Thrombophilia Screening Research Articles

Markers of Hereditary Thrombophilia with Unclear Significance.

Thrombophilia leads to an increased risk of venous thromboembolism. Widely accepted risk factors for thrombophilia comprise deficiencies of protein C, protein S, and antithrombin, as well as the factor V "Leiden" mutation, the prothrombin G20210A mutation, dysfibrinogenemia, and, albeit less conclusive, increased levels of factor VIII. Besides these established markers of thrombophilia, risk factors of unclear significance have been described in the literature. These inherited risk factors include deficiencies or loss-of-activity of the activity of ADAMTS13, heparin cofactor II, plasminogen, tissue factor pathway inhibitor (TFPI), thrombomodulin, protein Z (PZ), as well as PZ-dependent protease inhibitor. On the other hand, thrombophilia has been linked to the gain-of-activity, or elevated levels, of α2-antiplasmin, angiotensin-converting enzyme, coagulation factors IX (FIX) and XI (FXI), fibrinogen, homocysteine, lipoprotein(a), plasminogen activator inhibitor-1 (PAI-1), and thrombin-activatable fibrinolysis inhibitor (TAFI). With respect to the molecular interactions that may influence the thrombotic risk, more complex mechanisms have been described for endothelial protein C receptor (EPCR) and factor XIII (FXIII) Val34Leu. With focus on the risk for venous thrombosis, the present review aims to give an overview on the current knowledge on the significance of the aforementioned markers for thrombophilia screening. According to the current knowledge, there appears to be weak evidence for a potential impact of EPCR, FIX, FXI, FXIII Val34Leu, fibrinogen, homocysteine, PAI-1, PZ, TAFI, and TFPI on the thrombotic risk.

SARS-COV-2 infection in patients with hereditary thrombophilia: Is there a worsening in COVID-19 symptoms?

Patients with COVID-19 who progressed to a more advanced stage of the disease were observed to develop coagulation disorders. Mutations in genes encoding clotting factors, such as Prothrombin Factor II, Leiden Factor V and MTHFR are associated with the development of thromboembolism. The aim of this study was to determine the prevalence of genetic variants present in these genes in patients with COVID-19, and to associate their presence with disease severity and D-dimer values. 405 patients with different manifestations of COVID-19 were genotyped by qPCR; genotypes were associated with disease severity and D-dimer values. A slightly prevalence of the FVL mutated allele in the group with positive diagnosis was found; also, higher levels of D-dimer in patients who required treatment in intensive care were observed. Individuals with hereditary thrombophilia are at greater risk of developing a thrombolytic event after infection (long-term COVID). Our data show the benefits of performing genetic screening for hereditary thrombophilia in individuals infected with SARS-Cov-2 in order to establish, together with classical laboratory parameters, a risk factor for the development of thrombosis both during the infectious process and for post-COVID and thus avoid a vascular event.

Thrombophilia in children with venous thrombosis

Introduction. Venous thrombosis is a rare condition in children, but now there is a significant increase in cases among hospitalized children. Thrombosis in children is a multifactorial disorder, there are various risk factors, both inherited and acquired, such as a central venous catheter.The aim of the study is to evaluate the incidence of thrombophilia among patients aged 0 to 18 years after a history of deep vein thrombosis (DVT).Materials and methods. We have retrospectively analyzed the medical records of young patients (0–18 years) of from 2017 to 2021 of the Outpatient Consultative Unit of Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology and selected patients with objectively confirmed DVT, who were examined to exclude thrombophilia. Patients who did not have a full range of laboratory tests were not accounted for in the study. The patients who had DVT during infancy had additional tests at the age older than one year.All patients were divided into 2 groups: with and without thrombophilia. Chi-square test was used to assess the statistical significance of differences between groups.Results. We found 149 children with DVT: 103 patients were completely investigated for thrombophilia and a follow-up investigation is required for another 46 patients. Among 103 patients we didn’t confirm any prothrombotic condition in 54 of them, and thrombophilia was present in 49 patients. The prevalence of thrombophilia was estimated among children with DVT (n = 103): protein C deficiency – 3 %, antithrombin III deficiency – 4 %, protein S deficiency – 4 %, antiphospholipid syndrome – 1 %, mutation FV Leiden (hetero) – 7 %, FII G20210A (hetero) – 8 %, combined – 8 %, others – 13 % (increased concentration of fVIII, increased concentration of lipoprotein (a), high level of homocysteine).While comparing groups of patients with and without thrombophilia by age and sex, and by various clinical characteristics (localization of thrombus, underline clinical condition and some others) no statistically significant differences were revealed.Conclusion. Thrombophilias contribute to the occurrence of thrombosis in children. Results of thrombophilia screening rarely influence acute treatment decisions, so it is important to understand the limitations of this approach. Nevertheless, in some cases it is important to try to identify children with a tendency to develop thrombosis, since these patients may be candidates for prophylactic anticoagulation in situations of high risk of developing venous thromboembolism.

