Screening For Hereditary Thrombophilia Research Articles

Thrombophilia testing for whom, why and when – a review of current practices

Thromboembolic conditions have accounted for 1 in 4 deaths worldwide in 2010. Thrombosis, which is the common pathogenesis of myocardial infarction, ischaemic stroke, and venous thromboembolism (VTE), is the leading cause of death (1/5 deaths in 1990). Hospital-acquired VTE accounts for approximately 60 percent of all VTEs annually. Others include cancer-associated thrombosis and gender associated risks. In addition to the disease burden, it also causes a significant economic burden world-wide. Multiple diagnostic tests and treatment, prolonged hospital stay and follow-up care, including management of recurrent VTE can be extremely costly. Therefore, it is important to focus on VTE prevention so that health care systems can save money, improve outcomes and save lives. In this background, it is important to have a clear direction as to when, how and whom to test for thrombophilia. Testing for thrombophilias is often performed without a clear understanding of the clinical implications of such results. Guidelines vary in the appropriate use of thrombophilia testing. In this review, these variations in thrombophilia testing and the implications mentioned in the recent guidelines and other articles are discussed. The review of such guidelines, guidance statements, review articles conclude that screening for hereditary thrombophilia has very limited advantage in the management of patients with thrombosis. Screening for antiphospholipid syndrome (APLS) is more important given its high rate of recurrence in both venous and arterial thrombosis. Screening for underlying haematological conditions such as myeloproliferative neoplasms (MPN) and paroxysmal nocturnal haemoglobinuria (PNH) is also considered important.

Investigating the Impact on Long-Term Outcomes and the Necessity of Hereditary Thrombophilia Screening in Presumed or Perinatal Arterial Ischemic Stroke.

This study aimed to investigate the influence of prothrombotic risk factors on long-term outcomes of patients with perinatal arterial ischemic stroke. The study was conducted through an analysis of monitoring results that were regularly maintained for approximately 20 years at a tertiary stroke-monitoring center. The study assessed prothrombotic risk factors, radiological area of involvement, clinical presentation, treatments, clinical outcomes, and long-term outcomes of the 48 patients included in the study, with a mean monitoring time of 77.6 ± 45.7 months (range: 6-204). Our results showed that the presence of prothrombotic risk factors did not affect long-term outcomes. However, patients with middle cerebral artery infarction had the highest risk of developing cerebral palsy, whereas those with presumed stroke had the highest risk of developing epilepsy. This study suggests that prothrombotic risk factors should not be evaluated during the acute stage unless there is a strong suspicion of the patient's history, and prevention or early diagnosis of presumed stroke patients will positively impact their long-term prognosis.

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.

The Prevalence Of Specific Gene Polymorphisms Related To Thrombophilia In Egyptian Women With Recurrent Pregnancy Loss.

Background:Despite the enhanced progress in identifying a number of leading causes to fetal miscarriage, still some women suffer from recurrent pregnancy loss (RPL) for unknown cause. A hidden genetic influence of coexisting hereditary thrombophilia was assumed to have a role.Aim:The aim was to investigate the association between unexplained RPL and thrombophilic gene variants of angiotensin I-converting enzyme (ACE) (rs4646994) and β-fibrinogen (rs1800790) genes.Settings and Design:The present case–control study was conducted on unexplained RPL in eighty women and eighty matched controls with no history of previous pregnancy loss.Materials and Methods:Analysis of extracted DNA was performed using polymerase chain reaction-restriction fragment length polymorphism method.Statistical Analysis:The frequency of genotypes and alleles was compared between groups using Chi-square test or Fisher's exact test. Risk assessment was made by odds ratio (OR) at a 95% confidence interval (CI).Results:Women with RPL group had higher frequency of DD than controls (47.5%, 31.25%, respectively, P = 0.086). D allele frequency was 0.67 and 0.54 in the control (P = 0.022). D allele carriers were at higher risk of RPL than the control as OR was 1.694 at 95% CI from 1.08 to 2.67. There was no association between the rs1800790 variant of β-fibrinogen gene and RPL.Conclusion:Females who are carriers for D allele of ACE I/D gene polymorphism are more liable to suffer from RPL. Screening for hereditary thrombophilia in females who are planning to conceive and have a history of RPL of unidentified cause is of great value to provide proper management and genetic counseling to high-risk couples.

Consistency of thrombophilia testing in a reference center according to the current guidelines.

