Inherited Thrombophilia Research Articles

Impact of Inherited Thrombophilia in Women with Obstetric Antiphospholipid Syndrome: A Single-Center Study and Literature Review.

Inherited thrombophilia (IT) has been implicated as a potential causal factor of adverse pregnancy outcomes (APOs), including recurrent miscarriage with and without the presence of antiphospholipid syndrome (APS). The aim of this study was to assess the prevalence and impact of IT on fetal-maternal outcomes and thrombotic risk in women within the spectrum of obstetric APS. Three hundred and twenty-eight women with APS-related obstetric morbidity ever pregnant were included. Of these, 74 met the APS classification criteria, 169 were non-criteria (NC)-APS, and 85 were seronegative (SN)-APS. Patients with other autoimmune diseases were excluded. APOs included early pregnancy loss, fetal death, preeclampsia, abruptio placentae, and preterm birth. Successful pregnancy was defined as the achievement of a live newborn. A literature search was also performed. The mean age of the overall group was 33.9 ± 5.3 years, and the patients were followed up for 35 (11-79) months. During the study period, there were 1332 pregnancies. Nearly 14% of the patients had an associated IT. IT patients more frequently received the standard-of-care (SoC) therapy. The presence of IT was not associated with worse maternal-fetal outcomes in patients treated with SoC treatment. Overall, IT patients had a lower frequency of newborns without treatment, especially those without definite APS. In addition, IT did not increase the risk of thrombosis during pregnancy or the postpartum period. A detailed analysis of the literature review identified only four publications related to our study and did not show conclusive evidence of the impact of IT on patients with obstetric APS. The group of women with APS-related obstetric morbidity and IT who did not receive treatment, especially those without definite APS, had a worse prognosis in terms of a live birth. However, with SoC therapy, the prognosis is similar in those patients without IT. The association of IT with APS does not seem to predispose to the development of thrombosis during pregnancy and/or the postpartum period.

Outcomes of venous thromboembolism in patients with inherited thrombophilia treated with direct oral anticoagulants: insights from the RIETE registry.

While direct oral anticoagulants (DOACs) are frequently used to treat venous thromboembolism (VTE), the outcomes of patients with inherited thrombophilia (IT) receiving DOACs for VTE remain understudied. We used data from the international RIETE registry to compare the rates of VTE recurrences, major bleeding, and mortality during anticoagulant treatment in VTE patients with and without IT, grouped by the use of DOACs or standard anticoagulant therapy. Among 103,818 enrolled patients, 21,089 (20.3%) were tested for IT, of whom 8422 (39.9%) tested positive: Protein C deficiency 294, Protein S deficiency 726, Antithrombin deficiency 240, Factor V Leiden 2248, Prothrombin gene mutation 1434, combined IT 3480. Overall, 14,189 RIETE patients (6.2% with IT) received DOACs, and 89,629 standard anticoagulation (8.4% with IT), mostly with heparins followed by vitamin K antagonists. Proportions of patients receiving DOACs did not differ between IT-positive and IT-negative patients. Rates of VTE recurrence on anticoagulant treatment were highest in patients with AT deficiency (P < 0.01). Rates of on-treatment major bleeding and all-cause mortality were lowest among patients with Factor V Leiden (FVL) or PT G20210A mutations, compared with patients who tested negative. Patients with IT who received DOACs had lower rates of major bleeding than those receiving standard anticoagulation. Excluding FVL and Protein S deficiency, patients with IT had lower rates of VTE recurrence with DOACs than with standard anticoagulation. DOACs are equally safe and effective in VTE patients with IT, with lower bleeding rates than those on standard anticoagulation.

