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PubMed2006

Thrombin and prothrombin are expressed by neurons and glial cells and accumulate in neurofibrillary tangles in Alzheimer disease brain.

Thrombin is a serine protease that is generated by proteolytic cleavage of its precursor, prothrombin. We previously showed that thrombin proteolyses the microtubule-associated protein tau and that phosphorylation of tau inhibits this process. To characterize further the role of thrombin in the brain, we investigated prothrombin and thrombin expression in cultured brain cells and in brains of control, Alzheimer disease (AD) and parkinsonism-dementia complex of Guam (PDCG). We show by reverse transcriptase-polymerase chain reaction that prothrombin mRNA is expressed in brain tissues, neuroblastoma cells, and cultured human astrocytes, oligodendrocytes, and microglial cells. We also show by immunohistochemistry that the proteins prothrombin and thrombin are present in brain using specific monoclonal and polyclonal antibodies for both proteins. All antibodies stained residual serum in blood vessels, as well as normal pyramidal neurons and their processes, and some astrocytes. Additionally, in AD and PDCG cases, all antibodies stained extra- and intracellular neurofibrillary tangles (NFTs), senile plaques, and reactive microglial cells. The ubiquitous expression of prothrombin and thrombin in brain cells suggests that thrombin plays an important physiological role in normal brain. The accumulation of thrombin and prothrombin in NFTs supports the hypothesis that thrombin may be involved in tau proteolysis and that failure to metabolize tau may lead to its aggregation in neurodegenerative diseases.

Aged↗
PubMed2005

The role of factor V Leiden and prothrombin G20210A mutations in sudden sensorineural hearing loss.

OBJECTIVES: To investigate the incidence of factor V Leiden and prothrombin G20210A in sudden sensorineural hearing loss patients. STUDY DESIGN: The patient group for this study was selected prospectively in the case of 28 patients and retrospectively in the case of another 28. SETTING: Tertiary referral center. PATIENTS: Fifty-six patients (29 female, 27 male) with sudden sensorineural hearing loss (SSHL) and 95 control subjects (48 female, 47 male) were enrolled in this study. The age of the control subjects were between 26 and 76 (38 +/- 16.7), and that of the patients were between 10 and 87 (42.6 +/- 18.2). INTERVENTION: The factor V Leiden and prothrombin G20210A mutations were detected by rapid polymerase chain reaction amplification of genomic DNA extracted from the SSHL patients' peripheral blood cells. MAIN OUTCOME MEASURE: Thrombotic microangiopathic disorders are characterized by widespread microvascular thrombosis leading to end-organ injury. The mutations of factor V Leiden and prothrombin gene are known as genetic risk factors for thrombotic microangiopathy in normal patients. SSHL may occur with occlusion of the cochlear blood supply by microthromboangiopathy. RESULTS: Factor V Leiden mutation was found to be higher in SSHL patients when compared with control subjects (16.1% vs 5.3%). The difference between the two groups was found to be statistically significant (p = 0.02). However, statistical significance was not found between the groups in regard to prothrombin G20210A mutation. Factor V Leiden and prothrombin gene mutations were heterozygous in all of the subjects. CONCLUSION: A significant association between factor V Leiden mutation and idiopathic SSHL could be shown in this study. There was no correlation, however, between the occurrence of idiopathic SSHL and prothrombin mutation.

Adenine↗
PubMed2005

Prevalence of factor V Leiden, prothrombin G20210A, and MTHFR G677A among 594 thrombotic Jordanian patients.

Venous thromboembolism develops as the result of multiple interactions between non-genetic and genetic risk factors. In order to estimate the frequency of factor V Leiden, prothrombin G20210A, and MTHFR C677T mutations in Jordanian thrombotic patients, we studied 594 patients admitted to the King Hussein Medical Center for thrombophilia assessment. Polymerase chain reaction detected 25.7% (20.7% heterozygous, 5% homozygous), 6% (5.8% heterozygous, 0.2% homozygous) and 31.7% (25% heterozygous, 6.7% homozygous) for factor V Leiden, prothrombin G20210A and MTHFR C677T mutations, respectively. A one-stage clotting assay was used to measure prothrombin activity. None of the prothrombin G20210A mutant patients had high prothrombin activity. The high prevalence found among our study group of factor V Leiden and prothrombin G20210A confirms the importance of thrombophilia screening for patients with venous thrombosis with family history and those with additional risk factors. On the contrary, the high prevalence of the MTHFR C677T mutation among arterial thrombosis patients shows its importance in screening in arterial thrombosis patients. These results, which are close to the prevalence found by other studies in the region, suggests that the Eastern Mediterranean region is probably the area of origin of these mutations, especially factor V Leiden. The knowledge of these frequencies in the Middle East region through population-based studies will contribute to a better understanding of the interaction between genetic and environmental risk factors underlying the mentioned mutations.

