PT G20210A Research Articles

Bilateral multiple recurrent branch retinal vein occlusions secondary to hypercoagulopathy associated with multiple mutations: A rare case report

Abstract: Retinal vein occlusions (RVOs) are relatively common vascular disorders, often resulting in significant visual impairment. We present an intriguing case of a 53-year-old male with recurrent bilateral branch RVOs stemming from underlying hypercoagulopathy. This complex scenario encompassed simultaneous bilateral RVO occurrences and subsequent unilateral recurrences. Despite the absence of systemic comorbidities or conventional risk factors, genetic assessment unveiled notable heterozygous mutations involving Factor V Leiden (G1691A) and Factor II (PT G20210A), along with a homozygous methylenetetrahydrofolate reductase A1298C mutation. While routine hematological indicators remained largely unremarkable, the marked efficacy of anti-vascular endothelial growth factor (anti-VEGF) agents, particularly when administered promptly, emerged as a noteworthy therapeutic avenue. This case underscores the imperative of scrutinizing thrombotic mutations in youthful patients with recurrent RVOs, accentuating the favorable retinal response to anti-VEGF interventions and emphasizing the rewards of timely clinical intervention.

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.

MTHFR C677T, Prothrombin G20210A, and Factor V Leiden (G1691A) Polymorphism and Beta-Thalassemia Risk: A Meta-Analysis.

BackgroundBeta (β)-thalassemia major patients frequently suffer from many vascular problems. Thrombophilia is a blood disorder that comprises imbalances in the blood coagulating factor due to ecological and hereditary components. Previous evidence shows that thrombosis is the commonest risk in beta-thalassemia patients. Several studies have examined that MTHFR C677T, prothrombin G20210A (PT G20210A), and Factor V Leiden G1691A (FVL G1691A) polymorphism play a crucial role in the development of β-thalassemia major, yet the result was questionable and uncertain. Therefore, in this study, we executed the correlation between these gene polymorphisms with β-thalassemia major patients.MethodsSuitable keywords were used to search related articles in PubMed, Google Scholar, and Web of Science. In this random-effects meta-analysis, we analyzed the odds ratio (OR) for the estimation of risk.ResultsA total of nine research articles with 645 β-thalassemia major patients and 989 healthy controls were incorporated in this meta-analysis. The pooled OR was assessed in MTHFR C677T, PT G20210A, and FVL G1691A polymorphism. This random-effects meta-analysis demonstrated that MTHFR C677T, PT G20210A, and FVL G1691A gene polymorphism did not significantly associate with β-thalassemia major. Moreover, the heterogeneity was significantly found in genotype CC vs CT+TT C677T (I2=61%) and allele C vs T (I2=71%) of MTHFR and genotype GG vs GA (I2=95%), GG vs GA+AA (I2=95%), GA vs GG+AA (I2=95%), and allele G vs A (I2=93%) of FVL G1691A.ConclusionThe results of this meta-analysis show that MTHFR C677T, prothrombin G20210A, and Factor V Leiden (G1691A) gene polymorphism are not a risk factor for β-thalassemia major.

ABO Blood Groups and Thrombophilia Markers in Patients With Unstimulated Thrombosis in Kurdistan Region of Iraq.

Thromboembolism (TE) is a complex disease caused by various acquired and inherited factors. The common mutations; factor V Leiden G1691A (FVL G1691A), prothrombin G20210A (PTG20210A), and methylene tetrahydrofolate reductase C677T (MTHFR C677T) are important inherited causes in both venous and arterial thrombosis. The association between ABO blood groups and thrombophilia has been noted by researchers. We aimed to determine the frequency and association of ABO blood groups as a risk factor along with 3 thrombophilia mutations and another 3 thrombophilia markers in a group of patients with unstimulated thrombosis. In a prospective case-control study, we focused on 100 samples, 50 patients with documented thrombosis as well as 50 healthy age-matched controls. Multiplex polymerase chain reaction and reverse hybridization to oligonucleotide particular probes were employed to detect FVL G1691A, PT G20210A, and MTHFR C677T mutations. Analysis of other thrombophilia markers including protein C (PC), protein S (PS), and antithrombin (AT) assays was also performed. ABO blood group typing was done according to standard methods. Non-O blood group was significantly more frequent among cases than controls (76% vs 54%) with high odds of TE (odds ratio [OR] = 2.69). Positivity for at least 1 thrombophilia marker was more in cases (60%) than controls (34%; OR = 2.9). The combined effect of non-O blood group and thrombophilia markers raised the risk of TE (OR = 4.16, P = .001), particularly FVL (OR = 6.76). This study illustrates that harboring the non-O blood group poses an additive effect with other thrombophilia markers in the causation of TE.