The clinical relevance of hereditary thrombophilia (HT) testing in venous thromboembolic disease (VTE) is limited to specific guidelines. The present study aimed to evaluate the consistency of HT prescriptions in clinical practice according to the current French guidelines. This study was conducted from April 2017 to February 2018 in a specialized haemostasis centre and included 58 consecutive patients referred by their clinicians for thrombophilia screening (56 patients following a personal VTE event and 2 asymptomatic relatives of a first-degree patient who had had VTE). One experienced clinician met every patient and assessed a pre-test prediction for the presence or absence of HT based on the clinical characteristics of VTE which was compared to the HT biological results. Among the 58 patients referred to our specialized haemostasis centre, 60% were outside the scope of recommendations for thrombophilia screening. Eight patients were diagnosed with HT. Six out of 8 (75%) patients with diagnosed HT had a history of unprovoked VTE event. Familial history with VTE was a poor predictor for positive HT testing among relatives. The positive and negative predictive values of the clinical prediction were respectively of 19% and 89%. The present results underline that screening for HT remains too largely prescribed. Pre-test physician's feeling for the presence of HT was neither sensitive nor specific. Increasing physicians' awareness on this issue and current recommendations should limit prescriptions of HT tests while providing the best possible care for patients with VTE.

Тромбофилии и акушерские осложнения

This article discusses the relationship of thrombophilia with obstetric complications. In women with habitual miscarriage, do not perform screening for hereditary thrombophilia. With habitual miscarriage, women should undergo screening before pregnancy to detect antiphospholipid antibodies. Positive screening results are an indication for the appointment of LMWH and aspirin. Women with IVF do not investigate for hereditary thrombophilia and do not do LMWH therapy. Do not perform an assessment of congenital thrombophilia in women with miscarriage, with a history of childbirth with FGR, pre-eclampsia and premature detachment of the normally located placenta. Key words: thrombophilia, antiphospholipid syndrome, obstetric complications, miscarriage.

Longer Duration and Proper Titration of Low Molecular Weight Heparin (LMWH), Are Independent Factors for Successful Pregnancy Outcome. Retrospective Analysis from a Single Center

The role of thrombophilia and LMWH use in pregnancy loss (PL) and pregnancy complications (PC) is debated. In this retrospective study from a single center we analyzed the clinical outcome of pregnancies in relation to thrombophilic factors and the use of LMWH, aspirin and folic acid in 143 women followed up for a total of 173 pregnancies referred to our center from 2003 to 2016.Methods: Women were referred to our unit for: more than 2 unexplained PL (n=96, 78 experienced only early PL, 11 had only late PL, 7 had both early and late), one pregnancy loss(n=45) or one pregnancy complication (placenta abruption, intrauterine growth restriction, eclampsia, n=2). Mutations in Factor V-Leiden (FVL, G1691A), Prothrombin (PTG, G20210A) and MTHFR (C677T, A 1206C) were checked by DNA hybridization Kit. Plasma levels of antithrombin-III, protein-C, free Protein-S, APCR, FVIII, FXII, PT aPTT, fibrinogen, homocysteine and La-test were measured by photometry (DACO). Anticardiolopin and anti-β2GPI antibodies (IGG and IGM) were measured by ELISA in serum (APLA). End points were live birth and pregnancy complications.The prevalence of thrombophilia in our cohort was similar with previous studies and 34/143 (23,4%) women were negative for all thrombophilic factors. We observed mutations in FVL(11,6%), PTG (9,6%), MTHFR (homozygous or double heterozygous, 33,3%) and deficiencies of AT-III (3,3%), Prot-C (1,6%), Prot-S (8,8%), APS (8,7%). Combined severe trombophilic factors were found in 31 women (21,5%) (FVL+PTG 4/31, Natural Anticoagulants one out 3 Def + MTHFR 3/31, APS + MTHFR 2/31, FVL+MTHFR 16/31, PTG + MTHFR 6/31).We then separated our cohort into women with <2 complications or women with >2 complications. The second group had significantly higher incidence of FVL mutation (12,5 vs 8,3%, p=0.05) and deficiencies of AT-III and Free Prot-S ( 6,5 vs 0 %, p=0.01) compared to the first one. By contrast, women in the first group had higher incidence of La-test (12,5 vs 4,5%, p=0,03), APLA ( 12 vs 6,6%, p=0.03) and Prot.C deficiency (4,5 vs 0%, p=0.01).In univariate analysis both hereditary and acquired thrombophilic factors did not correlated with pregnancy outcome (live birth or pregnancy complications). Only age as a continuous parameter correlated negatively with live birth and positively with pregnancy complications (p=0.01 and p=0.025, respectively), whereas high BMI as a continuous parameter also negatively affected live births (p= 0.049). Logistic regression analysis reveals that the age of 35 is the cut off for unfortunate pregnancy outcome.Pregnancies were proceeded with (n=143, 81,7%) or without (n=32, 18,3%,) LMWH. The decision to use LMWH were based in a positive thrombophilia screening test (n=84) or to prior history >2 pregnancy complications with negative trombophilia testing (n=59). Concomitant use of ASA was prescribed in 78 pregnancies (dose less than 100 mg/day) and concomitant follic acid in 143 pregnancies. The percentage of live births were identical in women treated with LMWH (87,4%) or not (87,5%, p=0.9). In multivariate analysis, the only factor that was strongly correlated to live birth was the duration of LMWH treatment (odds ratio, OR =3,567, 95% CI (1.845, 6,894), p= 0,01) and the titration of the dose with anti-Xa (OR=5,138, 95% CI (1,717, 15,376), p = 0,01, fig.1a). By ROC analysis the duration of LMWH which correlated to live birth was ≥ 5.5 months(fig. 1b). The addition of ASA was insignificant for live birth (p=0.7), while the duration (>6months) of follic acid also appeared to add a benefit in combination with LMWH (p=0.01). Moreover, pregnancies proceeded without LMWH exhibited higher rates of pregnancy complications (18,75 vs 11,2%, p=0.08) and prematurity (14,3 vs 8,8%, p=0.05).In summary, our findings argue against hereditary thrombophilia screening in the cases of previous pregnancy loss or pregnancy complications. On the contrary, testing for APS even after the first event might be of value as this population often has laboratory evidence of APS and may benefit from proper anticoagulation. The use of LMWH and folic acid but not of ASA was related to less pregnancy complications or prematurity, whereas proper titration of LMWH by using anti-Xa and long duration of therapy were the only important factors for successful pregnancy outcome. DisclosuresNo relevant conflicts of interest to declare.