Adult↗
PubMed2002

Prothrombin G20210A mutation is not associated with recurrent miscarriages.

OBJECTIVE: To assess the association between prothrombin G20210A mutation and recurrent miscarriages. STUDY DESIGN: A literature review was performed in Medline identifying articles from 1966 to December 2000. Articles meeting inclusion criteria were systematically reviewed and included in a meta-analysis. RESULTS: Six trials, all case-controlled, were identified. These trials included 323 women with recurrent pregnancy loss. The odds ratio (OR) for heterozygous prothrombin mutation was 1.9 (95% confidence interval (CI) 0.98-4.14), and for homozygous prothrombin mutation was 3.76 (95% CI 0.75-18.77). The OR for prothrombin mutation and primary recurrent abortion was 2.19 (95% CI 0.61-7.89) and for prothrombin mutation and secondary recurrent abortion was 1.29 (95% CI 0.2-8.36). CONCLUSION: There is no evidence to support an association of prothrombin G20210A mutation with recurrent miscarriages.

Abortion, Habitual↗
PubMed1983

Determination of the amino acid substitution in human prothrombin type 3 (157 Glu leads to Lys) and the localization of a third thrombin cleavage site.

Prothrombin was purified from normal blood donors and individuals heterozygous for prothrombin type 3. Comparison of the purified prothrombin preparations by tryptic peptide mapping, amino acid analysis and automated sequencing after thrombin digestion, has indicated that prothrombin type 3 results from the substitution of a lysine residue for glutamic acid at position 157. This substitution can result from a single base change in the structural gene and explains the relatively slow electrophoretic mobility of prothrombin type 3 at alkaline pH. An additional thrombin cleavage site in profragment 1 has been identified at arginine 54 by automated sequence analysis of thrombin digests by prothrombin.

Amino Acid Sequence↗
PubMed1994

Inhibition of prothrombin activation by antiphospholipid antibodies and beta 2-glycoprotein 1.

Lupus anticoagulants, commonly found in the immunoglobulin fraction of patients with the antiphospholipid syndrome (APS), and the normal plasma protein beta 2-glycoprotein 1 (beta 2GP1) may both contribute to the in vitro impairment of prothrombin activation associated with the APS. We examined the effects upon prothrombin activation supported by phospholipid vesicles of plasma IgG preparations from APS patients in the presence and absence of beta 2GP1. Using a purified system for measurement of prothrombin activation to thrombin, we demonstrated significant phospholipid concentration-dependent inhibition of prothrombin activation in the absence of beta 2GP1 by 11 consecutive patient IgG preparations. The degree of inhibition of prothrombin activation by equivalent concentrations of patient IgG correlated well with the extent of prolongation of the plasma clotting time in lupus anticoagulant assays of whole patient plasma. Additional studies with eight patient IgG preparations indicated that the addition of beta 2GP1 to patient IgG-phospholipid vesicle mixtures resulted in either independently additive inhibition by the two protein species (six cases) or potential inhibition of beta 2GP1 of the IgG inhibitory activity demonstrable in the absence of beta 2 GP1 (two cases). In addition, beta 2GP1-independent inhibition of prothrombin activation also occurred with three patient IgG preparations obtained by affinity binding to cardiolipin.

Antibodies, Anticardiolipin↗
PubMed1995

Reciprocal regulation of prothrombin secretion and tyrosine aminotransferase induction in hepatocytes.

Multicellular spheroids of hepatocytes are known to maintain liver functions for a long period. Rat hepatocytes were isolated to form spheroids by rotation culture and immobilized within calcium alginate. Immobilized spheroids had a much higher extent of tyrosine aminotransferase induction, which is one of the liver-specific differentiated functions, than immobilized non-aggregated cells, while the spheroids secreted significantly less prothrombin than non-aggregated cells. Co-culture of hepatocytes and non-parenchymal liver cells in a monolayer enhanced tyrosine aminotransferase induction and suppressed prothrombin secretion, while conditioned medium prepared from non-parenchymal cells greatly stimulated tyrosine aminotransferase induction and suppressed the prothrombin secretion and DNA synthesis in monolayer-cultured hepatocytes. Prothrombin secretion in hepatocytes was subjected to cell-density-dependent regulation. In a similar manner to other growth-related functions, prothrombin secretion was stimulated at low cell density. It has been reported that thrombin activates the zymogen of hepatocyte growth factor activator [Shimomura, T., Kondo, J., Ochiai, M., Naka, D., Miyazawa, K., Morimoto, Y. & Kitamura, N. (1993) J. Biol. Chem. 268, 22,927-22,932]. Therefore, prothrombin secretion could be one of the growth-related functions and involved in wound healing and liver regeneration.

