Prevalence of factor V Leiden mutation and other hereditary thrombophilic factors in Egyptian children with portal vein thrombosis: results of a single-center case-control study

No identifiable cause can be found in more than half of the cases of portal vein thrombosis (PVT). Our aim was to assess the prevalence of factor V Leiden mutation and other thrombophilic factors as risk factors in the development of PVT in the pediatric age group. From March 2001 to January 2002, 40 children with PVT were enrolled in the study, in addition to 20 age-matched and sex-matched controls. Protein C, protein S, antithrombin III, and activated protein C resistance (APCR) were assayed. Molecular study of factor II and factor V mutations was carried out. Of the patients, 25 had detectable hereditary thrombophilia (62.5%), 12 had factor V Leiden mutation (30%), 11 had protein C deficiency (27.5%), 6 had factor II mutation (15%), 1 had antithrombin III deficiency (2.5%), and none had protein S deficiency. Five children had concurrence of more than one defect. Factor V Leiden mutation is the most common hereditary thrombophilia associated with PVT and the relative risk of factor V Leiden mutation, as a cause of PVT, was six times more than in controls (odds ratio=6). Concurrence of more than one hereditary thrombophilic factor was seen in 12.5% of our patients. Circumstantial risk factors (neonatal sepsis, umbilical sepsis, umbilical catheterization) were not more significantly prevalent among patients with hereditary thrombophilia than among those with no detectable abnormalities in anticoagulation.An erratum to this article can be found at     

Cerebral sinus thrombosis in a patient with hereditary protein S deficiency: Case report and review of the literature

Summary Hereditary protein S deficiency is an established risk factor for venous thrombosis. The common sites of thrombosis are the deep leg and pelvic veins. We report on a 38-year-old female patient with hereditary protein S deficiency and a previous history of deep leg vein thrombosis, who developed thrombosis of the cerebral straight and superior sagittal sinus while taking oral contraceptives. The diagnosis was established by computerized tomography and carotid angiography. Lysis of the thrombus occurred during heparin treatment. The hereditary nature of protein S deficiency was documented by family studies, since nine additional family members deficient in protein S were identified. Nineteen published cases of cerebral vein thrombosis and a deficiency of either antithrombin III, protein C, or protein S were reviewed. Compared with patients without a deficiency state, the clinical features of cerebral vein thrombosis were similar except for an earlier onset and a positive medical history of venous thromboembolic events in a considerable number of patients.     

Frequency of natural coagulation inhibitor (antithrombin III, protein C and protein S) deficiencies in Japanese patients with spontaneous deep vein thrombosis.

One hundred and thirteen consecutive Japanese patients with deep venous thrombosis (DVT) were studied for the incidences of antithrombin III (AT-III), protein C (PC) and protein S (PS) deficiencies, and the results were compared with those of normal subjects. Ten of the 392 normal Japanese subjects were found with PS deficiency (n = 8, 2.02%) or PC deficiency (n = 2, 0.5%). PS deficiencies comprised type I (1/8, 12.5%), type 11 (4/8, 50%), and type III (3/8, 37.5%). All PC deficiencies were type I. Among patients with DVT, 32 (28.3%) were deficient in AT-III, PC and PS. These patients consisted of two AT-III deficiency (1.77%), nine PC deficiency (7.96%), 20 PS deficiency (17.7%), and one combined deficiency of PC and PS (0.88%). Both of the patients with AT-III deficiency were classified as type II, all those with PC deficiency as type I, and those with PS deficiency as type I in 25% (5/20), type II in 55% (11/20) and type III in 20% (4/20). The frequency of PC and PS deficiencies in patients with DVT were 15.6 and 7.38 times the control population frequency, respectively, and this difference was statistically significant (P < 0.05). These data suggest that the Japanese population has a high frequency of PC and PS deficiencies. We recommend that PS activity should be measured for screening of thrombosis since type II deficiency accounted for approximately 50% of PS deficiency cases in both patients and the normal group in the Japanese.     

