BACKGROUND Alpha-fetoprotein(AFP),a commonly used biomarker for hepatocellular carcinoma(HCC),is normal in up to one-third of patients.AIM To evaluate the diagnostic performance of des-gamma-carboxy-prothrombin(DCP)al...BACKGROUND Alpha-fetoprotein(AFP),a commonly used biomarker for hepatocellular carcinoma(HCC),is normal in up to one-third of patients.AIM To evaluate the diagnostic performance of des-gamma-carboxy-prothrombin(DCP)alone and in combination with AFP.METHODS In this study,202 patients with radiologically proven HCC were enrolled,and their DCP and AFP levels were evaluated for their diagnostic performance.RESULTS The mean age of the enrolled patients was 58.5 years;72.0%were male.DCP was elevated in 86.6%(n=175)of all patients,100.0%(n=74)of patients with portal vein thrombus,and 87.4%(n=111)of patients with multicentric HCC.AFP was elevated in 64.3%(n=130)of all the patients,74%(n=55)of the patients with portal vein thrombus,and 71.6%(n=91)of the patients with multicentric HCC(P=0.030,0.001,and 0.015,respectively).In tumors less than 2 cm in size(n=46),DCP was increased in 32(69.5%)patients,and AFP was increased in 25(54.3%)patients(P=0.801).There was good pairing between DCP and AFP for HCCs of 2 cm size or larger(P<0.001);however,the pairing among tumors<2 cm size was not significant(P=0.210).In 69 of the patients(34.1%),only one of the tumor markers was positive;DCP was elevated alone in 57/202(28.2%)of all patients,and AFP alone was elevated in 12/202(5.9%)of the patients.The areas under receiver operating characteristic curves(AUROC)for tumors>2 cm was 0.74 for DCP and 0.59 for AFP;combining both markers resulted in an AUROC of 0.73.For tumors<2 cm,the AUROC was 0.25 for DCP and 0.40 for AFP.CONCLUSION DCP,as an individual marker,had a better diagnostic performance in many cases of HCC.Hence,DCP may replace AFP as the primary HCC biomarker.展开更多
AIM:To clarify the utility of using des-γ-carboxy prothrombin(DCP)andα-fetoprotein(AFP)levels to predict the prognosis of hepatocellular carcinoma(HCC)in patients with hepatitis B virus(HBV)and the hepatitis C virus...AIM:To clarify the utility of using des-γ-carboxy prothrombin(DCP)andα-fetoprotein(AFP)levels to predict the prognosis of hepatocellular carcinoma(HCC)in patients with hepatitis B virus(HBV)and the hepatitis C virus(HCV)infections.METHODS:A total of 205 patients with HCC(105patients with HBV infection 100 patients with HCV infection)who underwent primary hepatectomy between January 2004 and May 2012 were enrolled retrospectively.Preoperative AFP and DCP levels were used to create interactive dot diagrams to predict recurrence within 2 years after hepatectomy,and cutoff levels were calculated.Patients in the HBV and HCV groups were classified into three groups:a group with low AFP and DCP levels(LL group),a group in which one of the two parameters was high and the other was low(HL group),and a group with high AFP and DCP levels(HH group).Liver function parameters,the postoperative recurrence-free survival rate,and postoperative overall survival were compared between groups.The survival curves were compared by logrank test using the Kaplan-Meier method.Multivariate analysis using a Cox forward stepwise logistic regression model was conducted for a prognosis.RESULTS:The preoperative AFP cutoff levels for recurrence within 2 years after hepatectomy in the HBV and HCV groups were 529.8 ng/m L and 60 m AU/m L,respectively;for preoperative DCP levels,the cutoff levels were 21.0 ng/m L in the HBV group and 67 m AU/m L in the HCV group.The HBV group was significantly different from the other groups in terms of vascular invasion,major hepatectomy,volume of intraoperative blood loss,and surgical duration.Significant differences were found between the LL group,the HL group,and the HH group in terms of both mean disease-free survival time(MDFST)and mean overall survival time(MOST):64.81±7.47 vs 36.63±7.62 vs 18.98±6.17mo(P=0.001)and 85.30±6.55 vs 59.44±7.87 vs46.57±11.20 mo(P=0.018).In contrast,the HCV group exhibited a significant difference in tumor size,vascular invasion,volume of intraoperative blood loss,and surgical duration;however,no significant difference was observed between the three groups in liver function parameters except for albumin levels.In the LL group,the HL group,and the HH group,the MDFST was 50.09±5.90,31.01±7.21,and 14.81±3.08 mo(log-rank test,P<0.001),respectively,and the MOST was 79.45±8.30,58.82±7.56,and 32.87±6.31 mo(log-rank test,P<0.001),respectively.CONCLUSION:In the HBV group,the prognosis was poor when either AFP or DCP levels were high.In the HCV group,the prognosis was good when either or both levels were low;however,the prognosis was poor when both levels were high.High levels of both AFP and DCP were an independent risk factor associated with tumor recurrence in the HBV and HCV groups.The relationship between tumor marker levels and prognosis was characteristic to the type of viral hepatitis.展开更多
AIM: To evaluate whether DCP is better than AFP for differentiating HCC from nonmalignant liver disease and further evaluate the usefulness of DCP in early diagnosis of small HCC. METHODS: Serum DCP and AFP levels w...AIM: To evaluate whether DCP is better than AFP for differentiating HCC from nonmalignant liver disease and further evaluate the usefulness of DCP in early diagnosis of small HCC. METHODS: Serum DCP and AFP levels were determined in 127 patients. Among these patients, 32 were with noncirrhotic chronic hepatitis, 34 were with compensated cirrhosis, and 61 were with HCC. The cut-off value for the DCP and AFP were set as 40 mAU/mL and 20 ng/mL, respectively. To compare the diagnostic value of DCP and AFP in distinguishing HCC from nonmalignant chronic liver disease, receiver operating characteristic (ROC) curves were constructed for each assay. RESULTS: The accuracy, sensitivity, and specifidty of DCP were higher than AFP in detecting HCC (81.9%, 77%, and 86.4% vs 68.5%, 59%, and 77.3%, respectively). The area under the ROC (AUROC) curves revealed that DCP had a better accuracy than AFP in diagnosis of HCC (0.85 [95%CI, 0.78-0.91] vs 0.73 [95%CI, 0.65-0.81], P= 0.013). In 39 patients with solitary HCC, the positive rates of DCP were 100% in patients with tumor size larger than 3 cm, 66.7% in patients with tumor size 2-3 cm and 50% in patients with tumor size less than 2 cm. The positive rates of AFP in patients with tumor size larger than 3 cm, 2-3 crn and less than 2 cm were 55.6%, 50%, and 33.3%, respectively. The median level of DCP in HCC patients with tumor size larger than 3 cm was significantly higher than those with tumor size 2-3 cm and those with the size of less than 2 cm. CONCLUSION: Our study indicates that DCP has a better diagnostic value than AFP in differentiating HCC from nonmalignant chronic liver disease. DCP has not only a stronger correlation with HCC than AFP in tumor size but also more effectiveness than AFP in detecting small size of HCC.展开更多
