Prenatal diagnosis of hemoglobinopathies in Hacettepe University, Turkey.

Between 1983 and 2008, prenatal diagnostic procedures for identifying hemoglobinopathies were performed in 947 at-risk fetuses. Seventy-six percent of the fetuses were at risk for ß-thalassemia major and 16% for sickle cell anemia; only a small percentage (7%) were at risk for compound heterozygosity of ß-thalassemia and an abnormal hemoglobin of the ß chain. The results of the study showed that ß gene mutations in hemoglobinopathies have a very broad spectrum. Seven hundred and thirty of the 947 fetuses examined using the DNA technique showed 88 different combinations of 27 different mutations. Although the number of fetuses evaluated was far below the desired target, the termination of 261 affected fetuses provided both psychological and economic relief for the parents and was economically beneficial for the country in the long term.

The frequency of A91V in the perforin gene and the effect of tumor necrosis factor-α promoter polymorphism on acquired hemophagocytic lymphohistiocytosis.

OBJECTIVE: Numerous acquired etiological factors, such as infections, malignancies, and collagen tissue disorders, are involved in the development of acquired hemophagocytic lymphohistiocytosis (AHLH). Not everyone with the same etiological factors developments AHLH, which suggests the role of additional genetic or environmental predisposing factors that remain to be identified. METHODS: Perforin gene A91V missense transition (C>T change at position 272 in exon 2 of the perforin gene) and TNF-α gene promoter-1031 T>C nucleotide substitution are 2 candidate genetic predisposing factors due to their potential to alter inflammatory responses. In the present study these changes were investigated in healthy controls and AHLH patients. RESULTS: A91V transition was observed in 7 of the 159 (4.4%) controls. Among the 44 AHLH patients, 5 (11.3%) were heterozygous and the difference in the frequency of A91V transition, although striking (odds ratio: 2.8), was not statistically significant (p=0.09). All A91V-positive patients had infection. TNF-α-1031 T>C polymorphism was examined in 164 healthy controls and 40 AHLH patients, and the CC risk-elevating genotype was noted in 7 (4.3%) of the controls and 1 (2.5%) of the AHLH patients. The frequency of C and T alleles was 22.5% (n=18) and 77.5% (n=62) among the AHLH patients, and 22% (n=72) and 78% (n=259) among the controls, respectively. There wasn't a statistically significant difference between the groups in terms of allele frequencies (p>0.05). CONCLUSION: The present results indicate that compared to controls, A91V mutation was 2.8-fold more prevalent (according to the odds ratio) in the AHLH patients. A91V mutation is not uncommon in the general population and increases the risk of AHLH in patients with an underlying condition, especially those with an underlying infection.

Serum Erythropoietin Levels in Pediatric Hematologic Disorders and Impact of Recombinant Human Erythropoietin Use.

OBJECTIVE: In anemic patients, the correlation between serum erythropoietin (sEpo) level and the severity of anemia has been reported previously. However, in different anemia groups, different sEpo levels are measured in patients with similar hemoglobin levels and the etiology of this situation could not be explained. METHODS: We evaluated hemoglobin and sEpo levels in 31 iron deficiency anemia, 26 Fanconi anemia (FA), 21 thallasemia intermedia (TI), 15 acute lymphoblastic leukemia (ALL) patients at presentation and 12 healthy controls. RESULTS: In all disease groups, an inverse linear correlation was shown between hemoglobin and logarhytmic sEpo level. The covariance analyses according to corrected hemoglobin levels exhibited the highest sEpo level in FA, followed by ALL, TI and iron deficiency anemia, sequentialy. CONCLUSION: There was no statisticaly significant difference of sEpo levels in FA patients in terms of androgen treatment and this finding supports that androgen affects erythropoisis directly, and has no effect on erythropoietin. The results indicate that there is no erythropoietin deficiency in the anemia of these patients and the admnistration of exogenous erythropoietin offers no clinical benefit.

Red cell glucose-6-phosphate dehydrogenase deficiency in Turkey.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common erythrocyte enzyme deficiency in the world. The epidemiological, biochemical and molecular studies on G6PD enzyme deficiency performed over the past 50 years are summarized herein, with special emphasis on the findings of studies related to the enzyme deficiency in Turkey.

Plasminogen activator inhibitor-1 4G4G genotype is associated with myocardial infarction but not with stable coronary artery disease.

