Activated protein C resistance determined with a thrombin generation-based test is associated with thrombotic events in patients with lupus anticoagulants.

BACKGROUND: Several studies suggest that antiphospholipid antibodies interfere with the activity of activated protein C (APC). This acquired form of APC resistance has been proposed as a possible pathogenic mechanism underlying hypercoagulability associated with the antiphospholipid syndrome (APS). OBJECTIVES: We wanted to investigate the inhibitory effect of recombinant APC (rAPC) on ex vivo thrombin generation in plasma and the modification of this effect by the presence of lupus anticoagulants (LA). PATIENTS/METHODS: We analyzed plasmas from 81 patients with LA (52 patients fulfilling the criteria for the APS) and 91 controls. Percent inhibition of the endogenous thrombin potential (ETP) as a parameter of APC sensitivity was determined in plasmas using a thrombin generation-based APC resistance test probed with rAPC. All results were normalized using pooled normal plasma (PNP) as a reference. RESULTS: Normalized percent inhibition of ETP by APC was lower in patients with LA [61.4%, 95% confidence interval (CI) 45.8-74.5%] compared to controls (107.8%, 95% CI: 107.1-109.3%). In patients with LA and APS, median inhibition was lower than in patients with LA without APS (44.6%, 95% CI: 30.1-55.7% vs. 78.8%, 95% CI: 73.9-95.8%). This difference also persisted when patients on warfarin therapy were excluded from the APS subgroup. CONCLUSIONS: APC resistance can be demonstrated with a thrombin generation-based test in a majority of patients with the LA laboratory phenotype. A history of thrombotic events in patients with LA is associated with a stronger resistance to the anticoagulant effect of APC.

An international field study of the reliability and validity of a disease-specific questionnaire module (the QLQ-MY20) in assessing the quality of life of patients with multiple myeloma.

AIM: To test the reliability, validity and sensitivity of the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-MY24 questionnaire, designed to assess the quality of life of myeloma patients with the QLQ-C30. METHODS: The study was carried out through the EORTC Quality of Life Group using clinical trials in seven countries. All trials used the QLQ-C30 and QLQ-MY24 at baseline and a follow-up timepoint. RESULTS: Two hundred and forty patients participated. The questionnaires were acceptable to patients. The hypothesised scale structure (disease symptoms, side-effects, body image and future perspective) was confirmed by multi-trait scaling, internal consistency and correlation analysis. Most scales demonstrated sensitivity to change and discriminated between clinically different patients. The social support scale (4 items) was removed due to observed ceiling effects. CONCLUSION: The final questionnaire contains 20 items, QLQ-MY20, and is a reliable and valid instrument recommended for use with the QLQ-C30 in myeloma patients.

A randomized clinical trial of high-intensity warfarin vs. conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS).

BACKGROUND: The optimal intensity of oral anticoagulation for the prevention of recurrent thrombosis in patients with antiphospholipid antibody syndrome is uncertain. Retrospective studies show that only high-intensity oral anticoagulation [target international normalized ratio (INR) >3.0] is effective but a recent randomized clinical trial comparing high (INR range 3.0-4.0) vs. moderate (INR 2.0-3.0) intensities of anticoagulation failed to confirm this assumption. METHODS: We conducted a randomized trial in which 109 patients with antiphospholipid syndrome (APS) and previous thrombosis were given either high-intensity warfarin (INR range 3.0-4.5, 54 patients) or standard antithrombotic therapy (warfarin, INR range 2.0-3.0 in 52 patients or aspirin alone, 100 mg day(-1) in three patients) to determine whether intensive anticoagulation is superior to standard treatment in preventing symptomatic thromboembolism without increasing the bleeding risk. RESULTS: The 109 patients enrolled in the trial were followed up for a median time of 3.6 years. Mean INR during follow-up was 3.2 (SD 0.6) in the high-intensity warfarin group and 2.5 (SD 0.3) (P < 0.0001) in the conventional treatment patients given warfarin. Recurrent thrombosis was observed in six of 54 patients (11.1%) assigned to receive high-intensity warfarin and in three of 55 patients (5.5%) assigned to receive conventional treatment [hazard ratio for the high intensity group, 1.97; 95% confidence interval (CI) 0.49-7.89]. Major and minor bleeding occurred in 15 patients (two major) (27.8%) assigned to receive high-intensity warfarin and eight (three major) (14.6%) assigned to receive conventional treatment (hazard ratio 2.18; 95% CI 0.92-5.15). CONCLUSIONS: High-intensity warfarin was not superior to standard treatment in preventing recurrent thrombosis in patients with APS and was associated with an increased rate of minor hemorrhagic complications.

