Heterozygous Prothrombin Mutation Research Articles

Microsurgical Breast Reconstruction in Patients with Disorders of Hemostasis: Perioperative Risks and Management.

Surgical and technological advances have resulted in the widespread adoption of microsurgical breast reconstruction. Many comorbidities that potentially might impair vasculature and wound healing are no longer considered contraindications for these procedures. However, some uncertainty still prevails regarding the perioperative management of patients with disorders of hemostasis. The authors combined a literature review with a retrospective chart review of patients with disorders of hemostasis who had undergone microsurgical breast reconstruction at the senior author's (J.F.) center between 2015 to 2020. Several disorders associated with thrombotic and/or hemorrhagic complications were identified, and a standardized risk assessment and management strategy was developed in cooperation with a hematologist. Overall, 10 studies were identified comprising 29 patients who had a defined disorder of hemostasis and underwent microsurgical breast reconstruction. Seventeen microsurgical breast reconstructions were performed on 11 patients at the senior author's (J.F.) center. High factor VIII levels, heterozygous factor V Leiden, and heterozygous prothrombin mutation G20210A were the most common genetic or mixed genetic/acquired thrombophilic conditions. As expected, hereditary antithrombin, protein C, or protein S deficiencies were rare. Among hemorrhagic disorders, thrombocytopenia, platelet dysfunction, and von Willebrand disease or low von Willebrand factor levels were those factors most frequently associated with increased perioperative bleeding. Patients should be screened for elevated risk of thrombosis or bleeding before undergoing microsurgical breast reconstruction, and positive screening should prompt a complete hematologic evaluation. Interdisciplinary management of these disorders with a hematologist is essential to minimize risks and to obtain optimal reconstructive results. Risk, IV.

Canlı Vericili Karaciğer Naklinde Retrospektif Donör Hepatektomi Sonuçları- Tek Merkez Deneyimi

Objectives: We aimed to describe our technique and donor selection for donor hepatectomy, review our case series and report our complication rates and outcomes.
 Materials and Methods: We retrospectively reviewed 41 consecutive donor hepatectomy cases between October 2019 and November 2020 at Yeditepe University, Istanbul, Turkey. Complications were graded according to Clavien-Dindo classification. All cases were performed via laparotomy. 
 Results: Out of 41 donor cases, 38 (92,6%) were right lobe, 2 (4,8%) were left lobe and 1 (2,4%) was left lateral segment donor hepatectomy. Follow up was 9 ±2,2 months (4-16 months). There were 8 (19,5%) complications and all were minor (grade 1 or 2). There were no grade 3 or higher complications. Three (7,3%) of our donors are heterozygous for factor 5 leiden mutation and 4 (9,7%) of our donors had heterozygous prothrombin mutation. Length of stay was average 6.4±1,4 days (range=5-12). Ten donors lost weight with a supervised diet and exercise program. There was one wound complication in this subset of patients. 
 Conclusions: We present our single center donor hepatectomy series with excellent results. We also describe successful weight loss for donors with Body Mass Index (BMI) >30. Donor safety is the most important component of living donor liver transplantation. As donor results continue to improve, living donor liver transplant (LDLT) will continue expand worldwide.

Prothrombin R541W Mutation Impairs Protein C Activation and Constitutes a New Genetic Risk Factor for Venous Thrombosis