BACKGROUND: A case control study was conducted to test the hypothesis that plasminogen activator inhibitor type-1 (PAI-1) 4G/5G gene polymorphism confers an increased risk for myocardial infarction (MI) in patients with known coronary atherosclerosis. METHODS: One hundred fifty-six consecutive patients who presented with acute MI and 111 stable coronary artery disease (SCAD) patients with documented critical coronary artery stenoses were prospectively enrolled. PAI-1 4G/5G gene polymorphism and conventional atherosclerotic risk factors were studied in all patients. PAI-1 4G/5G gene polymorphism was studied in another 281 healthy blood bank donors. RESULTS: The frequency 4G4G genotype was significantly higher in the MI group as compared to SCAD group (32.7% vs. 15.3%, P = 0.001) while it was not statistically significant between MI and healthy control groups (32.7% vs. 26.0%, P = 0.136). Comparing with healthy controls SCAD group had significantly lower frequency of 4G4G genotype (P = 0.024). In comparison with SCAD group PAI-1 4G/4G genotype, male sex and smoking habits favored to MI in univariate analysis with a P value of less than 0.2. These variables were included in multivariate regression model to estimate the associated risk for MI. PAI-1 4G/4G genotype was the only independent variable (OR 2.67, 95%CI 1.43-4.96, P = 0.002) associated with MI in this regression model. Comparing with healthy control group 4G4G genotype was not associated with MI (OR 1.38, 95%CI 0.90-2.12). However, presence of 4G4G genotype had a protective effect against development of SCAD (OR 0.52, 96%CI 0.29-0.92). CONCLUSION: Compared to patients with critical coronary stenoses, PAI-1 4G/4G genotype was found to be an independent predictor for development of MI in this population. PAI-1 4G4G genotype have a protective effect against development of high grade stable coronary stenoses.

A complex splicing defect associated with homozygous ankyrin-deficient hereditary spherocytosis.

Defects in erythrocyte ankyrin are the most common cause of typical, dominant hereditary spherocytosis (HS). Detection of ankyrin gene mutations has been complicated by allelic heterogeneity, large gene size, frequent de novo mutations, and associated mRNA instability. Using denaturing high-performance liquid chromatography (DHPLC)-based mutation detection, a mutation in the splice acceptor of exon 17 was discovered in a Turkish family. Reticulocyte RNA and functional minigene splicing assays in heterologous cells revealed that this mutation was associated with a complex pattern of aberrant splicing, suggesting that removal of intron 16 is important for ordered ankyrin mRNA splicing. As predicted by clinical, laboratory, and biochemical studies, the parents were heterozygous and the proband was homozygous for this mutation. These data indicate that DHPLC offers a highly sensitive, economic, and rapid method for mutation detection and, unlike previously suggested, homozygosity for a mutation associated with dominant ankyrin-linked HS may be compatible with life.

Haematological findings in children with inborn errors of metabolism.

Early detection and therapy of haematological abnormalities and/or diseases may improve the prognosis of metabolic disorders. Accordingly, we aimed to evaluate the frequency and types of haematological abnormalities in children[-31pc] with various inherited metabolic disorders. The study group comprised 46 children with metabolic disorders who were followed at the Pediatric Metabolism Unit and were referred to the Pediatric Hematology Unit for evaluation of anaemia between June 2000 and 2005. The mean age of the children was 55.2 +/- 64.8 months at haematological evaluation (range 1 month-18 years, median 22.0 months); 16 were female and 30 were male. Of these 46 patients with anaemia, 25 of (54.3%) had anaemia of chronic disease (ACD), 9 (19.6%) had iron-deficiency anaemia (IDA), 7 (15.2%) had megaloblastic anaemia due to vitamin B(12) deficiency, 3 (6.5%) had chronic haemolytic anaemia, 2 (4.3%) had autoimmune haemolytic anaemia, 1 had beta-thalassaemia major, and 1 had hereditary spherocytosis. In addition to the anaemia, bicytopenia or pancytopenia was found in 8 of 46 children (17.4%). The study indicated that in organic acidaemias including methylmalonic acidaemia, propionic acidaemia, isovaleric acidaemia, and argininosuccinic acidaemia, the majority of patients had ACD (75%), which was followed by vitamin B(12) deficiency anaemia and IDA (p < 0.001). In PKU, both nutritional anaemias and ACD were present at about same frequency: 46.7% and 40%, respectively (p > 0.05). This study suggested that congenital anaemias such as hereditary spherocytosis or thalassaemias should be kept in mind as a coexisting haematological diseases in young patients with inborn errors of metabolism. In conclusion, ACD and nutritional anaemias are the most prevalent anaemias seen in patients with inborn errors of metabolism. Early detection of the disease, early administration of specific diet, and close monitoring of the patients are very important factors to prevent the development of haematological diseases in patients with inborn errors of metabolism.