The evaluation of clotting times in the laboratory detection of lupus anticoagulants.

Although there is international consensus regarding the general principles of testing for lupus anticoagulants (LAs), no agreement exists as far as the analysis of the clotting time results is concerned. Twenty-nine laboratories participating in the Fifth International Survey of Lupus Anticoagulants (ISLA-5) reported the activated partial thromboplastin time (APTT)-based clotting times obtained on seven defined test samples and a normal plasma (NP) using the same two reagents with low and high phospholipid (PL) concentrations, respectively. These clotting times were used to analyse how various methods of calculating the results may influence the apparent sensitivity of LA tests. We found that the use of a separate screening test may lead to the exclusion of samples where the presence of LA would have been detected by a combined screening and confirmatory method. For instance, the dilute APTT (dAPTT) gave a sensitivity of 53.5% (screening test), while the calculation of a ratio between the clotting times obtained with two different PL concentrations gave a sensitivity of 68.1% (confirmatory test). The normalisation of results by dividing with the corresponding results of NP increased the apparent sensitivity. The screening test ratio between dAPTT results of test samples and NP gave a sensitivity of 84.7%. The normalised ratio between the clotting times obtained with the two reagents (lupus ratio, LR) gave a sensitivity of 95.1%. We conclude that when testing for LA, all samples should be tested with both low (screening procedure) and high (confirmatory procedure) PL concentrations. These two clotting times should be evaluated in relation to each other and to the corresponding results obtained with a reference plasma (normalisation).

[High dose therapy with autologous stem cell support--finally a progress in myelomatosis]. / Høydosebehandling med autolog stamcellestøtte--endelig et fremskritt ved myelomatose.

BACKGROUND: Since the introduction of the simple cyclic oral treatment with melphalan and prednisone in the late 1960s, there has been no substantial improvement in the therapy of multiple myeloma. In 1994, the Nordic Myeloma Study Group initiated a population-based, prospective study to evaluate the impact on survival of high dose chemotherapy in newly diagnosed, symptomatic patients under 60 years of age, compared to a conventionally treated control group. MATERIAL AND METHODS: 274 patients were treated according to a specified high dose protocol and compared to 274 patients from previous population-based trials fulfilling the same eligibility criteria. RESULTS: Median survival was 44 months in the control group and 62 months in the intensive treatment group (risk ratio 1.65; 95% CI = 1.28-2.14, P = 0.0001). A study of health-related quality of life (HRQoL) which was integrated in the trial showed a moderately reduced HRQoL associated with the intensive treatment phase, but no statistically significant difference beyond the first year of follow-up. In a cost-utility analysis of the trial, the cost per (quality-adjusted life years) was estimated at USD 26,000. INTERPRETATION: The incremental cost of the treatment is within what is usually thought to be acceptable limits. Further improvement of the results and reduction of stay in hospital would give an even more favourable cost-utility ratio.

Cost-utility analysis of high-dose melphalan with autologous blood stem cell support vs. melphalan plus prednisone in patients younger than 60 years with multiple myeloma.