Protein C: an automated activity assay

Protein C in citrated plasma is found to be specifically activated by the snake venom derivative Protac, and the activator is used in a simple, automated assay method. The activation is completed in less than 120 s and an isolation of protein C from its inhibitor before activation is not necessary. The activated protein C is determined with the chromogenic substrate S-2366. Therapeutic concentrations of heparin in the test sample do not influence the result. A strong positive correlation to immunoassay of protein C was found (r = 0.92). Three cases of probable hereditary protein C deficiency belonging to the same family were discovered during the study.     

Thrombosis in congenital deficiencies of AT III, protein C or protein S: a study of 44 children

Abstract. Congenital deficiency in coagulation inhibitors is a cause of hereditary thrombotic disease. The severity of symptoms is variable and depends on the type of deficit. In this paper, 44 children suffering from deep venous thrombosis, with a mean age of 5 years, were studied. A search for Lupus anticoagulant (LA) and coagulation inhibitor deficiency showed: 3/44 cases (6.8%) had protein S deficiency, 2/44 cases (4.5%) had protein C deficiency, 1/44 cases (2.3%) had deficiencies in both protein C and S; no cases of AT III deficiency and LA was positive in 2/44 cases (4.5%). Only 1 case of APC resistance out of 13 studied was found. Four family studies were performed and confirmed the congenital origin of the disorder.     

Case report: portal vein thrombosis associated with hereditary protein C deficiency: a report of two cases

Protein C deficiency is one of the causes of curable or preventable portal vein thrombosis. We report two patients of portal vein thrombosis associated with hereditary protein C deficiency. The first patient presented with continuous right upper quadrant pain and high fever. The abdominal sonography revealed normal liver parenchyma but portal vein and superior mesenteric vein thrombosis. Based on a 55% (normal 70-140%) plasma protein C level, he was diagnosed as having protein C deficiency. A trace of his family history showed that his elder brother also had protein C deficiency with a 50% plasma C level. Both patients received anticoagulant therapy. The younger brother showed good response. Unfortunately, the elder one suffered from recurrent episodes of variceal bleeding and received a life-saving splenectomy and devascularization. We herein remind clinicians that early screening and therapy are helpful in preventing late complications of protein C deficiency with portal vein thrombosis.     

Resistance to activated protein C,the FV : Q506 allele,and venous thrombosis

 Vitamin K-dependent protein C is an important regulator of blood coagulation. After its activation on the endothelial cell surface by thrombin bound to thrombomodulin, it cleaves and inactivates procoagulant cofactors Va and VIIIa, protein S and intact factor V working as cofactors. Until recently, genetic defects of protein C or protein S were, together with antithrombin III deficiency, the established major causes of familial venous thromboembolism, but they were found in fewer than 5–10% of patients with thrombosis. In 1993, inherited resistance to activated protein C (APC) was described as a major risk factor for venous thrombosis. It is found in up to 60% of patients with venous thrombosis. In more than 90% of cases, the molecular background for the APC resistance is a single point mutation in the factor V gene, which predicts substitution of an arginine (R) at position 506 by a glutamine (Q). Mutated factor V (FV : Q⁵⁰⁶) is activated by thrombin or factor Xa in normal way, but impaired inactivation of mutated factor Va by APC results in life-long hypercoagulability. The prevalence of the FV : Q⁵⁰⁶ allele in the general population of Western countries varies between 2 and 15%, whereas it is not found in several other populations with different ethnic backgrounds. Owing to the high prevalence of FV : Q⁵⁰⁶ in Western populations, it occasionally occurs in patients with deficiency of protein S, protein C, or antithrombin III. Individuals with combined defects suffer more severely from thrombosis, and often at a younger age, than those with single defects, suggesting severe thrombophilia to be a multigenetic disease. Received: 18 December 1995 / Accepted: 24 January 1996     

Venous thromboembolic risk and protein S deficiency: ethnic difference and remaining issues