Outcome in children with purpura fulminans: report on 16 patients.

Purpura fulminans (PF) is a severe disorder of acute onset with high morbidity and mortality. In children, this rapidly progressive illness is usually associated with severe bacterial or viral infections. However, some other conditions may participate in the development of PF. Our objective was to investigate the underlying and associated disorders and the outcomes of the disease in 16 children, 7 males and 9 females ranging in age from 3.5 months to 12 years (median age, 2 years). Thirteen of the 16 children (81%) were 4 years of age or younger. The remaining 3 patients were 9, 10, and 12 years of age. Among these 13 infants and small children, 7 (43%) had infection, 2 infants had congenital cardiac disorders necessitating minor or major surgical intervention, and 1 infant and 3 children had different miscellaneous disorders. The factor V G1691A mutation was present in six of the 13 small children (46%). None of the 3 older children carried the mutation. Six (37.5%) of the 16 patients had protein C deficiencies, and 9 (56%) had protein S deficiencies. These deficiencies, except one for protein S, were acquired. Ten patients except two who were diagnosed at this center were treated with fresh frozen plasma. They were also given heparin. Nine (69%) of the 13 children 4 years of age or younger and one of the older children (33%) required amputation. Five of the six patients (83%) who had factor V G1691A mutation, and who also exhibited severe infection, required amputation. This study suggests that an age of 4 years or less is a risk factor for the development of PF during severe infections, especially in the presence of factor V G1691A mutation and congenital heart disease, necessitating major or minor surgical interventions. This study also shows that the amputation rate in 10 patients, after excluding the patients who had been referred to our center after development of sequelae, was 60%. The survival rate among these 10 patients may indicate that, with the treatment protocol, PF need not be regarded as a lethal disease any more. It is also suggested that effective immunization programs and better health care have probably resulted in some changes in the etiological profile of PF.

Nonradioactive vitamin B12 absorption test evaluated in controls and in patients with inherited malabsorption of vitamin B12.

BACKGROUND: Current tests for evaluation of vitamin B(12) absorption are problematic because they involve the use of radioactively labeled vitamin B(12). We describe a vitamin B(12) absorption test that circumvents this problem. METHODS: We measured cobalamin or transcobalamin saturated with cobalamin (holo-TC) 24 h after three 9-microg doses of vitamin B(12) given orally at 6-h intervals. We studied 17 patients with inherited malabsorption of vitamin B(12) attributable to Imerslund-Grasbeck syndrome (n = 13) or intrinsic factor deficiency (n = 4), their obligate heterozygous biological parents (n = 19), and healthy controls (n = 44). RESULTS: In the patients, the median (range) change of holo-TC after the B(12) load was not significant [1 (-42 to 5) pmol/L], nor was the change of cobalamin [-3 (-32 to 22) pmol/L], consistent with a lack of measurable active or passive absorption. In controls, however, the median (range) increases of holo-TC and cobalamin were 26 (-6 to 63) pmol/L and 41 (-37 to 109) pmol/L, respectively. Similarly, the parents showed increases of 23 (-2 to 47) pmol/L and 27 (-15 to 94) pmol/L. The mean areas under the ROC curves (95% confidence intervals) were 0.97 (0.93-1.0) for holo-TC and 0.87 (0.79-0.94) for cobalamin, distinguishing patients from controls. At a cutoff of 6 pmol/L for holo-TC, the diagnostic sensitivity (95% confidence interval) was 100 (81-100)%, and the diagnostic specificity was 92 (82-97)%. CONCLUSION: Measurement of holo-TC after administration of vitamin B(12) is a promising approach for evaluating vitamin B(12) absorption.

Hereditary juvenile cobalamin deficiency caused by mutations in the intrinsic factor gene.