AIM:To clarify the effect of a high des-gamma-carboxy prothrombin (DCP) level on the invasiveness and prognosis of small hepatocellular carcinoma. METHODS: Among 142 consecutive patients with known DCP levels, who und...AIM:To clarify the effect of a high des-gamma-carboxy prothrombin (DCP) level on the invasiveness and prognosis of small hepatocellular carcinoma. METHODS: Among 142 consecutive patients with known DCP levels, who underwent hepatectomy because of hepatocellular carcinoma, 85 patients met the criteria for small hepatocellular carcinoma, i.e. one ≤ 5 cm sized single tumor or no more than three ≤ 3 cm sized tumors. RESULTS: The overall survival rate of the 142 patients was 92.1% for 1 year, 69.6% for 3 years, and 56.9% for 5 years. Multivariate analysis showed that microscopic vascular invasion (P = 0.03) and serum DCP ≥ 400 mAU/mL (P = 0.02) were independent prognostic factors. In the group of patients who met the criteria for small hepatocellular carcinoma, DCP ≥ 400 mAU/mL was found to be an independent prognostic factor for recurrence-free (P = 0.02) and overall survival (P = 0.0005). In patients who did not meet the criteria, the presence of vascular invasion was an independent factor for recurrence-free (P = 0.02) and overall survivals (P = 0.01). In 75% of patients with small hepatocellular carcinoma and high DCP levels, recurrence occurred extrahepatically. CONCLUSION: For small hepatocellular carcinoma, a high preoperative DCP level appears indicative fortumor recurrence. Because many patients with a high preoperative DCP level develop extrahepatic recurrence, it is necessary to screen the whole body.展开更多
Objective To study the findings of serum antibodies against annexin V, prothrombin, ph-inositol, ph-acid, ph-ethanolamine, ph-serine, ph-glycerol, cardiolipin, and beta2-glycoprotein I and analyze the trophoblast anne...Objective To study the findings of serum antibodies against annexin V, prothrombin, ph-inositol, ph-acid, ph-ethanolamine, ph-serine, ph-glycerol, cardiolipin, and beta2-glycoprotein I and analyze the trophoblast annexin V receptors Methods Sera from 156patients aged 26-41 years with recurrent pregnancy loss (3-7 times) were investigated. Eighty-four fertile healthy women aged 24-38 years were included in a control group. ELISA methods were used for detecting a panel of sera anti-phospholipid antibodies. Immunolocalization of annexin V receptors in 143 trophoblast specimens of 156 patients was investigated by the immunofluorescence technique using Annexin V-FITC, Apoptosis and Annexin V-CY3 commercial kits. Results Positivity for anti-phospholipid antibodies mainly against ph-serine, ph- ethanolamine, and ph-inositol was found together in 80. 8%(126 out of 156 patients), anti-prothrombin antibodies in 12% (18), and anti-annexin V antibodies in 13. 5% (21) women. No significant levels of anti-phospholipid antibodies were found in 6 controls. Placenta immunohistopathology also exhibited some changes manifested by the presence of apoptotic and necrotic cells in trophoblast, and very few microthrombotization in some intervillous spaces. Conclusion Our detailed study demonstrated the prevalence of majority of antiphospholipid antibodies as a high risk factor for repeated reproductive failure. Very low microthrombosis in placentas could be explained by the changes of haemocoagulation properties out of uterus.展开更多
AIM: To investigate risk factors for development of hepatocellular carcinoma(HCC) in patients with hepatitis C virus-related liver cirrhosis(LC-C).METHODS: To evaluate the relationship between clinical factors includi...AIM: To investigate risk factors for development of hepatocellular carcinoma(HCC) in patients with hepatitis C virus-related liver cirrhosis(LC-C).METHODS: To evaluate the relationship between clinical factors including virological response and the development of HCC in patients with LC-C treated with interferon(IFN) and ribavirin, we conducted a multicenter, retrospective study in 14 hospitals in Japan. All patients had compensated LC-C with clinical or histological data available. HCC was diagnosed by the presence of typical hypervascular characteristics on computed tomography and/or magnetic resonance imaging.RESULTS: HCC was diagnosis in 50(21.6%) of 231 LC-C patients during a median observation period of 3.8 years after IFN and ribavirin therapy. Patients who developed HCC were older(P = 0.018) and had higher serum levels of pretreatment alpha-fetoprotein(AFP)(P = 0.038). Multivariate analysis revealed the following independent risk factors for HCC development: history of treatment for HCC [P < 0.001, odds ratio(OR) = 15.27, 95%CI: 4.98-59.51], AFP levels of ≥ 10 ng/m L(P = 0.009, OR = 3.89, 95%CI: 1.38-11.94), and des-γ-carboxy prothrombin(DCP) levels of ≥ 40 m AU/mL at 24 wk after the completion of IFN and ribavirin therapy(P < 0.001, OR = 24.43, 95%CI: 4.11-238.67).CONCLUSION: We suggested that the elevation of AFP and DCP levels at 24 wk after the completion of IFN and ribavirin therapy were strongly associated with the incidence of HCC irrespective of virological response among Japanese LC-C patients.展开更多
AIM: To examine whether hepatitis C virus (HCV)-infected patients who carry hypercoagulable mutationssuffer from increased rates of liver fi brosis. METHODS: We analyzed DNA samples of 168 HCV patients for three commo...AIM: To examine whether hepatitis C virus (HCV)-infected patients who carry hypercoagulable mutationssuffer from increased rates of liver fi brosis. METHODS: We analyzed DNA samples of 168 HCV patients for three common hypercoagulable gene mutations: prothrombin 20210 (PT20210), factor V Leiden (FV Leiden) and methylene tetrahydrofolate reductase (MTHFR). The patients were consecutively recruited as part of the prospective "Fibroscore Study" in France. The effect of the various mutations on the rate of fi-brosis was analyzed statistically and was correlated with epidemiological, clinical and biochemical data such as grade and stage of liver biopsies, patients' risk factors for liver cirrhosis, and timing of infection. RESULTS: Fifty two of the patients were categorized as "fast fi brosers" and 116 as "slow fi brosers"; 13% of the "fast fi brosers" carried the PT20210 mutation as compared with 5.5% of the "slow fi brosers", with an odds ratio of 4.76 (P = 0.033; 95% CI: 1.13-19.99) for "fast" liver fibrosis. Carriage of MTHFR or FV Leiden mutations was not associated with enhanced liver fi brosis. CONCLUSION: Carriage of the PT20210 mutation is related to an increased rate of liver fi brosis in HCV patients.展开更多