Thrombophilic risk factors for retinal vein occlusion

The aim is to study risk factors for retinal vein occlusion (RVO), such as thrombophilic and cardiovascular risk factors (CRF). A retrospective consecutive case series of 60 patients with RVO was made, tested for CRF, hyperhomocysteinemia, lupic anticoagulant, antiphospholipid antibody and 5 gene variants: factor V (FV) Leiden (G1691A), factor II (PT G20210A), 5,1-methylenetetra-hydrofolate reductase (MTHFR; 677 C > T and 1298 A > C), plasminogen activator inhibitor 1 (PAI-1; 4 G/5 G). More than 1 CRF were present in 36 patients (60%), which had a significantly higher mean age at diagnosis (66.7 ± 12.9 versus 59.5 ± 13.7 with ≤1 CRF, [t(57) = −2.05, p = 0.045, d = 0.54). Patients with thermolabile MTHFR forms with decreased enzyme activity (T677T or C677T/A1298C) had a significant lower mean age [57.6 ± 15.1; t (58) = 3.32; p = 0.002; d = 0.846] than patients with normal MTHFR enzyme activity (68.5 ± 10.2). Regarding CRF and thermolabile forms of MTHFR, the mean age at diagnosis could be significantly predicted [F(2,56) = 7.18; p = 0.002] by the equation: 64.8 − 10.3 × (thermolabile MTHFR) − 5.31 × ( ≤ 1CRF). Screening of MTHFR polymorphisms may be useful in younger RVO patients, particularly when multiple CRF are absent.

FVL G1691A and PT G20210A genes mutation and family history of thrombosis in Georgian myocardial infarction and ischemic stroke patients

The purpose of this study was to investigate the association of VDR polymorphism with development of retinopathy in a Han Chinese population with type 2 diabetes mellitus.A total of 204 T2DM patients were subdivided into groups without diabetic retinopathy (NDR, n = 110) and those with DR (n = 94). VDR rs2228570 (FokI:C > T), rs1544410 (BsmI:G > A), and rs7975232 (Apal:A > C) polymorphism was assayed by polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP).Diabetes duration (10.0 vs. 5.0 years, P < 0.01) was longer, systolic blood pressure (143.98 ± 24.31 vs. 135.11 ± 15.23, P < 0.01), and HbA1c (9.2 ± 2.06 vs. 8.35 ± 1.62, P < 0.01) were higher in DR than in NDR patients. Distribution frequencies of the rs2228570, rs1544410, and rs7975232 genotypes followed the Hardy–Weinberg equilibrium. VDR rs2228570 TT genotype frequency was significantly higher in DR (n = 30; 31.9%) than in NDR patients (n = 14; 12.7%; P < 0.01). DR patients carried more rs2228570 T alleles (n = 113; 60.1%) than did NDR patients (n = 89; 40.5%; P < 0.01). Genotype frequencies of rs1544410 and rs7975232 in NDR and DR patients were not different. Logistic analysis confirmed that diabetes duration (odds ratio (OR) 1.108, P < 0.01), SBP (OR 1.022, P < 0.05), HbA1c (OR 1.267, P < 0.05), and the VDR rs2228570 T allele (OR 1.467, P < 0.01) were independently associated with DR risk. TAA haplotype frequency was significantly higher in DR (24.0%) than in NDR (16.1%) patients (P < 0.05).Diabetes duration, SBP, HbA1c, and the rs2228570 T allele were associated with increased risk of DR. VDR rs2228570 might be good candidate biomarker of DR in Han Chinese T2DM patients.