Animals↗
PubMed1997

Prothrombin, albumin and immunoglobulin A form covalent complexes with alpha1-microglobulin in human plasma.

Molecules containing the 33-kDa plasma protein alpha1-microglobulin were isolated from human plasma by anti-(alpha1-microglobulin) affinity chromatography. Five major bands could be seen after electrophoretic separation of the alpha1-microglobulin-containing proteins under native conditions. Immunoblotting demonstrated alpha1-microglobulin in all five bands. Two of these have been described previously: free alpha1-microglobulin and alpha1-microglobulin complexed with IgA (IgA x alpha1-microglobulin). The other three bands were identified as prothrombin alpha1-microglobulin, albumin x alpha1-microglobulin and dimeric alpha1-microglobulin. Prothrombin x alpha1-microglobulin were 1:2 and 1:1 complexes which carried approximately 1% of total alpha1-microglobulin, had molecular masses of about 145 kDa and 110 kDa upon SDS/PAGE and dissociated completely to free alpha1-microglobulin and prothrombin (72 kDa) when reducing agents were added, suggesting that the complexes were stabilized by disulfide bonds. The alpha1-microglobulin molecules did not inhibit cleavage of prothrombin by factor Xa and were bound to the peptides which were released upon activation of prothrombin. Albumin x alpha1-microglobulin, corresponding to 7% of total plasma alpha1-microglobulin, was a mixture between 1:1 and 1:2 complexes, with masses upon SDS/PAGE of approximately 100 kDa and 135 kDa, respectively. Both these complexes dissociated only partially to free alpha1-microglobulin and albumin when reducing agents were added. The albumin x alpha1-microglobulin complexes carried a yellow-brown chromophore similar to free alpha1-microglobulin. The complex-binding to alpha1-microglobulin did not block the fatty-acid-binding ability of albumin. The plasma concentrations of albumin x alpha1-microglobulin and prothrombin x alpha1-microglobulin were estimated to 5.2 mg/l and 1.1 mg/l, respectively.

Alpha-Globulins↗
PubMed1990

Serial prothrombin time as prognostic indicator in paracetamol induced fulminant hepatic failure.

OBJECTIVE: To find out whether changes in the daily prothrombin time are of prognostic importance in patients with paracetamol induced fulminant hepatic failure. DESIGN: Retrospective study. SETTING: The Liver Unit, King's College Hospital, London. PATIENTS: 150 Consecutive patients with paracetamol induced fulminant hepatic failure admitted between October 1986 and February 1989. MAIN OUTCOME MEASURE: Death. RESULTS: Of the 150 patients, 72 (48%) died. In all, 34 of the 37 (92%) patients with a peak prothrombin time of greater than or equal to 180 seconds died as did 20 of the 41 (49%) with a time of 130-179 seconds, nine of the 25 (36%) with a time of 90-129 seconds, and nine of the 47 (19%) with a time of less than 90 seconds. Of the 42 patients with a continuing rise in prothrombin time between days 3 and 4 after overdose, 39 died (93%) compared with 21 of the 96 (22%) in whom the prothrombin time fell. CONCLUSIONS: These data indicate that a continued increase in prothrombin time on day 4 after overdose and a peak prothrombin time of greater than or equal to 180 seconds identify at an early stage those patients with a less than 8% chance of survival. Liver transplantation should be considered in patients meeting either of these criteria.

Acetaminophen↗
PubMed2003

Allele 4G of gene PAI-1 associated with prothrombin mutation G20210A increases the risk for venous thrombosis.

