The standardization of prothrombin time (PT) has been a problem for more than 50 years; by applying the methods to the same clinical material the analysis may explain why. The initial standardization by 2–3 times normal clotting time by Quick’s PT assay did not standardize presently used PT assays. The ratio method accepted by the WHO in 1977 was not satisfactory because the intercept was neglected. The revised ratio method (WHO 1983) recommended calibration between log clotting times of normal and abnormal plasmas and a simplified conversion into ratios. However, by including a high proportion of normal plasmas (up to 1/3 of abnormal) an erroneous calibration material was introduced; the conversion from clotting times into ratios was also more complex than predicted. The international sensitivity index, which is based on the simplified method, produced international normalized ratios (INR) that were not more standardized than not corrected ratios. Not corrected coagulation activities showed poor standardization due to the different sensitivity of assays for the protein induced by vitamin K absence (Pivka) inhibitor. The corresponding therapeutic ranges of INR and coagulation activities covered 70 and 10–20% of their scales, respectively. Standardization by Pivka-corrected coagulation activities against an international reference assay may be the preferable method.

Objective: To evaluate the addition of low-dose interferon-alpha 2b to standard melphalan-prednisone therapy in patients with multiple myeloma.Design: Randomized, multicenter, phase III study.Setting: 15 university hospitals and 92 county hospitals in Sweden, Norway, Denmark, Finland, and Iceland.Patients: 583 patients with symptomatic multiple myeloma.Intervention: All patients received melphalan-prednisone every 6 weeks. Melphalan-prednisone therapy was interrupted after at least 8 courses in responding patients who achieved a plateau phase, and it was reinstituted at time of relapse. Patients randomly assigned to receive melphalan-prednisone and interferon also received interferon, 5 MU three times weekly, from the start of treatment through response, plateau phase, and relapse, until definitive failure of melphalan-prednisone occurred.Measurements: Survival was the main outcome measure. Secondary measures were response rate, response and plateau phase duration, and toxicity. All analyses were done according to the principle of intention-to-treat.Results: 45% of patients receiving melphalan-prednisone and 44% of patients receiving melphalan-prednisone and interferon achieved at least a partial response. Response duration and plateau phase duration were longer for patients receiving melphalan-prednisone and interferon than for patients receiving melphalan-prednisone alone (P < 0.05); the difference in median duration was 5 to 6 months. Toxicity was higher with melphalan-prednisone and interferon, and this led to premature discontinuation of interferon therapy in one third of patients and to a reduced overall dose intensity for melphalan. The median survival time was 29 months for patients receiving melphalan-prednisone and 32 months for patients receiving melphalan-prednisone and interferon. The risk ratio for death for patients receiving melphalan-prednisone compared with patients receiving melphalan-prednisone and interferon was 1.02 (95% CI, 0.89 to 1.40).Conclusions: Adding continuous low-dose interferon to standard melphalan-prednisone therapy does not improve response rate or survival. However, response duration and plateau phase duration are prolonged by maintenance therapy with interferon.

Eighty-six patients with phlebographically verified deep vein thrombosis (DVT) of the femoral, iliac, and/or popliteal veins who had symptoms of up to 10 days' duration were enrolled in one of two prospective, multicenter, randomized, double-blind studies. In study A, each of the 47 patients received streptokinase therapy according to one of the following three dose schedules-3.0 million (M) IU of streptokinase over 2 hours (group 1), 6.0 M IU of streptokinase over 4 hours (group 2), or 9.0 M IU of streptokinase over 6 hours (group 3). In study B, each of the 39 enrolled patients received streptokinase according to one of the three dose schedules just described or according to a fourth schedule-4.5 M IU of streptokinase over 3 hours (group 4), Each patient received two infusions of the same dose on two successive days. Heparin was given between and after the infusions, followed by warfarin alone when the prothrombin time reached the therapeutic range. In the 76 patients evaluable for efficacy, phlebographically similar improvement in thrombus extension was observed in all groups without evidence of dose dependency. Group 2 had the highest success rate, while group 4 had the lowest. Eleven patients experienced streptokinase-related allergic reactions, which led to discontinuation of therapy in five patients, two of whom experienced serious adverse reactions. The frequency and severity of adverse events were not significantly different between groups. We conclude that the ultra-high-dose, short-term infusion regimen of streptokinase is more convenient than the conventional 3 to 5 days of continuous therapy in the treatment of DVT. Further studies are needed to establish an optimal dosage schedule.