Defective protein C (PC) pathway predisposes patients to venous thromboembolism (VTE)and is mostly, but not exclusively, attributed tohereditary PC or protein S (PS) deficiencies and activated PC resistance caused by factor V Leiden mutation. In a patient with acute mesenteric venous thrombosis and positive family history of VTE associated with the impaired PC pathway function determined by thrombin generation test, we identified a novel heterozygous prothrombin mutation p.Arg541Trp. Two more patients with positive family history of VTE carrying the same mutation were identified in a cohort of another 373 unrelated patients, making an overall prevalence of 0.8%. Family investigation revealed 11 individuals in the three pedigrees harboring the heterozygous prothrombin p.Arg541Trp mutation, and 8 of them (72%) had experienced episodes of VTE. Functional studies indicated the mutation moderately decreased procoagulant activity of prothrombin and had mild impact on the inactivation of thrombin by its inhibitor antithrombin. However, the amino acid residue substitution significantly compromised PC activation by thrombin, both in the absence and presence of soluble thrombomodulin, and thus rendered prothrombin function procoagulant biased. In conclusion, the prothrombin p.Arg541Trp mutation constitutes a new genetic risk factor of VTE by impairing function of PC pathway and tilting thrombin's procoagulant activity over anticoagulant function. Figure Disclosures Ding: Shanghai General Hospital affiliated to Shanghai Jiao Tong University, Shanghai: Patents & Royalties: W.W, Q.D and X.W of the co-authors are named as inventors on a patent application related to this work.. Wang:Ruijin Hospital, Shanghai Jiao Tong University School of Medicine: Patents & Royalties: W.W, Q.D and X.W of the co-authors are named as inventors on a patent application related to this work.. WU:Ruijin Hospital, Shanghai Jiao Tong University School of Medicine: Patents & Royalties: W.W, Q.D and X.W of the co-authors are named as inventors on a patent application related to this work..

One- Week Prophylaxis with Enoxaparin after Hospital Discharge Is Effective in Preventing Venous Thromboembolism in Living Liver Donors- Single Institution Retrospective Analysis

Background: Living donor liver transplant (LDLT) has expanded organ availability to patients with advanced liver failure. While this procedure decreased morbidity and mortality in recipients, it could pose a risk to the donors. Deep vein thrombosis and pulmonary embolism are known postoperative complications associated with morbidity and mortality in living liver donors. At our institution thrombophilia screening starts during donor selection process with antiphospholipid antibody panel and screening coagulation tests for all candidates. This is followed by hematology evaluation to determine the need for inherited thrombophilia screening and accordingly, hypercoagulability risk. Additionally, the institution strategy for venous thromboembolism (VTE) prevention in liver donors involves prophylactic subcutaneous heparin within 24 hours of the surgery and maintained until discharge followed by enoxaparin for 7 days after discharge. We conducted this retrospective analysis to evaluate the efficacy of these measures in reducing the rate of VTE in this population. Methods: Retrospective electronic medical chart review to analyze data on living liver donors in our institution between January 2000 and February 2019. Inclusion criteria: all adult living liver donors who underwent partial right hepatectomy and followed for at least 6 weeks after surgery. The primary endpoint is the rate of VTE within 6 weeks of liver donation in patients who received post-discharge enoxaparin for one week in comparison to donors who did not receive enoxaparin. Secondary endpoints: re-admission rate and bleeding events. All continuous data was presented using means, medians and standard deviation, while categorical data were presented using counts and percentages. Results: At our institution 112 liver donors underwent right hepatectomy. Baseline characteristics (Table-1): The average age was 34 years, 58% were females and 86% were white. 10% of donors reported family history of DVT/PE. 90% of donors were screened for antiphospholipid antibody syndrome, with one case with positive titers. 34% of donors were screened for protein C (PC), Protein S (PS) and Antithrombin deficiency (AT-III). There were no cases of PC or AT-III deficiency, but one case of mild PS deficiency was identified. 38% cases were screened for factor V Leiden and prothrombin mutations, with 3 donors carrying heterozygous factor V Leiden mutation and one with heterozygous prothrombin mutation. All donors received prophylactic heparin during their stay in the hospital. A total of 15 donors had coagulation factors checked before and after the surgery. Post operatively, there was significant transient deficiency in PC, PS and AT-III, as well as significant increase in factor VIII level. This imbalance peaked within one week of surgery, with PC mean activity of 48%, PS mean activity of 48%, AT-III mean activity of 53% and FVIII of 290%. Factor activities started to recover by third week of surgery and returned to baseline within 8 weeks (figure 1). A total of 100 patients received one week of prophylaxis with Enoxaparin after being discharged from the hospital (Table-2). There was no VTE incidents in this group. 14/100 were readmitted to the hospital within 6 weeks of initial hospital admission; none due to bleeding. A total of 12 patients did not receive any pharmacological preventive measures upon discharge; due to in-hospital bleeding in 3 cases, prior to starting this strategy in 4 cases, unknown reason in 5 cases. VTE events and subsequent readmissions occurred in 2/12 (16.7%) (figure 2). Odds ratio could not be performed due to the very small number of patients in the comparison group (Table-2). Conclusion: Partial hepatectomy for liver donation is associated with significant remote hypercoagulable state due to the sudden loss in liver volume and concomitant transient deficiency of PC, PS and AT-III as well as increasing Factor VIII activity. This thrombophilia peaks within one week after the surgery and starts to recover by the third week. Clinicians should consider performing baseline thrombophilia screening and subsequently exclude potential donors with preexisting hypercoagulable state. Extending pharmacological VTE prevention with enoxaparin for 7 days after hospital discharge has been successful in reducing the VTE risk without increasing risk of bleeding or readmission rate in our patient population. Disclosures Kuriakose: Alexion: Consultancy, Honoraria, Speakers Bureau; Bayer: Consultancy.

