Congenital thrombophilia in East-Asian venous thromboembolism population: a systematic review and meta-analysis.

Background: Various inherited traits contribute to the overall risk of venous thromboembolism (VTE). In addition, the epidemiology of thrombophilia in the East-Asian VTE population remains unclear; thus, we aimed to assess the proportion of hereditary thrombophilia via a meta-analysis. Methods: Publications from PubMed, EMBASE, web of science, and Cochrane before December 30, 2022, were searched. Studies from Japan, Korea, China, Hong Kong, Taiwan, Singapore, Thailand, Vietnam, Myanmar, and Cambodia were included. Congenital thrombophilia was described as diseases including protein C (PC) deficiency, protein S (PS) deficiency, antithrombin (AT) deficiency, factor (F)V Leiden (FVL), and prothrombin G20210A mutations. Studies were selected by 2 reviewers for methodological quality analysis. A random-effects model was used for the meta-analysis, assuming that estimated effects in the different studies are not identical. Results: Forty-four studies involving 6453 patients from 7 counties/regions were included in the meta-analysis. The prevalence of PC, PS, and AT deficiencies were 7.1%, 8.3%, and 3.8%, respectively. Among 2924 patients from 22 studies, 5 patients were carriers of FVL mutation. Among 2196 patients from 10 studies, 2 patients were carriers of prothrombin G20210A mutation in a Thailand study. Conclusion: The prevalence of PC, PS, and AT deficiencies was relatively high, while a much lower prevalence of FVL and prothrombin G20210A mutations were identified in East-Asian patients with VTE. Our data stress the relative higher prevalence of PC, PS, and AT deficiencies for thrombophilia in the East-Asian VTE population.

Prevalence, Genetic Background, and Clinical Phenotype of Congenital Thrombophilia in Chronic Thromboembolic Pulmonary Hypertension.

Background: The role of congenital thrombophilia in chronic thromboembolic pulmonary hypertension (CTEPH) remains unresolved. Objectives: The purpose of this study was to investigate the prevalence, genetic background, and clinical phenotype of congenital thrombophilia in CTEPH. Methods: In total, 367 patients with CTEPH from May 2013 to December 2020 were consecutively enrolled in this cross-sectional study in FuWai Hospital and Peking Union Medical College Hospital in China. The primary outcome was the occurrence of congenital thrombophilia diagnosed through tests for congenital anticoagulants activity (including protein C, protein S, and antithrombin III), factor V Leiden and prothrombin G20210A sequence variants. Next-generation sequencing was conducted for patients with congenital thrombophilia. Clinical phenotype was compared between patients with and without thrombophilia. Results: A total of 36 (9.8%; 95% CI: 6.8%-12.9%) patients were diagnosed as congenital thrombophilia, including 13 protein C deficiency (3.5%; 95% CI: 1.6%-5.4%), 19 protein S deficiency (5.2%; 95% CI: 2.9%-7.5%), and 4 antithrombin III deficiency (1.1%; 95% CI: 0%-2.2%). No factor V Leiden or prothrombin G20210A sequence variants were identified. Genotype for patients with thrombophilia revealed that 10 (76.9%) protein C deficiency patients were PROC sequence variant carriers, 4 (21.1%) protein S deficiency were PROS1 sequence variant carriers, and 2 (50.0%) antithrombin III deficiency were SERPINC1 sequence variant carriers. In the logistic regression model, male sex (OR: 3.24; 95% CI: 1.43-7.31) and proximal lesion in pulmonary arteries (OR: 4.10; 95% CI: 1.91-8.85) had significant differences between the congenital thrombophilia and nonthrombophilia group in CTEPH patients. Conclusions: Congenital thrombophilia was not rare. Male sex and proximal lesion in pulmonary arteries might be the specific clinical phenotype for CTEPH patients with congenital thrombophilia.

Thrombosis risk assessment in patients with congenital thrombophilia during COVID - 19 infection.