The fine art of vascular wall maintenance. Carriership of XPC, TP53 and APOE polymorphisms may be a risk factor for cerebral vascular accidents in the Bulgarian population

Efficient maintenance of the integrity of the endothelium of cerebral blood vessels is crucially important, especially when the vessel walls are subjected to greater-than-normal levels of stress. Persistently high levels of genotoxic stress may result from lower capacity to detect and repair DNA damage conferred by carriership of variants of key genes of DNA repair/maintenance of genomic integrity. Adult Bulgarian patients with a history of cerebral vascular accidents (CVAs) and age-matched healthy controls were analyzed for 11 markers, including 7 DNA polymorphisms in genes coding for proteins of DNA repair and maintenance of genomic integrity, 3 hypercoagulability markers and 1 marker for susceptibility for cerebral amyloidosis. Homozygous carriership of the del allele of the polymorphism XPCins83 was associated with decreased risk of CVAs (RR = 0.446, 95% CI:0.225–0.886, p = 0.021). In individuals carrying the 'protective' del/del XPCins83 genotype, carriership of the 'pro-apoptotic' genotype Arg/Arg in the TP53 locus was associated with increased risk of CVAs (RR = 1.845, 95% CI:1.049–3.244, p = 0.034). Carriers of the Lys751Gln genotype at the ERCC2 locus were at increased risk of CVAs (RR = 2.055, 95% CI:1.09–3.876, p = 0.025). Carriership of the E2/E3 genotype at the APOE locus decreased the risk of CVAs in Bulgarian males (RR = 0.279, 95% CI:0.090–0.873, p = 0.028). Male Bulgarian carriers of the APOE4 allele were at increased risk of CVAs. Carriership of the common prothrombotic mutations Factor V Leiden, PT G20210A, MTHFR C677T and PAI1 4G/5G had no significant effect on the risk of CVAs in Bulgarian adults.

The incidence of FVL and PT G20210A mutations in patients with idiopathic deep venous thrombosis

Background: Factor V Leiden (FVL), prothrombin gene (PT G20210A), and methylenetetrahydrofolate reductase (MTHFR) C677T mutations are known as molecular biomarkers to evaluate the predisposition of deep venous thrombosis (DVT). These hereditary risk factors affect the natural anticoagulant mechanisms and activate the coagulation mechanisms because of an imbalance between procoagulant and anticoagulant factors. Our study aimed to determine the prevalence of these mutations in Turkish patients presenting with idiopathic DVT. Methods: A total of 135 patients with idiopathic DVT admitted to our clinic were investigated for FVL, PT G20210A, and MTHFR (C677T, A1298C) gene mutations. Screening of polymorphisms was carried out by using SNaPshot® multiplex system (Applied Biosystems Inc.). Wild, heterozygous and homozygous genotypic distributions of these mutations were defined as number and percentage frequency. Results: There were 74 male and 61 female patients ranging in age from 18 to 85 years. FVL mutation was found in 66 (41.47%) patients (12 homozygotes 8.88%, 44 heterozygotes 32.59%), PT G20210A was found in 14 (10.36%) patients (1 homozygous 0.74%, 13 heterozygotes 9.62%). MTHFR C677T was found in 53 (39.25%) patients (10 homozygotes 7.40%, 43 heterozygotes 31.85%), and MTHFR A1298C was found in 84 (62.22%) patients (16 homozygotes 11.85%, 68 heterozygotes 50.37%).

Incidence of the genetic mutations in patients with coronary artery disease

Objectives . Coronary artery disease (CAD) is the leading cause of mortality in the world. It is a complex disorder resulting from the interaction between environmental risk factors and hereditary predisposition. The role of the factor V Leiden (FVL), protrombin gene (PT G20210A) and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphisms in the development of CAD is controversial. In this study, we investigated the incidence of these polymorphisms in order to delineate their roles in the development of CAD in a tertiary University hospital. Methods. This study included 58 consecutive CAD patients. Diabetic and hypertensive patients were excluded. FVL, PT G20210A, and MTHFR (C677T, A1298C) mutations were investigated in all patients. Polymerase chain reaction and the amplification refractory mutation system were used to identify these polymorphisms. Results. Thirty-six men and 22 women were enrolled with an age ranging between 41 to 85 (mean age: 62.75±9.18 years). The heterozygous PT G20210A genotype was identified in 5 (8.6%) patients (2 males, 3 females). The heterozygous FVL genotype was found in 8 (13.8%) patients (6 males and 2 females). The incidence of homozygous MTHFR C677T and homozygous MTHFR A1298 carriers was found to be 17.2% and 8.6%, respectively. There were no significant differences in the distribution of polymorphisms according to gender ( p >0.05). Conclusions. The FVL and PT G20210A polymorphisms most likely play a contributory role in the development of CAD. In contrast, the MTHFR C677T and MTHFR A1298C genotypes were not associated with a predisposition to the development of CAD. However, in compound MTHFR C677T/A1298C carriers, the presence of FVL or PT G20210 polymorphism may contribute the development of CAD. Further studies are needed to support these findings.