Hereditary thrombophilia in trauma patients with venous thromboembolism: Is routine screening necessary?

Venous thromboembolism (VTE), including deep venous thrombosis (DVT) and pulmonary embolism (PE), remains a common complication following trauma. The role of hereditary thrombophilia (HT) in posttraumatic VTE is unknown. In the general population with a first-time DVT, Factor V Leiden (FVL) and prothrombin G20210A mutation (PGM) are the most common types of HT with an incidence of 20% to 25% and 6% to 18%, respectively. The objective of this study was to identify the incidence of FVL and PGM in posttraumatic VTE to determine whether routine screening for HT in trauma should be performed. We conducted a prospective observational study at our Level I trauma center from 2013 to 2016 when 70 patients with posttraumatic DVT and PE were screened for FVL and PGM. Demographics, injury characteristics, and established risk factors for VTE were collected for each patient. Statistical analysis was performed to compare patients with and without HT. The incidence of FVL and PGM in posttraumatic VTE was 1.4% and 5.7%, respectively. All HT-positive patients had a DVT and one had an associated PE. Both the individual risk factors and the total number of risk factors for VTE were similar between the HT-positive group and the HT-negative group. There was a lower incidence of FVL and PGM in patients with posttraumatic DVT than in patients with a first-time DVT in the general population. HT does not appear to significantly contribute to posttraumatic VTE in our trauma population. Further research is warranted to determine whether routine screening for HT in trauma should be performed. Epidemiological study, level III; Care management/therapeutic study, level IV.

Prevention of arterial and venous thrombosis during art

Prevention of arterial and venous thrombosis during art

Arterial Ischemic Stroke in an Adolescent With Presumed Perinatal Ischemic Stroke

The risk of recurrent ischemic stroke after presumed perinatal stroke and the risk factors for such recurrence are rarely reported. Here, we present an adolescent with a history of presumed perinatal stroke who presented with arterial ischemic stroke recurrence at the age of 15 years. Hereditary thrombophilia screening performed at the time of his stroke recurrence demonstrated protein S deficiency. No evidence-based consensus guidelines on thrombophilia screening in children with presumed perinatal stroke exist, nor has the role of secondary prophylaxis been addressed. There is a risk of stroke recurrence after presumed perinatal stroke, and routine thrombophilia screening may identify those children who are at higher risk for recurrence and who might therefore benefit from secondary prophylaxis. Clear guidelines should be developed to standardize investigations and management of children with presumed perinatal ischemic stroke.