Clinical significance of hemostasiological screening for thrombophilia in pregnant women with former thrombosis

Introduction . Pregnancy management in post-thrombotic women is challenging, because women with previous episode of venous thromboembolic complications (VTEC) have a 3–4 times higher risk of its exacerbation during than outside of subsequent pregnancies. Aim : to improve effective prenatal counseling program for women with former venous thrombosis and ischemic stroke to prevent recurrence of arterial and venous complications as well as pregnancy outcomes for mother and fetus. Materials and Methods . A single-center observational study was conducted involving 50 patients with arterial and venous thrombosis and pregnancy complications in anamnesis and 40 patients with a physiological course of pregnancy. To improve existing methods of thrombosis prevention, risk factors such as gene polymorphisms for plasminogen activator inhibitor-1 (PAI-1), coagulation factor II (prothrombin; F2: Thr165Met), coagulation factor I (fibrinogen; FGB I/D) were investigated as potential new candidates of thrombosis risk markers in pregnant women and puerperas. Results . In 24 (48 %) of 50 women with former arterial and venous thrombosis and pregnancy complications, were found to develop thromboembolic complications during pregnancy. Risk assessment performed according to the existing thrombosis risk scales, revealed that only 7 (29.2 %) patients were considered as candidates for thromboprophylaxis and received anticoagulant therapy. The remaining 17 women who subsequently developed thrombosis received no anticoagulant therapy. Unfortunately, most women were not tested for thrombophilia despite a history of pregnancy complications (fetal loss, preeclampsia, fetal growth retardation). The hereditary thrombophilia of high thrombogenic risk occurred in 5 (20.8 %) of 24 women with thrombosis during pregnancy (3 – homozygous forms of factor V Leiden mutation, 1 – reduced protein C and 1 – deficiency of protein S and antithrombin). Circulation of various types of antiphospholipid antibodies was found in 13 (54.2 %) of 24 women. Homozygous polymorphisms of the PAI-1 4G/4G (45.8 %) and prothrombin F2 Thr165Met (20.8 %) genes were significantly more common in women with former thrombosis and obstetric complications compared with the control group (p < 0.001 and p = 0.023, respectively; odds ratio = 6.744; 95 % confidence interval = 1.195–38.056). Conclusion . In all cases examined, 24 women with thrombosis during pregnancy revealed to suffer from hereditary or acquired thrombophilia of high thrombogenic risk. After exclusion of high-risk thrombophilia, a number of gene polymorphisms exist that may be new candidates as a risk factor for thrombosis in pregnant women. More than 50 % of thrombosis cases in our study were associated with the homozygous genotype PAI-1 4G/4G (p < 0.001) and F2 Thr165Met (p < 0.001).

Combined oral contraceptives and the risk of venous thromboembolism carriers of antithrombin, protein C or S deficiency: Sub-analysis of a prospective cohort study