THE EFFICACY OF TISSUE FACTOR −603A/G AND +5466A&gt;G POLIMORPHISMS AT THE DEVELOPMENT OF VENOUS THROMBOEMBOLISM IN CANCER PATIENTS

Venous thromboembolism (VTE) is one of the most common complications in cancer patients. Although factor V Leiden (FVL) is the most common genetic defect causing thrombosis, the impact of gene abnormalities on thrombotic tendency in cancer patients remains poorly explored. Tissue factor (TF) is a major physiologic initiator of blood coagulation. This is the first study regarding the association of TF gene -603A/G and +5466A>G polymorphisms with VTE in malignancy. Materials and Me-thods: The study consists of two groups: cancer patients with VTE were included as Group 1 (n = 46); Group 2 comprises 196 cancer patients without VTE. Restriction fragment length polymorphism method was used for the detection of polymorphisms of TF -603A/G in the 5՛upstream region and TF 5466A/G in intron 2. FVL, PT G20210A and MTHFR C677T polymorphisms were determined by using commercially available Light Cycler kits. The genotype and allele frequencies between the groups were compared using χ2 or Fisher exact test, if appropriate. No differences were observed in the distribution of TF gene -603A/G genotype frequencies between the groups. Although a slightly increased incidence of +5466GA genotype was in Group 1 (17.4% vs 11.2%), it did not achieve statistical significance. The prevalence of FVL was significantly greater in Group 1 compared with Group 2 (41.3% vs 4.1%, p < 0.05). Difference in frequency of 677TT+CT (MTHFR) + 5466GG (TF) genotypes combination was found in women of two investigated Groups (p < 0.05). No differences were also in genotypes and allele frequencies of MTHFR C677T and PT G20210A between two Groups (p > 0.05). The present study did not show significant association of TF gene -603A/G and +5466A>G polymorphisms with VTE in malignancy, however, further larger studies including different ethnic population are needed to confirm our findings.

Variant alleles in factor V, prothrombin, plasminogen activator inhibitor-1, methylenetetrahydrofolate reductase and risk of thromboembolism in metastatic colorectal cancer patients treated with first-line chemotherapy plus bevacizumab.

Single-nucleotide polymorphisms (SNPs) related to hereditary thrombophilia were investigated as risk factors for thromboembolism in cancer patients. Their effect in metastatic colorectal cancer (mCRC) has never been explored so far. Our aim was to analyse the effect of coagulation factor V (FVL G1691A), prothrombin (PT G20210A), methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) and plasminogen activator inhibitor type 1 (PAI-1 5G/4G) allelic variants in this setting. Fifty-two patients treated with first-line chemotherapy plus bevacizumab who developed a thromboembolic event in their lifetime were initially genotyped. A contemporary cohort of 127 patients who did not experience any thromboembolic event was also analysed. DNA was extracted from peripheral blood and genotypes were determined by real-time PCR, using LightSNiP (TIB MOLBIOL) on LightCcler 480 (Roche). The association between thromboembolism and SNPs was investigated by univariable and multivariable analyses. All SNPs were in Hardy-Weinberg equilibrium (χ2 test P>0.20). FVL G1691A and PT G20210A were present only in heterozygosis in 4 (2.2%) and 7 (3.9%) patients, respectively; MTHFR C677T in homozygosis in 29 (16.2%), MTHFR A1298C in homozygosis in 13 (7.3%); PAI-1 5G/4G in 98 (54.7%) and 4G/4G in 41 (23%) patients. At univariable analysis, treatment duration was significantly associated with thromboembolism (P<0.001), whereas gender, age, obesity, platelets count and chemotherapy backbone were not. Similarly, FVL G1691A and PT G20210A as well as MTHFR C677T and PAI-1 4G allele were significantly associated, whereas MTHFR A1298C was not. At multivariable model including PT G20210A, MTHFR C677T and PAI-1 4G (age, obesity, treatment duration and chemotherapy backbone were included as adjustment factors), the three SNPs were significantlty associated with higher risk of thromboembolism (P=0.025, <0.0001 and P=0.033, respectively). Further validation studies are warranted in order to design a prospective trial of thromboprophylaxis in mCRC patients with high-risk genotypes.

