Natural Anticoagulant Deficiencies Research Articles

Deficiency of Natural Anticoagulants Involves in the Occurrence of Arterial Thrombosis

Background The role of natural anticoagulant deficiency in the development of arterial thrombosis (AT) is controversial. Objective Our objectives were to assess the deficiency of natural anticoagulants, including protein S (PS), protein C (PC), antithrombin III (AT III) and their involvement in the occurrence of AT. Design Retrospective cross-sectional study. Methods This study was conducted in 585 patients who were examined with PS, PC, and AT III tests. The activity of PC, PS (men, women), and ATIII under 70%, 75%, 60%, and 80% was recognized as a deficiency, respectively. Peripheral blood cell and coagulation tests were performed before starting treatment. Patients with previous AT, venous thromboembolism (VTE) or anticoagulant therapy were excluded. Results Patients without thrombosis were 222 (38%), patients with newly diagnosed VTE were 281 (48%), and patients with newly diagnosed AT were 82 (14%). The most common AT sites were in the lungs, brain, and lower extremities (31.2%, 20.8%, and 20.8%, respectively). Compared to the nonthrombosis group, the AT group had a lower PS activity (%) (82.77 ± 24.09 vs 91.31 ± 27.27), a higher fibrinogen (g/L) (4.25 ± 1.68 vs 3.74 ± 1.51), a higher D-dimer (mg/L FEU) (6.16 vs 1.95), and a higher neutrophil count (G/L) (8.57 vs 6.50) with P < .05. Compared to the VTE group, the AT group had higher hemoglobin (g/L) (135.95 ± 23.75 vs 129.02 ± 25.22) and a higher neutrophil count (G/L) (8.57 vs 7.28) ( P < .05). In the AT group, the frequencies of PC, PS, and AT III deficiency were 23.1%, 28%, and 17.1%, respectively. The AT group had a higher frequency of PS deficiency than the nonthrombosis group (28% vs 17.1%, P = .035). Patients with PS deficiency had a higher risk of AT compared to those without PS deficiency (OR = 1.888, 95% CI [1.041-3.422], P = .036). Conclusion PS deficiency may be considered a factor in increasing the risk of AT.

Detection of Unknown and Rare Pathogenic Variants in Antithrombin, Protein C and Protein S Deficiency Using High-Throughput Targeted Sequencing.

The deficiency of natural anticoagulants—antithrombin (AT), protein C (PC), and protein S (PS)—is a highly predisposing factor for thrombosis, which is still underdiagnosed at the genetic level. We aimed to establish and evaluate an optimal diagnostic approach based on a high-throughput sequencing platform suitable for testing a small number of genes. A fast, flexible, and efficient method involving automated amplicon library preparation and target sequencing on the Ion Torrent platform was optimized. The cohort consisted of a group of 31 unrelated patients selected for sequencing due to repeatedly low levels of one of the anticoagulant proteins (11 AT-deficient, 13 PC-deficient, and 7 PS-deficient patients). The overall mutation detection rate was 67.7%, highest in PC deficiency (76.9%), and six variants were newly detected—SERPINC1 c.398A > T (p.Gln133Leu), PROC c.450C > A (p.Tyr150Ter), c.715G > C (p.Gly239Arg) and c.866C > G (p.Pro289Arg), and PROS1 c.1468delA (p.Ile490fs) and c.1931T > A (p.Ile644Asn). Our data are consistent with those of previous studies, which mostly used time-consuming Sanger sequencing for genotyping, and the indication criteria for molecular genetic testing were adapted to this process in the past. Our promising results allow for a wider application of the described methodology in clinical practice, which will enable a suitable expansion of the group of indicated patients to include individuals with severe clinical findings of thrombosis at a young age. Moreover, this approach is flexible and applicable to other oligogenic panels.

Inherited Thrombophilia in the Era of Direct Oral Anticoagulants.

