Europe, namely Tozinameran (Pfizer-Biontech), CX-024414 (Moderna), CHADOX1 NCOV-19 (AstraZeneca), and AD26.COV2.S (Janssen). Data on thrombotic ADRs reported on EudraVigilance database between January 1, 2021 and July 30, 2021, were collected. ADRs referring to CVT were identified. The reporting rate of CVT was expressed as 1 million individual vaccinated-days with 95% confidence interval. Finally, an observed-to-expected (OE) analysis was performed. RESULTS: The reporting rate of CVT per 1 million person vaccinated-days was 1.92 (95% confidence interval [CI], 1.71-2.12) for Tozinameran, 5.63 (95% CI, 4.74-6.64) for CX-024414, 21.60 (95% CI, 20.16-23.11) for CHADOX1 NCOV-19, and 11.48 (95% CI, 9.57-13.67) for AD26.COV2.S. CVT occurred alongside thrombocytopenia for the four vaccines. The OE ratio was greater than one for all four vaccines, both with the lowest and the highest CVT background incidence. CONCLUSIONS: This report on EudraVigilance data strengthens anecdotal findings on CVT following COVID-19 vaccinations. Although the European Medicines Agency released an alert only for CHADOX1 NCOV-19 and AD26.COV2.S, Tozinameran and CX-024414 also are complicated by CVT, albeit to lesser extent.

Findings from a multicentre, observational study on reproductive outcomes in women with unexplained recurrent pregnancy loss: the OTTILIA registry.

STUDY QUESTION: What evaluation and care is offered to women after unexplained recurrent pregnancy loss (RPL) or intra-uterine foetal death (IUFD) and what are the reproductive outcomes? SUMMARY ANSWER: Women are assessed for thrombophilia and often treated with low-molecular weight heparin (LMWH) and/or low-dose aspirin (ASA). WHAT IS KNOWN ALREADY: Randomized controlled trials (RCTs) on possible efficacy of heparins and/or aspirin have been inconclusive due to limited power to detect a difference and patient heterogeneity. STUDY DESIGN, SIZE, DURATION: Prospective multicentre cohort study performed in 12 hospitals in three countries between 2012 and 2019. PARTICIPANTS/MATERIALS, SETTING, METHODS: All consecutive pregnant women with recurrent PL (≥3 losses or 2 losses in the presence of at least one euploid foetal karyotype) or at least one IUFD. Eligible women may have undergone thrombophilia testing before conception, at the discretion of local providers. The possible assignment of women to treatments (such as LMWH) was not decided a priori but was determined based on the responsible provider's current practice. Aims of the study were: (i) to evaluate factors associated with pregnancy outcome; (ii) to compare clinical management strategies in women with and without a subsequent successful pregnancy; and (iii) to evaluate characteristics of women who may benefit from antithrombotic therapy. A propensity score matching method was used to balance the differences in baseline characteristics. MAIN RESULTS AND THE ROLE OF CHANCE: A matched sample of 265 pregnant women was analysed, with all undergoing thrombophilia screening; 103 out of 119 (86.6%) with and 98/146 (67.1%) without thrombophilia were prescribed with LMWH and/or ASA. Overall, live-births were recorded in 204 cases (77%), PL or IUFD in 61 (23%) pregnancies. Logistic regression showed a significant interaction between thrombophilia and treatment with LMWH (P = 0.03). Findings from sensitivity analysis showed odds ratio (OR) for pregnancy loss in women with inherited or acquired thrombophilia in absence of any treatment was 2.9 (95% CI, 1.4-6.1); the administration of LMWH (with or without ASA) was associated with higher odds of live-birth (OR, 10.6; 95% CI, 5.0-22.3). Furthermore, in women without thrombophilia, the odds of live-birth was significantly and independently associated with LMWH prophylaxis (alone or in association with ASA) (OR, 3.6; 95% CI, 1.7-7.9). LIMITATIONS, REASONS FOR CAUTION: While the propensity score matching allows us to balance the differences in baseline characteristics, it does not eliminate all confounding. WIDER IMPLICATIONS OF THE FINDINGS: Antithrombotic prophylaxis during pregnancy may be effective in women with otherwise unexplained PL or IUFD, and even more useful in those with thrombophilia. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by Italian Ministry of Health (Ricerca Corrente 2018-2020). Dr G.P. has received research grant support from Bristol Myers Squibb/Pfizer Alliance, Janssen, Boston Scientific Corporation, Bayer, and Portola and consultant fees from Amgen and Agile Therapeutics. Dr E.G. has received consultant fees from Italfarmaco and Sanofi. All other authors declare that they have no conflict of interest. TRIAL REGISTRATION NUMBER: NCT02385461.