BACKGROUND: Coagulation dysfunction represents a serious complication in patients during the COVID-19 infection, while fulminant thrombotic complications emerge as critical issues in individuals with severe COVID-19. In addition to a severe clinical presentation, comorbidities and age significantly contribute to the development of thrombotic complications in this disease. However, there is very little data on association of congenital thrombophilia and thrombotic events in the setting of COVID-19. Our study aimed to evaluate the risk of COVID-19 associated thrombosis in patients with congenital thrombophilia. METHODS: This prospective, case-control study included patients with confirmed COVID-19 infection, followed 6 months post-confirmation. The final outcome was a symptomatic thrombotic event. In total, 90 COVID-19 patients, 30 with known congenital thrombophilia and 60 patients without thrombophilia within the period July 2020-November 2021, were included in the study. Evaluation of hemostatic parameters including FVIII activity and D-dimer was performed for all patients at 1 month, 3 months and 6 months post-COVID-19 diagnosis. RESULTS: Symptomatic thrombotic events were observed in 7 out of 30 (23 %) COVID-19 patients with thrombophilia, and 12 out of 60 (20 %) without thrombophilia, P = 0.715. In addition, the two patient groups had comparable localization of thrombotic events, time to thrombotic event, effect of antithrombotic treatment and changes in FVIII activity, while D-dimer level were significantly increased in patients without thrombophilia. CONCLUSION: Our findings suggest that patients with congenital thrombophilia, irrespective of their age, a mild clinical picture and absence of comorbidities, should receive anticoagulant prophylaxis, adjusted based on the specific genetic defect.

Congenital thrombophilia associated with intrahepatic cholestasis of pregnancy. A case report.

Intrahepatic cholestasis of pregnancy is pregnancy-specific liver disorder, characterized by pruritus as the main clinical symptom, and fasting liver function tests. The term thrombophilia is used to describe a group of conditions characterized by blood coagulation disorder with increased risk of blood clot formation, which may be congenital or acquired. In general, population the incidence of thrombophilia and intrahepatic cholestasis of pregnancy varies widely, depending on the type of disorder (in case of congenital thrombophilia) and geographical distribution (in case of intrahepatic cholestasis of pregnancy). A high incidence of pregnancy complications makes both congenital thrombophilia and intrahepatic cholestasis of pregnancy very important in clinical practice. At the same time, association between these two disorders is extremely complicated in management, due to perinatal risks. The key-point for the management is cooperation among obstetricians, hematologists, and hepatologists, being crucial for better outcomes.

Trombosis venosa profunda y trombofilia congénita / Deep-vein thrombosis and congenital thrombophilia

Introducción: La trombofilia es un desorden de la hemostasia congénito o adquirido que predispone al desarrollo de trombosis. Las trombofilias congénitas más frecuentes son las deficiencias de antitrombina III, proteína C y proteína S, el factor V Leiden, la mutación del gen de la protrombina (G20210A) y las mutaciones de la enzima metilentetrahidrofolato reductasa (MTHFR). Objetivo: Describir el manejo anestésico en un paciente portador de trombofilia congénita. Presentación del caso: Se reporta un paciente de 19 años de edad con antecedentes de historia familiar y personal de trombosis venosa profunda, tratamiento con doble antiagregación plaquetaria y asociación de tres mutaciones para trombofilia congénita, G20210A, A1298C MTHFR y C677T MTHFR que recibe anestesia espinal para una herniorrafia inguinal. Se mantiene tratamiento con aspirina, se suspende clopidogrel 7 días antes de la cirugía y durante ese tiempo se administra fraxiparina 0.6 Uds. subcutánea diarias hasta 12 h antes de la cirugía, se utiliza medias elásticas, deambulación precoz y reinicio de clopidogrel 24 h después de la cirugía, con evolución satisfactoria. Conclusiones: La tromboprofilaxis en pacientes portadores de trombofilia congénita es mandatoria, por eso resulta determinante la utilización de heparina de bajo peso molecular junto al resto de las medidas de prevención de la trombosis venosa profunda(AU)