We evaluated the costs and the cost utility of high-dose melphalan and autologous stem cell support followed by interferon maintenance relative to conventional treatment with melphalan and prednisone, in patients less than 60 yr of age with multiple myeloma. From March 1994 to July 1997, 274 patients with newly diagnosed, symptomatic multiple myeloma were enrolled in a prospective, non-randomized, population-based, multicenter study to evaluate the treatment with high-dose melphalan and autologous blood stem cell support. Health-related quality-of-life was measured prior to treatment and during follow-up, using the EORTC QLQ-C30 questionnaire. Resource consumption was also recorded prospectively. The intensive treatment yielded a significant increase in median survival time from 44 to 62 months compared to conventionally treated patients. The corresponding gain in quality-adjusted life years (QALY) was found to be 1.2. Cost per QALY gained by the treatment with high-dose melphalan and autologous blood stem cell support was estimated at NOK 249,000 (USD 27,000).

Health-related quality of life in multiple myeloma patients receiving high-dose chemotherapy with autologous blood stem-cell support.

In a population-based study, the Nordic Myeloma Study Group found a survival advantage for high-dose melphalan with autologous blood stem-cell support compared to conventional chemotherapy in myeloma patients under 60 yr of age (risk ratio: 1.62; confidence interval [CI] 1.22-2.15; p = 0.001). A study of health-related quality of life (HRQoL) was integrated in the trial, using the EORTC QLQ-C30 questionnaire. Of the 274 patients receiving intensive therapy 221 (81%) were compared to 113 (94%) of 120 patients receiving conventional melphalan-prednisone treatment. Prior to treatment, there were no statistically significant differences in any HRQoL score between the two groups. One month after the start of induction chemotherapy, the patients on intensive treatment had more sleep disturbance than the control patients. At 6 mo, corresponding to a mean of 52 d after high-dose melphalan, the patients on intensive treatment had moderately lower scores for global QoL and role and social functioning and there was also a significantly higher score for appetite loss. At 12 and 24 mo, the HRQoL was similar to that of the control patients. At 36 mo, there was a trend toward less fatigue, pain, nausea, and appetite loss in the intensive-treatment group. Thus, the 18 mo of prolonged survival seem to be associated with a good health-related quality of life. Despite the moderate HRQoL reduction associated with the early intensive chemotherapy phase, this treatment modality must be regarded as an important step forward in the care of multiple myeloma.

The Lupus Ratio test--an interlaboratory study on the detection of Lupus anticoagulants by an APTT-based, integrated, and semi-quantitative test. Fifth International Survey of Lupus Anticoagulants--ISLA 5.

The Lupus Ratio (LR) test for lupus anticoagulants integrates screening, mixing with normal plasma and confirmation procedures into one assay. The sensitivity and reproducibility of the APTT based version of this assay was tested in an interlaboratory study that was part of the Fifth International Survey of Lupus Anticoagulants (ISLA-5). One LA negative plasma containing heparin, six LA positive plasmas and a normal pooled plasma (NP) were distributed to 31 laboratories world-wide together with two APTT reagents, one with a high and one with a low phospholipid concentration. The laboratories performed two APTTs, one with each reagent, on 1:1 mixtures of test plasma and NP. The ratio between the two clotting times was divided by the corresponding ratio for the NP. This final ratio is the LR of that plasma. The overall sensitivity was found to be 95.1%, and the normal, heparin-containing sample was reported to be negative by all the laboratories. When the results were grouped in low, medium and high positive plasmas, a "consensus" regarding the strength of each plasma was easily found. 85.0% of the results were in agreement with this consensus. This study shows that with the LR test, it is possible to obtain high interlaboratory agreement regarding the presence or absence of LA as well as the semi-quantification of this inhibitor.

Impact on survival of high-dose therapy with autologous stem cell support in patients younger than 60 years with newly diagnosed multiple myeloma: a population-based study. Nordic Myeloma Study Group.