168. Comparison between frequency of thrombophilia in patients with and without severe preeclampsia in a Brazilian Tertiary Center.

Introduction In the last two decades studies have associated thrombophilia with the risk of developing severe preeclampsia (PE). Few of them, however, have been conducted in Latin America to assess the importance of thrombophilia in these patients. Objective Evaluate thrombophilia frequency among patients with and without severe preeclampsia in a Brazilian Tertiary Center. Methods From October 2009 to October 2015, a retrospective case-control study was conducted in pregnant women with severe PE and compared to normal pregnant women at Hospital das Clinicas, FMUSP. The patients with PE who had no gestational trophoblastic disease, foetal malformation or chromosomal abnormalities and who underwent thrombophilia screening during the postnatal period were included. Pregnant women without comorbidities and normal obstetric outcome were included to make up the normal group, and were screened for thrombophilia during prenatal care (when functional dosages were abnormal, they were repeated in the postnatal period). Factor V Leiden (FVL), G20210A prothrombin mutation (PM), antithrombin, protein C, protein S, homocysteine, lupus anticoagulant, and anticardiolipin IgG and IgM antibodies were analysed. The frequency of thrombophilia in the two groups was compared. Results We included 199 patients with severe pre-eclampsia and 50 normal pregnant women. In patients with severe PE we found 55 (27,6%) women that had at least one thrombophilia (14 Antiphospholipid Syndrome,10 heterozygous PM, 10 protein S deficiency, 9 hyperhomocysteinemia, 9 heterozygous FVL, 2 antithrombin deficiency, 4 association of thrombophilia). In the control group 2 (4%) women had positive thrombophilia research (1 heterozygous PM and 1 heterozygous FVL), p Discussion Our results show a higher rate of thrombophilia among the patients with servere PE (p

Thrombophilia and risk of VTE recurrence according to the age at the time of first VTE manifestation.

Whether screening for thrombophilia is useful for patients after a first episode of venous thromboembolism (VTE) is a controversial issue. However, the impact of thrombophilia on the risk of recurrence may vary depending on the patient's age at the time of the first VTE. Of 1221 VTE patients (42 % males) registered in the MAISTHRO (MAin-ISar-THROmbosis) registry, 261 experienced VTE recurrence during a 5-year follow-up after the discontinuation of anticoagulant therapy. Thrombophilia was more common among patients with VTE recurrence than those without (58.6 % vs. 50.3 %; p = 0.017). Stratifying patients by the age at the time of their initial VTE, Cox proportional hazards analyses adjusted for age, sex and the presence or absence of established risk factors revealed a heterozygous prothrombin (PT) G20210A mutation (hazard ratio (HR) 2.65; 95 %-confidence interval (CI) 1.71 - 4.12; p < 0.001), homozygosity/double heterozygosity for the factor V Leiden and/or PT mutation (HR 2.35; 95 %-CI 1.09 - 5.07, p = 0.030), and an antithrombin deficiency (HR 2.12; 95 %-CI 1.12 - 4.10; p = 0.021) to predict recurrent VTE in patients aged 40 years or older, whereas lupus anticoagulants (HR 3.05; 95%-CI 1.40 - 6.66; p = 0.005) increased the risk of recurrence in younger patients. Subgroup analyses revealed an increased risk of recurrence for a heterozygous factor V Leiden mutation only in young females without hormonal treatment whereas the predictive value of a heterozygous PT mutation was restricted to males over the age of 40 years. Our data do not support a preference of younger patients for thrombophilia testing after a first venous thromboembolic event.