Introduction: Thrombophilia is a congenital or acquired hemostasis disorder that predisposes to thrombosis development. The commonest congenital thrombophilias are deficiencies of antithrombin III, protein C and protein S, factor V Leiden, prothrombin gene mutation (G20210A), and methylenetetrahydrofolate reductase (MTHFR) mutations. Objective: To describe the anesthetic management in a patient with congenital thrombophilia. Case presentation: The case is reported of a 19-year-old patient with a family and personal history of deep-vein thrombosis, treatment with double antiplatelet therapy and association of three mutations for congenital thrombophilia (G20210A, A1298C MTHFR and C677T MTHFR), who receives spinal anesthesia for an inguinal herniorrhaphy. Aspirin treatment is maintained. Clopidogrel is suspended seven days before surgery. During this time, fraxiparin is administered subcutaneously in 0.6-mL units daily, up to twelve hours before surgery. Elastic stockings are used, early ambulation is allowed, and clopidogrel is restarted 24 hours after surgery, with satisfactory evolution. Conclusions: Thromboprophylaxis in patients with congenital thrombophilia is mandatory, a reason why the use of low-molecular-weight heparin, together with the rest of the prevention measures against deep-vein thrombosis, is decisive(AU)

Aortic Mural Thrombus Associated with Congenital Protein C Deficiency in an Elderly Patient.

Thrombophilia increases the risk of venous thrombosis, but is rarely responsible for aortic thrombosis. Aortic mural thrombus (AMT) may be associated with a protein C deficiency. However, it is necessary to determine whether the protein C deficiency is congenital/hereditary or secondary/acquired (consumption of protein C during the process of thrombus formation). This study describes a 77-year-old Japanese woman with incidentally diagnosed AMT, who had a protein C deficiency (activity 54%, antigen 42%). Sequencing of the protein C gene revealed a heterozygous mutation of c.1268delG, p.Gly423Valfs＊82 in exon 9, indicating a congenital protein C deficiency. These findings indicate that very late onset AMT can occur in an adult with congenital protein C deficiency.

Diagnosis and management of congenital thrombophilia in the era of direct oral anticoagulants.

Direct oral anticoagulants (DOAC)s are often preferred to other anticoagulants as they are more practical and do not require routine laboratory monitoring. Less is known about their use in congenital thrombophilia. Efficacy of DOACs in congenital thrombophilia, effect of DOACs and other anticoagulants on diagnostic tests as well as efficacy and safety of anticoagulant use in this population is still a matter of debate. In this review we intended to analyze the potential pitfalls of testing for thrombophilia in patients using DOACs and vitamin K antagonists (VKA)s as well as to suggest strategies to improve diagnostic accuracy in this setting. We also reviewed the literature for evidence regarding the safety and efficacy of DOACs in patients with congenital thrombophilia. Some evidence was found supporting the use of DOACs in low risk thrombophilia, although evidence for their use in high risk thrombophilia is limited to small series and case reports. Our findings support the generation of better evidence to support DOAC use for congenital thrombophilia, especially in the high risk subgroups.

Recurrent venous thrombosis during direct oral anticoagulant therapy in a patient with protein S deficiency.

Protein S (PS) deficiency is an inherited thrombophilia associated with an increased risk of venous thromboembolism (VTE). In Japan, unfractionated heparin followed by warfarin has been historically applied for the treatment of VTE. Recent evidence showed that direct oral anticoagulants (DOACs) were non-inferior to standard therapy with warfarin, with significantly less bleeding in patients with VTE. However, it is unknown whether DOACs are effective for the treatment of VTE in patients with thrombophilia, including protein S deficiency, due to lack of evidence. Here, we report a case of recurrent venous thrombosis during edoxaban therapy in a patient with protein S deficiency, which was successfully treated using high-dose apixaban therapy. J.Med. Invest. 66 : 182-184, February, 2019.

[A case of recurrent cerebral vein thrombosis with protein C gene mutation identified].