Several studies have tried to clarify the role of polymorphism 4G/5G of the PAI-1 gene in venous thromboembolism without reaching any final conclusion. It has been demonstrated that this polymorphism may induce an increased risk for venous thromboembolism (VTE) in patients with thrombophilic defects. We studied the association of prothrombin mutation G20210A with 4G/5G polymorphism in 402 VTE patients and 466 healthy controls. Patients affected by prothrombin mutation G20210A, with or without the concomitant presence of allele 4G, had a 3.7 thrombotic risk (C.I. 95% 2.3-6.0; p<0.0001). Moreover, genotype 4G/4G is a mild risk factor for VTE, irrespectively of whether the prothrombin mutation was present. Logistic regression analysis showed that patients carrying the G20210A prothrombin mutation with allele 4G gave an odds ratio for VTE of 6.1 (C.I. 95% 3.2-11.4; p<0.001). The risk increased up to 13.0 (C.I. 95% 3.0-60.4; p<0.001) when we considered the association of the prothrombin mutation with genotype 4G/4G. The G20210A mutation without allele 4G (5G/5G) was not a risk factor for VTE. In conclusion, we believe that patients affected by VTE with concomitant presence of the G20210A prothrombin mutation could be tested for genotype 4G/4G to better define their thrombotic risk.

Adult↗
PubMed1999

Study of the prothrombin gene 20201 GA variant in FV:Q506 carriers in relationship to the presence or absence of juvenile venous thromboembolism.

The G20210A transition of the prothrombin gene has been identified as a common but probably mild hereditary risk factor for venous thromboembolism (VTE). However, the prothrombin gene variant might contribute to the penetrance of thromboembolic disease in many patients with other prothrombotic defects, such as the FV:R506Q mutation. In this investigation, the A20210 allele was found in 9 of 450 healthy controls (2%). Among 89 asymptomatic FV:Q506 carriers, 3 subjects were doubly affected (3.4%). In contrast, of 263 unrelated carriers of the FV:Q506 mutant with a history of juvenile VTE, 30 also had the prothrombin gene G20210A variant (11.4%), including 25 of 220 patients who were heterozygous (11.4%) and 5 of 43 homozygous (11.6%) for FV:Q506. Thus, the A20210 allele of the prothrombin gene is significantly overrepresented in symptomatic FV:Q506 carriers compared with healthy controls (P<0.0001) and asymptomatic relatives carrying the FV mutant (P=0.02). Persons homozygous for the 20210A allele were not found. A statistically significant increase in the prevalence of more unusual sites of venous thrombosis at clinical onset was found in doubly affected patients (9 of 30; 30%) compared with patients without the prothrombin gene variant (26 of 233; 11. 1%) (P=0.004). First VTE occurred spontaneously in 53.3% of all doubly affected patients (16 of 30) and in 28.3% of all simply affected patients (66 of 233) (P=0.005). Among patients with VTE preceded by circumstantial risk factors, the A20210 allele was found in 7.7% (14 of 181). We conclude that the A20210 allele of the prothrombin gene is frequently coinherited in symptomatic FV:Q506 carriers and possibly influences age, site, and type of thrombotic onset manifestation in these patients.

Adolescent↗
PubMed1998

Interaction of coagulation defects and cardiovascular risk factors: increased risk of myocardial infarction associated with factor V Leiden or prothrombin 20210A.

BACKGROUND: A genetic variation located in the 3'-untranslated region of the prothrombin gene (prothrombin 20210 G-->A) was recently described as a risk factor for venous thrombosis. We examined how the presence of this mutation affected the risk of myocardial infarction in a population-based case-control study. Furthermore, we studied the risk of myocardial infarction associated with the simultaneous presence of a coagulation defect (ie, the 20210 AG genotype of prothrombin or the factor V Leiden mutation) and Major cardiovascular risk factors. METHODS AND RESULTS: Among 560 men with a first myocardial infarction before the age of 70 years, 1.8% were heterozygous carriers of the 20210 variant of the prothrombin gene. The control group consisted of 646 men who were frequency matched by age. In the latter group, the frequency of the 20210 AG genotype was 1.2%. The risk of myocardial infarction in the presence of the AG genotype was increased by 50% (odds ratio, 1.5; 95% confidence interval [95% CI], 0.6 to 3.8). The risk of myocardial infarction for carriership of factor V Leiden mutation was increased by 40% (odds ratio, 1.4; 95% CI, 0.8 to 2.2). When a coagulation defect was present (ie, the 20210 AG prothrombin genotype or the factor V Leiden mutation), the risk of myocardial infarction for carriers versus noncarriers was 1.4 (95% CI, 0.9 to 2.2). This risk was substantially increased when one of the major cardiovascular risk factors of smoking, hypertension, diabetes mellitus, or obesity also was present, with odds ratios varying between 3 and 6. These risks exceeded those of the single effects of the cardiovascular risk factors (ie, in the absence of the coagulation defect). CONCLUSIONS: We conclude that in men the 20210 G-->A variant of prothrombin is associated with an increased risk of myocardial infarction. The combined presence of major cardiovascular risk factors and carriership of a coagulation defect increases the risk considerably.