Mesenteric venous thrombosis(MVT)is a rare but life threatening form of bowel ischemia.It is implicated in 6%-9% of all cases of acute mesenteric ischemia.The proportion of patients with primary(or idiopathic)MVT vari...Mesenteric venous thrombosis(MVT)is a rare but life threatening form of bowel ischemia.It is implicated in 6%-9% of all cases of acute mesenteric ischemia.The proportion of patients with primary(or idiopathic)MVT varies from 0% to 49%,with a decrease in frequency secondary to more recent availability of newer investigations for hypercoagulability.The presence of factor Ⅴ Leiden(FVL)and prothrombin G20210A mutations(PGM)have been well documented in these cases.However,there have been scarce case reports describing MVT in heterozygotes of both these mutations occurring simultaneously and its implications on long term management.Our case describes acute MVT in a previously asymptomatic young patient with no prior history of venous thromboembolism.The patient was found to be heterozygous for FVL and PGM and treated with lifelong anticoagulation with warfarin(goal international normalized ratio:2-3)and avoidance of hormonal contraceptives.展开更多
To the Editor: Although des-gamma-carboxy prothrombin(DCP) is considered a complementary biomarker to alpha-fetoprotein(AFP) in the diagnosis of hepatocellular carcinoma(HCC), its cut-off value has not been recommende...To the Editor: Although des-gamma-carboxy prothrombin(DCP) is considered a complementary biomarker to alpha-fetoprotein(AFP) in the diagnosis of hepatocellular carcinoma(HCC), its cut-off value has not been recommended in any guideline. This study aimed to explore the diagnostic efficacy of DCP on HCC.展开更多
BACKGROUND Supported by the National Natural Science Foundation of China,No.The prognostic value of coagulation disorder in coronavirus disease 2019(COVID-19)patients should be demonstrated.AIM To investigate the abno...BACKGROUND Supported by the National Natural Science Foundation of China,No.The prognostic value of coagulation disorder in coronavirus disease 2019(COVID-19)patients should be demonstrated.AIM To investigate the abnormalities of coagulation parameters in the patients with COVID-19 and their prognostic values.METHODS Consecutive patients admitted in the isolation ward of Renmin Hospital of Wuhan University from January 31 to February 5,2020 with confirmed COVID-19 were included.The primary outcomes were death and survival as of March 11.Demographics,vital signs,comorbidities and laboratory tests were collected and compared between those who died and survivors.Logistic regression analysis for prognostic factors was performed.Kaplan-Meier analysis was used to compare the estimated survival rate between patients with prolonged prothrombin time and normal prothrombin time.RESULTS The total number of patients with confirmed COVID-19 who were enrolled was 213.The median age was 62 years,and 95 patients(44.6%)were men.Fifty-one patients were critical(23.9%),79 patients were severe(37.1%)and 83 patients were moderate(39%).As of March 11,2020,99 patients were discharged(46.5%),79 patients(37.1%)stayed in the hospital and 35 patients(16.2%)died.Median time to death was 6(4-8)d,while median hospital stay was 32(22-36)d in survivors(P<0.001).More men(P=0.002)and elderly patients(P<0.001)were found in the group of those who died.The respiration rate at admission was higher in the group of those who died(P<0.001).The incidences of hypertension(P=0.028),cerebrovascular disease(P<0.001),chronic kidney disease(P=0.02)and chronic obstructive pulmonary disease(P<0.001)were higher in the group of those who died.Platelet count was decreased in the group of those who died(P=0.002)whereas prothrombin time(P<0.001),activated partial thromboplastin time(P=0.033),concentration of D-dimer(P<0.001)and fibrin degradation products(P<0.001)were increased in the group of those who died.Prothrombin time[odds ratio(OR):2.19,P=0.004],respiration rate(OR:1.223,P<0.001),age(OR:1.074,P<0.001)and fibrin degradation products concentration(OR:1.02,P=0.014)were predictors of death.The survival rate was significantly lower in patients with prolonge CONCLUSION Prothrombin time,concentration of fibrin degradation products,respiration rate and age were predictive factors for clinical outcomes of COVID-19 patients.展开更多
Portal vein thrombosis is an uncommonly reported complication of percutaneous transhepatic cholangiography (PTC). A thorough review of the available literature shows no reported cases. In this case, a 29 year old fema...Portal vein thrombosis is an uncommonly reported complication of percutaneous transhepatic cholangiography (PTC). A thorough review of the available literature shows no reported cases. In this case, a 29 year old female presented on two separate occasions with portal vein thrombosis following PTC without drain placement. This unusual complication of image guided percutaneous biliary access is unreported in the literature and prompted evaluation of the patient's coagulation parameters. A thrombophilia screen demonstrated a mutation in the Prothrombin (Factor Ⅱ) gene. A thorough literature review shows no reported cases of portal vein thrombosis following percutaneous biliary access, is an unusual complication, and should raise suspicion of an underlying pro-coagulant state.展开更多