Antithrombin, protein C and S defects are well-recognized inherited risk factors for venous thromboembolism (VTE). Although these defects have been reported to increase the risk of VTE in fertile women under combined oral contraceptives (COCs), the magnitude of this association is uncertain. In a sub-analysis of a prospective cohort study, we evaluated the incidence of VTE occurring during treatment with COCs in fertile women who were family members of a proband with an objectively diagnosed VTE event and a documented defect of antithrombin, protein C or S. Of the 197 women of child-bearing age from 88 families who qualified for this analysis in a 17-year period, 112 (57%) were carriers of an inherited defect (23 antithrombin, 41 protein C and 48 protein S), whereas the remaining 85 were free from these abnormalities. Estrogen-progestin therapy was used by 19 of the 112 (17%) carriers of inherited thrombophilia for an overall period of 276 months, and by 17 of the 85 (20%) non-carriers for an overall period of 992 months. VTE events developed in 12 of the 19 (63%) carriers, leading to a monthly event rate of 4.3% (95% CI: 2.2 to 7.6), and in 2 of the 17 (12%) non-carriers, leading to a monthly rate of 0.2% (95% CI: 0.02 to 0.7), for a relative risk of 21 (95% CI, 4.7 to 92). Among family members of probands with inherited defects of antithrombin, protein C or S defects, the use of estrogen-progestin therapy in carriers of these abnormalities results in a risk of VTE events that is more than 20 times as high as that expected in non-carriers. Accordingly, the systematic screening for thrombophilia in these families has the potential to identify those subjects in whom this kind of hormonal treatment should be strongly discouraged.

The association of thrombophilia in women with severe obstetric complications.

Thrombophilia, where multiple genetic and acquired risk factors interact synergistically, are associated with thrombosis and pregnancy-related complications. Despite being studied profusely, an inconsistent association exists between thrombophilia and pregnancy complications. Between 2018 and 2020, ninety-three women with pregnancy complications were enrolled in the study. Twenty-five healthy pregnant women without pregnancy complications reported to the same hospital were also recruited as controls. Blood samples were tested for homocysteine, coagulation studies, and molecular diagnosis included FVL, PTH and MTHFR genes amplified using PCR strip assay (Vienna Lab Diagnostics, Austria). Other thrombophilia screening, including testing for AT, PC, and LA, were done by chromogenic assays (Dade Diagnostica, Munich, Germany). Homocysteine level was determined by fluorescence polarization immunoassay technology (Axsym, Abbot company, Germany). Overall, 29.03% of women with pregnancy complications had thrombophilia relative to 16% in the control group. However, the difference between the case and control groups did not reach a significant level (p=0.1175). Additionally, combined thrombophilia was more prevalent among cases (10.75%) than in the control group (4%). However, the difference did not reach statistical significance (p=0.1046). Our study demonstrated that the frequency of thrombophilia among healthy women was 16%, and among women with pregnancy-related complications, 29%. Relative to control, all measured thrombophilia markers were more frequent in women with pregnancy-related complications except for LA. Including all the studies on the Saudi population in a meta-analysis study could reveal more information about thrombophilia and pregnancy-related complications in our population.

Actividades preventivas en la mujer. Actualización PAPPS 2022

In the 2022 PAPPS update we present those specific preventive activities for women's health, except those related to cancer prevention (which are included in another document) and those aspects related to differential gender morbidity, a cross-cutting aspect for all working groups.Contraception is an essential preventive activity, considering basic the right to decide both the number of children and the time to have them. We must inform about the possible contraceptive methods, guaranteeing the monitoring of their safety, efficacy and effectiveness (tables are included on changing from one method to another to preserve contraceptive protection). We must inform about emergency contraception and propose it in the event of unprotected intercourse. All this will be done through opportunistic screening without requiring screening for thrombophilia or dyslipidemia, but for arterial hypertension.Pregnancy is an important life experience and the family doctor should not remain oblivious. We must be competent both in the preconception consultation (recommending the intake of folic acid, avoiding exposure to occupational and environmental risks, screening for certain pathologies and assessing the intake of drugs not indicated during pregnancy) and in the monitoring of pregnancy. Whether or not we monitor the pregnancy, we must not disregard its control, taking advantage of this period to promote healthy lifestyles and participating in the intercurrent processes that may occur.Menopause in general and osteoporosis in particular exemplify the strategy of medicalization of vital processes that has been followed from different instances and organizations. In our update we address the prevention and treatment of symptoms secondary to estrogen deprivation. We also propose the prevention of osteoporosis, including carrying out densitometry based on the risk of fracture in the next 10 years, and therefore densitometric screening is not recommended in women under 60 years of age. In risk assessment we recommend the use of the frax tool or better, the calibration of the risk of hip fracture with prevalence data from our setting. We linked the indication for treatment with the Z-Score (bone mineral density compared with women of the same age), as it is a condition associated with aging.

