Improvement in the regulation of the vitamin K antagonist acenocoumarol after a standard initial dose regimen: prospective validation of a prescription model

Background In a retrospective study we have developed a model which determines the dose of acenocoumarol based on the age of the patient and on the first INR obtained after a standard initial loading dose. The group of patients of this study was used as the control group of the present study. Aim The aim of this study was to prospectively validate the model and to assess whether the use of this model improves the quality of the treatment in the 0-2 months study period. Patients and methods In 197 patients the model was evaluated by (1) in the initial phase: comparison of INRs with the control group, after assessing the dose according to the model, and (2) in the 0-2 months period: calculation of the percentage of time spent in the therapeutic target range compared to the control group. Furthermore, the eventual dose was compared to the dose of the model when the INRs were within the therapeutic target range for the first time and on two successive occasions. Results (1) When dosed according to the model, 50% of INRs in the total group were within the therapeutic target range compared to 45% in the control group, and (2) the percentage time spent within this range was 68 in the total group compared to 63 in the control group (P = 0.0013). When the INRs were within the range for the first time and successively twice, the eventual doses were similar to the model in 59 and 50%, respectively. About 20% of the patients did not achieve two successive INRs within the range. Conclusions Using the model the quality of treatment improved. We advice to use a standardized individualized dose regimen at the initiation of vitamin K antagonist treatmen

Analytical variation in factor VIII one-stage and chromogenic assays: Experiences from the ECAT external quality assessment programme

Background: Both one-stage (OSA) and chromogenic substrate assays (CSA) are used to measure factor VIII (FVIII) activity. Factors explaining analytical variation in FVIII activity levels are still to be completely elucidated. Aim: The aim of this study was to investigate and quantify the analytical variation in OSA and CSA. Methods: Factors determining analytical variation were studied in sixteen lyophilized plasma samples (FVIII activity <0.01-1.94 IU/mL) and distributed by the ECAT surveys. To elucidate the causes of OSA variation, we exchanged deficient plasma between three company set-ups. Results: On average, 206 (range 164-230) laboratories used the OSA to measure FVIII activity and 30 (range 12-51

The influence on INRs and coagulation factors of the time span between blood sample collection and intake of phenprocoumon or acenocoumarol: consequences for the assessment of the dose

Managing treatment with vitamin K antagonists, the prothrombin time (PT), expressed as international normalized ratio (INR), may not represent the INR during the entire 24 hour (h) period, and this variation may be different between long-acting phenprocoumon and short-acting acenocoumarol. For both drugs we investigated the variation in 24 h of the PT/INR, the consequencesfor the assessment of the doses and which vitamin K-dependent factor causes the daily variation. Patients on self-management took their medication at 6 p.m. and determined their INRs for eight weeks, once a week and three times daily (8.30 a.m., 6 p.m. and 11 p.m., thus 14.5 h, 24 h and 29 h after taking the medication, respectively). Acenocoumarol showed a significant variation in INRs over the 24 h period, with 22 out of 80 INRs >20% lower at 11 p.m. versus 8.30 a.m. Phenprocoumon showed only few variations. Patients managed by the anticoagulation clinic took their medication at 6 p.m. for four weeks and then at 8 a.m. for four weeks, 15 h and 25 h, respectively, before the weekly blood collection. PT/INR and coagulation factors VII, X and II were determined. With acenocoumarol, taken 25 h before blood collection, the INRs were significantly different compared to 15 h, especially attributed to plasma levels of factor VII. Those on phenprocoumon were equal. These variations of INRs during 24 h may have major effects on the prescribed dose of short-acting vitamin K antagonists, such as acenocoumarol, especially for INRs at the limits of the therapeutic range

Invasive procedures in the outpatient setting: managing the short-acting acenocoumarol and the long-acting phenprocoumon

Treatment with vitamin K antagonists (VKAs) has to be interrupted when invasive procedures are planned. We compared various methods of interruption in patients on acenocoumarol or phenprocoumon in a prospective study. In patients on acenocoumarol (n = 141), 99 stopped three days before the intervention and 42 stopped two days before. All patients on phenprocoumon (n = 111) received vitamin K two days before the intervention, and 55 of these patients discontinued phenprocoumon, whereas 56 did not stop. In a subset of 30 patients we determined International Normalized Ratios (INRs) and coagulation factors II, VII, X and protein C. The mean INR after stopping acenocoumarol for three days was significantly lower than after two days (1.1 vs. 1.3, p = <0.0001), but its clinical relevance may be trivial. In patients using phenprocoumon, the mean INR on the day of the intervention was only slightly lower after stopping the VKAs (1.5 vs. 1.6, p = 0.0407), but a similar proportion of patients had an INR <or=1.4. On the day of the intervention, in the acenocoumarol group mean plasma levels of all coagulation factors were higher than 50% and in the phenprocoumon group higher than 25%. We conclude that acenocoumarol can be stopped two days before an invasive procedure that is associated with a low or moderate bleeding risk and three days before an intervention with a higher bleeding risk. For phenprocoumon, administration of vitamin K two days before an intervention results in an acceptable INR during the intervention, regardless whether phenprocoumon is interrupted or no

Association between renal failure and red blood cell alloimmunization among newly transfused patients