Adult↗
PubMed1999

G20210A mutation in prothrombin gene and risk of myocardial infarction, stroke, and venous thrombosis in a large cohort of US men.

BACKGROUND: A single base pair mutation in the prothrombin gene has recently been identified that is associated with increased prothrombin levels. Whether this mutation increases the risks of arterial and venous thrombosis among healthy individuals is controversial. METHODS AND RESULTS: In a prospective cohort of 14 916 men, we determined the prevalence of the G20210A prothrombin gene variant in 833 men who subsequently developed myocardial infarction, stroke, or venous thrombosis (cases) and in 1774 age- and smoking status-matched men who remained free of thrombosis during a 10-year follow-up (control subjects). Gene sequencing was used to confirm mutation status in a subgroup of participants. Overall, carrier rates for the G20210A mutation were similar among case and control subjects; the relative risk of developing any thrombotic event in association with the 20210A allele was 1.05 (95% CI, 0.7 to 1.6; P=0.8). We observed no evidence of association between mutation and myocardial infarction (RR=0.8, P=0.4) or stroke (RR=1.1, P=0.8). For venous thrombosis, a modest nonsignificant increase in risk was observed (RR=1.7, P=0.08) that was smaller in magnitude than that associated with factor V Leiden (RR=3.0, P<0. 001). Nine individuals carried both the prothrombin mutation and factor V Leiden (5 controls and 4 cases). One individual, a control subject, was homozygous for the prothrombin mutation. CONCLUSIONS: In a large cohort of US men, the G20210A prothrombin gene variant was not associated with increased risk of myocardial infarction or stroke. For venous thrombosis, risk estimates associated with the G20210A mutation were smaller in magnitude than risk estimates associated with factor V Leiden.

Adult↗
PubMed1977

Generation of the combined prothrombin activation peptide (F1-2) during the clotting of blood and plasma.

We have investigated the pathway of prothrombin activation in blood and plasma. By means of a rapid purification procedure involving chromatography on DEAE-cellulose and hydroxyapatite, we demonstrated that the major prothrombin fragment in serum is that representing the amino-terminal half of prothrombin (i.e. F1-2). The F1-2 isolated was characterized by its size, amino acid and antigenic compositions, amino-terminal residue, and the peptides (designated F1 and F2, respectively) it yielded upon hydrolysis by thrombin. Measurements by the isotope dilution technique showed that F1-2 could account for the fate of at least 90% of the prothrombin originally present in plasma. By contrast, the serum concentration of the fragment representing the amino-terminal third of prothrombin (viz. F1) was less than 10% that of F1-2. These results demonstrated that the major route of prothrombin conversion in blood or plasma involves the removal of the combined activation fragment (F1-2) as a single peptide.

Amino Acid Sequence↗
PubMed1981

Relationship between platelet secretion and prothrombin cleavage in native whole blood.

To determine the relationship between platelet secretion and prothrombin conversion in whole blood, the release of platelet factor 4 and the generation of a X(a)-specific cleavage product of prothrombin, fragment 1 + 2, were measured during the coagulation of whole blood. There was a parallel increase in the concentration of the two proteins. Over the first 5 min of incubation, platelet factor 4 concentration increased 6 ng/ml per min, and after 6-7 min, the rate of release increased to 750 ng/ml per min. Over the initial 5-7 min of incubation, fragment 1 + 2 concentration increased 1.5 pmol/ml per min with a subsequent increase of 45 pmol/ml per min. Incubation with 10 muM prostaglandin E(1) or 15 muM prostaglandin I(2) inhibited secretion of platelet factor 4 and delayed the onset of the rapid phase of fragment 1 + 2 generation by 8 min, while stimulation of platelet secretion with 1 mug/ml collagen suspension enhanced production of fragment 1 + 2. The addition of either 10 muM epinephrine or 100 ng/ml collagen suspension to whole blood did not affect either platelet factor 4 release or fragment 1 + 2 generation, although the combination of 3 muM epinephrine and 100 ng/ml collagen suspension enhanced platelet release and prothrombin cleavage. The relationship between platelet factor 4 release and prothrombin cleavage was also studied in Factor VIII-deficient blood. When 0.001 U/ml factor VIII activity was present, <80 ng/ml platelet factor 4 were released, and no fragment 1 + 2 was generated after 30 min of incubation. The addition of 0.008-0.08 U/ml Factor VIII activity progressively increased platelet factor 4 release and prothrombin cleavage. Platelet factor 4 release was normal at 0.08 U/ml Factor VIII activity, whereas prothrombin cleavage was still delayed. Very little thrombin, the amount generated by the cleavage of 3-5 nM fragment 1 + 2, was needed to induce release of platelet factor 4.