S1277 The Selection of Donors in Living Donors of Liver Transplantation Based on Results of Thrombophilia Screening Tests and Prophylactic Strategy for Venous Thromboembolic Events (VTE)

Introduction: Vascular events after living donor liver transplantation (LDLT) are one of the most feared complications that usually lead to graft and donor loss. The main aim of this study was to determine the frequency of hereditary thrombophilia in the Pakistani population and share our centers’ safety and venous thromboembolic events (VTE) prophylaxis protocols in the borderline and high-risk groups in live liver donors. Methods: This prospective, observational study included thrombophilia testing, which was done on 567 living donor candidates between July 2018 and April 2021. Donors were divided into the normal, border-line, and high-risk groups according to the Caprini scoring system. Usual prophylaxis with enoxaparin along with elastic stockings and intermittent pneumatic compression (IPC) was given postoperatively to donors in the borderline and high-risk groups. The safety endpoints were VTE occurrence, bleeding complications, or mortality. Results: Among 567 donors, 21 (3.7%) donors were deficient in protein C, 14(2.5%) were deficient in anti-thrombin-III and 45(7.9%) were having Leiden factor-V mutation. 31/416 (7.45%) were deficient in factor-II. IgM & IgG Anti-phospholipids antibodies were positive in 2/567(0.4%) and 2/567(0.4%) respectively. Donor operation was performed on 44 candidates in the borderline group and 7 in the high-risk group. Complications after surgery were comparable between the 2 groups (p >0.05). One donor in the normal donor group developed pulmonary embolism, but none of the donors in either borderline or high-risk group developed VTE. (Table) Conclusion: Early hepatic artery thrombosis (eHAT), deep venous thrombosis, and pulmonary embolism are one of the most common vascular events after liver transplantation.The majority of LDLT centers exclude donors from high-risk groups (according to the Caprini scoring system) and are used to give low molecular weight heparin in borderline donor groups. But we are the only LDLT center where not only did we perform right lobe hepatectomy on high-risk donor group on thrombophilia screening tests, but we also gave usual prophylaxis with enoxaparin (rather than low molecular weight heparin) along with elastic stockings, and intermittent pneumatic compression (IPC) postoperatively to donors in the borderline and high-risk groups (Fifty-one donors ) to decrease the risk of VTE. Table 1. - Comparison of demographics, surgical features, and postoperative complications of LLDs in donor groups Variables Normal Group (n=516) Borderline Group (n=44) High-Risk Group (n=7) P-value Mean age (Years) 23.43 ± 5.53 23.91± 5.25 26.86 ± 6.54 0.17 Mean BMI (Kg/m2) 21.40 ± 7.99 20.5 ± 2.71 21.53 ± 3.29 0.69 GenderMaleFemale 290(56.2%)226(43.7%) 24(54.5%)20(45.4%) 4(57.1%)3(42.8%) 0.97 Marital statusUnmarriedMarried 351(68.1%)165 (31.9%) 25(56.9%)19 (43.1%) 5(71.4%)2(28.5%) 0.06 Donor's relation to recipientsSonBrotherNephewDaughterSisterFatherSwapOthersType of Graft Modified right lobe graftModified extended right lobe graftLeft lobe graftLeft lateral segment graftGRWRMean warm ischemia time (minutes)Mean operation time (hours)Mean blood loss (ml)Blood transfusions (no of patients/ %) 63 (12.2%)99 (19.1%)25 (4.8%)35 (6.7%)32 (6.2%)88 (17.1%)10 (1.9%)157(30.4%)437 (84.6%)62 (12.0%)4 (0.7%)11 (2.1%)6(1.1%)1.26 ± 0.6310.99 ± 6.09407.94 ± 64.86516 6 (13.6%)5 (11.3%)5(11.3%)5 (11.3%)5 (11.3%)3 (6.8%)011 (25.0%)36 (81.8%)8 (18.1%)7 (15.9%)001.4 ± 0.6810.68 ± 4.08412.27 ± 89.1144 1(14.2%)2(28.5%)1(14.2%)00003(42.8%)6(85.7%)1(14.2%)001.2 ± 0.6313.86 ± 7.26422.86 ± 62.377 0.008NSNSNS0.76 Personal History of Thrombosis 0 0 0 _ Total number of complications 62 (12.0%) 15 (34.1%) 2(28.5%) 0.43 Grade 1 & 2 Wound infections Wound hematoma UTI Fever Paralytic ileus 20 (3.8%)2 (0.3%)4 (0.7%)3 (0.5%)2 (0.3%) 3 (6.8%)1 (2.2%)2 (4.5%)2 (4.5%)1 (2.2%) 2(28.5%)0000 0.12 Grade 3A Bile leakage Bile duct stricture Post-op bleeding Pleural effusion/Aspiration ERCP & Stenting 6 (1.1%)3(0.5%)3 (0.5%)9 (1.7%)3 (0.5%) 1 (2.2%)01 (2.2%)1 (2.2%)1 (2.2%) 00000 0.15 Grade 3B Re-open 6(1.1%) 1 (2.2%) 0 0.45 Grade 4A Need ICU care/ ventilatorGrade 4B Multi-organ failure 1 (0.1%)0 1 (2.2%)0 00 0.95-- Grade 5 0 0 0 -- Mean ICU stay (Days) 3 ± 1 2.53 ± 1 3 ± 1 0.15 Mean hospital stay (Days) 6 ± 2 5 ± 2 6 ± 2 0.17 Mortality 0 0 0 -- Abbreviations: BMI: body mass index; GRWR= graft to recipient weight ratio; ICU: Intensive care unit; UTI: Urinary tract infection.