AIM: To analyze the prevalence of the two commonest thrombophilic mutations, factor V Leiden and prothrombin G20210A, in patients with gastric cancer. METHODS: One hundred and twenty-one patients with primary gastri...AIM: To analyze the prevalence of the two commonest thrombophilic mutations, factor V Leiden and prothrombin G20210A, in patients with gastric cancer. METHODS: One hundred and twenty-one patients with primary gastric carcinoma and 130 healthy subjects, comparable for age and sex, were investigated. Factor V Leiden was detected by using polymerase chain reaction and restriction enzyme digestion, and prothrombin G20210A gene mutation by allele-specific PCR. RESULTS: Among the 121 cancer patients, factor V Leiden was found in 4 cases (GA genotype: 3.3%) and prothrombin G20210A in 10 cases (GA genotype: 8.3%). Of the 130 control subjects, factor V Leiden was detected in 6 cases (GA genotype: 4.6%) and prothrombin G20210A in 8 cases (GA genotype: 6.1%). No double heterozygous carriers of both mutations were found in either group. The prevalence of both factor V Leiden and prothrombin G20210A variant was not statistically different between the cancer patients and the healthy subjects. CONCLUSION: Our study suggests that, in gastric cancer, the risk factors of thrombophilic cancer state are on acquired rather than on a genetic basis and that prothrombin G20210A does not seem to be a cofactor in gastric cancer pathogenesis.展开更多
Concerns on the coagulation variables, Prothrombin Time (PT) and Activated Partial Thromboplastin Time (APTT) which are part of coagulation parameters used in assessing haemostatsis in haematology, led to the study of...Concerns on the coagulation variables, Prothrombin Time (PT) and Activated Partial Thromboplastin Time (APTT) which are part of coagulation parameters used in assessing haemostatsis in haematology, led to the study of the effects of naphthoquinone and chloroquine on the PT and APTT of mice infected with <em>Plasmodium berghei</em>, and treated with graded concentrations of chloroquine and naphthoquinone. Using brain thromboplastin with calcium and rabbit brain cephalosporin ad kaolin respectively the experiment aimed at demonstrating the effect of chloroquine with purity of 99.79% and naphthoquinone with purity of 97.00%, upon a three-day intraperitoneal administration at concentrations of 0.1 mg/kg, 0.5 mg/kg, 1.0 mg/kg and 2.0 mg/kg. Result showed that the APTT and PT of naphthoquinone at 2.0 mg/kg, were 196.67 seconds, and 67.63 seconds respectively, while the APTT and PT of chloroquine were 3.63 seconds and 1.40 seconds respectively for the same concentration. Also, naphthoquinone showed lower APTT but sustained PT at concentrations below 1.50 mg/kg whereas both APTT and PT increased from concentrations above 1.50 mg/kg. On the other hand chloroquine showed a lowered APTT between 0.00 to 0.15 mg/kg while PT was sustained, but both APTT and PT increased from concentration of 0.15 mg/kg gradually. This study conclusively showed that chloroquine has a shorter APTT and PT than naphthoquinones, even though they elicited similar actions. Apart from this, naphthoquinone and chloroquine belonging to the same family, naphthoquinone could be more toxic than chloroquine at the dosages equivalent to 1.50 mg/kg, therefore, any administration of naphthoquinone above this dosage should be closely monitored to avoid any form of danger to the patient.展开更多
Objectives: To better understand the etiologic factors that can influence preeclampsia, we inves- tigated hereditary factors for thrombosis, FV Leiden, F II 20210A mutation and the polymorphism C677T of the MTHFR, as ...Objectives: To better understand the etiologic factors that can influence preeclampsia, we inves- tigated hereditary factors for thrombosis, FV Leiden, F II 20210A mutation and the polymorphism C677T of the MTHFR, as singly and as in association, in a group of women from Ceará state-Northeast Brazil with severe preeclampsia. Material and Methods: We conducted a case-control study. 101 cases of severe preeclampsia were recruited from School Maternity Assis Chateaubriand, a reference Maternity of State of Ceará, Brazil, from December 2009 to December 2010. For clinical correlations, women were interrogated about fetal low weight (less than2500 grams) and fetal loss in previous pregnancies. Low weight, fetal loss and necessity of neonatal intensive care unit (neonatal ICU) related to current pregnancy were registered. 245 healthy voluntary women were recruited from the blood bank donors to verify the frequency of FV Leiden, FII and MTHFR as a control group. The study was approved by the Committee on Ethics in Human Research of Maternidade Escola Assis Chateubriand and all individuals gave their informed consent to participate in the study. Standard veinipuncture, with EDTA as anticoagulant, was used to collect blood samples. Genomic DNA was extracted, soon after, using a salting out method. Agarose gel electrophoresis with ethidium bromide staining was performed to ensure the quality of DNA extraction. Results: The frequencies of FV Leiden and FII mutation carrier were 0.99% (1/101) for both factors in the preeclampsia patients and 1.86% (4/214) and 0.93% (2/214), respectively, in control group. All mutates were heterozygous and concomitance of both mutations was not found. The genotype distribution of the MTHFR C677T in the patients and controls frequencies was in Hardy-Weinberg equilibrium (p ≤ 0.05). No statistical difference was observed between cases and controls in MTHFR genotypes or alleles. Conclusions: The FV Leiden, FII G20210A mutation and MTHFR C677T were not risks for preeclampsia development. FV Leiden and FII G20210A mutations had low frequency in the population studied, which may justify the absence of association.展开更多
Objective: The objective of this study was to analyse the reversibility of the anticoagulant effect of warfarin by comparing prothrombin complex concentrate (PCC) versus frozen fresh plasma (FFP) in cardiology patient...Objective: The objective of this study was to analyse the reversibility of the anticoagulant effect of warfarin by comparing prothrombin complex concentrate (PCC) versus frozen fresh plasma (FFP) in cardiology patients with serious warfarin intoxication. Methods: This was an observational and retrospective study comprising 67 patients (18 in group I [PCC] and 49 in group II [FFP]). The primary endpoint was the reversal of anticoagulant effect of warfarin after 2 and 24 hours of PCC or FFP administration. Comparisons between the groups were made using T-test and Q-square. Multivariate analyses were conducted using logistic regression, and the results were considered significant when p Results: The medium dose used was 27.6 UI/kg of PCC and 14.5 ml/kg of FFP. Significant differences were observed between groups I and II in the INR reversibility measurements after 2 hours (33.3% vs. 6.1%, p = 0.001) and 24 hours (38.9% vs. 12.2%, p = 0.009) as well as in the occurrence of pulmonary edema (5.6% vs. 42.9%, OR = 11.10, p = 0.04). The AUC for PCC was 0.891 (CI 95% [0.72 - 1.0]), and for FFP, it was 0.291 (CI 95% [0.09 - 0.49]). Conclusions: PCC is better than FFP treatment in reversing the warfarin intoxication after 2 and 24 hours of administration. Furthermore, PCC showed lower pulmonary edema in cardiology patients.展开更多