The HABIT: Heparin and Aspirin on Birth in Inherited Thrombophilia, an International Multicenter Phase IIb Randomized Triple Blinded Clinical Trial

Background/Objective: In pregnant women with inherited thrombophilia (IT) and recurrent pregnancy loss, there is no higher-level evidence proving the beneficial effects of anticoagulation or platelet inhibition in preventing miscarriages. We hypothesize that anticoagulation with low molecular weight heparin (LMWH) and/or platelet aggregation inhibition with aspirin will increase the proportion of live birth in this population. Methods: In this phase IIb, factorial, randomized, triple blinded, placebo-controlled (double dummy) clinical trial, pregnant women age 18 to 40 with a history of IT and 2 or more previous miscarriages will be randomized and stratified by age and number of miscarriages in a 2x2 factorial design will be allocated equally to one of the four arms. The primary outcome of live birth will be analyzed through logistic regression analysis, controlling for strata, and results will be reported as odds ratio (OR) and 95% confidence intervals (CIs). Analyzed similarly, the secondary outcomes will include pregnancy loss, maternal mortality, major bleeding events, medication-associated adverse events, placental abruption, preterm birth, and gestational age at delivery. We will perform subgroup analysis for smoking status, weight, age, number of miscarriages, and type of thrombophilia. Discussion: There is lack of evidence for the use of anticoagulants to prevent pregnancy loss in women with inherited thrombophilia, despite the common diverging prescribing practice predominantly extrapolated from observations in acquired thrombophilia. With this study, we aim to provide an evidence base to create a standard of care in cases of recurrent pregnancy loss in women with IT. Keywords: heparin; aspirin; inherited thrombophilia; pregnant; live birth

Association between non-O blood type and early unexplained recurrent spontaneous abortion in women with and without inherited thrombophilia

We retrospectively evaluated the prevalence of non-O blood type – the most frequently inherited prothrombotic factor – and inherited thrombophilia (IT) in a group of women with recurrent spontaneous abortion (RSA). All consecutive women with a history of early unexplained RSA who underwent a screening for IT between December 2008 and December 2021 were considered for enrolment. A group of healthy, age-matched women with ≥1 normal pregnancy and no adverse pregnancy outcomes acted as controls. Two hundred and seventeen women were enrolled. The adjusted odds ratio (aOR) of RSA in non-O vs. O blood type was 1.37 (95% CI, 1.04-2.78), and in women with vs. without IT was 1.26 (95% CI, 1.08-3.61); aOR of RSA in women with non-O blood type and IT was 2.52 (95% CI, 1.12-5.47). We observed a significant association between non-O blood group or IT and RSA. The concomitant presence of non-O blood group and IT further increases RSA risk.

Validation of a predictive model for identifying an increased risk for recurrence in adolescents and young adults with a first provoked thromboembolism

BackgroundTo develop and validate a predictive model to determinate patients at increased risk to suffer from recurrence following a first provoked deep vein thrombosis (VTE).Methods: Predictive variables, i.e. male sex [1 point], inherited thrombophilia (IT) status (none [0 points], single [1 point], combined variants [2 points]), blood group non-0, and age at first VTE onset were included into a risk assessment model, which was derived in 511 patients and then validated in 509 independent subjects. ResultsVTE recurrence risk score (maximum 4 points, range 0–3) was below two for patients scored as low-risk (LRS) and ≥2 for patients at high-risk (HRS). Within a median time of 3 years after withdrawal of anticoagulation (AC) recurrence rate in LRG (derivation) was 11.8% versus 26.0% in HRS (p < 0.001). In the validation cohort within 2.2 years the recurrence rate was 9.8% in LRS versus 30.1% in HRS (p < 0.001). In multivariable analysis adjusted for age at first VTE and blood group the recurrent risk in HRS was significantly increased compared with the LRS (derivation: hazard/95% confidence interval: 3.7/1.75–7.91; validation: 4.7/2.24–9.81; combined 5.2/1.92–13.9). Model specificity (sensitivity) was 79.0% (52.0%) in the derivation cohort compared with 78.0% (43.0%) in the validation group.In conclusion, in the prediction model presented here the risk of VTE recurrence was associated with male gender and combined ITs. Based on the negative predictive value calculated the model may identify patients with a first provoked VTE not being at risk for recurrence.

Association of Inherited Thrombophilia with Recurrent Pregnancy Loss in A Population of Lebanese Women: A Case Control Study.