The standardization of prothrombin time (PT) assays needs two steps: (1) calibration of PT assays towards a reference assay or reference thromboplastin, (2) correction of PT assays according to the calibration. The present recommended calibration by clotting times is favored for the linearity between assays; the clotting times of abnormal plasma are partly prolonged due to the protein induced by vitamin K absence (Pivka) inhibitor. Calibration by coagulation activities also demonstrated linearity between PT assays; the regression line for abnormal plasma deviated from the line of identity due to differences in sensitivity of assays for the Pivka inhibitor. The corrected PT assays demonstrated similar results using calibration by clotting time or coagulation activities, but the correction was simpler for coagulation activities. Patient plasma was the preferable material in calibration by clotting times as well as by coagulation activities. The corrections between the reference assay and other PT assays were equal to the differences in sensitivities for the Pivka inhibitor. The corrected PT assays did not differ from the reference assay by statistical analysis; any of the six PT assays tested might be used as reference assay.

A serum cobalamin level lower than 250 pmol/l combined with high values of plasma homocysteine and serum methylmalonic acid confirms the diagnosis of vitamin B12 deficiency. A low serum and erythrocyte folate level and high plasma homocysteine confirm folate deficiency. If the cobalamin level is higher than 250 pmol/l no further tests are needed. In patients with neurologic or psychiatric disorders combined with elevated levels of homocysteine and methylmalonic acid, cobalamin deficiency is likely if these levels decrease during vitamin B12 therapy. The causes of elevated homocysteine levels are often obscure, and homocysteine should therefore not be used as a screening test.

An analysis of prothrombin time (PT) standardization methods is presented. The present recommended ratio method demonstrated complex calibration and wide therapeutic ranges. Standardization by coagulation activities resulted in different therapeutic ranges due to the different sensitivity of assays for the protein induced by vitamin K absence (Pivka) inhibitor. A new method--the modified coagulation activity method--applied a reference assay against which any PT assay can be calibrated by clotting times, and the results were expressed in coagulation activities by the reference assay. This method was preferable due to simple calibration, narrow therapeutic ranges and identical results by any PT assay.

A female patient developed warfarin resistance after 2 years of satisfactory therapy. Only a third of orally administered warfarin was absorbed, the clearance of warfarin was normal. The patient was also resistant for dicoumarol, while phenindione had satisfactory effect on the prothrombin time (PT).

The calibration of prothrombin time (PT) assays was studied. A simple calibration between pooled normal plasma and pooled stable plasma was as satisfactory as more complex calibration methods based on linear or orthogonal regression between log clotting times of abnormal and/or normal plasmas.

One-hundred-and-fifty-one patients with previously untreated multiple myeloma were allocated to treatment with either NOP regimen (mitoxantrone 16 mg/m2 and vincristine 2 mg day 1 and prednisolone 250 mg day 1-4 and 17-20) or M+P regimen (melphalan 0.25 mg/kg and prednisolone 100-200 mg/day day 1-4). Both regimens were repeated every 4 weeks and were scheduled for 1 year. Seventy-seven patients were treated with NOP and 74 patients with M+P. No major clinical differences were recorded between the groups before treatment. Sixty percent of the patients responded (CR+PR) to NOP versus 64% to M+P (NS). The time to progression was 16 months (95% C.L. 14-51) in the NOP group versus 21 months (95% C.L. 15-27) in the M+P group (NS). The median survival was 14 months (7-21) in the NOP group and 31 months (21-43) in the M+P group (p = 0.02). NOP was significantly more toxic than M+P. Seven patients treated with NOP died due to infection and neutropenia and 1 patient died of cardiac toxicity, in contrast to 1 death due to infection and neutropenia in the M+P group. Gastrointestinal toxicity was acceptable in both groups. In conclusion, NOP was inferior to M+P as primary treatment of multiple myeloma.

Coagulation factors that interfere with the one-stage prothrombin time (PT) were investigated. PT responded with identical activities (adequately) against coagulation factors VII or X, only half as expected against factor IX, less than expected and nonlinearly against factor II. In multiple coagulation factor deficiencies PT did not differ from factor VII, which was the most reduced coagulation factor in warfarin therapy or liver disease. PT may also be influenced by factor VII at high activities.