Protein S deficiency is an autosomal dominant disorder that results from mutations in the protein S gene (PROS1). Inherited deficiency of protein S constitutes a risk factor for venous thromboembolism. Protein S functions as a nonenzymatic cofactor for activated protein C in the proteolytic degradation of coagulation factors V a and Villa. The frequency of protein S deficiency seems to differ between populations. More than 200 rare mutations in PROS1 have been identified in patients with protein S deficiency. Among the prevalent mutations within PROS1, the S460P substitution (known as Heerlen polymorphism) detected in Caucasians and the K196E substitution (known as protein S Tokushima) found in Japanese have been intensively studied for their structures and potential functions in the disorder of protein S deficiency. Until now, causative mutations in PROS1 have been found in only approximately 50% of cases with protein S deficiency. Co-segregation analysis of microsatellite haplotypes with protein S deficiency in families with protein S deficiency suggests that the causative defects in the PROS1 mutation-negative patients are located in or close to the PROS 1 gene. Large PROS 1 gene deletions have been identified in 3 out of 9 PROS 1 mutation-negative Swedish VTE families with protein S deficiency and 1 out of 6 PROS1 mutation-negative Japanese patients with protein S deficiency. Intensive sequencing of the entire PROS 1 gene, including introns, may be needed to identify the cryptic mutations in those patients, and these efforts might uncover the pathogenesis of protein S deficiency.     

Management with antithrombin III concentrate in a pregnant woman with hereditary antithrombin III deficiency

Pregnant women with hereditary antithrombin III (AT-III) deficiency are frequently associated with thromboembolic disorders. We have treated a pregnant woman with hereditary AT-III deficiency, who had suffered from thromboembolic disorders at her past three gestations, with AT-III concentrate. Dosage of AT-III concentrate to maintain plasma AT-III activity over 80% was 3,500 units per week during second and third trimesters, but more frequent administration was necessary around delivery. In recent reports, pregnant women with hereditary AT-III deficiency had been treated with heparin or warfarin except for during abortion and delivery, in which time AT-III concentrate was widely utilized. But the use of heparin or warfarin during gestation is occasionally harmful, AT-III concentrate should be chosen for management in pregnancy in women with hereditary AT-III deficiency.     

Heterozygous protein C deficiency type I

Summary Protein C is a vitamin K-dependent plasma protein which has anticoagulatory and profibrinolytic properties as a result of inactivating coagulation factors Va and VIIIa and enhancing fibrinolysis. Heterozygous protein C deficiency is well known to be a risk factor for thromboembolic diseases. We here present a family with 16 members deficient in protein C, out of which only two persons were suffering from thromboembolic disorders. In patients suffering from heterozygous protein C deficiency thromboembolic complications in childhood are rare and are not obligatory in adults. These patients should therefore not be treated with oral anticoagulants unless thromboembolic complications have already occurred or are imminent. Coumarin anticoagulation implicates a serious risk of coumarin skin necrosis in protein C deficient patients during the initial therapeutic phase. This risk may be avoided by initiating coumarin therapy with low doses of the drug and in cases of thromboembolic complications by overlapping with heparin anticoagulation.     

Protein C system defects in Indian children with thrombosis

As ethnic variations are known to exist in inherited genetic defects, the clinico-haematological profile of Indian children with thrombophilia may be different from that of Caucasians. The aim of the study was to analyse the phenotypic and genotypic causes of thrombophilia in Indian children. Forty patients with arterial (21 patients) and venous (19 patients) thrombosis were the subjects of the study. Their age ranged from 6 days to 15 years. All of the patients were initially screened by Pro C Global assay. Activated protein C resistance (APCR) was measured. In cases with low Pro C Global values, protein C (PC), protein S (PS) and factor V G1691A, prothrombin G20210A and MTHFR C677T polymorphism were tested in all 40 cases. Of the 21 patients with arterial thrombosis, 4 (19%) had PC deficiency, 7 (33.3%) had PS deficiency and 1 (4.8%) had combined deficiency of PC and PS. Of the 19 patients with venous thrombosis, 5 (26.3%) each had PC and PS deficiency and 4 (21%) had combined PC and PS deficiency. Heterozygous factor V G1691A defect was seen in one (4.8%) patient with arterial thrombosis and three (15.8%) patients with venous thrombosis. Heterozygous MTHFR C677T polymorphism was seen in five (23.8%) patients with arterial thrombosis and in four (21%) patients with venous thrombosis. Prothrombin G20210A polymorphism was absent in all patients and controls. Protein C system defect is common in Indian children with thrombosis.     