EHIT with pulmonary embolism and heterozygous prothrombin mutation

A 56-year-old male patient initially presented in our clinic in January 2008 with visible skin changes and tired, heavy legs. Ultrasound examination showed bilateral insufficiency of the great saphenous vein (GSV), grade IV according to Hach, with bilateral varicosis of the lateral saphenous branches in the lower legs with grade II chronic venous insufficiency (CVI) and CEAP 4a without insufficiency of the deep veins. Secondary findings were arterial hypertension, appendectomy in 1965, tonsillectomy in 1967, reconstruction of the right cruciate ligament in 1990, partial rightsided meniscal resection in 1999 and history of gastric ulcer. As treatment measures, we recommended the continuous wearing of class 2 compression stockings and surgical treatment of the varicose veins in stages. The patient presented for the second time almost exactly 5 years later in January 2013. Findings had changed only minimally and the patient had recently suffered from thrombophlebitis of the right GSV, with occlusion extending from the mid-calf to mid-thigh. Surgical treatment was again recommended, primarily on the left side. The patient was no longer wearing the compression stockings. Therapy

Sporadic Hemiplegic Migraine with ATP1A2 and Prothrombin Gene Mutations

Background. Hemiplegic migraine is a rare type of migraine that may present in children and adolescents. Both familial and sporadic hemiplegic migraines have similar prevalence and clinical characteristics. Patient. We report an adolescent with sporadic hemiplegic migraine who previously had a similar attack in the past and who was initially evaluated for a possible acute ischemic event. Results. Magnetic resonance angiography showed dilatation of the left middle cerebral artery that resolved in a follow-up study. She was also found to have a ATP1A2 (c.2273 G>C) mutation and a heterozygous prothrombin mutation. Conclusions. We suggest that patients with sporadic hemiplegic migraine be tested for both ATP1A2 mutations which in some cases may be pathogenic, and prothrombin mutations which increase the stroke risk for this patient population.

The G1691A Mutation of the Factor V Gene (Factor V Leiden) and the G20210A Mutation of the Prothrombin Gene as Risk Factors in Thrombotic Microangiopathies

Factor V Leiden (FVL) mutation and prothrombin G20210A mutation are common hereditary risk factors for venous thrombosis. In the current study, 40 patients (mean age +/- standard deviation, 35 +/- 11 years) and 764 healthy control subjects (mean age +/- standard deviation, 37 +/- 14 years) were enrolled to assess the potential role of these mutations in the manifestation of thrombotic microangiopathies. Compared with controls, neither the heterozygous FVL mutation (7.5% vs 8.5%; P = 1) nor the heterozygous prothrombin mutation (2.5% vs 2.8%; P = 1) was more prevalent in the patients. The findings do not support a significant role of FVL and prothrombin mutations as risk factors for the manifestation of thrombotic microangiopathies. Thus, screening for these mutations does not allow the identification of individuals at increased risk for these rare thrombotic disorders.