Hereditary juvenile megaloblastic anemia due to vitamin B12 (cobalamin) deficiency is caused by intestinal malabsorption of cobalamin. In Imerslund-Grasbeck syndrome (IGS), cobalamin absorption is completely abolished and not corrected by the administration of intrinsic factor (IF); if untreated, the disease is fatal. Biallelic mutations either in the cubilin (CUBN) or amnionless (AMN) gene cause IGS. In a series of families clinically diagnosed with likely IGS, at least six displayed no evidence of mutations in CUBN or AMN. A genome-wide search for linkage followed by mutational analysis of candidate genes was performed in five of these families. A region in chromosome 11 showed evidence of linkage in four families. The gastric IF (GIF) gene located in this region harbored homozygous nonsense and missense mutations in these four families and in three additional families. The disease in these cases therefore should be classified as hereditary IF deficiency. Clinically, these patients resembled those with typical IGS; radiocobalamin absorption tests had been inconclusive regarding the nature of the defect. In the diagnosis of juvenile cobalamin deficiency, mutational analysis of the CUBN, AMN, and GIF genes provides a molecular characterization of the underlying defect and may be the diagnostic method of choice.

Analysis of some clinical and laboratory aspects of adolescent patients with thrombosis.

A total of 360 pediatric patients aged 1 month to 18 years were diagnosed as having thrombosis between January 1998 and April 2003. Of these patients, those aged 11-18 years (n=131) were regarded as adolescents and the rest as children. The proportion of adolescents in the whole group excluding the neonates was 36%. The peak age of diagnosis in adolescents was 11-14 years, comprising 58% of all thrombotic events in adolescents. In 73% of the adolescents, there was at least one risk factor. The four most common underlying disorders were infection, malignancy, connective tissue and cardiac disorders, in decreasing order of frequency. In children, on the other hand, infection was followed by congenital heart disease, malignancy and liver disease. Three common types of thrombosis in adolescents were deep venous thrombosis, cerebro-vascular events and portal venous thrombosis, while cerebro-vascular events were the most common in children. The frequency of factor V G1691A mutation in the adolescents (22.1%) was significantly higher than that found in a group of healthy controls (7.4%) and this mutation was associated with a 3.6-fold increase in the risk of developing thrombosis (95% confidence interval, 1.4-9.0). The carrier frequency of prothrombin G20210A mutation (3.1%) in adolescents did not differ significantly from that of the healthy population (2.3%) and no association was observed between this mutation and a risk of developing thrombosis in this group (odds ratio, 1.3; 95% confidence interval, 0.2-7.5). The rate of recurrent thrombosis was 6%.

Clinical and laboratory evaluation of Turkish children with thrombosis for homozygous factor V G1691A mutation.

Factor V (FV) G1691A mutation, in a heterozygous state, is one of the most common inherited risk factors for development of thrombosis. However, the clinical manifestations of homozygosity for the FV G1691A mutation in children is largely unknown because of the limited number of studies reported. The purpose of this study was to evaluate the clinical manifestations and laboratory findings of children with thrombosis who were homozygous for this mutation. Ten patients (four male/six female; mean age, 4.5 years; age range, 1-13 years) who were found to be homozygous for the FV G1691A mutation among 360 consecutive children with thrombosis (2.8%) were the subjects of this study. Six of the 10 patients had venous thrombosis, two had purpura fulminans, one had diffuse skin ecchymosis and one had arterial thrombosis. No history of thrombosis was present in their family members. Seven of the 10 children were under the age of 5 years. One or more additional risk factors (infection, protein S and protein C deficiencies, elevated factor VIII, etc.) were also present in nine of these patients. None of these patients had prothrombin G20210A mutation but one patient had risk-associated plasminogen activator inhibitor-1 gene 4G/4G genotype. These findings suggest that, in the presence of other underlying risk factors, homozygosity for FV G1691A mutation may lead to development of thrombosis at a very young age.

Characterization of MTHFR, GSTM1, GSTT1, GSTP1, and CYP1A1 genotypes in childhood acute leukemia.