Evaluation of Factor V G1691A, prothrombin G20210A, Factor XIII V34L, MTHFR A1298C, MTHFR C677T and PAI-1 4G/5G genotype frequencies of patients subjected to cardiovascular disease (CVD) panel in south-east region of Turkey

Cardiovascular disease (CVD) risk factors, such as arterial hypertension, obesity, dyslipidemia or diabetes mellitus, as well as CVDs, including myocardial infarction, coronary artery disease or stroke, are the most prevalent diseases and account for the major causes of death worldwide. In the present study, 4,709 unrelated patients subjected to CVD panel in south-east part of Turkey between the years 2010 and 2013 were enrolled and DNA was isolated from the blood samples of these patients. Mutation analyses were conducted using the real-time polymerase chain reaction method to screen six common mutations (Factor V G1691A, PT G20210A, Factor XIII V34L, MTHFR A1298C and C677T and PAI-1 -675 4G/5G) found in CVD panel. The prevalence of these mutations were 0.57, 0.25, 2.61, 13.78, 9.34 and 24.27 % in homozygous form, respectively. Similarly, the mutation percent of them in heterozygous form were 7.43, 3.44, 24.91, 44.94, 41.09 and 45.66%, respectively. No mutation was detected in 92 (1.95%) patients in total. Because of the fact that this is the first study to screen six common mutations in CVD panel in south-east region of Turkey, it has a considerable value on the diagnosis and treatment of these diseases. Upon the results of the present and previous studied a careful examination for these genetic variants should be carried out in thrombophilia screening programs, particularly in Turkish population.

Hereditary Thrombophilia, Anti‐Beta2 Glycoprotein 1 IgM, and Anti‐Annexin V Antibodies in Recurrent Pregnancy Loss

We investigated the beta2-glycoprotein I and anti-annexin V antibodies as anti-phospholipid-cofactor antibodies; and factor V G1691A Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase (MTHFR) C677T mutations as hereditary thrombophilia in recurrent pregnancy losses (RPL). Study group consisted of 84 women with recurrent pregnancy loss and control group consisted of 84 women having at least one live birth. Methylenetetrahydrofolate reductase C677T homozygous mutation was detected in 28.5% of the study group and in 14.2% of the controls, and the difference was highly significant (P < 0.001). Heterozygous mutation of this gene was found in 64.3% of the study population and in 38.1% of the controls, and difference in heterozygous mutation frequency was also significant (P < 0.001). Both homozygous and heterozygous mutations of PT G20210A and factor V G1691A were not different between the groups. There was no significant difference in anti-annexin V levels and anti-beta2-gp 1 levels of the groups. We concluded that both homozygous and heterozygous mutations of MTHFR C677T were related with RPL in Caucasian women.

Thrombotic gene polymorphisms and postoperative outcome after coronary artery bypass graft surgery

BackgroundEmerging perioperative genomics may influence the direction of risk assessment and surgical strategies in cardiac surgery. The aim of this study was to investigate whether single nucleotide polymorphisms (SNP) affect the clinical presentation and predispose to increased risk for postoperative adverse events in patients undergoing coronary artery bypass grafting surgery (CABG).MethodsA total of 220 patients undergoing first-time CABG between January 2005 and May 2008 were screened for factor V gene G1691A (FVL), prothrombin/factor II G20210A (PT G20210A), angiotensin I-converting enzyme insertion/deletion (ACE-ins/del) polymorphisms by PCR and Real Time PCR. End points were defined as death, myocardial infarction, stroke, postoperative bleeding, respiratory and renal insufficiency and event-free survival. Patients were compared to assess for any independent association between genotypes for thrombosis and postoperative phenotypes.ResultsAmong 220 patients, the prevalence of the heterozygous FVL mutation was 10.9% (n = 24), and 3.6% (n = 8) were heterozygous carriers of the PT G20210A mutation. Genotype distribution of ACE-ins/del was 16.6%, 51.9%, and 31.5% in genotypes I/I, I/D, and D/D, respectively. FVL and PT G20210A mutations were associated with higher prevalence of totally occluded coronary arteries (p < 0.001). Furthermore the risk of left ventricular aneurysm formation was significantly higher in FVL heterozygote group compared to FVL G1691G (p = 0.002). ACE D/D genotype was associated with hypertension (p = 0.004), peripheral vascular disease (p = 0.006), and previous myocardial infarction (p = 0.007).ConclusionsFVL and PT G20210A genotypes had a higher prevalence of totally occluded vessels potentially as a result of atherothrombotic events. However, none of the genotypes investigated were independently associated with mortality.