Recurrent pregnancy loss (RPL) complication is a challenge of reproductive medicine due to its often unknown etiology. A case-control study was carried out between June 2019 and April 2020 to examine the correlation between RPL and inherited thrombophilia (IT), namely mutations in factor V Leiden (FVL G1691A), prothrombin (FII G20210A), and methylenetetrahydrofolate reductase (MTHFR C677T). A total of 120 Lebanese women with RPL was studied and compared, for the frequency of these mutations, to 100 healthy reproductive Lebanese women. The association between the zygosity status of the three tested mutations, the existence of more than one prothrombotic single nucleotide polymorphisms (SNPs), and the increased risk of RPL were examined using Chi-square or two-tailed fisher exact test, and the student t test. The predictive factors of RPL were analyzed using a multiple logistic regression model. P<0.05 was considered to be statistically significant. Our results showed statistically significant higher frequencies of FVL G1691A and FII G20210A mutations among the cases with RPL compared to the control group. Thus, RPL is associated with FVL G1691A and FII G20210A mutations. These mutations seem to increase the risk of RPL in the Lebanese women. Therefore, we suggest thrombophilia screening and adequate genetic counseling for women with RPL and at high-risk to plan for primary prevention, avoiding thromboembolic or obstetric accidents, and reducing the associated morbidity and mortality among Lebanese women.

Reduced expression of annexin A2 is associated with impaired cell surface fibrinolysis and venous thromboembolism

AbstractReduced plasma fibrinolysis has been identified as a potential risk factor for venous thromboembolism (VTE), but the role of cell surface fibrinolysis in VTE is unknown. The annexin A2/S100A10 complex serves as a coreceptor for plasminogen and tissue plasminogen activator (tPA), augmenting plasmin generation by 60-fold on the endothelial cell surface. Several studies in both mice and humans support the concept that A2 regulates fibrin homeostasis and intravascular thrombosis in vivo. Here, we examined A2 protein expression and function in 115 adult subjects with VTE and 87 healthy controls. Using peripheral blood mononuclear cells as a surrogate for endothelial cells, we found a 41% mean decrease in cell surface tPA-dependent fibrinolytic activity in subjects who had a positive personal and family history of VTE but tested negative for known inherited thrombophilias (ITs). A2 protein was reduced on average by 70% and messenger RNA levels by 30%, but neither decrease correlated with anticoagulant therapy. Neither cell A2 protein nor cell surface plasmin generation correlated with plasma-based clot lysis times, suggesting that the plasma and cell surface fibrinolytic systems operate independently of one another. These data suggest that reduced expression of annexin A2 protein is associated with cell surface hypofibrinolysis and may represent a novel risk factor for IT.

Combined hereditary thrombophilias are responsible for poor placental vascularization development and low molecular weight heparins (LMWH) prevent adverse pregnancy outcomes in these patients

Background Even though thrombophilias are associated with negative pregnancy outcomes (PO), there is not a consensus of when thrombophilias should be screened for, or how they affect placental vascularization during pregnancy. Therefore, the main aim of this study was to discover inherited thrombophilias (IHT) in the first trimester in women with otherwise no indications for thrombophilia screening, based on their vascularization parameters. LMWH treatment in improvement of placental vascularization and PO was also assessed. Finally, the classification of thrombophilias based on observed obstetric risks was proposed. Methods Women were included in study based on their poor gestational sac and later utero-placental juncture vascularization signal and screening for inherited thrombophilias. LMWH were then initiated and Resistance index of Uterine artery (RIAU) was followed alongside PO (preterm birth, preeclampsia, placental abruption, intrauterine growth reduction). Study group consisted of women with combined inherited thrombophilias. Control group consisted of patients with inherited thrombophilias who have received LMWH therapy since pregnancy beginning. Findings Out of 219 women, 93 had IHT, and 43 had combined IHT. All pregnancies both in both groups ended up with live births. Vaginal birth was more present in the control group (p < .001), and all women in study group delivered by CS. Premature birth was present in 8.4% of patients in control group, and in 32.55% of the patients in the study (p < .001). PE wasn’t noted, and only 1 case of PA in control group. In the control group, 6.5% patients had IUGR, and 32.55% in the study group (p < .05). Based on RIAU and PO, thrombophilia categories were established: S (severe), MO (moderate), MI (mild) and L (low). Higher risk thrombophilias had higher RIAU later in the pregnancy, earlier pregnancy termination and Intrauterine Growth Reduction (IUGR). Conclusions Thrombophilias should be considered and screened when poor vascularization is noted early in the pregnancy with Doppler sonography. Intervention with LMWH prevents adverse PO in these patients.