Severe inherited thrombophilia includes rare deficiencies of natural anticoagulants (antithrombin and proteins C and S) and homozygous or combined factor V Leiden and FII G20210A variants. They are associated with a high thrombosis risk and can impact the duration of anticoagulation therapy for patients with a venous thromboembolism (VTE) event. Therefore, it is important to diagnose thrombophilia and to use adapted anticoagulant therapy. The widespread use of direct anticoagulants (DOACs) for VTE has raised new issues concerning inherited thrombophilia. Concerning inherited thrombophilia diagnosis, DOACs are directed toward either FIIa or FXa and can therefore interfere with coagulation assays. This paper reports DOAC interference in several thrombophilia tests, including the assessment of antithrombin, protein S, and protein C activities. Antithrombin activity and clot-based assays used for proteins C and S can be overestimated, with a risk of missing a deficiency. The use of a device to remove DOACs should be considered to minimize the risk of false-negative results. The place of DOACs in the treatment of VTE in thrombophilia patients is also discussed. Available data are encouraging, but given the variability in thrombosis risk within natural anticoagulant deficiencies, evidence in patients with well-characterized thrombophilia would be useful.

Factor V Leiden Thrombophilia Causing Recurrent Thrombosis

Normal hemostasis requires a delicate balance between the natural procoagulant and anticoagulant systems. Thrombophilia is an abnormality of the coagulation or fibrinolytic system that results in a hypercoagulable state and increases the risk for thrombotic event by forming intravascular thrombus. The predisposition to form such blood clot may be inherited or acquired. In inherited thrombophilia, there is deficiency of natural anti-coagulants, e.g. anti-thrombin III, protein C and S or increase formation of human coagulant factors, e.g., factor V Leiden or prothrombin gene 20210A. Factor V Leiden thrombophilia is extremely rare in Bangladesh. We report this unique case of a young lady of 46-year-old presented with continuous headache and found to have extensive cerebral venous thrombosis with bilateral 6th cranial nerve palsy. She had suffered from acute arterial occlusion of left upper limb in September 2016, 2 years prior to current presentation. We suspect thrombophilia according to her presentation. The subsequent step is to screen for-human natural anti-coagulant factors deficiency or presence of mutated form of factor V (factor V Leiden) and prothrombin gene mutation. We screened for and found to have presence of factor V Leiden in our patient. We always should remember that, thrombotic events are increasingly recognized as a significant source of mortality and morbidity, so screening should be considered in selected individuals if criteria suggests. Bangladesh Crit Care J September 2021; 9 (2): 104-108

Hereditary thrombophilia and adverse pregnancy outcomes

Background: Multiple studies have found a relatively increased risk of placenta-mediated pregnancy complications in women with congenital thrombophilia, especially early recurrent pregnancy loss, fetal loss, early-onset preeclampsia, intrauterine growth restriction, and premature abruption of normally positioned placenta. However, the extent of the association and the absolute risk are very modest, but they significantly increase in pregnant women with severe obstetric complications. Conclusions: There is convincing evidence that deficiency of natural anticoagulants (antithrombin, protein C, protein S) is a risk factor for late fetal loss. Factor V Leiden G1691A gene mutation and prothrombin G20210A gene mutation are associated with a double risk for early and unexplained recurrent pregnancy loss and for non-recurrent late fetal loss. The association of congenital thrombophilia with preeclampsia is much more uncertain, being probably limited factor V Leiden G1691A gene mutation and more severe cases of preeclampsia. Fewer data are available on intrauterine growth restriction (IUGR) and premature abruption of the normally positioned placenta. There is insufficient evidence to suggest an association of other forms of congenital thrombophilia with adverse pregnancy outcomes. In addition, genetic and epidemiological research suggests that placenta-mediated pregnancy complications are of polygenic multifactorial etiology, with a risk determined by the interaction of multiple genetic variants and other risk factors.

Analysis of the Coagulation Profile in Children with HIV Infection-Effect of Disease and Anti Retroviral Therapy.

The pathogenesis of hypercoagulability in HIV infection is multifactorial and usually more than one factor is responsible for a thromboembolic episode. The present study was conducted to evaluate the effect of HIV infection and antiretroviral therapy on various coagulation parameters in paediatric patients. Forty two newly diagnosed paediatric patients with HIV infection who were enrolled at the Anti-Retro viral Therapy (ART) centre of Kalawati Saran Children's Hospital were included in the study. The patients were grouped into 4 clinical stages according to the WHO clinical staging of HIV disease. Coagulation tests [PT, aPTT, fibrinogen, D-Dimer and coagulation inhibitors i.e. Protein C (PC), Protein S (PS) and antithrombin III (AT III), Lupus anticoagulant (LA) and Anti phospholipid antibody (APLA)] were performed in all the patients at the time of diagnosis and repeated after 6months. All the patients were started on antiretroviral therapy within 2months of their diagnosis. At the time of diagnosis, prolonged PT and aPTT were observed in 30.9% and 23% of the cases respectively. Hyperfibinogenemia was seen in 11.9% of patients. D-Dimer was raised in 83.3% of patients. PS, PC & AT activities were reduced in 90.4%, 42.8% & 11.9% of cases respectively. A reduction in the PC and AT activity was seen from clinical stage 1 to 4, but the change was not statistically significant. On follow up after 6months, a statistically significant reduction in the level of fibrinogen and D-Dimer was seen. Even though there was improvement in the activity of all the coagulation inhibitor after 6months, statistically significant improvement was seen only for PS. The current study shows that HIV produces a hypercoagulable state in children. Raised d-dimer level and deficiency of natural anticoagulants contribute to the thrombophilic state.