Hereditary thrombophilia in an unselected cohort of venous thrombosis patients in Singapore

AimHereditary thrombophilic markers are commonly screened among patients diagnosed as having venous thromboembolism, but optimal patient selection and the goals of screening may differ between populations. Determining the patterns of...

Inappropriate use of protein C, protein S, and antithrombin testing for hereditary thrombophilia screening: an experience from a large university hospital

Deficiencies of protein C, protein S, and antithrombin are the main inherited risk factors in Thai patients with venous thromboembolism, although the prevalence is not high. To evaluate the appropriate use of the testing for these proteins, the test orders of 503 patients were retrospectively reviewed using the proposed guidelines. Inter-rater reliability between two investigators was also calculated. Of 503, 459 (91%; 95% confidence interval 88-93%) of the test orders were inappropriate. The most common cause of inappropriateness was testing during acute thrombosis (42.5%). Results were inconclusive in 105 (20.9%) patients who had isolated decrease in one of the proteins, mostly owing to lack of confirmation of the abnormal results. Kappa index for the reliability of two investigators was 0.79. To enhance the appropriate use of hereditary thrombophilia screening tests, physician education concerning the patient selection, suitable timing for testing and repetition of the tests with abnormal results should be emphasized.

Inferior vena cava agenesis and deep vein thrombosis: 10 patients and review of the literature

Inferior vena cava agenesis (IVCA) is a rare condition, found in almost 5% of patients under 30 years old with unprovoked deep venous thrombosis (DVT). We describe 10 consecutive patients with IVCA-associated DVT and conducted an extensive literature review to investigate the typical spectrum of IVCA-associated DVT. Among our patients (eight men and two women; mean age, 25 ± 4.5 years), DVT followed intense and unusual (major) physical activity for eight of them. DVT was bilateral in six patients and unilateral in four. Ultrasonography was unable to detect IVCA, which was visualized by computed-tomography scans for seven patients, and magnetic resonance imaging and angiography for 10. Hereditary thrombophilia screening, to detect factor V Leiden or prothrombin gene heterozygosity (G20210A mutation), was positive for only two patients. Wearing elastic stockings and taking an indefinite or long-term vitamin K antagonist were prescribed for all 10 patients and nine complied with the latter. To date, 62 patients with IVCA-associated DVT have been reported in the English literature. Analysis of them and our patients yielded a typical spectrum of IVCA-associated DVT characteristics: IVCA occurs in young adults, particularly males, and is revealed by proximal DVT following major physical exertion. All were treated with a prolonged vitamin K antagonist and advised to wear elastic stockings. No precise duration of anticoagulation has been established.

Ocular artery thrombosis as an initial presentation of a prothrombin G20210A mutation

The G20210A mutation in the prothrombin gene is an established risk factor for venous thrombosis. There is controversy as to the role played by this mutation in arterial thrombotic disease. We present the case of a 56-year-old man who presented with a central retinal artery occlusion of the left eye. Evaluation revealed hypercholesterolemia, smoking, and heterozygosity for the prothrombin G20210A mutation. The literature concerning hereditary thrombophilia and retinal artery occlusion was reviewed. The synergistic effect of multiple risk factors is emphasized. Screening for hereditary thrombophilia should be considered, regardless of patient age. The prothrombin G20210A mutation may be associated with central retinal artery occlusion.

Hereditary Thrombophilia and Venous Thromboembolism: Critical Evaluation of the Clinical Implications of Screening

Venous thromboembolism is a complex disease resulting from the interactions of several risk factors from diverse origins: genetic, environmental and behavioral. Numerous studies have evidenced an association between genetic thrombophilia defects and venous thromboembolism. However, the clinical relevance of genetic thrombophilia to recurrent venous thromboembolism is not clear and the risks of long-term anticoagulant treatment usually outweigh any benefits of hereditary thrombophilia screening. Therefore, in everyday clinical practice (outside of research protocols) hereditary thrombophilia screening should be performed only in cases where such testing is likely to influence patient management.

Low-molecular-weight heparin in pediatric patients.