We reported a 31-year-old man with recurrent cerebral venous thrombosis caused by congenital protein C deficiency. He was diagnosed with cerebral venous thrombosis before 7 months. He was transferred to our hospital with numbness of right hand and right side of face, and dysarthria. The blood examination showed that his protein C antigen level and protein C activity were decreased than the lower limits of normal. Brain magnetic resonance venography showed poor visualization of the superior sagittal sinus and cortical veins. Genetic analysis revealed a single-base substitution (C>T) at the codon 811 (Arg to Trp) in the 9th exon portion of the protein C gene. Taking those results, he was diagnosed with recurrent cerebral venous thrombosis due to congenital protein C deficiency. Cerebral venous sinus thrombosis that occurred in the absence of an incidents of disease or internal history when there is a juvenile onset, a past history, or a family history, is suspected of congenital thrombophilia and needs blood tests and genetic tests.

Pediatric thromboembolism: a national survey in Japan.

Thromboembolism is being detected at increasing rates in pediatric tertiary care hospitals. The incidence of pediatric thrombophilia differs across countries, and is unknown in Japan. We sent a survey to 520 pediatric department heads and 629 specialists, requesting details on patients who developed symptomatic thromboembolism between 2006 and 2010. Of 280 eligible cases, congenital thrombophilia and other conditions were reported. Congenital thrombophilia (n = 54, 19.3 %) comprised defects in protein C (27), protein S (9), and antithrombin (7). None had mutations in factor V Leiden or prothrombin G20210A, both of which are frequent in Caucasians. Non-congenital causes of thrombophilia included congenital heart disease, the use of central venous catheters, nephrotic syndrome, antiphospholipid syndrome, and malignancy with or without use of L-asparaginase. Patients with congenital thrombophilia developed thromboembolism at a significantly younger age (median 1.0 vs. 5.0 years, p = 0.014), had a higher frequency of consanguinity (35.2 vs. 1.8 %, p < 0.001) and post-thrombotic syndromes (29.6 vs. 13.3 %, p = 0.007) than those who did not. Thromboembolism in children with congenital thrombophilia recurred more frequently (50.0 vs. 13.7 %, p < 0.001) and was associated with more sequelae (61.1 vs. 37.2 %, p = 0.009) than in children without congenital thrombophilia. This nationwide survey provides the first comprehensive study of Japanese children with symptomatic thromboembolism. Significant recurrence and sequelae require optimized standards.

Livedoid vasculopathy and popliteal artery occlusion in a patient with protein S deficiency.

Livedoid vasculopathy (LV) is a chronic disease with recurrent reticularis and ulcers, mainly affecting the feet and lower legs. The pathogenesis of LV has not been yet thoroughly understood, but thrombosis is thought to play a major role because fibrin deposition within both the wall and lumen of affected vessels is pathologically detected. A 68-year-old woman first presented to our hospital in 2004 with a 6-year history of a reticular rash and ulceration on the lower legs. Screening tests for vasculitis and collagen disease were mostly normal, leading to diagnosis of LV. After failed treatment with steroid and aspirin, she was started on warfarin, to which she had a favorable response. However, she had to be admitted to the hospital because complication of swelling and infection in her left lower leg in 2004 + 10. Contrast-enhanced computed tomography showed thrombosis in the left popliteal artery. Screening tests for thrombotic tendency revealed that protein S activity was low (27%) although total protein S antigen was within normal range (73%). Analysis of protein S-alpha gene revealed 155 Lys>Glu mutation in exon VI, which was reported in 1994 and named as protein S Tokushima. Thus, we conclude that protein S deficiency could contribute to LV.

Study of the frequency of occurrence of genetic and acquired thrombophilia in infertile women prior IVF.

This study of infertile women prior in vitro fertilization (IVF) is focused at the genetic and acquired thrombophilia before the IVF program, the identification of the frequency of occurrence of thrombophilia in them, the impact of thrombophilia of the offensive, the course and outcome of pregnancies, to improve the quality of cycles in terms of a pregnancy and childbirth. Forty-five women with infertility were examined. Thirty-two (71%) were identified thrombophilia: genetic thrombophilia in 32 cases (100%), among them a combination of several forms of genetic thrombophilia - 21 (63%) of them, other forms of thrombophilia (genetic and acquired) - in 5 of them (16%). In IVF 23 (72%) women became pregnant. In 87% of pregnancies ended in spontaneous birth, in 13% of cases of preterm birth.