Deficiency of natural anticoagulants: how should we manage cardiovascular prevention?

Deficiency of natural anticoagulants: how should we manage cardiovascular prevention?

The risk of arterial thrombosis in carriers of natural coagulation inhibitors: a prospective family cohort study

BackgroundWhether the carriership of inherited antithrombin (AT), protein C (PC), and protein S (PS) deficiency increases the risk of arterial thromboembolic events (ATE) is controversial. This information has the potential to inform the management of family members of probands with inherited deficiency of natural anticoagulants.Patients/methodsWe conducted a large prospective family cohort study in 640 subjects (of whom 341 carriers and 299 non-carriers) belonging to 86 families with inherited deficiency of AT, PC, or PS.ResultsA total of 4240 and 3810 patient-years were available for carriers and non-carriers, respectively. Risk factors for atherosclerosis were similarly distributed in the two groups. Of the 26 ATE that were recorded, 19 occurred in carriers (5.6%), as compared to 7 in non-carriers (2.3%) [p = 0.07]. After adjusting for confounders, the hazard ratio (HR) for ATE was 4.9 (95% CI 1.5–16.3) in carriers as compared to non-carriers.ConclusionsAmong family members of probands with an inherited deficiency of natural anticoagulants, carriers exhibit a risk of ATE that is almost five times higher than in non-carriers.

Thrombophilias: therapeutic employment of direct oral anticoagulants in venous hypercoagulable states

Thrombophilia or hypercoagulable state is a predisposition to form clots. Thrombophilia can be inherited or acquired, and prevalently involves venous vessels. Inherited thrombophilia consists of congenital conditions, as methylenetetrahydrofolate reductase polymorphism, Factor V Leiden and prothrombin gene mutations, natural anticoagulant deficiencies, high level of factor VIII, or dysfibrinogenemia. These congenital disorders can be responsible for venous thromboembolism, particularly deep venous thrombosis, pulmonary embolism, and, less frequently, mesenteric veins thrombosis, kidneys’ veins thrombosis or retinal vein occlusion. Acquired thrombophilia can be associated both with venous and arterial thrombosis and may be caused by antiphospholipid syndrome, aging, some malignancies, oral contraceptive use, heparin-induced thrombocytopenia, and human immunodeficiency virus. Antiplatelets’ drugs are employed in arterial thrombosis, while, heparins/oral vitamin K antagonists are indicated for acute and long-term anticoagulation. However, new oral anticoagulants can be usefully used for venous thromboembolic events. Recent experiences demonstrated that their employment is useful in some thrombophilias only, whereas other investigations are requested to evaluate their use in all hypercoagulable disorders.

A clinical case of protein C deficiency revealed in a patient during surgery for cyanotic heart defect

Background. Protein C deficiency is a rare condition. However, this pathology occurs more frequently in premature babies with cyanotic heart disease.Aim. To present a clinical case of an intraoperative detection of protein C deficiency in a patient operated for cyanotic heart disease.General findings. A clinical case of an intraoperative recurrent thrombosis of systemic-to-pulmonary shunts in a newborn patient with cyanotic heart disease is described. Newborn and premature babies with cyanotic heart defects belong to a high risk group of developing intraoperative thrombosis due to a deficiency of natural anticoagulants, which can occur as a result of genetically conditioned protein C deficiency, prematurity, immaturity of the liver or its reduced synthetic function, heart failure and hypoxemia. Additional pre-operative screening is required for detecting a deficiency of natural anticoagulants in this group of patients. The hospitals that perform such surgery should be equipped with protein C concentrates.