The frequency of FV G1691A and PT G20210A mutations in an Albanian population.

The frequency of FV G1691A and PT G20210A mutations in an Albanian population.

Genetic Mutations in Turkish Population With Pulmonary Embolism and Deep Venous Thrombosis

Venous thromboembolism (VTE) is a universal health hazard. Inherited and acquired risk factors increase the risk of VTE. We evaluated the relationship between factor V (G1691A, A1090G, and A1299G), prothrombin (PT G20210A), methylenetetrahydrofolate reductase (MTHFR C677T) mutations, plasminogen activator inhibitor 1 (PAI-1 -675) polymorphism, and VTE in Turkish population. In all, 80 patients with VTE and 104 controls were included. Heterozygous factor V Leiden (FVL) mutation was significantly higher among patients (P = .04) with allele frequency of 6.3% (P = .01). Heterozygous PT G20210A mutation was also significantly higher among patients (P = .001) with allele frequency of 6.9% (P = .003). MTHFR 677TT genotype was significantly higher in patients (P = .009) with allele frequency of 23.8% (P = .005). No significant difference was found in FV A1090G and FV A1299G mutation rate as well as PAI-1 genotypes and their allele frequencies (P > .05). Thus, frequencies of FV G1691A, PT G20210A, and MTHFR C677T mutations are higher in patients with VTE. FV A1090G, FV A1299G mutations, and PAI-1 gene polymorphisms may not be a risk factor for VTE in Turkish population.

Major and Potential Prothrombotic Genotypes in Patients with Venous Thrombosis and in Healthy Subjects from Slovenia

The objective of our study was to investigate the prevalence of the polymorphisms factor V Leiden (FVL), prothrombin G20210A (PT G20210A), methylenetetrahydrofolate reductase C677T (MTHFR C677T), plasminogen activator inhibitor type 1 –675 4G/5G (PAI-1 4G/5G) and factor XII –4 C/T (FXII –4 C/T) in 295 Slovenian patients with venous thrombosis (VT) and 223 healthy controls in order to establish their contribution to the risk for VT. The major genetic risk factor was FVL, while PT G20210A, MTHFR 677 C/T, PAI-1 4G/5G and FXII –4 C/T polymorphisms were not. However, PT G20210A increased the risk of recurrent VT, MTHFR C677T increased the risk in older patients, while the FXII –4 T allele suggested a possible protective effect in younger patients. The risk of VT increased with increasing number of genetic defects.

Spontaneous Resolution of Extreme Essential Thrombocytosis in a Child

Essential Thrombocytosis (ET) is rare in children and its clinical course is considered to be different from the adult disease. Unlike adults, most children with ET do not need treatment; however, children with extreme thrombocytosis present the treating physician with a therapeutic dilemma. We report a girl with a spontaneous resolution of extreme essential thrombocytosis. A 13 year old previously healthy girl presented to our ER with a 3 months history of intermittent mild abdominal pain with short episodes of diarrhea, intermittent episodes of paraesthesia in lower limbs and 3000 × 109/L platelets on CBC with pseudohyperkalemia of 6.4 mEq/L. Physical examination was unremarkable except for some diffuse mild tenderness on abdominal palpation. Laboratory work-up revealed normal WBC and Hb, Platelets 4100 × 109/L, mild microcytosis, Iron - 21.9 mcg/dL, transferin saturation 5.6%, serum potassium − 6.5 mEq/L, LDH 1000 IU. Liver, renal and thyroid function tests were within normal limits. PTT was mildly elevated 49.3 seconds (normal – 24.3–35), LAC-R mildly positive – 1.205 (0.8–1.20), KCT 58.2 sec. Anticardiolipin IgG −4.82 U/ml (negative), IgM - 11.24 U/ml (negative < 7 U/ml). Anti dsDNA and Anti nuclear antibodies were negative. Studies for hypercoagulable state included Protein C, Antitrombin, Factor VIII, IX, XI, Factor V R506Q, and Apolipoprotein a; all were normal. A heterozygosity for PT G20210A was found, as well as homozygosity for MTHFR C667T with a normal level of Homocysteine (7.7mmole/L). Bone marrow aspiration showed increased cellularity of all cell lines, with many young megakaryocytes including some in clusters. No malignant cells were seen. Reticulin score on bone marrow biopsy was 0. Platelets function tests with adenosine di-phosphate and epinephrine were normal. Serum TPO level was 31.0 pg/ml (normal). A karyotype examination revealed a normal 46XX female. FISH for BCR/ABL was negative. DNA mutations for JAK2 on both the 12 and the14 exons and c-mpl mutations were not found. Spontaneous clone formation was normal. Helicobacter pylori IgG was 2.89 U/ml (normal) and stool was negative for parasites. Imaging studies included high resolution abdominal contrast CT scan, upper gastrointestinal tract imaging with gastrografin, Doppler sonography of splanchnic vessels and capsule endoscopy; all were interpreted as normal. Aspirin 75 mg/d was started without antimetabolite therapy. Abdominal pain and diarrhea gradually improved. After 3 month of antiagregant therapy, platelets count declined, gradually but steadily. One year after presentation the child is asymptomatic with platelet count of 600 × 109/L. The spontaneous remission of the extreme ET achieved by conservative treatment with no complications adds to the growing evidence, that childhood ET is a unique entity with different biology than adult ET, which might not need antimetabolite therapy.