Protein S Deficiency with Recurrent Deep Vein Thrombosis and Post Thrombotic Syndrome: A Case Report

deep vein thrombosis; protein S deficiency; rivaroxaban.

Transcatheter Patent Foramen Ovale Closure in Stroke Patients with Thrombophilia: Current Status and Future Perspectives.

Transcatheter patent foramen ovale (PFO) closure is a safe and effective treatment for secondary prevention after a PFO-associated stroke as demonstrated in multiple large randomized clinical trials. However, these trials excluded a significant proportion of patients who could have benefited from percutaneous PFO closure due to coexisting potential confounders such as additional thromboembolic risk factors, namely thrombophilia. Since scarce and conflicting data existed on such patients, current clinical management guidelines on patients with PFO mainly recommended against PFO closure in patients with thrombophilia and failed to provide any recommendation on the type and duration of antithrombotic treatment after transcatheter PFO closure. In the past 2 years, there has been new evidence supporting transcatheter PFO closure as a clinically meaningful alternative (vs. medical treatment) in this high-risk group of patients, along with additional data supporting the important role of systematic screening for thrombophilia in PFO-associated cerebrovascular events. This review article provides an updated overview of the incidence, clinical characteristics and outcomes of PFO closure in patients with thrombophilia, also commenting on the most appropriate medical treatment after PFO closure and future perspectives in the field.

P24 A case of limited cutaneous systemic sclerosis evolving into an overlap syndrome with systemic lupus erythematosus and pyoderma gangrenosum

P24 A case of limited cutaneous systemic sclerosis evolving into an overlap syndrome with systemic lupus erythematosus and pyoderma gangrenosum

Pulmonary Embolism at High Altitude: Analysis of Risk Factors

Objective: To analyze the risk factors for pulmonary embolism stationed at high altitudes with high altitude as one of the determinants.
 Study Design: Retrospective longitudinal study.
 Place and Duration of Study: Combined Military Hospital Skardu Pakistan, from Jan 2016 to Jan 2020.
 Methodology: A total of 25 consecutive cases with pulmonary embolism reported to this hospital during the study period were enrolled. Medical records of all patients were retrospectively analyzed to determine the risk factors. In addition, patient demographic data, clinical features, and laboratory and radiological findings were recorded.
 Results: Mean age of the patient was 30.68±5.37 years with a range from 23 to 40 years, the mean height of deployment was 17223.00±3577.00 feet, while the mean duration of stay was 53.92±44.76 days. Dyspnoea (84%) was the commonest clinical presentation followed by palpitation, chest pain, headache and haemoptysis. Most patients (88%) were non-smokers, while no patient had known significant risk factors. Thrombophilia and vascultitic screening were negative for all patients. In the absence of any significant hereditary or acquired risk factor, high altitude remains the only thrombogenic risk factor patients deployed at heights.
 Conclusion: Stay at a high altitude is a major risk factor for pulmonary embolism in young patients without any other known risk factor.