Risk Factors, Clinical Manifestations, Treatment Duration and Outcomes in Carriers of Severe Inherited Thrombophilias

Background Severe Inherited thrombophilia comprisses deficiencies of natural anticoagulants (antithrombin (AT), protein C (PC), and protein S (PS), and homozygosity for factor V Leiden (FVL) or prothrombin gene mutation (PGM) or double heterozygosity or other combined thrombophilia. Carriers of AT, PC and PS have a high risk of thrombosis starting at a young age, usually several members of the same family are affected and thrombosis may occur at unusual locations. Conversely homozygotes for either FVL, PGM or double heterozygotes may not have a family history of thrombosis and the first thrombotic event may present later on life. It is also unclear what is the duration and type of anticoagulation and long-term outcomes of these carriers. The purpose of this study was to compare risk factors, clinical manifestations, type and duration of anticoagulation and clinical outcomes between carriers of anticoagulant deficiencies and those with gain of function mutations (homozygosity or double heterozygosity for FVL and PGM). Methods Retrospective evaluation of electronic medical records of patients with severe inherited thrombophilia referred to the Center for Blood Disorders at Weill Cornell Medicine-New York Presbyterian Hospital between January 2009 and June 2019. Severe deficiencies of AT, PC and PS were defined and (AT ≤ 60%, PC ≤ 50% and PS ≤ 40% (2). Patients without confirmatory laboratory results for the anticoagulant deficiencies were excluded from the study. We collected demographic data, risk factors for thrombosis, family history, type of thrombotic events, pregnancy complications in females, type and duration of anticoagulant and outcomes. Statistical analysis was performed using descriptive statistics and chi-square test was applied for comparison of variables between anticoagulant deficiency carriers and gain of function mutation carriers. Results Of a total of 107 patients identified,17 were excluded due to absence of confirmatory results. A total of 90 patients were analyzed; 70 (78%) females; mean age and range 44 (22- 82). There were 34 (38%)patients with anticoagulant deficiencies (10 AT, 6 PC and 18 PS) and 56 (62%) homozygotes for FVL, PGM or double heterozygote. Of those, 23 (39%) homozygote for FVL with one also heterozygote for the PGM, 2 (3.6%) homozygote PGM and 31(55.4%) double heterozygote. Overall risk factors for thrombosis were similar in both groups. There were no identified thrombosis risk factors in 12 and 19 patients in the anticoagulant deficiency and gain of function mutation respectively. The most common type of clinical presentation in both groups was deep vein thrombosis and pulmonary embolism. A positive family history of either thrombosis of thrombophilia in a first degree family member was equal in both groups. Likewise age less than 40 at first thrombotic event was similar. The most frequent anticoagulant prescribed in the patients with anticoagulant deficiency was a direct oral anticoagulant in 26.%% and vitamin K antagonists 22.3% in the ones with gain of function mutation. More patients with anticoagulant deficiencies remain on anticoagulation for more than 1 year than the ones with a gain of function mutation (88.5% vs 64%) and had more recurrent thrombotic events (20.6% vs.5.4%). Within the 70 female patients, 5 (7%) had first trimester pregnancy loss and 14 (20%) had multiple pregnancy losses. Conclusions: Our results suggest that patients with severe inherited antithrombin, protein C and S deficiencies have worse outcomes despite longer duration of anticoagulation than patients homozygote or double heterozygote for gain of function mutations. Disclosures De Sancho: Apellis Pharmaceuticals: Other: Advisory Board; BPL: Other: Advisory Board.

Compound heterozygous mutations identified in severe type I protein S deficiency impaired the secretion of protein S

AimsHereditary protein S (PS) deficiency is one of the natural anticoagulant deficiencies causing thrombophilia. We herein described a young male with recurrent deep venous thrombosis, who was diagnosed as type...