High-dose therapy has become a common treatment for myeloma. The objectives of this study were to estimate in a prospective, population-based setting the impact on survival of high-dose therapy in newly diagnosed, symptomatic patients less than 60 years old and to compare the results with those of conventionally treated historic controls. The prospective population comprised 348 patients. Of these, 274 were treated according to a specified intensive-therapy protocol (Nordic Myeloma Study Group [NMSG] #5/94) and constituted the intensive-therapy group. The historic population consisted of 313 patients identified from 5 previous population-based Nordic studies. Of these, 274 fulfilled the eligibility criteria for high-dose therapy stated in NMSG #5/94 and constituted the control group. The expected numbers of patients in the prospective population and the historic population were 450 and 410, respectively, estimated from previously established data on the incidence in this population and the population base for each study. Survival was prolonged in the intensive-therapy group compared with the control group (risk ratio for the control group 1.62; 95% confidence interval 1.22-2.15; P =.001). These groups represented more than 60% of the expected number of patients. When survival for all the registered patients in the 2 populations was compared, representing more than 75% of the expected number of patients, the advantage for the prospective population persisted (risk ratio for the historic population 1.46; 95% confidence interval 1.14-1.86; P =. 002). These results indicate that the introduction of high-dose therapy for newly diagnosed myeloma has resulted in prolonged survival for the total patient population aged less than 60 years. (Blood. 2000; 95:7-11)

Health-related quality of life and patients' perceptions in interferon-treated multiple myeloma patients. Nordic Myeloma Study Group.

The effect of interferon on the health-related quality of life in multiple myeloma was assessed in two trials carried out by the Nordic Myeloma Study (Group (NMSG). In both trials, the EORTC QLQ-C30 questionnaire, supplemented with 11 items relating to interferon toxicity, was used. The first was a randomized controlled trial (NMSG 4/90) evaluating the addition of interferon alpha-2b to melphalan and prednisone during induction, maintenance and relapse. During the first 12 months, patients on interferon reported more chills, fever, fatigue, pain, nausea/vomiting, appetite loss and dry skin than the control patients, and a slight reduction of global health and quality of life. From 12 months onward there were no significant differences in any score between the two groups. In a later trial (NMSG 5/94) evaluating the effect of high-dose chemotherapy with stem cell support in patients under 60 years of age with newly diagnosed myeloma, interferon was used as maintenance. During the maintenance phase, symptom and toxicity scores were not significantly different from those in control patients under 60 years of age in the previous trial. Thus, interferon appeared to be well tolerated after high-dose chemotherapy with stem cell support.

Prognostic evaluation in multiple myeloma: an analysis of the impact of new prognostic factors.

We have analysed the prognostic information for survival of presenting features in an unselected series of 394 myeloma patients. 15 variables with significant prognostic information were identified, among these were some not previously or only recently reported: serum levels of hepatocyte growth factor (HGF), interleukin-6 (IL-6), C-terminal cross-linked telopeptide of collagen I (ICTP) and soluble interleukin-6 receptor (sIL-6R). In a multivariate Cox analysis six variables were significantly and independently associated with poor survival: high age, low W.H.O.-performance status (PS), high serum levels of calcium, beta-2-microglobulin (beta-2M), IL-6 and sIL-6R. A risk score formed to predict survival for each percentile of the patient population allowed an efficient separation of prognostic groups. The discriminating power of the model compared favourably with three other previously published staging systems applied to the study population. Exclusion of IL-6 and sIL-6R from the model only marginally decreased the efficacy of the separation. The predictive value of some variables (sIL-6R, beta-2M and W.H.O.-PS) decreased significantly over time. We conclude that formation of a risk score based on independent variables is an efficient way to separate prognostic groups, that the contribution of new and not easily available parameters should be thoroughly evaluated before inclusion in prognostic models for clinical use and that the predictive value of parameters may decrease over time.

Assessing the consistency of psychometric properties of the HRQoL scales within the EORTC QLQ-C30 across populations by means of the Mokken Scaling Model.

This paper demonstrates how the Mokken Scaling Model and other statistical tools may be useful in assessing the consistency of psychometric properties of health-related quality of life (HRQoL) scales across various populations. The main focus is the psychometric performance of the scales proposed for the EORTC QLQ-C30 in seven patient groups totalling more than 2,000 cancer patients. All scales performed satisfactorily in the total sample with the exception of the role functioning and cognitive functioning scales, which failed in terms of reliability and item discriminant validity. The descriptive statistics for the scales show that several of them, particularly those that build upon only two items, have discrimination problems at the extremes, visible in the high percentages at the maximum or the minimum observed values. The scalability analysis in the subsamples showed that the essential assumption in the Mokken Scaling Model of equal item step order does not hold for the cognitive functioning, emotional functioning and physical functioning scales. We conclude that the Mokken Scaling Model is well suited to the purpose of examining the generalizability of HRQoL scales across subpopulations although a global statistical test of the fit of the measurement model is not available.