BACKGROUND Thrombophilia contributes to a significant increased risk of venous thromboembolism and can be either inherited or acquired.Hereditary thrombophilia may arise from various gene mutations,some of which have ...BACKGROUND Thrombophilia contributes to a significant increased risk of venous thromboembolism and can be either inherited or acquired.Hereditary thrombophilia may arise from various gene mutations,some of which have not even been adequately reported or poorly understood.Previous studies reported a rare and novel missense mutation in the prothrombin gene(p.Arg596Gln),known as prothrombin Belgrade.The mechanisms and therapeutic strategies associated with prothrombin Belgrade mutation have not been fully elucidated.CASE SUMMARY We present the case of a 26-year-old woman with recurrent systemic thrombosis induced by prothrombin Belgrade mutation.The patient suffered from cerebral venous sinus thrombosis that rapidly progressed to systemic thrombosis,alongside a family history of cerebral thrombosis,and no traditional risk factors or abnormal coagulation function.Whole-genome sequencing detected a novel and rare heterozygous prothrombin missense mutation,c.1787G>T(p.Arg596Gln),which was responsible for the major etiology of the systemic thrombosis.CONCLUSION This case strengthens our understanding about hereditary basis of thrombophilia and provokes considerations for therapeutic options on prothrombin Belgrade mutation.展开更多
文摘BACKGROUND Alpha-fetoprotein(AFP),a commonly used biomarker for hepatocellular carcinoma(HCC),is normal in up to one-third of patients.AIM To evaluate the diagnostic performance of des-gamma-carboxy-prothrombin(DCP)alone and in combination with AFP.METHODS In this study,202 patients with radiologically proven HCC were enrolled,and their DCP and AFP levels were evaluated for their diagnostic performance.RESULTS The mean age of the enrolled patients was 58.5 years;72.0%were male.DCP was elevated in 86.6%(n=175)of all patients,100.0%(n=74)of patients with portal vein thrombus,and 87.4%(n=111)of patients with multicentric HCC.AFP was elevated in 64.3%(n=130)of all the patients,74%(n=55)of the patients with portal vein thrombus,and 71.6%(n=91)of the patients with multicentric HCC(P=0.030,0.001,and 0.015,respectively).In tumors less than 2 cm in size(n=46),DCP was increased in 32(69.5%)patients,and AFP was increased in 25(54.3%)patients(P=0.801).There was good pairing between DCP and AFP for HCCs of 2 cm size or larger(P<0.001);however,the pairing among tumors<2 cm size was not significant(P=0.210).In 69 of the patients(34.1%),only one of the tumor markers was positive;DCP was elevated alone in 57/202(28.2%)of all patients,and AFP alone was elevated in 12/202(5.9%)of the patients.The areas under receiver operating characteristic curves(AUROC)for tumors>2 cm was 0.74 for DCP and 0.59 for AFP;combining both markers resulted in an AUROC of 0.73.For tumors<2 cm,the AUROC was 0.25 for DCP and 0.40 for AFP.CONCLUSION DCP,as an individual marker,had a better diagnostic performance in many cases of HCC.Hence,DCP may replace AFP as the primary HCC biomarker.
基金Supported by Grant-in-Aid for Scientific Research from the Ministry of Education,Culture,Sports,Science and Technology,Japan,[Grant No.24791437 and No.26461920(to Meguro M),No.13377023(to Hirata K),and No.23591993(to Mizuguchi T)]A grant from the Yuasa Memorial Foundation was awarded to Mizuguchi T
文摘AIM:To clarify the utility of using des-γ-carboxy prothrombin(DCP)andα-fetoprotein(AFP)levels to predict the prognosis of hepatocellular carcinoma(HCC)in patients with hepatitis B virus(HBV)and the hepatitis C virus(HCV)infections.METHODS:A total of 205 patients with HCC(105patients with HBV infection 100 patients with HCV infection)who underwent primary hepatectomy between January 2004 and May 2012 were enrolled retrospectively.Preoperative AFP and DCP levels were used to create interactive dot diagrams to predict recurrence within 2 years after hepatectomy,and cutoff levels were calculated.Patients in the HBV and HCV groups were classified into three groups:a group with low AFP and DCP levels(LL group),a group in which one of the two parameters was high and the other was low(HL group),and a group with high AFP and DCP levels(HH group).Liver function parameters,the postoperative recurrence-free survival rate,and postoperative overall survival were compared between groups.The survival curves were compared by logrank test using the Kaplan-Meier method.Multivariate analysis using a Cox forward stepwise logistic regression model was conducted for a prognosis.RESULTS:The preoperative AFP cutoff levels for recurrence within 2 years after hepatectomy in the HBV and HCV groups were 529.8 ng/m L and 60 m AU/m L,respectively;for preoperative DCP levels,the cutoff levels were 21.0 ng/m L in the HBV group and 67 m AU/m L in the HCV group.The HBV group was significantly different from the other groups in terms of vascular invasion,major hepatectomy,volume of intraoperative blood loss,and surgical duration.Significant differences were found between the LL group,the HL group,and the HH group in terms of both mean disease-free survival time(MDFST)and mean overall survival time(MOST):64.81±7.47 vs 36.63±7.62 vs 18.98±6.17mo(P=0.001)and 85.30±6.55 vs 59.44±7.87 vs46.57±11.20 mo(P=0.018).In contrast,the HCV group exhibited a significant difference in tumor size,vascular invasion,volume of intraoperative blood loss,and surgical duration;however,no significant difference was observed between the three groups in liver function parameters except for albumin levels.In the LL group,the HL group,and the HH group,the MDFST was 50.09±5.90,31.01±7.21,and 14.81±3.08 mo(log-rank test,P<0.001),respectively,and the MOST was 79.45±8.30,58.82±7.56,and 32.87±6.31 mo(log-rank test,P<0.001),respectively.CONCLUSION:In the HBV group,the prognosis was poor when either AFP or DCP levels were high.In the HCV group,the prognosis was good when either or both levels were low;however,the prognosis was poor when both levels were high.High levels of both AFP and DCP were an independent risk factor associated with tumor recurrence in the HBV and HCV groups.The relationship between tumor marker levels and prognosis was characteristic to the type of viral hepatitis.
