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Bleeding in outpatients treated with warfarin: relation to the prothrombin time and important remediable lesions.

PURPOSE: To determine the relation of bleeding to prothrombin times and important remediable lesions in outpatients treated with warfarin. PATIENTS AND METHODS: An inception cohort of 565 patients starting outpatient therapy with warfarin on discharge from a university hospital was assembled. Detailed records of outpatient prothrombin times were obtained for 103 of 130 case subjects with major or minor bleeding and for 117 control patients without bleeding. A nested case-control design was used to evaluate the association of bleeding with temporally related prothrombin times; odds ratios were estimated using multivariate logistic regression analysis to control for known predictors of major bleeding. The relation of bleeding to important remediable lesions was determined in all 130 cases of bleeding. RESULTS: For each 1.0 increase in the prothrombin time-to-control ratio, the odds ratio for major bleeding during the week after a prothrombin time measurement increased 80%; the odds ratio for minor bleeding increased 50%. These odds ratios were lower during the first month of therapy and higher thereafter. Bleeding was related to important remediable lesions in 49 of 130 cases (38%), but these lesions were unknown before bleeding in only 22 cases (17%). The mean prothrombin time rose sharply at the time of bleeding in patients without important remediable lesions, but not in patients with lesions. New, previously unknown lesions (including nine malignancies) were discovered in 20 of 59 case subjects (34%) with gastrointestinal bleeding or hematuria, but in only two of 71 case subjects (3%) with other bleeding (p less than 0.001). CONCLUSION: Our results provide a valid quantitative basis for estimating the odds of bleeding in relation to the prothrombin time and the yield of diagnostic evaluation in patients with bleeding.

Aged↗

Comparison of the native prothrombin antigen and the prothrombin time for monitoring oral anticoagulant therapy.

We have measured the fully carboxylated (native) prothrombin antigen and the undercarboxylated (abnormal) prothrombin antigen in patients treated with sodium warfarin using specific immunoassays to evaluate a new approach for monitoring oral anticoagulant therapy. Plasma and serum samples (391) were assayed for the prothrombin time, native prothrombin antigen, and abnormal prothrombin antigen. The results were correlated with the presence of bleeding or thromboembolic complications at the time of phlebotomy. The native prothrombin antigen correlated with the occurrence of complications in 95% of samples. Of 13 samples from patients with bleeding complications, 13/13 (100%) had a native prothrombin of 12 micrograms/mL or lower. Of seven samples from patients with thromboembolic complications, 6/7 (86%) had a native prothrombin of 24 micrograms/mL or greater. By comparison, a prothrombin time index of 1.5 to 2.5, 1.5 to 2.2, 1.5 to 2.0, or 1.3 to 1.8 identified 6/20 (30%), 9/20 (45%), 11/20 (55%), or 12/20 (60%) patients at risk, respectively. Although the prothrombin time index did correlate with the presence of bleeding complications, the native prothrombin antigen correlated closely with the presence of bleeding and thromboembolic complications. According to these results, the native prothrombin antigen, maintained in a range of 12 to 24 micrograms/mL by regular adjustment of the warfarin dosage, may be associated with a reduced risk of complications due to excessive or insufficient warfarin therapy. On the basis of these preliminary data, we recommend that the native prothrombin antigen be considered to monitor warfarin therapy.

Administration, Oral↗

Prevalence and clinical associations of prolonged prothrombin time in adult untreated coeliac disease.

INTRODUCTION: Untreated coeliac disease may induce malabsorption of many nutrients. It may also induce vitamin K deficiency, which causes prolongation of the prothrombin time. The aim of the present study was to evaluate the prevalence and associations of prolonged prothrombin time in a series of coeliac adults. METHODS: We carried out a cross-sectional analysis of data collected on 390 adults with untreated coeliac disease diagnosed from January 1997 to December 2000. Prolonged prothrombin time was defined as INR > or = 1.4. RESULTS: A prolonged prothrombin time was found in 72 coeliac patients (18.5%). Parenteral vitamin K therapy was required in 5.6% of patients. Patients with prolonged prothrombin time had significant lower values of haemoglobin, iron, proteins, cholesterol and serum aspartate transaminase, and significantly higher prevalence of diarrhoea, weight loss, abdominal pain and low bone mineral density in comparison with patients with normal prothrombin time. However, low bone density was present in 11.6% of patients with normal INR. A prolonged prothrombin time was only found in a few patients with subclinical coeliac disease (0.9%). CONCLUSIONS: Data indicate that the prevalence of prolonged prothrombin time is about 20% in a large series of adult untreated coeliac patients. A prolonged prothrombin time was significantly related to all the markers of severe malabsorption, including low mineral density. Our suggestion is that vitamin K related proteins may also play a role in determining or worsening calcium homeostasis disorders in coeliac disease. The very low prevalence of coagulation disorders in subclinical coeliac disease indicates that there is no need to screen for coeliac disease in patients with isolated coagulation disorders.

Adult↗

Prothrombin time as an index of mortality in kwashiorkor.