Natural anticoagulant deficiencies in Thais: A population-based study

IntroductionIn contrast to Caucasians, hereditary anticoagulant deficiencies are more common in Asians and mutations are heterogeneous among different countries. This study aimed to determine the prevalence and genetic basis of protein C and protein S deficiencies in Thai population. MethodsHealthy volunteers were tested for protein C activity and free protein S antigen. Subjects with low values were requested for repeated testing and exclusion of acquired causes. Cases with persistently low levels were assayed for respective gene mutations using direct sequencing and multiplex ligation-dependent probe amplification (MPLA) when PROS1 point mutation was undetectable. ResultsFor protein C activities (N = 5234), the values of men were lower than those of post-menopausal women (P < 0.001). In 17 of 18 subjects, there were 7 types of PROC mutations, 64.7% of which were p.R189W and 2 were previously unreported. Protein S levels (N = 5242) were highest in men, followed by post-menopausal and pre-menopausal women, respectively (P < 0.001). The repeatedly low protein S was mostly in female (88.2%). Among 29 subjects with protein S below the sex-specific 2.5 percentile cut-points, 4 types of mutations were found in 5 subjects (17.2%) with one previously unreported mutation. Free protein S levels were below 30 U/ml in all cases with mutations. The estimated prevalence of PROC and PROS1 mutations in Thai population was 0.69% and 0.22%, respectively. ConclusionsPROC mutations, especially p.R189W, are common in Thais. However, mildly depressed protein S levels were frequently found in women with undetectable PROS1 mutation.

The obstetric complications in women with hereditary thrombophilia.

All congenital thrombophilias are associated with an increased risk of venous thromboembolism (VTE) during pregnancy. Several studies have confirmed the increased risk of obstetric complications in women with congenital thrombophilias. Case-control, cohort and transversal studies have shown that hereditary thrombophilia is more prevalent in the cohorts of women with pregnancy losses, early onset preeclampsia, abruptio placentae and IUGR. However, despite the increase in the relative risk, the absolute risk of VTE and adverse pregnancy outcomes is low. There is convincing evidence that the deficiency of natural anticoagulants (AT, protein C, protein S) is a risk factor for late fetal loss. The mutations of the FVL (G1691A) gene and the prothrombin (G20210A) gene are associated with a double risk for unexplained RPL and non-recurrent late fetal loss. The association of congenital thrombophilia and preeclampsia is much more uncertain, being, probably, limited to the FVL G1691A gene mutation and more severe cases of preeclampsia. Fewer data are available for IUGR and abruptio placentae. In addition, genetic and epidemiological research suggest that obstetric complications during pregnancy have a polygenic multifactorial etiology, with a risk determined by the interaction of multiple genetic variants and other risk factors.

Direct Oral Anticoagulant Vs Vitamin K Antagonist As Anticoagulant Therapy in Patients with Inherited and Acquired Thrombophilia

BACKGROUNDThe patients with venous thromboembolism (VTE) and thrombophilia have historically been treated with vitamin K antagonist (VKA) therapy. Nowadays, direct oral anticoagulants (DOAC) are broadly used in the treatment and prevention of VTE. However, the use of DOAC in the treatment of inherited and acquired thrombophilia remains unclear.AIMSTo assess the safety and effectiveness in both cohorts according to DOAC or VKA treatment in a cohort of patients with VTE and thrombophilia.METHODSWe included adult patients with VTE and thrombophilia treated with DOAC or VKA (2016-2018) from the beginning of treatment. Patients in the VKA group received acenocoumarol. Demographic, laboratory, thrombophilia diagnosis data and clinical presentation of VTE were collected. All patients with history of at least one VTE episode were included. The diagnosis of VTE was established by a positive finding of duplex sonography. Pulmonary embolism was diagnosed based on positive results of high resolution computed tomography. Inherited trombophilia included homozygous and heterozygous Factor V Leiden and prothrombin G20210A, natural anticoagulant deficiencies (protein C, protein S, or antithrombin) or combined defects. Patients with antiphospholipid syndrome (APS) were considered to have acquired thrombophilia. Bleeding events were classified according to ISTH criteria.RESULTSAmong 181 patients, 96 (45.5%) were treated with DOAC (6 Dabigatran, 45 Rivaroxaban, 12 Apixaban and 33 Edoxaban) and 85 were treated with VKA. Among patients receiving VKA, the time in therapeutic range was 58.5%. Mean Follow - Up (FU) were 8.1 and 6.8 months (DOAC vs VKA, p:0.77). Demographic characteristics, thrombophilia subtypes and clinical features of VTE are summarised in table 1. The most frequent previous anticoagulant treatment was low molecular weight heparin (DOAC 71.6% vs VKA 98%, p:0.15). During FU, 9 recurrent VTE episodes were reported: 2 (2.1%) vs 5 (5.9%) [DOAC vs VKA, p: 0.57] and 5 (5.2%) vs 17 (20%) major and clinically relevant non-major bleeding events [DOAC vs VKA, p: 0.001] occurred. There were 2 arterial thromboembolic events in the VKA group (APS and antithrombin deficiency patient's in the periprocedural setting).CONCLUSIONSIn our study, the effectiveness of DOAC treatment for VTE in patients with thrombophilia had a similar profile to VKA and caused significantly less major and clinically relevant non-major bleeding. This suggests that DOAC could be a good treatment option in this clinical setting. However, additional evaluation of DOAC use in patients with thrombophilia is necessary in order to provide more evidence. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Thrombophilia Caused by Beta2-Glycoprotein I Deficiency: In Vitro Study of a Rare Mutation in APOH Gene.