Aspirin↗
PubMedDate not supplied

Fat emulsion effects on prothrombin time in warfarin anticoagulated patients: an in vitro study.

The effect of lipid emulsions on prothrombin time in blood from anticoagulated patients was determined. Blood samples were obtained from 23 patients therapeutically anticoagulated with warfarin (prothrombin time 1.3-2.0 x control). Varying amounts of an intravenous lipid emulsion (Intra-lipid) were added to the blood to simulate concentrations seen in vivo with a constant lipid infusion. The prothrombin time was measured on the plasma from these samples and compared to the prothrombin time of the plasma samples without lipid. The mean decrease in prothrombin times were: 0.29 sec at 50 micrograms/ml, 0.23 sec at 100 micrograms/ml, and 0.29 sec at 200 micrograms/ml. All concentrations showed a statistically significant decrease (p less than 0.05) when compared to the control by the Scheffe test. Lipid emulsions appear to decrease the prothrombin times in anti-coagulated patients. The differences however, were small and not of clinical significance at the concentrations tested.

Fat Emulsions, Intravenous↗
PubMed2003

Anti-prothrombin antibodies cause thrombosis in a novel qualitative ex-vivo animal model.

Anti-prothrombin antibodies (aPT) are associated with thrombotic manifestations, and their association with reproductive failure is debatable. The aim of this study was to examine whether aPT could induce thrombosis and other clinical manifestations of the anti-phospholipid syndrome (APS). Mice were immunized with either prothrombin, beta2-glycoprotein-I (beta2GPI), or beta2GPI followed by prothrombin. The presence of clinical manifestation of APS, including thrombocytopenia, lupus anticoagulant and fetal resorption rates, was evaluated in all mice groups compared with nonimmunized mice. Thrombosis was studied in a novel ex-vivo model in which the aorta was sutured for 1 min and the presence or absence of visible thrombus was qualitatively evaluated. Immunized mice developed high autoantibody levels directed towards their immunizing autoantigens. The groups immunized with beta2GPI or beta2GPI/prothrombin, but not with prothrombin alone, developed prolonged aPTT, thrombocytopenia and increased fetal resorption rate. All prothrombin-immunized mice as well as most beta2GPI/prothrombin-immunized mice developed visible thrombus within the aorta. Some beta2GPI immunized mice developed very mild thrombus. None of the CFA/PBS-injected or the nonimmunized mice developed such thrombus. Active immunization with prothrombin or beta2GPI/prothrombin is associated with prothrombotic activity of blood in an ex-vivo model. This is the first direct evidence for thrombus induction by aPT.

Animals↗
PubMed1999

Relationship between clinical features and binding domains of anti-prothrombin autoantibodies in patients with systemic lupus erythematosus and antiphospholipid syndrome.

Autoantibodies against prothrombin, including lupus anticoagulant antibodies (LAC), have been identified in patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). To identify the epitopes of LAC in patients with SLE and APS, we analyzed B cell epitopes of anti-prothrombin Abs. Prothrombin was purified from fresh plasma samples from healthy subjects, and fragmented by thrombin. Two fragments (prethrombin-1, 50 kDa, and fragment-1, 22 kDa) were separated and used for further experiments. The two fragments were coated on irradiated plate and the binding activities of sera from 13 patients with anti-prothrombin Abs (SLE, 7; APS, 4; SLE+APS, 2) were determined by using ELISA. The assay was conducted under the following conditions: use of irradiated plates, and TBS containing Tween-20. We detected two types of anti-prothrombin Abs. The first was anti-prethrombin-1 (n=5) while the other was Ab against fragment-1 (n=8). There were no patients with Abs that showed binding activities to both fragments. A higher proportion of patients with thrombosis were positive for anti-prethrombin-1 Abs (80%) than for anti-fragment-1 Abs (25%). Two patients with anti-prethrombin-1 Ab were positive for LAC and negative for anti-cardiolipin-beta2 glycoprotein I antibody (aCL-beta2GPI). Our results strongly support the notion that both prethrombin-1 and fragment-1 on prothrombin molecule are B cell epitopes.

Antibody Specificity↗