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

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

Hereditary protein s deficiency with a history of recurrent myocardial infarction.

Protein S is a vitamin K-dependent plasma protein that inhibits the process of blood coagulation via activation of protein C, another vitamin K-dependent plasma protein A 58-year-old man with hereditary protein S deficiency had repeated attacks of acute myocardial infarction at age 52 and 58 years.     

Plasma protein S deficiency in familial thrombotic disease

A family with a history of severe recurrent venous thromboembolic disease was studied to determine if a plasma protein deficiency could account for observed disease. Protein S levels in plasma were determined immunologically using the Laurell rocket technique. The propositus, his mother, his aunt, and his cousin who were clinically affected had 17% to 65% of the control levels of protein S antigen (normal range, 71% to 147%). Since three of these patients were receiving oral anticoagulant therapy, the ratios of protein S to prothrombin, factor X, and protein C in these patients were compared with values for a group of orally anticoagulated controls. These results suggested that protein S is half-normal in all family members with thrombotic disease. Other proteins known to be associated with familial thrombotic disease, including antithrombin III, plasminogen, fibrinogen, and protein C, were normal. Because plasma protein S serves as a cofactor for the anticoagulant activity of activated protein C and because protein C deficiency is associated with recurrent thrombotic disease, it is suggested that recurrent thrombotic disease in this family is the result of an inherited deficiency of protein S.     

Thrombosis in congenital deficiencies of AT III, protein C or protein S: a study of 44 children

Abstract. Congenital deficiency in coagulation inhibitors is a cause of hereditary thrombotic disease. The severity of symptoms is variable and depends on the type of deficit. In this paper, 44 children suffering from deep venous thrombosis, with a mean age of 5 years, were studied. A search for Lupus anticoagulant (LA) and coagulation inhibitor deficiency showed: 3/44 cases (6.8%) had protein S deficiency, 2/44 cases (4.5%) had protein C deficiency, 1/44 cases (2.3%) had deficiencies in both protein C and S; no cases of AT III deficiency and LA was positive in 2/44 cases (4.5%). Only 1 case of APC resistance out of 13 studied was found. Four family studies were performed and confirmed the congenital origin of the disorder.     

Mesenteric vein thrombosis as presenting manifestation of hereditary protein S deficiency

Protein S deficiency is inherited as an autosomal dominant trait. Heterozygotes with a reduction of 50% in the plasma protein S concentration are at risk for the development of venous thromboembolism, often occurring at an early age without an apparent cause. In the majority of the patients thrombosis is restricted to the superficial or deep venous system of the legs. In this case report we describe the presence of mesenteric vein thrombosis in a 30-yr-old man with hereditary protein S deficiency. In his family protein S deficiency was also recognized in his mother, brother, and niece. Both his mother and brother had a history of thrombotic disease.     

Pathogenetic factors underlying juvenile deep vein thrombosis (DVT) in Indians.