Activated protein C resistance impact on Syrian candidates for in vitro fertilisation and the benefit of anticoagulation therapy: a retrospective cohort study

Activated protein C resistance (APCR) is a common thrombophilia, caused mainly by a mutation. The impact of APCR on the efficacy of In Vitro Fertilization (IVF) are still unclear, and no solid recommendations for its management were published. To investigate the effect of APCR on IVF outcomes and assess the efficacy of our management protocol, we retrospectively scanned the medical records of women who were tested with APCR assay in 2019 at our fertility centre. The 66 women (12%) positive for APCR had lower odds of reaching clinical pregnancies after IVF 0.18 [95% CI: 0.07–0.47] and fewer live births. The administration of low-molecular-weight heparin and aspirin associated with more implantation in treated compared to untreated APCR-positive women with an odds ratio of 43.2 [7.51–248.6]. In conclusion, APCR negatively affects the number of clinical pregnancies after IVF, but anticoagulation therapy can mitigate this effect and significantly increase clinical pregnancies. Impact Statement What is already known on this subject? The evidence about the impact of APCR on IVF outcomes is still inconclusive. According to the Canadian guideline, routine screening for thrombophilia in patients with recurrent pregnancy loss is not recommended. No clear recommendations regarding the management of APCR in the planning for IVF are yet available. What do the results of this study add? APCR significantly increases implantation failure among infertile women who conduct IVF. Management of APCR using LMWH and aspirin was effective in mitigating this effect and increasing successful implantation. What are the implications of these findings for clinical practice and/or further research? Our findings can support the recommendation to include APCR assay in the routine tests for infertile women conducting IVF, and suggest the combination between LMWH and aspirin as an effective therapy to increase successful implantation in APCR positive candidates. However, more controlled clinical trials are still needed to confirm our results.

HIGH FACTOR VIII AND CORONARY ARTERY DISEASE A CASE REPORT

High factor VIII is the risk factor for venous thrombosis and coronary artery disease. Here we are presenting a case of coronary artery disease with high Factor VIII. Thrombophilia screening does not include screening of factor VIII. By this study we come to the conclusion that high factor VIII is one of the risk factor of thrombosis and should be considered as one of the test for screening patients with thrombosis.

Thrombophilia screening in women with recurrent first trimester miscarriage: is it time to stop testing? – a cohort study and systematic review of the literature

ObjectiveThere are numerous studies reporting a disproportionally high prevalence of thrombophilia in women with a history of recurrent miscarriage (RM), which has led to overdiagnosis and treatment without an improvement...

Predicting the risk of recurrent venous thromboembolism: Impact and therapeutic consequences of inherited thrombophilia.

Over the past decades, thrombophilia testing in patients with venous thrombo-embolism has increased tremendously. However, the role of inherited thrombophilie in prediction the risk of recurrence remains controversial. Consequently, it is still unclear whether thrombophilia testing influences decisions regarding duration of anticoagulation in clinical practices. The aim of this study was to evaluate the impact if inherited thrombophilia on venous thrombosis treatment decisions and on predicting the risk of recurrence. A retrospective longitudinal study (January 2011-Decembre 2016) including 131 patients with confirmed venous thrombo-embolism referred to the hematology laboratory from the internal medicine department for inherited thrombophilia screening was carried out. The mean age patients was 39.4 years and the sex ratio (M/F) was 0.61. Inherited thrombophilia was confirmed in 27.5% of patients. A long term anticoagulation was decided in 46.9% of patients with thrombophilia. There was no significant difference in the duration of anticoagulation between patients with or without thrombophilia. Thrombosis recurrence was recorded in 16 (17%) patients. The 24 years cumulative incidence of recurrence was 19% in patients with thrombophilia and 17% in those without (plog Rank= 0.6). Inherited thrombophilia was not associated with increased risk of recurrence after treatment withdrawal (Hazard ratio=1.31 IC (0.47-3.63); P=0.6). In clinical practice, inherited thrombophilia did not influence anticoagulation duration and was not associated with a higher venous thrombosis risk of recurrence. It seems to be less relevant for decision making than presumed.