Background: Renal failure and renal replacement therapy (RRT) affect the immune system and could therefore modulate red blood cell (RBC) alloimmunization after transfusion. Study Design and Methods: We performed a nationwide multicenter case-control study within a source population of newly transfused patients between 2005 and 2015. Using conditional multivariate logistic regression, we compared first-time transfusion-induced RBC alloantibody formers (N = 505) with two nonalloimmunized recipients with similar transfusion burden (N = 1010). Results: Renal failure was observed in 17% of the control and 13% of the case patients. A total of 41% of the control patients and 34% of case patients underwent acute RRT. Renal failure without RRT was associated with lower alloimmunization risks after blood transfusion (moderate renal failure: adjusted relative rate [RR], 0.82 [95% confidence interval (CI), 0.67-1.01]); severe renal failure, adjusted RR, 0.76 [95% CI, 0.55-1.05]). With severe renal failure patients mainly receiving RRT, the lowest alloimmunization risk was found in particularly these patients [adjusted RR 0.48 (95% CI 0.39-0.58)]. This was similar for patients receiving RRT for acute or chronic renal failure (adjusted RR, 0.59 [95% CI, 0.46-0.75]); and adjusted RR, 0.62 [95% CI 0.45-0.88], respectively). Conclusion: These findings are indicative of a weakened humoral response in acute as well as chronic renal failure, which appeared to be most pronounced when treated with RRT. Future research should focus on how renal failure and RRT mechanistically modulate RBC alloimmunization

Association of Blood Transfusion From Female Donors With and Without a History of Pregnancy With Mortality Among Male and Female Transfusion Recipients

Importance: Transfusion of red blood cells from female donors has been associated with increased mortality in male recipients. Objective: To quantify the association between red blood cell transfusion from female donors with and without a history of pregnancy and mortality of red blood cell recipients. Design, Setting, and Participants: Retrospective cohort study of first-time transfusion recipients at 6 major Dutch hospitals enrolled from May 30, 2005, to September 1, 2015; the final follow-up date was September 1, 2015. The primary analysis was the no-donor-mixture cohort (ie, either all red blood cell transfusions exclusively from male donors, or all exclusively from female donors without a history of pregnancy, or all exclusively from female donors with a history of pregnancy). The association between mortality and exposure to transfusions from ever-pregnant or never-pregnant female donors was analyzed using life tables and time-varying Cox proportional hazards models. Exposures: Red blood cell transfusions from ever-pregnant or never-pregnant female donors, compared with red blood cell transfusions from male donors. Main Outcomes and Measures: All-cause mortality during follow-up. Results: The cohort for the primary analyses consisted of 31 118 patients (median age, 65 [interquartile range, 42-77] years; 52% female) who received 59 320 red blood cell transfusions exclusively from 1 of 3 types of donors (88% male; 6% ever-pregnant female; and 6% never-pregnant female). The number of deaths in this cohort was 3969 (13% mortality). For male recipients of red blood cell transfusions, all-cause mortality rates after a red blood cell transfusion from an ever-pregnant female donor vs male donor were 101 vs 80 deaths per 1000 person-years (time-dependent "per transfusion" hazard ratio [HR] for death, 1.13 [95% CI, 1.01-1.26]). For receipt of transfusion from a never-pregnant female donor vs male donor, mortality rates were 78 vs 80 deaths per 1000 person-years (HR, 0.93 [95% CI, 0.81-1.06]). Among female recipients of red blood cell transfusions, mortality rates for an ever-pregnant female donor vs male donor were 74 vs 62 per 1000 person-years (HR, 0.99 [95% CI, 0.87 to 1.13]); for a never-pregnant female donor vs male donor, mortality rates were 74 vs 62 per 1000 person-years (HR, 1.01 [95% CI, 0.88-1.15]). Conclusions and Relevance: Among patients who received red blood cell transfusions, receipt of a transfusion from an ever-pregnant female donor, compared with a male donor, was associated with increased all-cause mortality among male recipients but not among female recipients. Transfusions from never-pregnant female donors were not associated with increased mortality among male or female recipients. Further research is needed to replicate these findings, determine their clinical significance, and identify the underlying mechanism

Red cell alloimmunisation in patients with different types of infections

Red cell alloantigen exposure can cause alloantibody-associated morbidity. Murine models have suggested that inflammation modulates red cell alloimmunisation. This study quantifies alloimmunisation risks during infectious episodes in humans. We performed a multicentre case-control study within a source population of patients receiving their first and subsequent red cell transfusions during an 8-year follow-up period. Patients developing a first transfusion-induced red cell alloantibody (N = 505) were each compared with two similarly exposed, but non-alloimmunised controls (N = 1010) during a 5-week 'alloimmunisation risk period' using multivariate logistic regression analysis. Transfusions during 'severe' bacterial (tissue-invasive) infections were associated with increased risks of alloantibody development [adjusted relative risk (RR) 1·34, 95% confidence interval (95% CI) 0·97-1·85], especially when these infections were accompanied with long-standing fever (RR 3·06, 95% CI 1·57-5·96). Disseminated viral disorders demonstrated a trend towards increased risks (RR 2·41, 95% CI 0·89-6·53), in apparent contrast to a possible protection associated with Gram-negative bacteraemia (RR 0·58, 95% CI 0·13-1·14). 'Simple' bacterial infections, Gram-positive bacteraemia, fungal infections, maximum C-reactive protein values and leucocytosis were not associated with red cell alloimmunisation. These findings are consistent with murine models. Confirmatory research is needed before patients likely to develop alloantibodies may be identified based on their infectious conditions at time of transfusion