The role of hereditary antithrombotic protein defects in juvenile deep vein thrombosis (DVT) was evaluated. Fifty six young patients (age <45 yr) with doppler-proven DVT were investigated for the presence of resistance to activated protein C (APC-R), lupus anticoagulant (LA), anticardiolipin antibodies and deficiencies of protein C, protein S, ATIII activities. Fifty nine normal healthy individuals served as controls. APC-R was observed to be the commonest defect underlying the Indian DVT as seen in 39.2% of patients followed by elevated ACA (5.3%), PAI (2.8%), presence of LA (2.8%) and reduced ATIII levels (2.8%). None of the subjects had protein C or S deficiency. APC-R was associated with ATIII deficiency in one case, and elevated ACA in two cases. In two subjects, APC-R was associated with elevated PAI levels. Patients with more than one prothrombotic factor had a higher prevalence of pulmonary thromboembolism, suggesting that the thrombogenic potential of APC-R is enhanced by the presence of coexisting hereditary or acquired prothrombotic defect.     

Hereditary deficiency of antithrombin III, protein C and protein S: prevalence in patients with a history of venous thrombosis and criteria for rational patient screening.

Data in the literature on the prevalence of hereditary deficiency of the natural coagulation inhibitors are conflicting. We conducted a prospective study on 680 consecutive patients with a history of venous thrombosis to determine the prevalence of hereditary deficiency of antithrombin III (AT III), protein C(PC) and protein S(PS) and to establish selection criteria for rational patient screening. The mean age of the patients at investigation was 44.3 +/- 15.4 years, while that at the first thrombotic event was 38.5 +/- 14.8 years. The total prevalence of inhibitor deficiency states was 48/680 (7.1%). 19/680 patients (2.8%) had AT III-deficiency, 17 (2.5%) PC-deficiency, nine (1.3%) PS-deficiency and three (0.4%) a combined deficiency. In 37/48 deficient patients family studies were performed and the hereditary nature was established in 19 cases (2.8% of total patient population, six with AT III-deficiency, eight with PC-deficiency, four with PS-deficiency and one with a combined deficiency). Family studies in these 19 patients revealed 46 additional individual patients with a hereditary deficiency state. A positive family history was found in 15/19 (79%) with a proven hereditary deficiency state, in 153/619 (25%) of non-deficient patients and in 11/29 (38%) of deficient patients without established hereditary nature. The mean age at the first thrombotic event was significantly lower in patients with a hereditary deficiency state (26.8 years) compared with the other two groups (39.0 and 39.7 years, respectively). In all patients with a hereditary deficiency the first thrombotic event occurred before the age of 45 years.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hereditary protein S deficiency

Protein S is a vitamin K-dependent plasma protein that serves as a cofactor of activated protein C(APC) in its inhibitory action on activated factor V and factor VIII and in its stimulation of fibrinolytic activity. In plasma, part of the protein S is complexed with the C4b-binding protein. Only the free protein S has APC cofactor activity. In our laboratory, 30 patients from 8 nonrelated families were detected that fulfilled the criteria of an isolated protein S deficiency. All patients were heterozygotes for the defect that is inherited as an autosomal-dominant disorder. Patients with a protein S deficiency were found to be at risk for the development of venous thrombotic disease at a relatively young age.     

Protein S deficiency occurs in the nephrotic syndrome

Protein S activity may be compromised in patients with the nephrotic syndrome and contribute to a thrombotic diathesis. Protein S is found in two forms in plasma as free and functionally active protein S, and complexed to C4b-binding protein. When compared with controls, patients with nephrotic syndrome had reduced functional levels of protein S (69% +/- 27% [SD], p less than 0.001) despite having elevated levels of total protein S antigen (139% +/- 42%, p less than 0.001). Decreased protein S activity was caused by significant reductions in free (active) protein S levels (90% +/- 38%, p less than 0.05) due to the selective urinary loss of free protein S and elevation of C4b-binding protein levels (170% +/- 52%, p less than 0.001) that favors complex formation; and in the specific activity of the circulating free protein S (0.76; p less than 0.001). Along with this reduction in specific activity, we noted the abnormal electrophoretic mobility of the protein S in the presence of calcium ions. We conclude that acquired protein S deficiency occurs in the nephrotic syndrome and may be a risk factor for the development of the thromboembolic complications.