Pregnancy after Combined Oral Contraceptive-Associated Venous Thromboembolism: An International Retrospective Study of Outcomes.

Few data are available on thrombotic outcomes during pregnancy and puerperium occurring after an initial provoked venous thromboembolic (VTE) event. To describe thrombotic outcomes during pregnancy after a first combined oral contraceptive (COC)-associated VTE and the factors associated with recurrence. This was an international multicentric retrospective study on patients referred for thrombophilia screening from January 1, 2010 to January 1, 2021 following a first COC-associated VTE, including women with neither inherited thrombophilia nor antiphospholipid antibodies and focusing on those who had a subsequent pregnancy under the same thromboprophylaxis treatment. Thrombotic recurrences during pregnancy and puerperium as well as risk factors for recurrence were analyzed. We included 2,145 pregnant women. A total of 88 thrombotic events, 58 antenatal and 29 postnatal, occurred, mostly during the first trimester of pregnancy and the first 2 weeks of puerperium. Incidence rates were 49.6 (37-62) per 1,000 patient-years during pregnancy and 118.7 (78-159) per 1,000 patient-years during puerperium. Focusing on pulmonary embolism, incidence rates were 1.68 (1-4) per 1,000 patient-years during pregnancy and 65.5 (35-97) per 1,000 patient-years during puerperium.Risk factors for antenatal recurrences were maternal hypercholesterolemia and birth of a very small-for-gestational-age neonate. A risk factor for postnatal recurrence was the incidence of preeclampsia. Our multicentric retrospective data show significant rates of VTE recurrence during pregnancy and puerperium in women with a previous VTE event associated with COC, despite a unique low-molecular-weight heparin-based thromboprophylaxis. These results may provide benchmarks and valuable information for designing future randomized controlled trials.

Dabigatran in Cerebral Sinus Vein Thrombosis and Thrombophilia.

Background and Purpose: Thrombophilic gene alterations are a major risk factor for cerebral sinus vein thrombosis (CSVT). Up to 30% of all patients with cerebral sinus vein thrombosis (CSVT) are found to have thrombophilic defects such as prothrombin mutation (PTM) or factor V Leiden (FVL). Their repercussions on the plasma levels of dabigatran etexilate are unclear. In this prospective case–control study, we aimed to investigate whether thrombophilia in CSVT has an influence on dabigatran peak-plasma levels. Methods: We monitored 10 patients over 12 months with acute CSVT, genetic thrombophilia with off-label use of dabigatran etexilate 150 mg twice a day and measured dabigatran peak-plasma levels and radiological outcome. We also monitored patients without genetic thrombophilia with dabigatran etexilate 150 mg twice a day and compared the efficiency and dabigatran peak-plasma levels. Results: Patients with homozygote PTM had significantly lower dabigatran peak concentration compared to patients with FVL or the control group (23 ± 4.2 vs. 152.3 ± 27.5 and 159.6 ± 63.08; p-value ≤ 0.05) There was no significant difference in dabigatran etexilate plasma levels between the heterozygote PTM group compared to patients with FVL or the control group (p = 0.29). There was no correlation between dabigatran peak concentration and delayed thrombus dissolution. Conclusions: Dabigatran peak concentration was stable in patients with heterozygote FVL and heterozygote PTM, but not in homozygote PTM, compared to controls. Genetic screening for thrombophilia in patients after CSVT may be useful to make patient tailored therapeutic decisions regarding oral anticoagulation and may decrease thrombotic events.

