The effect of different treatment regimens in reducing fasting and postmethionine-load homocysteine concentrations.

OBJECTIVES: To determine the homocysteine-lowering effect of different treatment regimens on both fasting and postmethionine-load plasma total homocysteine (tHcy) concentrations. DESIGN: Descriptive study of consecutive hyperhomocysteinaemic subjects per treatment regimen. Homocysteine was measured in the fasting state and 6 h after methionine loading, both before and after 8 weeks of vitamin therapy. Hyperhomocysteinaemia was defined as a fasting tHcy and/or increase in tHcy (postmethionine-load minus fasting tHcy concentration) exceeding the 95th percentile of local controls. SETTING: Outpatient clinic of internal medicine of a large non-academic teaching hospital. SUBJECTS: One hundred and seventeen hyperhomocysteinaemic subjects (vascular patients and first-degree relatives). INTERVENTIONS: There were four regimens: pyridoxine, 200 mg; folic acid, 5 mg; combination of folic acid 0.5 mg and pyridoxine 100 mg; and folic acid, 0.5 mg daily. RESULTS: All regimens, except pyridoxine 200 mg, significantly reduced fasting tHcy without differences in the percentage reduction (32-38%). All regimens produced a significant reduction in the increase in tHcy and postmethionine-load tHcy. The reduction in postmethionine-load tHcy was smaller for pyridoxine 200 mg than for combination therapy. No differences were found in the percentage reduction (for both increase in tHcy and postmethionine-load tHcy) between folic acid 5 mg and folic acid 0.5 mg. CONCLUSIONS: Monotherapy folic acid (0.5 mg daily) is the lowest effective therapy for reducing both fasting and postmethionine-load tHcy concentrations, with the same results as high-dose folic acid (5 mg daily). Pyridoxine has no additional value.

Combination of low-dose folic acid and pyridoxine for treatment of hyperhomocysteinaemia in patients with premature arterial disease and their relatives.

Hyperhomocysteinaemia is an independent risk factor for atherosclerotic disease and venous thrombosis. The optimal homocysteine-lowering vitamin dose and target total homocysteine (tHcy) concentration are currently unknown. We prospectively studied the homocysteine-lowering effect after 8 weeks low-dose combination of folic acid (0.5 mg) and pyridoxine (100 mg) in 49 hyperhomocysteinaemic persons (33 patients with documented premature arterial disease and 16 of their first-degree relatives). Hyperhomocysteinaemia was in both sexes defined as fasting tHcy concentration > 12 micromol/l and/or post-methionine load tHcy concentration > 38 micromol/l. Low-dose vitamin therapy significantly reduced fasting tHcy concentration (median 13.9 to 9.3 micromol/l, reduction 32% (95% CI: 27-37%)) and post-load tHcy concentration (median 55.2 to 36.5 micromol/l, reduction 30% (95% CI: 25-35%)). Fasting tHcy reduction was similar in women and men, as well as in patients and relatives. Post-load tHcy reduction was significantly less in men compared to women (P = 0.04) and in relatives compared to patients (P = 0.03). Although low-dose combination of folic acid and pyridoxine results in a substantial reduction of tHcy concentrations (30-32%) in subjects with hyperhomocysteinaemia, the normalisation percentage to predefined criteria was less impressive (49%).

Methionine loading test is necessary for detection of hyperhomocysteinemia.

Hyperhomocysteinemia, defined as an elevated concentration of homocysteine in the fasting state or after methionine loading, is an independent risk factor for premature atherosclerosis and venous thrombosis. The role of the methionine loading test (MLT) is, however, controversial. To determine the additional value of the MLT for diagnosis of hyperhomocysteinemia, we prospectively studied 281 patients with premature arterial disease and 148 of their first-degree relatives in the outpatient clinic of a general hospital. Total plasma homocysteine (fasting and 6 hours after methionine loading), folic acid, cobalamin, pyridoxine, and creatinine concentrations were measured. Hyperhomocysteinemia was defined as a fasting homocysteine concentration and/or an increase in homocysteine concentration after methionine loading exceeding the 95th percentile of a healthy control group. Hyperhomocysteinemia was found in 141 (33%) of the 429 subjects: 15% were diagnosed by fasting homocysteine concentration and 18% by MLT. Seventy-eight (55%) of the 141 hyperhomocysteinemic persons were diagnosed only by the MLT. Folic acid was lower in the group with an elevated fasting homocysteine concentration than in those with only an abnormal MLT result (11 versus 15 nmol/L, p = 0.002). Folic acid was significantly negatively correlated, and creatinine significantly positively correlated, with both fasting homocysteine concentration and increase in homocysteine concentration. Negative correlations of cobalamin and pyridoxine with fasting homocysteine concentration were found. In conclusion, the MLT is necessary for diagnosis of hyperhomocysteinemia, because a considerable number of hyperhomocysteinemic persons (55%) remain undiagnosed with the determination of a fasting homocysteine concentration alone.