Infodemiology of antiphospholipid syndrome: Merging informatics and epidemiology.

To investigate trends in Internet search volumes linked to Antiphospholipid Syndrome (APS), using Big Data monitoring and data mining. Based on the large amount of data generated by Google Trends and scientific search tools (SCOPUS, Medline/Pubmed, and ClinicalTrails.gov), we performed a longitudinal analysis based on the term "antiphospholipid" in a 5-year web-based research. Google Trends captured that APS-related digital interest was generally steady in the study period (Relative Search Volume [RSV] mean value 71.1±9.3% [95%CI 55.6-89.4], median 72.0), with no significant peak based on different seasons (e.g. winter vs. summer time). When comparing the APS-related digital interest with search volumes generated in the same time period for Inherited Thrombophilias (IT) and Systemic Lupus Erythematosus (SLE), we found a digital interest 35-times higher for APS than for IT (RSV mean value 71.1±9.3% [95%CI 55.6-89.4] vs. 2±3.2% [95%CI 0.7-7.4]). When compared to SLE, APS reached a similar RSV, showing a comparable digital interest (RSV mean value 71.1±9.3% [95%CI 55.6-89.4] vs. 87±11.8% [95%CI 60.7-107.9]). When adjusting for relative search volumes of Google Trends, we found a relative prevalence of search volumes of 35.5% in Europe, 12.3% in the United States, 11.5% in South America, 11.2% in Australia, 9.2% in Canada, 9.2% in Japan, and 5.1% in India. We observed an overall similar distribution of search volumes from Google Trends compared to results from Medline/Pubmed, SCOPUS, and ClinicalTrials.gov. In brief, the United States and Europe (mainly Italy, the United Kingdom, Spain, France, and Germany) presented the higher RSV. Similarly, these countries showed a higher number of research publications and on-going trials in the field of APS. In this study, we demonstrated that the interest in APS is not equally distributed globally. Thus, geopolitical differences might represent a challenge when attempting to estimate the prevalence of APS or designing worldwide investigations in APS. Combining the expanding framework of infodemiology with scientific networking collaborative efforts, such as AntiPhospholipid Syndrome Alliance For Clinical Trials and InternatiOnal Networking (APS ACTION), will help better define the syndrome in terms of prevalence, event occurrence ratios, and thrombosis risk assessment.

PERCUTANEOUS CLOSURE OF PATENT FORAMEN OVALE IS ASSOCIATED WITH LOWER INCIDENCE CRYPTOGENIC STROKES AMONG PATIENTS WITH INHERITED THROMBOPHIALIAS TREATED WITH ANTICOAGULANT OR ANTIAGGREGANT THERAPY

Background: Cryptogenic stroke is a dreadful outcome for patients with patent foramen ovales (PFO's). Higher incidences of cryptogenic strokes are reported in patients with PFO's and inherited thrombophilias (ITs) such as the Prothrombin and Factor V Leiden mutations. Since carriers of IT's are

Thrombophilia and Recurrent Pregnancy Loss : Is Heparin Still the Drug of Choice ? = أهبة التخثر و فقدان الحمل المتكرر : هل الهيبارين لايزال العلاج المفضل ؟

The association between thrombophilia and recurrent pregnancy loss (RPL) has become an undisputed fact. Thorombophilia creates a hypercoaguable state which leads to arterial and/or venous thrombosis at the site of implantation or in the placental blood vessels. Anticoagulants are an effective treatment against RPL in women with acquired thrombophilia due to antiphospholipid syndrome. The results of the use of anticoagulants for treating RPL in women with inherited thrombophilia (IT) are encouraging, but recently four major multicentre studies have shown that fetal outcomes (determined by live birth rates) may not be as favourable as previously suggested. Although the reported side-effects for anticoagulants are rare and usually reversible, the current recommendation is not to use anticoagulants in women with RPL and IT, or for those with unexplained losses. This review examines the strength of the association between thrombophilia and RPL and whether the use of anticoagulants can improve fetal outcomes.

