INR vs. thrombin generation assays for guiding VKA reversal: a retrospective comparison.

BACKGROUND: Prothrombin complex concentrate (PCC) is used to reverse vitamin K antagonist (VKA)-induced anticoagulation. Prothrombin time-derived international normalized ratio (INR) measurements are widely used in determining the required PCC dose, but this approach requires reappraisal. The aim of the present study was to determine the added value of the thrombin generation assay (TGA) compared with the INR in guidance of VKA reversal by PCC. METHODS: In an open, observational study, INR and TGA measurements were carried out on plasma samples from phenprocoumon-treated patients receiving VKA reversal. Following both analytical methods, PCC dosing correlates were calculated and compared retrospectively. Alternatively, in vitro PCC spiking experiments were performed. RESULTS: As expected, an exponential relationship between PCC dose and INR was found. For the TGA parameters peak thrombin and endogenous thrombin potential (ETP), however, this relationship was found to be linear throughout the full therapeutic range. Additional computational analysis showed a positive correlation (r²=0.7) between the initial INR and PCC dose required for a target INR of 2.1, which was completely lost at a lower target INR. In contrast, a positive correlation (r²=0.8) between initial ETP as well as peak height and PCC dose required to obtain parameter normalization was found. These correlates appeared useful for calculating PCC dose. CONCLUSIONS: Our results support the current debate questioning the rationale for the use of the INR in the management of anticoagulation by VKA. Compared with INR, TGA-based calculations may enable a more accurate PCC dosing regimen for patients requiring VKA reversal.

Comparison of the direct antiglobulin test and the eluate technique for diagnosing haemolytic disease of the newborn.

OBJECTIVE: The direct antiglobulin test (DAT) is an important tool for identification of haemolytic disease of the newborn (HDN) caused by erythrocyte immunization. Although this test has been used for decades, accurate insights into its diagnostic properties and optimal use in the diagnosis of HDN are limited. We aimed to gain more insight into the diagnostic properties of the DAT for HDN by comparing it with erythrocyte eluate screening. DESIGN AND METHODS: DAT and erythrocyte eluate screening was performed in umbilical cord blood of neonates obtained from 317 consecutive deliveries. Clinical jaundice was scored 4-6 days after delivery for the determination of HDN. RESULTS: In 21 neonates a positive DAT and in 61 neonates a positive eluate screening was found, while only 4 cases of HDN were observed. For the overall population the positive predictive value (PPV) and specificity of the DAT for HDN were 10% and 93% respectively and in the population of neonates with abnormal post-partum jaundice population the PPV and specificity were both 100%. The DAT missed two cases of HDN. These missed cases were, however, positive in the erythrocyte eluate screening. CONCLUSION: The detection of clinically irrelevant ABO immunization limits the specificity of the DAT and eluate for HDN in ABO-incompatible pregnancies. For optimal use, the DAT should be requested only in cases of jaundice and be interpreted in the context of ABO-incompatibility. Finally, a negative DAT does not rule out HDN. When clinical suspicion is high, an eluate should be added following a negative DAT.

Comparative study of blood collection tubes and thromboplastin reagents for correction of INR discrepancies: a proposal for maximum allowable magnesium contamination in sodium citrate anticoagulant solutions.

International normalized ratio (INR) discrepancies were noted between clinical laboratories using various prothrombin time (PT) systems. We studied the influence of different commercial blood collection tubes and different PT systems on INR measurements. INRs of fresh patient samples were determined by 3 laboratories, each using different PT systems. In the first part of the study, samples were drawn with Vacutainer tubes and in the second part with Monovette tubes. In the first part of the study, the maximum bias for all patients amounted to 0.46 INR (14%), and in the second part, to 0.14 INR (4.9%). The maximum bias for all patients could be reduced further by local system calibration using frozen pooled plasma specimens. The sodium citrate solutions in the blood collection tubes were contaminated with magnesium ions (approximately 2.7 mmol/L and 0.3 mmol/L in the Vacutainer and Monovette, respectively). INR discrepancies could be explained largely by this influence of blood collection tubes. The maximum allowable magnesium contamination in sodium citrate anticoagulant solutions should be less than 1 mmol/L.

Introduction of a new cobalamin (vitamin B12) assay: lessons from a flawed validation study.

BACKGROUND: Plasma vitamin B12 [cobalamin (Cbl)] concentrations are usually measured as a screening marker for vitamin B12 deficiency. Siemens Healthcare Diagnostics has introduced Cbl assays for various platforms, i.e., the immulite (IML) 2000 and 2500. In our laboratories, regular validation studies for the IML 2500 were conducted and showed acceptable quality specifications. After the introduction of the IML 2500 Cbl assay, clinicians in the department of internal medicine reported an increased frequency of patients with Cbl-concentrations less than 148 pmol/L. METHODS: In order to investigate this claim from the clinicians, we retrospectively analyzed the internal and external quality control (QC) of the Cbl assay. In addition, the monthly patient means for the Cbl assay were analyzed both before and after the introduction of the new Cbl assay. RESULTS: No abnormalities were found in the internal and external QCs. However, the monthly patient means for the Cbl assay showed a statistically significant decrease in cobalamin concentrations. Siemens acknowledged the problems and formulated a new Cbl assay, which was subsequently validated in our laboratories and showed equivocal Cbl results when compared to the IML 2000 Cbl assay. CONCLUSIONS: We report a flawed validation study conducted by the manufacturer that resulted in an undetected analytical problem in the IML 2500 Cbl assay, its subsequent introduction on the market, the final recognition of the poor performance of the assay by our clinicians, and the eventual resolution by the manufacturer. Hence, it emphasizes the utmost importance for thorough comparison between assays over the entire measurement range, even when both assays are produced by the same manufacturer.

[Prolonged activated partial thromboplastin time (aPTT): not always indicative of increased risk of bleeding]. / Een verlengde geactiveerde partiële tromboplastinetijd (APTT): niet altijd een verhoogde bloedingsneiging.

A 69-year-old man of Jewish descent with a second local relapse of rectal carcinoma was found to have a markedly prolonged activated partial thromboplastin time (aPTT). Further evaluation revealed a homozygous factor XI deficiency. Despite various operations in the past he had never displayed any bleeding problems. Severe factor XI deficiency did not prevent venous thrombosis in this patient. The management of patients with prolonged aPTT is described and insight into the pathophysiology of factor XI deficiency is provided. The differential diagnosis in patients with a prolonged aPTT depends on their bleeding tendency. There is a large variability in bleeding tendency in patients with factor XI deficiency. Patients with factor XI deficiency and an increased bleeding tendency can be treated with antifibrinolytic agents prior to small interventions, such as tooth extraction, or with plasma prior to surgery.

Simple and safe exclusion of pulmonary embolism in outpatients using quantitative D-dimer and Wells' simplified decision rule.

A safe and effective management strategy is pivotal in excluding pulmonary embolism (PE). The combination of Wells' simplified dichotomous clinical decision rule and D-dimer test is non-invasive and could be highly efficient, though its safety has not been widely studied. We evaluated safety and efficiency of this combination in excluding PE. Wells clinical decision rule was performed in 941 consecutive patients with suspected PE and, if patients had a score