Prothrombin time, serum albumin, aminotransferases and liver size were evaluated in 40 consecutive cases of kwashiorkor. Eleven (27.5%) of the 40 patients died. Eight out of the 11 patients who died had a prolonged prothrombin time of more than 3 s above the control compared to only 4 out of the 29 who survived (p = 0.005). Mean serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) albumin, globulin and liver size were abnormal but similar in both groups. These results may indicate a predictive mortality value of prothrombin time in kwashiorkor.

Bacterial Infections↗

Drotrecogin alfa activated (recombinant human activated protein C) in combination with heparin or melagatran: effects on prothrombin time and activated partial thromboplastin time.

Recombinant human activated protein C (rhAPC) has recently been demonstrated to be a promising candidate to improve the outcome for patients with severe sepsis. Plasma-derived activated protein C and unfractionated heparin (UH) exert anticoagulant synergy due to mechanisms that simultaneously decrease thrombin generation. Melagatran, a new direct thrombin inhibitor, does not bind to plasma proteins or requires antithrombin as a cofactor. The latter is often consumed in patients with severe sepsis. We investigated the anticoagulant efficiency in combined administration of rhAPC and UH or melagatran in terms of prolongation of the standard clotting assays activated partial thromboplastin time (aPTT) and prothrombin time (PT) in pooled plasma samples in vitro. RhAPC dose-dependently prolonged the aPTT but not the PT. The ability of UH and melagatran to prolong the aPTT was significantly enhanced in combination with rhAPC. The combined administration of rhAPC and melagatran, but not UH, resulted in additive prolongation of the PT. In control measurements the capability of rhAPC to suppress prothrombin fragment 1.2 generation dose-dependently increased in combination with heparin and melagatran. Our study demonstrates the respective effects of rhAPC, UH, melagatran and further different additive effects in combined administration of rhAPC and UH or melagatran on the prolongation of the aPTT and PT clotting assays usually used to monitor anticoagulant treatment.

Azetidines↗

The prediction of prothrombin time system performance using secondary standards.

A method for the comparison of prothrombin time systems using single large lots of lyophilized plasma in the College of American Pathologists Surveys is presented. Systematic biases for prothrombin time methods as well as for thromboplastins have been measured, and their use allows a very accurate (within 2.25%) prediction of the prothrombin time for the great number of prothrombin time systems presently being used in the United States.

Blood↗

Randomized prospective trial comparing the native prothrombin antigen with the prothrombin time for monitoring oral anticoagulant therapy.

The dosage of the anticoagulant warfarin sodium is based upon the prolongation of the prothrombin time into an optimal therapeutic range. We have developed a new assay for the native prothrombin antigen that measures the fully gamma-carboxylated prothrombin using a radioimmunoassay. Based on preliminary data that indicated that the native prothrombin antigen predicted both bleeding and thrombotic complications more accurately than the prothrombin time in patients anticoagulated with warfarin sodium, we have performed a randomized prospective trial comparing the complication rate in warfarin-treated patients monitored with the native prothrombin antigen or the prothrombin time. Patients with indications for anticoagulation were randomized to be monitored by the native prothrombin antigen (therapeutic range, 12 to 24 micrograms/mL) or the prothrombin time index (therapeutic range, 1.5 to 2.0). Of the prothrombin time group (N = 80), seven (8.8%) had bleeding or thrombotic complications, with a complication rate of 9.5%/patient-year. In the native prothrombin antigen group (N = 76), one subject (1.3%) had a bleeding complication. The complication rate per patient-year was 1.5%. These results indicate an 85% reduction in the complication rate of the native prothrombin antigen group compared with the complication rate of the prothrombin time group. This difference is statistically significant by the Fisher exact test (P = .037) and by Kaplan Meier survival analysis (P = .040). This study suggests that the use of the native prothrombin antigen assay has the potential to decrease the complications associated with anticoagulation therapy with warfarin sodium.

Humans↗

Recombinant factor VIIa in preterm neonates with prolonged prothrombin time.

The purpose of the study was to estimate the effects of a minimal and a normal dose of rFVIIa on prothrombin time, and to compare it to the effect of a standard volume of fresh frozen plasma. Recombinant factor VIIa (rFVIIa) was tested in babies with gestational age less than 33 weeks and prothrombin time greater than 48 s (reference 23.7 s; i.e. inclusion at international normalized ratio 2.0) during the first 7 days of life. Firstly, 5 microg/kg rFVIIa was given to five babies. One hour after the bolus, prothrombin time had significantly shortened from a mean of 64 s (range 53-79 s) to 46 s (range 39-56 s). Next, the effect of 80 microg/kg rFVIIa was compared to the effect of 10 mL/kg fresh frozen plasma. Prothrombin time at inclusion was 68 s (range 53-92 s). One hour after treatment, prothrombin time was 33 s (range 21-42 s) in the six babies given rFVIIa, compared with 51 s (range 40-59 s) in four babies given fresh frozen plasma (P = 0.02). Prothrombin time remained lower in the rFVIIa group (P = 0.01) at 3 h than in the frozen plasma group, whereas at 6 and 12 h the differences were statistically insignificant. One baby continued to have slight bleeding from the umbilical site and one baby developed severe pulmonary haemorrhage in spite of rFVIIa treatment. In conclusion, rFVIIa partially normalized prothrombin time in preterm babies. There was no evidence of side effects. Future randomized studies are needed to evaluate the haemostatic effect.

Blood Coagulation Disorders↗

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↗