This study aimed to explore the mechanism of a novel mutation (p.Lys38Glu) in apolipoprotein H (APOH) gene causing hereditary beta2-glycoprotein I (β2GPI) deficiency and thrombosis in a proband with thrombophilia. The plasma level of β2GPI was measured by ELISA and Western blotting, and anti-β2GPI antibody by ELISA. Lupus anticoagulant (LA) was assayed using the dilute Russell viper venom time. Deficiency of the major natural anticoagulants including protein C (PC), protein S (PS), antithrombin (AT) and thrombomodulin (TM) was excluded from the proband. A mutation analysis was performed by amplification and sequencing of the APOH gene. Wild type and mutant (c.112A>G) APOH expression plasmids were constructed and transfected into HEK293T cells. The results showed that the thrombin generation capacity of the proband was higher than that of the other family members. Missense mutation p.Lys38Glu in APOH gene and LA coexisted in the proband. The mutation led to β2GPI deficiency and thrombosis by impairing the protein production and inhibiting the platelet aggregation. It was concluded that the recurrent thrombosis of the proband is associated with the coexistence of p.Lys38Glu mutation in APOH gene and LA in plasma.

Prothrombotic genetic risk factors in patients with very early ST-segment elevation myocardial infarction

The contribution of prothrombotic genetic risk factors in the pathogenesis of premature acute myocardial infarction (MI) is controversial. We examined the prevalence of prothrombotic polymorphisms (G1691A of factor V gene [FV Leiden] and G20210A of prothrombin [FII] gene), deficiencies of natural anticoagulants (protein C, protein S and antithrombin III) and antiphospholipid syndrome (APS) in patients with early ST-segment elevation MI (STEMI). We recruited 255 consecutive patients who had survived a STEMI ≤ 35 years of age (224 men). The control group consisted of 400 healthy individuals matched with cases for age and sex. G20210A polymorphism of FII gene was more frequent in young patients than in controls (7.4 vs. 3.5%, p = 0.023). The odds ratio (OR) for STEMI for carriers versus non-carriers was 2.239 (95% CI 1.102-4.250). The adjusted OR for major cardiovascular risk factors was 2.569 (95% CI 1.086-6.074). The risk was increased by 22-fold (95% CI 9.192-66.517) when G20210A polymorphism was present in combination with smoking. There was no difference in the prevalence of FV Leiden between patients and controls (7.8 vs. 6.5%, p = 0.512). There was only one patient (0.4%) with protein C deficiency and one with APS (0.4%). G20210A polymorphism of FII gene may be associated with increased risk of premature STEMI and the risk increases substantially when smoking is present. The contribution of other prothrombotic disorders such as deficiencies of protein C, protein S and antithrombin III and APS was minimal in this cohort.

Economy class syndrome: what is it and who are the individuals at risk?

The term ‘economy class syndrome’ refers to the occurrence of thrombotic events during long-haul flights that mainly occur in passengers in the economy class of the aircraft. This syndrome results from several factors related to the aircraft cabin (immobilization, hypobaric hypoxia and low humidity) and the passenger (body mass index, thrombophilia, oral contraceptives or hormone replacement therapy, cancer), acting together to predispose to excessive blood coagulation, which can result in venous thromboembolism. Several risk factors, both genetic and acquired, are associated with venous thromboembolism. The most important genetic risk factors are natural anticoagulant deficiencies (antithrombin, protein C and protein S), factor V Leiden, prothrombin and fibrinogen gene mutations and non-O blood group individuals. Acquired risk factors include age, pregnancy, surgery, obesity, cancer, hormonal contraceptives and hormone replacement therapy, antiphospholipid syndrome, infections, immobilization and smoking. People who have these risk factors are predisposed to hypercoagulability and are more susceptible to suffer venous thromboembolism during air travel. For these individuals, a suitable outfit for the trip, frequent walks, calf muscle exercises, elastic compression stockings and hydration are important preventive measures. Hence, it is essential to inform about economic class syndrome in an attempt to encourage Brazilian health and transport authorities to adopt measures, in partnership with the pharmaceutical industry, to prevent venous thromboembolism.