P1682: MTHFR C677T GENOTYPE IN CORRELATION WITH THROMBOSIS AND ASSOCIATION WITH FVIII COAGULANT ACTIVITY IN GREEK PAEDIATRIC POPULATION

Background: The polymorphism C>T substitution in position 677 (C677T) of the encoding gene of methylenetetrahydrofolate reductase (MTHFR), creates a thermolabile enzyme with reduced activity that may predispose to hyperhomocysteinemia, an established risk factor for arterial thrombosis and premature atherosclerosis and a probable risk factor for venous thromboembolic disease and its recurrence in the general population. There are conflicting results as to the role of the MTHFR C677T polymorphism as a risk factor for thrombosis. Although the homozygous substitution is often associated with hyperhomocysteinemia, mainly in folate deficiency, a clear association between this genetic marker and thrombosis has not yet been established. Aims: Primary aim was to evaluate the prevalence of mutant C677T MTHFR and its association with thrombosis in the Greek paediatric population. Secondary aim was to evaluate whether different MTHFR genotype is associated with evidence of activation of coagulation cascade through increased factor VIII activity. Methods: Data were retrospectively collected from children referred to our Haemostasis and Thrombosis Centre for laboratory screening of thrombophilia between 2018 and 2020. Some of them were checked due to history of thrombosis. Children were categorized according to MTHFR C677T genotype. FVIII Coagulant activity (%) was measured by One Stage Assay, away from acute thrombosis. The identification of mutations was based on polymerase chain reaction (PCR) and reverse- hybridization. Statistical analysis was performed with t-test and ANOVA. Results: A total of 688 children (boys: 49 %) of mean age 8.9± 8 years (0-18) were investigated. Twelve percent (81/688) of them had history of thrombosis, mainly venous thromboembolic disease. Children were categorized as follows: homozygous MTHFR C677T (15%), heterozygous (47%) and normal (38%). There was thrombosis history in 12% of homozygous MTHFR C677T, 11% heterozygous and 12 % of normal, fact showing that there is no association between MTHFR C677T genotype with thrombosis. Children with homozygosity MTHFR C677T, compared to children with heterozygosity and normal MTHFR C677T showed increased factor VIII values (132.8 vs 126.4 and 131.6, %, respectively), but without statistically significant difference. However, independently of MTHFR C677T genotype, mean factor VIII values were significantly increased in all children, with thrombosis history when they were compared to children without thrombosis history (161.3 vs 125.1, %, p<0.001). Interestingly, in children with thrombosis, mean factor VIII level was statistically increased in heterozygous and normal MTHFR C677T in contrast to children with MTHFR C677T homozygosity, in whom no statistically significant increase was found (166.9 vs 121.4, %-p<0.05, 160.2 vs 127.6, %-p<0.05 and 148.3 vs 130.6, %-p>0.05, respectively). Finally, it should be noticed that during the year 2020 mean factor VIII values were much increased in all children in comparison to the years 2018, 2019 and 2021 (137 vs 129, 123 and 127, %, respectively), probably reflecting the effects of unknown pandemic COVID-19 which initiated in 2020, and showing that factor VIII could be an evidence of stress condition. Summary/Conclusion: There is no probably association between MTHFR C677T genotype and thrombosis in our paediatric population. Moreover, it was not proved that different MTHFR genotypes affect factor VIII activity.

Thromboembolic hazard in hereditary hemorrhagic telangiectasia.

A 23-year-old woman with hereditary hemorrhagic telangiectasia was found in her bedroom presenting right-side hemiparesis and aphasia. Brain computed tomography angiography (CTA) showed a complete occlusion of left-medium cerebral artery (Panel A) that required mechanical thrombectomy. CTA revealed the typical arteriovenous malformations in the lungs (Panel B) but not in the brain or liver. A bubble contrasted echocardiography ruled out intracardiacal shunts. Furthermore, repletion defects were found in subsegmentarial pulmonary arteries (Panel C, amplified in the inset). No thrombus was detected in lower extremity veins with Doppler-ecography, and thrombophilia screening was negative. Urgent thrombectomy, rehabilitation, and anticoagulation reduced neurological sequels to hand dizziness and mild concentration complaints. Arteriovenous malformations were embolized. Hereditary hemorrhagic telangiectasia, also known as Rendu–Osler–Weber disease, is an autosomical-dominant condition characterized by angiodysplastic lesions and arteriovenous malformations. Traditionally, the hemorrhagic manifestations have received all the attention. Nonetheless, arteriovenous malformations can bypass pulmonary circulation and permit paradoxical embolisms (see Figure 1). The authors declares they have no conflicts of interest. Patient gave informed consent for the publication of this case report.