The role of methylenetetrahydrofolate reductase (MTHFR C677T), glutathione S-transferases (GSTM1 and GSTT1 null, GSTP1 Ile105Val), and cytochromes p450 (CYP1A1*2A) genotypes in the etiology of childhood leukemia was simultaneously investigated. 144 Turkish children with acute lymphoblastic leukemia (ALL) and 33 with acute nonlymphoblastic leukemia (ANLL) were studied and compared with 185 healthy pediatric controls. The frequency of MTHFR genotype was insignificantly higher in ALL (7.7%) and ANLL (6.3%) than in controls (4.4%). Equal distribution of the GSTM1 null genotype was detected between ALL patients and controls (55%), while its incidence was slightly higher in ANLL patients (61.3%). Although GSTT1 null genotype was insignificantly lower in ALL patients (20.9%) than controls (22.7%), it was significantly underrepresented in ANLL patients (6.5%) (P = 0.05, OR 0.24, 95% CI 0.05-1.03). The homozygous frequency of GSTP1 genotype did not differ significantly between groups of ALL (3.7%), ANLL patients (9.1%) and controls (4.9%). Homozygous CYP1A1*2A genotype was underrepresented in ALL patients (1%) as compared to control (4.8%) but the differences did not reach to statistical significance (OR 0.21; 95% CI 0.03-1.72). Homozygosity for this genotype was not detected in ANLL patients. No particular association was noted between different combinations of combined genotypes and risk of development of childhood ALL and ANLL. These results suggested that there are no significant associations between the studied genotypes and the risk of developing either form of acute leukemia except GSTT1 null and homozygosity for CYP1A1 genotypes that may play protective roles in the development of ANLL in Turkish children.

Identification of an inframe deletion and a missense mutation in the factor XIIIA gene in two Turkish patients.

We report two novel mutations in factor XIIIA (FXIIIA) gene that caused congenital factor XIII deficiency in two unrelated patients. The first alteration, a missense mutation Leu235Arg in exon 6 of FXIIIA gene, is located in the putative calcium-binding part of the core domain of the enzyme. Replacement of non-polar hydrophobic leucine residue with positively charged arginine residue is likely to effect protein folding thus destabilizing the molecule. The second mutation is a 3-bp deletion in exon 14 of FXIIIA gene. This deletion is located in beta barrel 2 domain of the protein and results in translation of an aberrant FXIIIA molecule that lacks lysine residue either at positions 677 or 678. As this inframe deletion is located in a direct repetetive sequence of AAGAAG, that codes for two lysine residues, the exact location of deletion could not be detected.

Incidence of high erythrocyte count in infants and young children with iron deficiency anemia: re-evaluation of an old parameter.

PURPOSE: To investigate the frequency of high erythrocyte count (red blood cell count >or=5.0 x 106/microL) in infants and young children with iron deficiency anemia and to document the differences in hematologic parameters at diagnosis and during iron therapy in IDA patients with and without a high erythrocyte count. PATIENTS AND METHODS: A total of 140 infants and young children aged 6 to 48 months with nutritional IDA without a history of any bleeding disorder were the subjects of this study. The patients were divided into three groups according to the severity of anemia. Group A1 children had Hb values 8.0 g/dL or less (severe anemia); group A2, 8.1 to 10.0 g/dL (moderate anemia); and group A3, 10.1-11.0 g/dL (mild anemia). All children received oral iron (3-5 mg/kg per day) for 12 weeks. Complete blood counts were done weekly during treatment. RESULTS: A total of 36 of the 140 patients (26%) had a high erythrocyte count. Of the 140 patients, 37 were in group A1, 80 in A2, and 23 in A3. The frequency of high erythrocyte count was 11%, 23%, and 61% in groups A1, A2, and A3, respectively. The patients with a high erythrocyte count had significantly higher Hb and Hct but significantly lower mean corpuscular volume and mean corpuscular hemoglobin (MCH) values than those with a low erythrocyte count (n = 104). A continuous elevation in the erythrocyte count has been observed in patients with a high red cell count, as in those with a low red cell count, after the institution of iron therapy. CONCLUSIONS: A high erythrocyte count is a common feature of iron deficiency anemia in infants and young children, with an increasing frequency from severe to moderate to mild anemia. High erythrocyte count cannot be regarded as a reliable preliminary parameter in differentiating iron deficiency from thalassemias in infants and children aged up to 48 months.

Molecular characterization of Turkish patients with pyrimidine 5' nucleotidase-I deficiency.