Whole Exome Sequencing Reveals Severe Thrombophilia in Acute Unprovoked Idiopathic Fatal Pulmonary Embolism

BackgroundAcute unprovoked idiopathic fatal pulmonary embolism (IFPE) causes sudden death without an identifiable thrombogenic risk. We aimed to investigate the underlying genomic risks of IFPE through whole exome sequencing (WES). MethodsWe reviewed 14years of consecutive out-of-hospital fatal pulmonary embolism records (n=1478) from the ethnically diverse population of New York City. We selected 68 qualifying IFPE cases for WES. We compared the WES data of IFPE cases to those of 9332 controls to determine if there is an excess of rare damaging variants in the genome using ethnicity-matched controls in collapsing analyses. FindingsWe found nine of the 68 decedents (13·2%) who died of IFPE had at least one pathogenic or likely pathogenic variant in one of the three anti-coagulant genes: SERPINC1 (Antithrombin III), PROC, and PROS1. The odds ratio of developing IFPE as a variant carrier for SERPINC1 is 144·2 (95% CI, 26·3–779·4; P=1·7×10−7), for PROC is 85·6 (95% CI, 13·0–448·9; P=2.0×10−5), and for PROS1 is 56·4 (95% CI, 5·3–351·1; P=0·001). The average age-at-death of anti-coagulant gene variant carriers is significantly younger than that of non-carriers (28·56years versus 38·02years; P=0·01). InterpretationThis study showed the important role of severe thrombophilia due to natural anti-coagulant deficiency in IFPE. Evaluating severe thrombophilia in out-of-hospital fatal PE beyond IFPE is warranted.

Combined oral contraceptives, thrombophilia and the risk of venous thromboembolism: a systematic review and meta‐analysis

Essentials We performed a meta-analysis on thrombosis risk in thrombophilic oral contraceptive (COC)-users. The results support discouraging COC-use in women with a natural anticoagulant deficiency. Contrary, additive risk of factor V Leiden (FVL) or prothrombin-G20210A (PT) mutation is modest. Women with a FVL/PT-mutation as single risk factor can use COCs if alternatives are not tolerated. Background Combined oral contraceptives (COCs) are associated with an increased risk of venous thromboembolism (VTE), which is shown to be more pronounced in women with hereditary thrombophilia. Currently, WHO recommendations state that COC-use in women with hereditary thrombophilias (antithrombin deficiency, protein C deficiency, protein S deficiency, factor V Leiden and prothrombin-G20210A mutation) is associated with an unacceptable health risk. Objective To perform a meta-analysis evaluating the additional risk of VTE in COC-users with thrombophilia. Methods The MEDLINE and EMBASE databases were searched on 10 February 2015 for potential eligible studies. A distinction was made between 'mild' (factor V Leiden and prothrombin-G20210A mutation) and 'severe' thrombophilia (antithrombin deficiency, protein C deficiency, protein S deficiency, double heterozygosity or homozygosity of factor V Leiden and prothrombin-G20210A mutation). Results We identified 12 case-control and three cohort studies. In COC-users, mild and severe thrombophilia increased the risk of VTE almost 6-fold (rate ratio [RR], 5.89; 95% confidence interval [CI], 4.21-8.23) and 7-fold (RR, 7.15; 95% CI, 2.93-17.45), respectively. The cohort studies showed that absolute VTE risk was far higher in COC-users with severe thrombophilia than in those with mild thrombophilia (4.3 to 4.6 vs. 0.49 to 2.0 per 100 pill-years, respectively), and these differences in absolute risks were also noted in non-affected women (0.48 to 0.7 vs. 0.19 to 0.0), but with the caveat that absolute risks were estimated in relatives of thrombophilic patients with VTE (i.e. with a positive family history). Conclusion These results support discouraging COC-use in women with severe hereditary thrombophilia. By contrast, additive VTE risk of mild thrombophilia is modest. When no other risk factors are present, (e.g. family history) COCs can be offered to these women when reliable alternative contraceptives are not tolerated.