基金Supported by the Taipei Institute of Pathology, Taipei, Taiwan and Eisai Co., Tokyo, Japan
文摘AIM: To evaluate whether DCP is better than AFP for differentiating HCC from nonmalignant liver disease and further evaluate the usefulness of DCP in early diagnosis of small HCC. METHODS: Serum DCP and AFP levels were determined in 127 patients. Among these patients, 32 were with noncirrhotic chronic hepatitis, 34 were with compensated cirrhosis, and 61 were with HCC. The cut-off value for the DCP and AFP were set as 40 mAU/mL and 20 ng/mL, respectively. To compare the diagnostic value of DCP and AFP in distinguishing HCC from nonmalignant chronic liver disease, receiver operating characteristic (ROC) curves were constructed for each assay. RESULTS: The accuracy, sensitivity, and specifidty of DCP were higher than AFP in detecting HCC (81.9%, 77%, and 86.4% vs 68.5%, 59%, and 77.3%, respectively). The area under the ROC (AUROC) curves revealed that DCP had a better accuracy than AFP in diagnosis of HCC (0.85 [95%CI, 0.78-0.91] vs 0.73 [95%CI, 0.65-0.81], P= 0.013). In 39 patients with solitary HCC, the positive rates of DCP were 100% in patients with tumor size larger than 3 cm, 66.7% in patients with tumor size 2-3 cm and 50% in patients with tumor size less than 2 cm. The positive rates of AFP in patients with tumor size larger than 3 cm, 2-3 crn and less than 2 cm were 55.6%, 50%, and 33.3%, respectively. The median level of DCP in HCC patients with tumor size larger than 3 cm was significantly higher than those with tumor size 2-3 cm and those with the size of less than 2 cm. CONCLUSION: Our study indicates that DCP has a better diagnostic value than AFP in differentiating HCC from nonmalignant chronic liver disease. DCP has not only a stronger correlation with HCC than AFP in tumor size but also more effectiveness than AFP in detecting small size of HCC.
文摘AIM:To clarify the effect of a high des-gamma-carboxy prothrombin (DCP) level on the invasiveness and prognosis of small hepatocellular carcinoma. METHODS: Among 142 consecutive patients with known DCP levels, who underwent hepatectomy because of hepatocellular carcinoma, 85 patients met the criteria for small hepatocellular carcinoma, i.e. one ≤ 5 cm sized single tumor or no more than three ≤ 3 cm sized tumors. RESULTS: The overall survival rate of the 142 patients was 92.1% for 1 year, 69.6% for 3 years, and 56.9% for 5 years. Multivariate analysis showed that microscopic vascular invasion (P = 0.03) and serum DCP ≥ 400 mAU/mL (P = 0.02) were independent prognostic factors. In the group of patients who met the criteria for small hepatocellular carcinoma, DCP ≥ 400 mAU/mL was found to be an independent prognostic factor for recurrence-free (P = 0.02) and overall survival (P = 0.0005). In patients who did not meet the criteria, the presence of vascular invasion was an independent factor for recurrence-free (P = 0.02) and overall survivals (P = 0.01). In 75% of patients with small hepatocellular carcinoma and high DCP levels, recurrence occurred extrahepatically. CONCLUSION: For small hepatocellular carcinoma, a high preoperative DCP level appears indicative fortumor recurrence. Because many patients with a high preoperative DCP level develop extrahepatic recurrence, it is necessary to screen the whole body.
基金This study was supported by grants of Czech Ministry of Health (VU 96/69).
文摘Objective To study the findings of serum antibodies against annexin V, prothrombin, ph-inositol, ph-acid, ph-ethanolamine, ph-serine, ph-glycerol, cardiolipin, and beta2-glycoprotein I and analyze the trophoblast annexin V receptors Methods Sera from 156patients aged 26-41 years with recurrent pregnancy loss (3-7 times) were investigated. Eighty-four fertile healthy women aged 24-38 years were included in a control group. ELISA methods were used for detecting a panel of sera anti-phospholipid antibodies. Immunolocalization of annexin V receptors in 143 trophoblast specimens of 156 patients was investigated by the immunofluorescence technique using Annexin V-FITC, Apoptosis and Annexin V-CY3 commercial kits. Results Positivity for anti-phospholipid antibodies mainly against ph-serine, ph- ethanolamine, and ph-inositol was found together in 80. 8%(126 out of 156 patients), anti-prothrombin antibodies in 12% (18), and anti-annexin V antibodies in 13. 5% (21) women. No significant levels of anti-phospholipid antibodies were found in 6 controls. Placenta immunohistopathology also exhibited some changes manifested by the presence of apoptotic and necrotic cells in trophoblast, and very few microthrombotization in some intervillous spaces. Conclusion Our detailed study demonstrated the prevalence of majority of antiphospholipid antibodies as a high risk factor for repeated reproductive failure. Very low microthrombosis in placentas could be explained by the changes of haemocoagulation properties out of uterus.
基金Supported by A Grant--in--Aid from the Japanese Ministry of Health,Welfare and Labour
文摘AIM: To investigate risk factors for development of hepatocellular carcinoma(HCC) in patients with hepatitis C virus-related liver cirrhosis(LC-C).METHODS: To evaluate the relationship between clinical factors including virological response and the development of HCC in patients with LC-C treated with interferon(IFN) and ribavirin, we conducted a multicenter, retrospective study in 14 hospitals in Japan. All patients had compensated LC-C with clinical or histological data available. HCC was diagnosed by the presence of typical hypervascular characteristics on computed tomography and/or magnetic resonance imaging.RESULTS: HCC was diagnosis in 50(21.6%) of 231 LC-C patients during a median observation period of 3.8 years after IFN and ribavirin therapy. Patients who developed HCC were older(P = 0.018) and had higher serum levels of pretreatment alpha-fetoprotein(AFP)(P = 0.038). Multivariate analysis revealed the following independent risk factors for HCC development: history of treatment for HCC [P < 0.001, odds ratio(OR) = 15.27, 95%CI: 4.98-59.51], AFP levels of ≥ 10 ng/m L(P = 0.009, OR = 3.89, 95%CI: 1.38-11.94), and des-γ-carboxy prothrombin(DCP) levels of ≥ 40 m AU/mL at 24 wk after the completion of IFN and ribavirin therapy(P < 0.001, OR = 24.43, 95%CI: 4.11-238.67).CONCLUSION: We suggested that the elevation of AFP and DCP levels at 24 wk after the completion of IFN and ribavirin therapy were strongly associated with the incidence of HCC irrespective of virological response among Japanese LC-C patients.