W217 SERUM MARKERS OF INHERITED THROMBOPHILIA AND ANTIPHOSPHOLIPID ANTIBODIES ASSOCIATED WITH SEVERE PREECLAMPSIA – A CASE CONTROL STUDY

International Journal of Gynecology & ObstetricsVolume 119, Issue S3 p. S775-S775 Poster presentations W217 SERUM MARKERS OF INHERITED THROMBOPHILIA AND ANTIPHOSPHOLIPID ANTIBODIES ASSOCIATED WITH SEVERE PREECLAMPSIA – A CASE CONTROL STUDY E.A. Figueiro-Filho, E.A. Figueiro-FilhoSearch for more papers by this authorV.M. Oliveira, V.M. OliveiraSearch for more papers by this authorL.R. Coelho, L.R. CoelhoSearch for more papers by this authorI. Breda, I. BredaSearch for more papers by this author E.A. Figueiro-Filho, E.A. Figueiro-FilhoSearch for more papers by this authorV.M. Oliveira, V.M. OliveiraSearch for more papers by this authorL.R. Coelho, L.R. CoelhoSearch for more papers by this authorI. Breda, I. BredaSearch for more papers by this author First published: 22 October 2012 https://doi.org/10.1016/S0020-7292(12)61941-9AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume119, IssueS3Abstracts of XX FIGO World Congress of Gynecology and ObstetricsOctober 2012Pages S775-S775 RelatedInformation

Inherited thrombophilia in children with venous thromboembolism and the familial risk of thromboembolism: an observational study

AbstractScreening for inherited thrombophilia (IT) is controversial; persons at high risk for venous thromboembolism (VTE) who benefit from screening need to be identified. We tested 533 first- and second-degree relatives of 206 pediatric VTE patients for IT (antithrombin, protein C, protein S, factor V G1691A, factor II G20210A) and determined the incidence of symptomatic VTE relative to their IT status. The risk for VTE was significantly increased among family members with, versus without, IT (hazard ratio = 7.6; 95% confidence interval [CI], 4.0-14.5; P < .001) and highest among carriers of antithrombin, protein C, or protein S deficiency (hazard ratio = 25.7; 95% CI, 12.2-54.2; P < .001). Annual incidences of VTE were 2.82% (95% CI, 1.63%-4.80%) among family members found to be carriers of antithrombin, protein C, or protein S deficiency, 0.42% (0.12%-0.53%) for factor II G202010A, 0.25% (0.12%-0.53%) for factor V G1691A, and 0.10% (0.06%-0.17%) in relatives with no IT. Given the high absolute risk of VTE in relatives with protein C, protein S, and antithrombin deficiency, we suggest screening for these forms of hereditary thrombophilia in children with VTE and their relatives. Interventional studies are required to assess whether thromboembolism can be prevented in this high-risk population.

Prevalence rate for inherited thrombophilia in patients with chronic and recurrent venous leg ulceration

The aim of the study was to determine the prevalence rate for inherited thrombophilia (IT) in patients with chronic (CVU) and recurrent venous leg ulceration. We also investigated and evaluated the severity of the clinical pattern of CVU in patients with and without IT. We examined 110 patients with CVU (the study group) and 110 healthy subjects (the control group). We prepared a questionnaire to be completed by each study participant. Ultrasound Doppler color imaging or/and duplex ultrasonography was performed to evaluate the efficiency of the venous system. The ankle-brachial index was calculated to determine the efficiency of the arterial system. We examined both groups for the presence of IT. IT was diagnosed in 30% of study group and in 1.8% of control group. Our diagnoses of deep vein thrombosis (DVT) were based on medical interviews, physical examinations, and an ultrasonography of the venous system and concerned 64 study group patients (58.2%), 35 of whom (31.8%) experienced recurrent DVT. Proximal and/or distal DVT was determined in an interview and/or by an ultrasonography performed for all patients with CVU and IT. In 94% of these patients, DVT was recurrent, and in 88% of patients with CVU and IT, we observed recurrent DVT and CVU. It recurred more often and persisted longer when compared to patients with CVU and no IT, despite similar management. No differences were observed in ulcer size, localization, or pain level related to ulceration between patients with CVU and IT and those with CVU and no IT.