Survival in conventionally treated younger (<60 years) multiple myeloma patients: no improvement during two decades. Nordic Myeloma Study Group (NMSG).

The patient registers of five prospective population based Nordic studies were reviewed for patients <60 yr. A total of 313 patients with symptomatic multiple myeloma were identified. Thirty-nine of them were judged retrospectively to have been ineligible for intensive chemotherapy regimens. The remaining 274 patients were considered appropriate as a historical control group for comparison with patients treated with high-dose chemotherapy and autologous stem cell support. Of these, 32 had been diagnosed during the period 1970-83, 101 during the period 1984-89 and 141 during the period 1990-92. The median age was 54 yr. Six percent were Durie/Salmon stage I, 38% stage II and 56% stage III. Melphalan-prednisone was used for initial therapy in 87%. Median survival for all patients with symptomatic myeloma was found to be 41 months, and for those selected for the control group 44 months, with no noted differences between the aforementioned diagnostic periods. We conclude that the expected median survival is 44 months for myeloma patients <60 yr who may be considered for high-dose therapy protocols. New developments in chemotherapy and supportive therapy, achieved during the two decades which preceded the use of high-dose chemotherapy with stem cell rescue, have not changed the overall prognosis in multiple myeloma.

Do antiphospholipid antibodies interfere with tissue factor pathway inhibitor?

This study was conducted to investigate whether antiphospholipid antibodies (APA) can interfere with the phospholipid-dependent inhibition of coagulation exerted by tissue factor pathway inhibitor (TFPI). Eleven patients with APA and eleven healthy controls matched for age and gender were enrolled. Blood samples were drawn before and 5 minutes after an intravenous injection of unfractionated heparin 5000 IE, which is known to cause TFPI release in healthy individuals. The preheparin samples showed significantly higher TFPI free antigen levels in the APA positive patients than in the controls (21.7 vs. 14.2 ng/ml, p = 0.03). TFPI activity as measured in a chromogenic substrate assay also was higher in patients, but this difference was not statistically significant (1.13 vs. 1.01 U/ml, p = 0.2). The TFPI levels showed a considerable rise in both patients and controls after heparin injection. In both assays, the postheparin levels were significantly higher in patients than in controls (TFPI antigen: 179 vs. 153 ng/ml, p = 0.05; TFPI activity: 3.26 vs. 2.51 U/ml, p = 0.03). A modified diluted prothrombin time assay (dPT) was used to measure TFPI anticoagulant activity. In this assay, samples from the patients with the strongest effect of lupus anticoagulants (LAs) on preheparin coagulation times showed little or no increase after heparin injection. This result may reflect an inhibition of TFPI anticoagulant activity by strong LAs. In conclusion, we have found that patients with APA have higher TFPI amidolytic activity/antigen level both before and after heparin stimulation of TFPI release. These observations do not explain the higher thrombotic risk in these patients but may reflect an upregulated tissue factor activity, which has been demonstrated in these patients. TFPI anticoagulant activity, however, as measured in a dPT assay, may be inhibited by strong LAs.

Development of an EORTC questionnaire module to be used in health-related quality-of-life assessment for patients with multiple myeloma. European Organization for Research and Treatment of Cancer Study Group on Quality of Life.