文摘AIM: To examine whether hepatitis C virus (HCV)-infected patients who carry hypercoagulable mutationssuffer from increased rates of liver fi brosis. METHODS: We analyzed DNA samples of 168 HCV patients for three common hypercoagulable gene mutations: prothrombin 20210 (PT20210), factor V Leiden (FV Leiden) and methylene tetrahydrofolate reductase (MTHFR). The patients were consecutively recruited as part of the prospective "Fibroscore Study" in France. The effect of the various mutations on the rate of fi-brosis was analyzed statistically and was correlated with epidemiological, clinical and biochemical data such as grade and stage of liver biopsies, patients' risk factors for liver cirrhosis, and timing of infection. RESULTS: Fifty two of the patients were categorized as "fast fi brosers" and 116 as "slow fi brosers"; 13% of the "fast fi brosers" carried the PT20210 mutation as compared with 5.5% of the "slow fi brosers", with an odds ratio of 4.76 (P = 0.033; 95% CI: 1.13-19.99) for "fast" liver fibrosis. Carriage of MTHFR or FV Leiden mutations was not associated with enhanced liver fi brosis. CONCLUSION: Carriage of the PT20210 mutation is related to an increased rate of liver fi brosis in HCV patients.
文摘Mesenteric venous thrombosis(MVT)is a rare but life threatening form of bowel ischemia.It is implicated in 6%-9% of all cases of acute mesenteric ischemia.The proportion of patients with primary(or idiopathic)MVT varies from 0% to 49%,with a decrease in frequency secondary to more recent availability of newer investigations for hypercoagulability.The presence of factor Ⅴ Leiden(FVL)and prothrombin G20210A mutations(PGM)have been well documented in these cases.However,there have been scarce case reports describing MVT in heterozygotes of both these mutations occurring simultaneously and its implications on long term management.Our case describes acute MVT in a previously asymptomatic young patient with no prior history of venous thromboembolism.The patient was found to be heterozygous for FVL and PGM and treated with lifelong anticoagulation with warfarin(goal international normalized ratio:2-3)and avoidance of hormonal contraceptives.
文摘To the Editor: Although des-gamma-carboxy prothrombin(DCP) is considered a complementary biomarker to alpha-fetoprotein(AFP) in the diagnosis of hepatocellular carcinoma(HCC), its cut-off value has not been recommended in any guideline. This study aimed to explore the diagnostic efficacy of DCP on HCC.
基金the National Natural Science Foundation of China,No.81570450 and No.81900455.
文摘BACKGROUND Supported by the National Natural Science Foundation of China,No.The prognostic value of coagulation disorder in coronavirus disease 2019(COVID-19)patients should be demonstrated.AIM To investigate the abnormalities of coagulation parameters in the patients with COVID-19 and their prognostic values.METHODS Consecutive patients admitted in the isolation ward of Renmin Hospital of Wuhan University from January 31 to February 5,2020 with confirmed COVID-19 were included.The primary outcomes were death and survival as of March 11.Demographics,vital signs,comorbidities and laboratory tests were collected and compared between those who died and survivors.Logistic regression analysis for prognostic factors was performed.Kaplan-Meier analysis was used to compare the estimated survival rate between patients with prolonged prothrombin time and normal prothrombin time.RESULTS The total number of patients with confirmed COVID-19 who were enrolled was 213.The median age was 62 years,and 95 patients(44.6%)were men.Fifty-one patients were critical(23.9%),79 patients were severe(37.1%)and 83 patients were moderate(39%).As of March 11,2020,99 patients were discharged(46.5%),79 patients(37.1%)stayed in the hospital and 35 patients(16.2%)died.Median time to death was 6(4-8)d,while median hospital stay was 32(22-36)d in survivors(P<0.001).More men(P=0.002)and elderly patients(P<0.001)were found in the group of those who died.The respiration rate at admission was higher in the group of those who died(P<0.001).The incidences of hypertension(P=0.028),cerebrovascular disease(P<0.001),chronic kidney disease(P=0.02)and chronic obstructive pulmonary disease(P<0.001)were higher in the group of those who died.Platelet count was decreased in the group of those who died(P=0.002)whereas prothrombin time(P<0.001),activated partial thromboplastin time(P=0.033),concentration of D-dimer(P<0.001)and fibrin degradation products(P<0.001)were increased in the group of those who died.Prothrombin time[odds ratio(OR):2.19,P=0.004],respiration rate(OR:1.223,P<0.001),age(OR:1.074,P<0.001)and fibrin degradation products concentration(OR:1.02,P=0.014)were predictors of death.The survival rate was significantly lower in patients with prolonge CONCLUSION Prothrombin time,concentration of fibrin degradation products,respiration rate and age were predictive factors for clinical outcomes of COVID-19 patients.
文摘Portal vein thrombosis is an uncommonly reported complication of percutaneous transhepatic cholangiography (PTC). A thorough review of the available literature shows no reported cases. In this case, a 29 year old female presented on two separate occasions with portal vein thrombosis following PTC without drain placement. This unusual complication of image guided percutaneous biliary access is unreported in the literature and prompted evaluation of the patient's coagulation parameters. A thrombophilia screen demonstrated a mutation in the Prothrombin (Factor Ⅱ) gene. A thorough literature review shows no reported cases of portal vein thrombosis following percutaneous biliary access, is an unusual complication, and should raise suspicion of an underlying pro-coagulant state.
基金Supported by a Research Grant from the University of Siena (PAR)
文摘AIM: To analyze the prevalence of the two commonest thrombophilic mutations, factor V Leiden and prothrombin G20210A, in patients with gastric cancer. METHODS: One hundred and twenty-one patients with primary gastric carcinoma and 130 healthy subjects, comparable for age and sex, were investigated. Factor V Leiden was detected by using polymerase chain reaction and restriction enzyme digestion, and prothrombin G20210A gene mutation by allele-specific PCR. RESULTS: Among the 121 cancer patients, factor V Leiden was found in 4 cases (GA genotype: 3.3%) and prothrombin G20210A in 10 cases (GA genotype: 8.3%). Of the 130 control subjects, factor V Leiden was detected in 6 cases (GA genotype: 4.6%) and prothrombin G20210A in 8 cases (GA genotype: 6.1%). No double heterozygous carriers of both mutations were found in either group. The prevalence of both factor V Leiden and prothrombin G20210A variant was not statistically different between the cancer patients and the healthy subjects. CONCLUSION: Our study suggests that, in gastric cancer, the risk factors of thrombophilic cancer state are on acquired rather than on a genetic basis and that prothrombin G20210A does not seem to be a cofactor in gastric cancer pathogenesis.