Increased warfarin consumption and residual fibrin turnover in thrombotic patients with primary antiphospholipid syndrome

Introduction Anedoctal reports suggest that some thrombotic primary antiphospholipid antibody syndrome (PAPS) patients on oral anticoagulation require higher than average doses to achieve given targets international normalized ratios (INR). Materials and methods To test the hypothesis of relative warfarin resistance in thrombotic PAPS and the effect of baseline IgG anticardiolipin antibodies, the cytochrome CYP2C9 and the vitamin K epoxide reductase (VKORC1) haplotypes we compared weekly warfarin consumption of 40 TPAPS (mean age 44 ± 16 years) with that of 65 thrombotic patients with inherited thrombophilia (IT) (mean age 52 ± 18) at similar target INR 2.0-3.0 followed up between January-1994 and January 2003. To investigate an involvement of the epoxidation pathway in this difference and to assess enhanced residual fibrin turnover decarboxylated prothrombin (PIVKA-II) and D-dimers (DD) were cross-sectionally investigated in the same patients between March and May 2008. Results CEX7 and VKORC1 polymorphisms explained 45.1% of the variability in warfarin consumption, whose age-adjusted mean weekly consumption was greater in PAPS than IT (27.62 vs 21.24 mg, p = 0.03). In PAPS baseline IgG aCL and VKORC1 predicted weekly warfarin consumption (p = 0.028 and p = 0.024). IgG β 2GPI and warfarin dose independently predicted plasma PIVKA-II (p = 0.01 and p = 0.02). Age and sex adjusted DD was greater in PAPS than IT (132 ± 34 vs 83 ± 37 mg/dl, p = 0.03). Conclusions Thrombotic PAPS exhibit a degree of warfarin resistance partly accounted by antiphospholipid antibodies and are in a state of enhanced fibrin turnover despite oral anticoagulation that might have implications for re-thrombosis and atherosclerosis.

Clinical Relevance of Nitric Oxide Metabolites and Nitrative Stress in Thrombotic Primary Antiphospholipid Syndrome

To assess the role of nitrite (NO(2)(-)), nitrate (NO(3)(-)), and nitrative stress in thrombotic primary antiphospholipid syndrome (PAPS). We investigated 46 patients with PAPS: 21 asymptomatic but persistent carriers of antiphospholipid antibodies (PCaPL), 38 patients with inherited thrombophilia (IT), 33 patients with systemic lupus erythematosus (SLE), and 29 healthy controls (CTR). IgG anticardiolipin (aCL), IgG anti-beta(2)-glycoprotein I (anti-ß(2)-GPI), IgG anti-high density lipoprotein (aHDL), IgG anti-apolipoprotein A-I (aApoA-I), crude nitrotyrosine (NT) (an indicator of nitrative stress), and high sensitivity C-reactive protein (CRP) were measured by immunoassays. Plasma nitrite (NO(2)(-)), nitrate (NO(3)(-)), and total antioxidant capacity (TAC) were measured by colorimetric spectroscopic assays. Average plasma NO(2)(-) was lower in PAPS, PCaPL, and IT (p < 0.0001); average NO(3)(-) was highest in SLE (p < 0.0001), whereas average NT was higher in PAPS and SLE (p = 0.01). In thrombotic PAPS, IgG aCL titer and number of vascular occlusions negatively predicted NO(2)(-) (p = 0.03 and p = 0.001, respectively), whereas arterial occlusions and smoking positively predicted NO(3)(-) (p = 0.05 and p = 0.005), and CRP positively predicted NT (p = 0.004). In the PCaPL group IgG aCL negatively predicted NO(3)(-) (p = 0.03). In the SLE group IgG aCL negatively predicted NO(2)(-) (p = 0.03) and NO(3)(-) (p = 0.02). PAPS is characterized by decreased NO(2)(-) in relation to type and number of vascular occlusions and to aPL titers. Nitrative stress and low grade inflammation are linked phenomena in PAPS and may have implications for thrombosis and atherosclerosis.

Impact of Thrombophilia On Arterial Ischemic Stroke or Cerebral Venous Sinus Thromboses in Children: A Systematic Review & Meta-Analysis of Observational Studies.