A multiple myeloma-specific quality-of-life questionnaire module has been designed in collaboration with the EORTC Quality-of-Life Study Group to be used in clinical trials with the EORTC QLQ-C30, a general cancer questionnaire. Strict methodology was employed to ensure thorough and appropriate development of the module. An extensive literature review was performed to identify health-related quality-of-life issues relevant to patients with multiple myeloma. Semi-structured interviews were then carried out in several European countries with health-care providers experienced in the treatment of patients with multiple myeloma, and with a group of patients with multiple myeloma, to identify the issues which were most important to patients. A questionnaire was devised from the list of issues, using a 1-week time-frame and response categories consistent with the EORTC QLQ-C30. The provisional questionnaire and the EORTC QLQ-C30 were administered to patients with multiple myeloma in each participating country with further semi-structured interviews to refine the content and design of the questionnaire. A review of the results obtained in each stage of development resulted in a 24-item myeloma-specific module, the EORTC QLQ-MY24, which assesses disease-specific symptoms and their impact on everyday life, treatment side-effects, social support, and future perspective. The module is currently undergoing further international field-testing to assess its psychometric properties.

Hemostatic variables as independent predictors for fetal growth retardation in preeclampsia.

BACKGROUND: Preeclampsia is a major contributor to perinatal disease and fetal growth retardation (FGR). It has been suggested that increased intravascular coagulation, fibrin deposition in spiral arteries and hypoperfusion of the placenta are involved in these pregnancy complications. METHODS: Multiple variables of the hemostatic system and lipid metabolism, as well as clinical features, were entered into univariate and multivariate models in order to examine the association with preeclampsia and FGR. RESULTS: Two hundred women with preeclampsia and 97 normotensive pregnant women were examined. Plasma levels of the thrombin-antithrombin complex (TAT), tissue factor pathway inhibitor free antigen (TFPI-Fag), protein S free antigen, plasminogen activator inhibitor type-1 (PAI-1) activity and serum levels of triglycerides were significantly increased, whereas plasma levels of antithrombin (AT), fibrinogen, C4b-binding protein (C4b-BP), PAI-2 antigen and serum HDL-cholesterol levels were decreased in the presence of preeclampsia. In the multivariate regression analysis, high TFPI-Fag plasma levels were associated with the presence of preeclampsia. The presence of FGR was in the univariate analysis associated with decreased PAI-1 activity and lower concentrations of fibrin, fibrinogen, factor VII antigen and PAI-2 antigen, as well as with evidence of macroscopic placental infarction. In a multivariate regression model, low maternal weight, placental infarction and low PAI-2 levels were predictors for low birth weight. In a logistic regression model, with the presence or absence of FGR as the dependent variable, male sex of the infant, placental infarction, low PAI-1 activity and factor VII antigen or PAI-2 antigen levels were independent predictors. CONCLUSIONS: Our results are consistent with activated coagulation in the placental vessels in preeclampsia. A low concentration of PAI-2 antigen in plasma emerged as the most consistent risk factor for preeclampsia and FGR.

Therapeutic options in the treatment of multiple myeloma: pharmacoeconomic and quality-of-life considerations.

A review of current treatment options in multiple myeloma is presented, including data on health-related quality of life and pharmacoeconomics. For induction chemotherapy, no combination of cytostatic drugs has been shown to be consistently superior to the simple cyclic oral treatment with melphalan and prednisone that has been available for 30 years. The total resource consumption and direct costs per patient treated with melphalan and prednisone is approximately $US10,000 (1995 values). As median survival is prolonged from less than a year in untreated patients to 30 to 36 months, this treatment must be considered cost effective. Interferon-alpha has a modest effect on progression-free and overall survival when added to chemotherapy regimens. However, the high cost and toxicity of this drug results in an unfavourable cost-utility ratio, estimated to be between $US50,000 to $US100,000 per quality-adjusted life-year gained. Clinical trials suggest that high dose chemotherapy followed by autologous stem cell support administered to patients who have achieved disease stabilisation or objective response to conventional induction chemotherapy, prolongs median survival by about 1.5 years. Preliminary cost-utility analyses suggest a cost per life-year gained of $US30,000 to $US40,000. Further potential improvements of this therapeutic modality are under way. Several bisphosphonates have been tested for the ability to prevent the skeletal complications of multiple myeloma. Monthly infusions of pamidronate have been shown in 1 randomised trial to significantly reduce the rate of skeletal complications. Unfortunately, the rapid and widespread acceptance of this therapy seems to preclude further prospective, placebo-controlled trials with cost-utility evaluation.