Osteonecrosis of the Jaws in Patients with Hereditary Thrombophilia/Hypofibrinolysis—From Pathophysiology to Therapeutic Implications

Osteonecrosis of the jaws (ONJ) usually has a clear etiology. Local infection or trauma, radiotherapy and drugs that disrupt the vascular supply or bone turnover in the jaws are its major contributors. The thrombotic occlusion of the bone’s venous outflow that occurs in individuals with hereditary thrombophilia and/or hypofibrinolysis has a less known impact on jaw health and healing capability. Our research provides the most comprehensive, up-to-date and systematized information on the prevalence and significance of hereditary thrombophilia and/or hypofibrinolysis states in ONJ. We found that hereditary prothrombotic abnormalities are common in patients with ONJ refractory to conventional medical and dental treatments. Thrombophilia traits usually coexist with hypofibrinolysis traits. We also found that frequently acquired prothrombotic abnormalities coexist with hereditary ones and enhance their negative effect on the bone. Therefore, we recommend a personalized therapeutic approach that addresses, in particular, the modifiable risk factors of ONJ. Patients will have clear benefits, as they will be relieved of persistent pain and repeated dental procedures.

Combined Oral Contraceptives and Venous Thromboembolism: Review and Perspective to Mitigate the Risk

Many factors must be considered and discussed with women when initiating a contraceptive method and the risk of venous thromboembolism (VTE) is one of them. In this review, we discuss the numerous strategies that have been implemented to reduce the thrombotic risk associated with combined oral contraceptives (COCs) from their arrival on the market until today. Evidences suggesting that COCs were associated with an increased risk of VTE appeared rapidly after their marketing. Identified as the main contributor of this risk, the dosage of the estrogen, i.e., ethinylestradiol (EE), was significantly reduced. New progestins were also synthetized (e.g., desogestrel or gestodene) but their weak androgenic activity did not permit to counterbalance the effect of EE as did the initial progestins such as levonorgestrel. Numerous studies assessed the impact of estroprogestative combinations on hemostasis and demonstrated that women under COC suffered from resistance towards activated protein C (APC). Subsequently, the European Medicines Agency updated its guidelines on clinical investigation of steroid contraceptives in which they recommended to assess this biological marker. In 2009, estradiol-containing COCs were marketed and the use of this natural form of estrogen was found to exert a weaker effect on the synthesis of hepatic proteins compared to EE. In this year 2021, a novel COC based on a native estrogen, i.e., estetrol, will be introduced on the market. Associated with drospirenone, this preparation demonstrated minor effects on coagulation proteins as compared with other drospirenone-containing COCs. At the present time, the standard of care when starting a contraception, consists of identifying the presence of hereditary thrombophilia solely on the basis of familial history of VTE. This strategy has however been reported as poorly predictive of hereditary thrombophilia. One rationale and affordable perspective which has already been considered in the past could be the implementation of a baseline screening of the prothrombotic state to provide health care professionals with objective data to support the prescription of the more appropriate contraceptive method. While this strategy was judged too expensive due to limited laboratory solutions, the endogenous thrombin potential-based APC resistance assay could now represent an interesting alternative.

Assessment of the economic potential of assisted reproductive technologies in a child with hereditary thrombophilia

Введение. Вспомогательные репродуктивные технологии (ВРТ) проводятся у бесплодных пар, имеющих в том числе факторы тромбогенного риска, которые наследуются их детьми и могут быть причиной формирования инвалидности при развитии сосудистых катастроф. Оценка экономического потенциала ВРТ должна учитывать заболеваемость, инвалидность и смертность детей, зачатых при помощи этих методик. Цель исследования: оценить экономический потенциал ВРТ у ребенка, зачатого при помощи репродуктивных методик, и имеющего инвалидность. Материалы и методы. Проведено наблюдательное исследование за ребенком, зачатым при использовании ВРТ, имеющим наследственную тромбофилию. Оценка экономического потенциала ВРТ проводилась с учетом показателя валового регионального продукта. Результаты. Ребенок на фоне наследственной тромбофилии в генах плазменного (FGB –455 G > A), фибринолитического (PAI-1–675 5G > 4G) и тромбоцитарного (ITGA2 807 C > T) звеньев гемостаза, генах фолатного цикла, гипергомоцистеинемии тяжелой степени имел артериальный тромбоз брюшного отдела аорты, который послужил причиной ампутации стопы и голени, нефрэктомии и формирования инвалидности. Заключение. Учитывая показатель младенческой смертности (4,5‰) и инвалидности (2,9%) в группе детей, зачатых при помощи ВРТ (n = 2206), в регионе отмечается 11,8-кратный возврат затраченных правительством вложений при трудовой занятости в производстве будущего специалиста. Дети, рожденные в семьях, имеющих факторы тромбогенного риска, нуждаются в получении услуг ранней помощи. Introduction. Assisted reproductive technologies (ART) are performed in infertile couples who have, among other things, thrombogenic risk factors that are inherited by their children and can cause disability in the development of vascular catastrophes. The assessment of ART economic potential should take into account the morbidity, disability and mortality of children conceived using these methods. Objectives: to assess ART economic potential in a child conceived with reproductive methods and who has a disability. Patients/Methods. An observational study was conducted on a child conceived using ART and having hereditary thrombophilia. The assessment of ART economic potential was carried out taking into account the indicator of the gross regional product. Results. The child with hereditary thrombophilia in the genes of plasma (FGB –455 G > A), fibrinolytic (PAI-1–675 5G > 4G) and platelet (ITGA2 807 C > T) units of hemostasis, in folate cycle genes, and severe hyperhomocysteinemia had disseminated arterial thrombosis of the abdominal aorta, which caused amputation of the foot and lower leg, nephrectomy and the formation of disability. Conclusions. Taking into account the infant mortality rate (4.5%) and disability (2.9%) in the group of children conceived with ART (n = 2206), the region has an 11.8-fold return on the government’s investment in employment in the production of future specialists. Children born in families with thrombogenic risk factors need early care services.