Abstract 3993Poster Board III-929 BackgroundThe incidence of stroke in children is estimated at about 2.6 per 100,000 per year. Risk factors include congenital heart malformations, trauma, hemolytic anemias, collagen tissue diseases, inborn metabolic disorders, and infectious diseases. Apart from acquired thrombophilic risk factors, such as the presence of antiphospholipid antibodies, inherited thrombophilias (IT) have been found to be associated with stroke in infants and children. However, results of single studies on the risk of stroke onset associated with IT have been contradictory or inconclusive, mainly due to lack of statistical power. The aim of this study was to estimate the impact of thrombophilia (IT) on risk of childhood stroke via meta-analysis of published observational studies. Methods and ResultsA systematic search of electronic databases (Medline, EMBASE, OVID, Web of Science, The Cochrane Library) for studies published from 1970 to 2009 was conducted using key words in combination both as MeSH terms and text words. Citations were independently screened by two authors and those meeting the a priori defined inclusion criteria were retained. Data on year of publication, study design, country of origin, number of patients/controls, ethnicity, stroke type (arterial ischemic stroke [AIS]; cerebral venous sinus thrombosis [CSVT]) were abstracted. Publication bias indicator and heterogeneity across studies were evaluated, and summary odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using both fixed-effects and random-effects models. Twenty-one of 185 references found met inclusion criteria. 1698 patients (AIS: 1291; CSVT: 407) and 2913 controls aged neonate to 18 years were enrolled. No significant heterogeneity was discerned across studies, and no publication bias was detected. A statistically significant association with stroke onset was demonstrated for each IT trait evaluated, with no difference found between AIS (table) and CSVT. Summary ORs/CIs (random-effects model) for AIS & CSVT cohorts were as follows: Protein C-deficiency (8.76/4.53-16.96), FV G1691A (3.34/2.66-4.26), FII G20210A (2.50/1.67-3.74), MTHFR T677T (1.61/1.21-2.14), antiphospholipid antibodies (5.84/3.06-11.18), elevated lipoprotein (a) (6.24/4.51-8.64), and combined ITs (8.85/3.32-23.57). Carrier rates reported for antithrombin- or protein S deficiency among patients were 1.5% and 1.6% as compared with 0.06% (p<0.001) and 0.4% (p=0.003) in healthy controls. ConclusionsThe present meta-analysis indicates that IT serve as risk factors for incident stroke. However, the impact of IT upon outcome and recurrence risk needs to be further investigated.Table 1Summary odds ratios (ORs)/95%-confidence intervals (CIs: meta-analysis) including testing for heterogeneity (I2), non-combinability, and publication bias for thrombophilic risk factors associated with a first AIS onset in childrenIT [N of studies]patients / controls (N)OR/ CI; p-value: fixed modelOR/ CI; p-value: random modelI2 [%], p-valuebias indicator (Harbord):acquired risk factorsprotein C-def. [n=8]844/120711.0/5.13-23.599.74/4.61-20.570, p=0.96p=0.60APS/LA* [n=8]930/11946.95/3.67-13.145.84/3.05-11.170, p=0.82p=0.86genetic risk factorslipoprotein (a) [n=5]722/9096.27/4.52-8.696.24/4.51-8.640.0, p=0.91p=0.64FV G1691A [n=15]981/21903.70/2.82-4.853.75/2.85-4.920, p=0.67p=0.22FII G20210A [n=11]1000/18582.60/1.66-4.082.73/1.70-4.390, p=0.46p=0.78MTHFR TT** [n=10]718/12871.58/1.20-2.081.61/1.21-2.143.5, 0.40p=0.42> 2 genetic traits [n=9]701/126518.75/6.49-54.14;12.58/3.89-40.61;0, p=0.59p=0.61 Disclosures:Manco-Johnson:Baxter BioScience: Honoraria; Bayer HealthCare: Honoraria; CSL Behring: Honoraria; NovoNordisk: Honoraria; Octapharma: Honoraria. Off Label Use: Enoxaparin (LMWH) is used off-label in children to prevent symptomatic thromboembolism.