The incidence of thromboembolic events (TEs) in childhood is greatly underestimated. Two age groups account for approximately 70% of TEs in childhood: infants and teenagers. There are several predisposing risk factors for newborns such as small vessels, high hematocrit, and a unique neonatal hemostatic system. Central venous lines contribute to 80% of deep vein thrombosis in newborns. Other risk factors for all children are shock syndromes, trauma, surgery, heart and kidney disease, and acquired or hereditary thrombophilias. The best prophylaxis is to recognize, avoid, and remove risk factors if possible. This is particularly relevant in childhood, where risk factors can be found in the majority of TEs. The serious sequelae of TEs (mortality, and short- and long-term morbidity) require therapeutic intervention. Unfractionated heparin (UFH) has the following disadvantages: age-dependent unpredictable pharmacokinetics, the need for intravenous access for therapy and monitoring, delays in achieving therapeutic ranges, bleeding risk, the risk of heparin-induced thrombocytopenia, and osteoporosis with long-term use. Oral anticoagulants, in addition to some of these disadvantages, show considerable variation by diet (especially if there is a change from breast to bottle feeding), medication, and intercurrent illness. Review of case reports and cohort studies on 728 children treated with low-molecular-weight heparin (LMWH) indicate the following advantages over UFH: minimal monitoring, ease of administration (subcutaneous), and possibly equivalent efficacy and safety. Dose recommendations for pediatric patients cannot be directly extrapolated from those for adult patients. If dosages are calculated according to body weight, infants < 3 months (or < 5 kg) need approximately 50% more LMWH than older children or adults to reach prophylactic or therapeutic anti-factor Xa levels. Further studies are necessary to address the following: the importance of risk factors, the necessity of screening for hereditary thrombophilia, the efficacy and safety of treatment, and side effects and duration of treatment. Thromboembolic events (TEs) are considered to be rare in children. However, recent surveys reveal that TEs in children occur more often than suspected. The incidence is greatly underestimated because TEs are usually overlooked. Retrospective surveys in children treated for acute lymphoblastic leukemia with corticosteroids and asparaginase revealed clinically symptomatic TE in only 2 to 12% of patients. However, in prospective studies with routine imaging, the incidence was more than 20%. The objectives of this article are to update the present knowledge on TEs in children, including incidence, predominant age groups, risk factors, diagnosis, and indications for prophylaxis and therapy; and to discuss the use of low-molecular-weight heparin (LMWH) in children.

Prevalence of hereditary thrombophilia in patients with thrombosis in different venous systems.

The prevalence of hereditary thrombophilia is well known in patients with lower-extremity thrombosis but only poorly studied in patients with thrombosis at unusual sites. Consequently, it is still unclear whether such patients should generally be screened for hereditary thrombophilia. We retrospectively analyzed 260 patients with thrombosis at unusual sites including thrombosis in portal, cerebral, retinal, and upper-extremity veins with respect to the prevalence of FV Leiden, prothrombin G20210A, protein C, protein S, and antithrombin deficiency. In addition, all thrombotic episodes were analyzed for circumstantial risk factors. Used as controls, healthy volunteers (120) and patients with lower-extremity thrombosis (292) showed overall prevalence of hereditary thrombophilia of 9.1% and 39.0%, respectively. The corresponding numbers were 33.3%, 34.3%, and 39.0% in patients with portal vein, upper-extremity, and lower-extremity thrombosis, respectively. In patients with cerebral vein thrombosis, however, the prevalence was significantly lower (23.5%). Patients with retinal vein occlusion did not show an increased frequency of thrombophilia at all (5.9%). In all five groups FV Leiden was by far the most frequent defect (4.4-27.1%), while prothrombin G20210A occurred rarer (2.5-7.6%). Protein C, protein S, and antithrombin deficiency were much less prevalent (0-3.1%) except for patients with portal vein thrombosis (4.8-7.1%). Compared to healthy individuals, the relative risk of thrombosis was 4.3 (2.2-8.1), 3.8 (1.8-7.7), 2.5 (1.0-6.1), 3.7 (1.5-8.6), and 0.6 (0.2-2.1) for patients with lower-extremity, upper-extremity, cerebral vein, portal vein, and retinal vein thrombosis, respectively. Circumstantial risk factors were more frequent in patients without than with hereditary thrombophilia and were found most often in patients with upper-extremity thrombosis. In each group the most frequent circumstantial risk factor was different. However, oral contraceptives and cancer were found in all five groups. In conclusion, independent upon the presence of circumstantial risk factors, screening for hereditary thrombophilia is warranted in all patients with thrombosis at unusual sites except in those with retinal vein occlusion.