P–358 Characteristics of patients with inherited thrombophilia and anticoagulant treatment in repeated implantation failure (RIF) and recurrent pregnancy loss (RPL)

Study question Do patients with inherited thrombophilia associated to RIF and RPL benefit from anticoagulant therapy? Summary answer Low molecular weight heparin (LMWH) in patients with medium and high risk of hereditary thrombophilia, associated with RIF could improve the reproductive prognosis. What is known already Thrombophilia is a condition that can be acquired and/or inherited genetically, that is characterized by the predisposition of patients to form venous and arterial thromboembolic events. Inherited thrombophilia has been associated with different complications during pregnancy, such as RPL. Genetic variants linked to hereditary thrombophilia can be classified by the thromboembolic risk: low (F12, F13A1, FGB), medium (MTHFR, PROCR, PROS1, SERPINC1, SERPINC1 PAI–1) and high (F2, F5, GP1BA), according to Martinez - Zamora. RPL rate may reduce with anticoagulant therapy. However, there is no conclusive evidence that prophylactic treatment improves the pregnancy rate in infertile women during IVF. Study design, size, duration We performed a prospective observational study which included patients referred to Ceras Clinic between March 2018 and March 2020, due to RPL (n = 38) and RIF (n = 40). All patients underwent genetic analysis for hereditary thrombophilia(F13, F2, F5, FGB, GP1BA, MTHFR C677T, MTHFR A1298C, PAI1,, PROCR, SERPIN1 CM910058, SERPIN 1 CM920113 ,F12, PROS1) by Sanger sequencing. The characteristics of anticoagulant therapy with clinical pregnancy rate and LBR were analyzed, using chi-squared test with STATA version 16. Participants/materials, setting, methods Patients have been included in the study according to their past medical history (stroke or myocardial infarction, personal or familiar history of deep vein thrombosis or pulmonary embolism, smoking, hormone replacement therapy), and reproductive history. Two groups were formed, the first group (n = 40) corresponds to RIF, and the second (n = 38), RPL. Genetic study of hereditary thrombophilia (11 genes) was performed to examine the genetic risk and assess the administration of anticoagulant therapy. Main results and the role of chance The prevalence of pathological antecedents in patients with RIF and RPL was not statistically significant (p > 0,05), indicating that the factors that contribute to poor reproductive outcomes in these two groups of patients could be similar. Patients with RIF had a medium risk of thrombophilia in 65%, followed by low risk in 32.5% and high risk in 2.5%. RPL group presented 78.95%, 15.79% and 5.26%, respectively. All patients with medium and high risk for trombophilia received anticoagulation. Clinical pregnancy rate (69.7%) and live birth rate (63.64%) were not statistically significant (p > 0.05) in RPL with anticoagulant therapy, compared to RPL group who did not received treatment (clinical pregnancy rate and live birth rate in 60%). Therefore, it is proposed that there may be other factors associated with abortions that require investigation. However, clinical pregnancy rate (77.14%) and live birth rate (74.29%) were statistically significant (p < 0.05) in RIF with anticoagulant therapy, compared to RIF group that did not received treatment (clinical pregnancy rate and live birth rate in 20%). This suggests that there could be a beneficial factor due to anticoagulation. Further studies are needed to assess that anticoagulant treatment could improve obstetric outcomes in patients with RIF and RPL. Limitations, reasons for caution The small number of patients assessed is the main limitation of this work. Larger studies must be designed to accurately determine participation of each mutation associated with recurrent implantation failure and recurrent pregnancy loss. The role of anticoagulant therapy should be evaluated in randomized clinical trials. Wider implications of the findings: Establishing a stronger evidence base implies that future studies should include large population groups. It is primordial to assess whether it is cost-effective to determine the risk of inherited thrombophilia in RIL and RPL, to increase the live birth rate by anticoagulant therapy. The information is controversial to this day. Trial registration number ‘not applicable’

Osteonecrosis of the Femoral Head in Patients with Hypercoagulability—From Pathophysiology to Therapeutic Implications

Osteonecrosis of the femoral head (ONFH) is a debilitating disease with major social and economic impacts. It frequently affects relatively young adults and has a predilection for rapid progression to femoral head collapse and end-stage hip arthritis. If not diagnosed and treated properly in the early stages, ONFH has devastating consequences and leads to mandatory total hip arthroplasty. The pathophysiology of non-traumatic ONFH is very complex and not fully understood. While multiple risk factors have been associated with secondary ONFH, there are still many cases in which a clear etiology cannot be established. Recognition of the prothrombotic state as part of the etiopathogeny of primary ONFH provides an opportunity for early medical intervention, with implications for both prophylaxis and therapy aimed at slowing or stopping the progression of the disease. Hereditary thrombophilia and hypofibrinolysis are associated with thrombotic occlusion of bone vessels. Anticoagulant treatment can change the natural course of the disease and improve patients’ quality of life. The present work focused on highlighting the association between hereditary thrombophilia/hypofibrinolysis states and ONFH, emphasizing the importance of identifying this condition. We have also provided strong arguments to support the efficiency and safety of anticoagulant treatment in the early stages of the disease, encouraging etiological diagnosis and prompt therapeutic intervention. In the era of direct oral anticoagulants, new therapeutic options have become available, enabling better long-term compliance.