Präeklampsie-Screening im 1. und 2. Trimenon

Pre-eclampsia is a pregnancy-associated disease of the second part of the pregnancy, occurring mainly after 20th weeks gestation. The prevalence of hypertension in pregnancy is between 5 to 11% and affects mainly women under 20 years of age. An inadequate invasion of trophoblasts with consequential placental ischemia as a result of insufficiently dilated uterine spiral arteries is thought to be an initial cause in the pathogenesis of pre-eclampsia. The clinical symptoms of pre-eclampsia, such as loss of intravascular volume and edema, are caused by generalized endothelial dysfunction. These symptoms are potentiated by hypertension and reduced colloid osmotic pressure in the plama. The organs being affected by pre-eclampsia are those of the vascular-, hepatic-, renal-, cerebral- and coagulatory systems. The prognosis is much more severe when pre-eclampsia develops very early in the pregnancy. The symptoms include elevated blood pressure (over 140 mmHg systolic, 90 mmHg diastolic) combined with proteinuria. Frequent symptoms are hyperreflexia and edema. The etiology of pre-eclampsia has not been clearly defined. Risk factors/triggers for the development of pre-eclampsia can include chronic hypertension, advanced maternal age at first pregnancy (over 35 y), nephropathy, thrombophilia (heterozygous factor V Leiden mutation, antiphospholipid syndrome, heterozygous prothrombin mutation and homozygous MTHFR), multiple gestation and prior pregnancy with preeclampsia. The incidence of preeclampsia is higher in nulliparous than multiparous women. In many countries pre-eclampsia is still most frequent cause of maternal perinatal mortality. HELLP-Syndrome (haemolysis-elevated liver enzyme- low platelets) is a severe progressive course of this disease. Eclampsia, characterized by generalized tonic-clonic convulsion, is the most dangerous complication of pre-eclampsia, and may develop before or after delivery. This form of pre-eclampsia is associated with higher maternal and fetal mortality. Constant maternal hypertension potentially alter vascular integrity of the placenta with further consequences in fetal blood supply leading to growth restriction or zero growth and subsequently resulting in low birth weight or fetal death. The sooner the disease is detected and confirmed, the better the maternal and fetal prognoses are. This is the reason why it is major importance, together with the employment of preventive measures, to identify patients with risk factors with pre-eclampsia though an adequate screening method, thereby detecting the disease earlier and ensuring better pregnancy outcomes for both mother and child.

Mitral valve thrombosis and infective endocarditis in a patient with prothrombin mutation

This report deals with a 25-year-old female patient, who was admitted to a medical centre with complaints of fatigue and arthralgia. A non-homogeneous mass originating from the posterior papillary muscle and reaching the posterior and anterior cusps of the mitral valve was evident on the patient’s echocardiogram. Her intractable fever, despite adequate antibiotic therapy, led us to consult with the cardiac surgeons.A mitral valve replacement was performed on the 8th day of admission.The pathological examination of the mitral valve and the vegetative lesion revealed the presence of organized thrombus and infective endocarditis.The patient had a history of oral contraceptive use for one year and at genetic examination we detected a heterozygous prothrombin mutation (G20210A). The association of infective endocarditis with native mitral valvular thrombosis in a case with prothrombin mutation and history of oral contraceptive use encouraged us to share our experience with our colleagues.

Cardiology patient pages. Prothrombin 20210 mutation (factor II mutation).

Testing for the prothrombin 20210 mutation, also called factor II mutation, may have been offered by your doctor because you or someone in your family, has had (1) a blood clot in one of the deep veins of the body (also called deep vein thrombosis or DVT); (2) a blood clot that has traveled to the lung (called a pulmonary embolism or PE); (3) a blood clot in an unusual site (such as the mesenteric or cerebral sinus vein); (4) a heart attack or stroke at a young age; or (5) a history of recurrent pregnancy loss or stillbirth. A history like this in yourself or a family member may be indicative of an underlying thrombophilia. Thrombophilia is a term that describes a state in which the blood has an increased tendency to clot. People can have this increased tendency because they (1) have one or more inherited (genetic) risk factors, (2) have developed a chronic condition that puts them at increased risk, such as obesity, cancer, inflammatory bowel disease, or the persistence of certain antibodies (antiphospholipid antibodies), or (3) have a temporary condition that leads to an increased clotting tendency, such as recent surgery, trauma, a cast, prolonged immobility, pregnancy, or the use of oral contraceptives or hormone replacement therapy. The purpose of this Cardiology Patient Page is to provide more information about the prothrombin mutation, which is the second most common cause of hereditary thrombophilia. Normally, there is a fine balance in the body which ensures that there is not too much bleeding or blood clotting. If this balance is disrupted, a blood clot may occur. Throughout the course of a normal day, the blood vessels sustain many minor injuries of which you are not aware. In response, the body naturally triggers the “clotting cascade”—a sequence of events …