Pyrimidine 5' nucleotidase-I (P5N-I) deficiency is a rare autosomal recessive disorder associated with hemolytic anemia, marked basophilic stippling, and accumulation of high concentrations of pyrimidine nucleotides within the erythrocyte. Recently, the structure and location of the P5N-I gene have been published. This paper presents the results of a study characterizing the molecular pathologies of P5N-I deficiency in a total of 6 Turkish patients from 4 unrelated families of consanguineous marriages. Mutation analysis in the P5N-I gene led to the identification of 3 novel mutations in these patients. In 4 patients from 2 families, a homozygous insertion of double G at position 743 was detected in exon 9 (743-744insGG), leading to premature termination of translation 23 bp downstream. In one family, a homozygous T to G transition at position 543 (543T>G) in exon 8 resulted in the replacement of tyrosine (Tyr) with a stop codon (Tyr181Stop). In another family, a homozygous insertion of a single A in exon 7 (384-385insA) created a stop signal at the codon nearby. In all families, the parents were heterozygous for the relevant mutations. None of these changes was detected in 200 chromosomes from a healthy Turkish population. These mutations were not correlated with any particular phenotype.

Serum alpha-fetoprotein level in Fanconi's anemia: evaluation of 33 Turkish patients.

Recently, measurement of serum alpha-fetoprotein (sAFP) was introduced as a preliminary test for diagnosis of Fanconi's anemia (FA). In the present study, sAFP levels were measured in order to determine its sensitivity and specificity in 33 Turkish FA patients (17 males and 16 females) with a mean age of 11.6 +/- 7.7 (1.0-28.0) (median 10.0). Complementation groups were available in 12 patients. Nineteen age-matched healthy children, 17 patients with bone marrow failure syndromes, 37 FA heterozygotes, and 37 children with acute leukemia served as negative control groups. The sAFP was measured by particle immunoassay. The level of sAFP was found to be higher than the cut-off value, 8 IU/mL in 46% and was within normal limits in 54% of the FA patients. The AFP values were within normal limits in all of the subjects belonging to the control groups. This method provided 46% sensitivity and 100% specificity in the diagnosis of FA. The sAFP values were high in 4 of 17 (24%) FA patients who did not receive any androgen therapy, while the sAFP level was high in 7 of 9 (78%) patients who received such a therapy. The statistical analysis of incidence of a high sAFP level between these two groups indicated a significant difference (P = 0.014), suggesting that androgen therapy might be a contributing factor for elevation of sAFP. The comparison of several clinical and laboratory parameters between FA patients with high and normal levels of AFP revealed no statistically significant differences. The level of sAFP was elevated in only 5 of the 11 patients with complementation group A; in addition, variable levels of sAFP were noted among the affected members in 4 families, indicating that complementation groups, type of mutation, or familial factors were not responsible for elevation of sAFP.

PAI-1 gene 4G/5G genotype: A risk factor for thrombosis in vessels of internal organs.

Although the common 4G/5G polymorphism in the promoter of the PAI-1 gene was suggested to be a risk factor for some of the thrombotic disorders, its significance in the development of thrombosis is still controversial. This study presents the data on a total of 357 patients with different types of thrombosis and 281 unrelated healthy controls. It was found that the 4G/4G genotype is associated with a higher risk of thrombosis (OR, 1.7; 95% CI, 1.1-2.5). Patients were divided into five distinct groups according to the site of thrombosis. Both 4G/4G and 4G/5G genotypes were associated with a higher risk of thrombosis development in a group of 69 patients with internal organ thrombosis (OR, 6.35; 95% CI, 2.5-16.1 and OR, 4.85; 95% CI, 2.0-12.1, respectively). Interestingly, this association was even stronger in a subgroup of 33 patients with portal vein thrombosis (PVT) and 4G/4G and 4G/5G genotypes conferred more than 10- and 6-fold increases in the risk of developing PVT (95% CI: 2.3-47.1 and 1.4-28.8), respectively. No statistically significant association was found between 4G/4G genotype and the groups of deep vein thrombosis (126 patients), cerebral thrombosis (80 patients), retinal thrombosis (72 patients), and purpura fulminans (16 patients). Factor V Leiden or prothrombin G20210A mutations did not emerge as additional risk factors for thrombosis in any of the groups studied. To conclude, this study suggests that there may be an association between 4G/4G and 4G/5G genotypes and the thrombosis in vessels of internal organs especially in the portal veins.