Impact of Inherited Thrombophilia on Venous Thromboembolism in Children

The aim of the present study was to estimate the impact of inherited thrombophilia (IT) on the risk of venous thromboembolism (VTE) onset and recurrence in children by a meta-analysis of published observational studies. A systematic search of electronic databases (Medline, EMBASE, OVID, Web of Science, The Cochrane Library) for studies published from 1970 to 2007 was conducted using key words in combination as both MeSH terms and text words. Citations were independently screened by 2 authors, and those meeting the inclusion criteria defined a priori were retained. Data on year of publication, study design, country of origin, number of patients/controls, ethnicity, VTE type, and frequency of recurrence were abstracted. Heterogeneity across studies was evaluated, and summary odds ratios and 95% CIs were calculated with both fixed-effects and random-effects models. Thirty-five of 50 studies met inclusion criteria. No significant heterogeneity was discerned across studies. Although >70% of patients had at least 1 clinical risk factor for VTE, a statistically significant association with VTE onset was demonstrated for each IT trait evaluated (and for combined IT traits), with summary odds ratios ranging from 2.63 (95% CI, 1.61 to 4.29) for the factor II variant to 9.44 (95% CI, 3.34 to 26.66) for antithrombin deficiency. Furthermore, a significant association with recurrent VTE was found for all IT traits except the factor V variant and elevated lipoprotein(a). The present meta-analysis indicates that detection of IT is clinically meaningful in children with, or at risk for, VTE and underscores the importance of pediatric thrombophilia screening programs.

Thrombophilia in the young

SummaryVenous thromboembolism (VTE) is a rare disease that is being increasingly diagnosed and recognized in paediatrics in the past decade, usually as a secondary complication of primary severe underlying diseases. Apart from acquired thrombophilic risk factors, such as lupus anticoagulants, inherited thrombophilias (IT) have been established as risk factors for venous thromboembolic events in adults. In children with idiopathic VTE and in paediatric populations in which thromboses were associated with underlying medical diseases, IT have been described as additional prothrombotic risk factors. Follow-up data for VTE recurrence in children are available and suggest a recurrence rate of approximately 3% in neonates and 8% in other children. Here we present a review of the impact of IT on early onset of VTE and recurrence in children. Statistically significant associations between the IT traits investigated, e.g. factor V G1691A, factor II G20210A, protein C-, protein S-, antithrombin deficiency, elevated lipoprotein (a), combined IT and VTE onset were reported. In addition, statistically significant associations with recurrent VTE were calculated for protein S-, antithrombin-deficiency, and the factor II variant and combined IT. The absolute risk increase for VTE recurrence associated with IT ranged from 9.8 % for children carrying the factor II variant to 26% and 29% in children with combined IT and protein S-deficiency, respectively. Data obtained gave evidence that the detection of IT is clinically meaningful in children with VTE and underlines the importance of a paediatric thrombophilia screening program. Based on these data treatment algorithms have to be discussed.

Thrombophilia in the young

Venous thromboembolism (VTE) is a rare disease that is being increasingly diagnosed and recognized in paediatrics in the past decade, usually as a secondary complication of primary severe underlying diseases. Apart from acquired thrombophilic risk factors, such as lupus anticoagulants, inherited thrombophilias (IT) have been established as risk factors for venous thromboembolic events in adults. In children with idiopathic VTE and in paediatric populations in which thromboses were associated with underlying medical diseases, IT have been described as additional prothrombotic risk factors. Follow-up data for VTE recurrence in children are available and suggest a recurrence rate of approximately 3% in neonates and 8% in other children. Here we present a review of the impact of IT on early onset of VTE and recurrence in children. Statistically significant associations between the IT traits investigated, e.g. factor V G1691A, factor II G20210A, protein C-, protein S-, antithrombin deficiency, elevated lipoprotein (a), combined IT and VTE onset were reported. In addition, statistically significant associations with recurrent VTE were calculated for protein S-, antithrombin-deficiency, and the factor II variant and combined IT. The absolute risk increase for VTE recurrence associated with IT ranged from 9.8 % for children carrying the factorII variant to 26% and 29% in children with combined IT and protein S-deficiency, respectively. Data obtained gave evidence that the detection of IT is clinically meaningful in children with VTE and underlines the importance of a paediatric thrombophilia screening program. Based on these data treatment algorithms have to be discussed.