Nonstroke arterial thrombosis in children: Hacettepe experience

Of the 488 pediatric patients with thrombosis in a single center, 50 (10.2%) had nonstroke arterial thrombosis. Half of the nonstroke arterial thrombosis patients had a preceding arterial catheterization history. Infection was a common contributing underlying disorder among both catheterized and overall groups (28 and 42%, respectively). The third most common underlying risk factor for development of arterial thrombosis was associated cardiac disease, and 70% of these patients had congenital heart disease and 30% had dilated cardiomyopathy. The most common site of arterial thrombosis was the heart, and 22% of the patients developed arterial thrombosis following cardiac surgery for congenital heart diseases. The prothrombotic risk factors were also analyzed in the study group and factor V G1691A and PT G20210A heterozygous mutations were detected to be higher (16 and 4%, respectively) than those in healthy controls (7.4 and 2.3%, respectively). In addition to factor V G1691A and PT G20210A mutations, other prothrombotic risk factors including protein C and protein S deficiencies and elevated factor VIII levels were commonly associated with pediatric nonstroke arterial thrombosis cases in the present study. This finding indicates the importance of these factors in arterial thrombosis development, similar to venous thrombosis. Another striking factor of the study is the higher number of prothrombotic risk factors (more than three) in patients who had persistent thrombosis, indicating the need for more intensive treatment in these patients.

Thrombotic events in systemic lupus erythematosus. Its association with acquired and inherited thrombophilic defects

Systemic lupus erythematosus (SLE) is characterised by increased venous and arterial thrombotic risk. Although antiphospholipid antibodies (APAs) have been shown to be related with thrombotic tendency in these patients, in more than 40% of them, thrombosis occurs without the presence of such antibodies. We analysed the association of venous and arterial thrombotic events with acquired (anticardiolipin antibodies (ACAs) and lupus anticoagulant (LA)) and inherited (antithrombin (AT), protein C (PC), protein S (PS) deficiencies, factor V Leiden and the prothrombin G20210A mutation), thrombophilic risk factors in 86 SLE patients and 89 healthy controls. Patients showed a higher significant percentage of ACAs titres IgG>41 GPL u/ml and LA than controls (P=0.009; P<0.001, respectively), although no differences in AT, PC, PS deficiencies, factor V Leiden and prothrombin G20210A mutation was observed (P>0.05). When patients with and without thrombosis were compared, those with thrombosis showed a statistically higher percentage of ACAs IgG>41 GPL u/ml and LA (P=0.048; P=0.001, respectively), OR 4.33; 95% CI 1.01-18.50 and OR 11.57; 95% CI 3.28-40.75, respectively. When venous and arterial thrombotic events were considered separately, the presence of LA constituted a risk factor for arterial thrombosis (P=0.010), OR 11.33; 95% CI 1.86-68.89, as well as for venous thrombosis (P=0.005), OR 10.15; 95% CI 2.12-48.64, while ACAs IgG>41 GPL u/ml on their own, were not associated with arterial or venous thrombosis (P=0.142, P=0.233, respectively). In addition inherited thrombophilic risk factors AT, PC, PS deficiencies, factor V Leiden and PT G20210A mutation do not seem to increase thrombotic risk in SLE patients.