文摘Concerns on the coagulation variables, Prothrombin Time (PT) and Activated Partial Thromboplastin Time (APTT) which are part of coagulation parameters used in assessing haemostatsis in haematology, led to the study of the effects of naphthoquinone and chloroquine on the PT and APTT of mice infected with <em>Plasmodium berghei</em>, and treated with graded concentrations of chloroquine and naphthoquinone. Using brain thromboplastin with calcium and rabbit brain cephalosporin ad kaolin respectively the experiment aimed at demonstrating the effect of chloroquine with purity of 99.79% and naphthoquinone with purity of 97.00%, upon a three-day intraperitoneal administration at concentrations of 0.1 mg/kg, 0.5 mg/kg, 1.0 mg/kg and 2.0 mg/kg. Result showed that the APTT and PT of naphthoquinone at 2.0 mg/kg, were 196.67 seconds, and 67.63 seconds respectively, while the APTT and PT of chloroquine were 3.63 seconds and 1.40 seconds respectively for the same concentration. Also, naphthoquinone showed lower APTT but sustained PT at concentrations below 1.50 mg/kg whereas both APTT and PT increased from concentrations above 1.50 mg/kg. On the other hand chloroquine showed a lowered APTT between 0.00 to 0.15 mg/kg while PT was sustained, but both APTT and PT increased from concentration of 0.15 mg/kg gradually. This study conclusively showed that chloroquine has a shorter APTT and PT than naphthoquinones, even though they elicited similar actions. Apart from this, naphthoquinone and chloroquine belonging to the same family, naphthoquinone could be more toxic than chloroquine at the dosages equivalent to 1.50 mg/kg, therefore, any administration of naphthoquinone above this dosage should be closely monitored to avoid any form of danger to the patient.
文摘Objectives: To better understand the etiologic factors that can influence preeclampsia, we inves- tigated hereditary factors for thrombosis, FV Leiden, F II 20210A mutation and the polymorphism C677T of the MTHFR, as singly and as in association, in a group of women from Ceará state-Northeast Brazil with severe preeclampsia. Material and Methods: We conducted a case-control study. 101 cases of severe preeclampsia were recruited from School Maternity Assis Chateaubriand, a reference Maternity of State of Ceará, Brazil, from December 2009 to December 2010. For clinical correlations, women were interrogated about fetal low weight (less than2500 grams) and fetal loss in previous pregnancies. Low weight, fetal loss and necessity of neonatal intensive care unit (neonatal ICU) related to current pregnancy were registered. 245 healthy voluntary women were recruited from the blood bank donors to verify the frequency of FV Leiden, FII and MTHFR as a control group. The study was approved by the Committee on Ethics in Human Research of Maternidade Escola Assis Chateubriand and all individuals gave their informed consent to participate in the study. Standard veinipuncture, with EDTA as anticoagulant, was used to collect blood samples. Genomic DNA was extracted, soon after, using a salting out method. Agarose gel electrophoresis with ethidium bromide staining was performed to ensure the quality of DNA extraction. Results: The frequencies of FV Leiden and FII mutation carrier were 0.99% (1/101) for both factors in the preeclampsia patients and 1.86% (4/214) and 0.93% (2/214), respectively, in control group. All mutates were heterozygous and concomitance of both mutations was not found. The genotype distribution of the MTHFR C677T in the patients and controls frequencies was in Hardy-Weinberg equilibrium (p ≤ 0.05). No statistical difference was observed between cases and controls in MTHFR genotypes or alleles. Conclusions: The FV Leiden, FII G20210A mutation and MTHFR C677T were not risks for preeclampsia development. FV Leiden and FII G20210A mutations had low frequency in the population studied, which may justify the absence of association.
文摘Objective: The objective of this study was to analyse the reversibility of the anticoagulant effect of warfarin by comparing prothrombin complex concentrate (PCC) versus frozen fresh plasma (FFP) in cardiology patients with serious warfarin intoxication. Methods: This was an observational and retrospective study comprising 67 patients (18 in group I [PCC] and 49 in group II [FFP]). The primary endpoint was the reversal of anticoagulant effect of warfarin after 2 and 24 hours of PCC or FFP administration. Comparisons between the groups were made using T-test and Q-square. Multivariate analyses were conducted using logistic regression, and the results were considered significant when p Results: The medium dose used was 27.6 UI/kg of PCC and 14.5 ml/kg of FFP. Significant differences were observed between groups I and II in the INR reversibility measurements after 2 hours (33.3% vs. 6.1%, p = 0.001) and 24 hours (38.9% vs. 12.2%, p = 0.009) as well as in the occurrence of pulmonary edema (5.6% vs. 42.9%, OR = 11.10, p = 0.04). The AUC for PCC was 0.891 (CI 95% [0.72 - 1.0]), and for FFP, it was 0.291 (CI 95% [0.09 - 0.49]). Conclusions: PCC is better than FFP treatment in reversing the warfarin intoxication after 2 and 24 hours of administration. Furthermore, PCC showed lower pulmonary edema in cardiology patients.
文摘BACKGROUND Thrombophilia contributes to a significant increased risk of venous thromboembolism and can be either inherited or acquired.Hereditary thrombophilia may arise from various gene mutations,some of which have not even been adequately reported or poorly understood.Previous studies reported a rare and novel missense mutation in the prothrombin gene(p.Arg596Gln),known as prothrombin Belgrade.The mechanisms and therapeutic strategies associated with prothrombin Belgrade mutation have not been fully elucidated.CASE SUMMARY We present the case of a 26-year-old woman with recurrent systemic thrombosis induced by prothrombin Belgrade mutation.The patient suffered from cerebral venous sinus thrombosis that rapidly progressed to systemic thrombosis,alongside a family history of cerebral thrombosis,and no traditional risk factors or abnormal coagulation function.Whole-genome sequencing detected a novel and rare heterozygous prothrombin missense mutation,c.1787G>T(p.Arg596Gln),which was responsible for the major etiology of the systemic thrombosis.CONCLUSION This case strengthens our understanding about hereditary basis of thrombophilia and provokes considerations for therapeutic options on prothrombin Belgrade mutation.