[Acute tumor lysis syndrome due to mono-therapy with a corticosteroid in a patient with non-Hodgkin lymphoma]. / Acuut tumorlysissyndroom door monotherapie met een corticosteroïd bij een patiënt met non-Hodgkin-lymfoom.

A 20-year-old man was hospitalised because he nearly suffocated when lying on his back. After bronchoscopy which revealed severe external compression of the airways, suddenly respiratory insufficiency developed. Because a malignant lymphoma was suspected chemotherapy was started, using monotherapy with prednisolone as the risk of acute tumour lysis syndrome (ATLS) is high with polychemotherapy of bulky tumours. Nevertheless ATLS developed, for which haemodialysis had to be applied. The tumour, a T-cell lymphoblastic non-Hodgkin lymphoma with high grade malignancy, was treated successfully with cyclophosphamide, doxorubicin, vincristine en prednisone. ATLS is characterized by hyperkalaemia, hyperuricaemia, hyperphosphataemia, hypocalcaemia, lactate acidosis and acute renal failure. It can occur in the course of aggressive cytoreductive therapy in rapidly growing lymphoproliferative malignancies with large tumour size, due to massive tumour cel lysis. Corticosteroid monotherapy is a very rare cause of ATLS.

Mondor's disease as first thrombotic event in hereditary protein C deficiency and anticardiolipin antibodies.

A 45-year-old Caucasian woman presented with superficial thrombophlebitis of the right arm and right anterior thoracic wall after bilateral breast surgery followed by spontaneous left anterior thoracic vein thrombophlebitis 3 months later. Besides breast surgery and use of oral contraceptives, hereditary protein C deficiency and anticardiolipin antibodies were found as causes for this bilateral Mondor's disease.

[A patient with an unexplained low level of high density lipoprotein cholesterol]. / Een patiënt met een onbegrepen lage concentratie 'high-density'-lipoproteïnecholesterol.

A non smoking male patient 42 years old complained of pain in the calves after exercise and had a low 'high density'-lipoprotein (HDL) cholesterol serum concentration. Angiography of the leg vessels revealed no abnormalities. Treatment with simvastatin and gemfibrozil did not affect HDL cholesterol concentrations. Blood tests of relatives made familial hypo-alpha-lipoproteinaemia unlikely. It appeared that the patient had used anabolic steroids; these increase hepatic lipase activity leading to a higher metabolism of HDL and reduced HDL cholesterol levels.

Risk factors for bleeding during treatment of acute venous thromboembolism.

OBJECTIVE: Identification of risk factors for bleeding and prospective evaluation of two bleeding risk scores in the treatment of acute venous thromboembolism. DESIGN: Secondary analysis of a prospective, randomized, assessorblind, multicenter clinical trial. SETTING: One university and 2 regional teaching hospitals. PATIENTS: 188 patients treated with heparin or danaparoid for acute venous thromboembolism. MEASUREMENTS: The presenting clinical features, the doses of the drugs, and the anticoagulant responses were analyzed using univariate and multivariate logistic regression analysis in order to evaluate prognostic factors for bleeding. In addition, the recently developed Utrecht bleeding risk score and Landefeld bleeding risk index were evaluated prospectively. RESULTS: Major bleeding occurred in 4 patients (2.1%) and minor bleeding in 101 patients (53.7%). For all (major and minor combined) bleeding, body surface area < or = 2 m2 (odds ratio 2.3, 95% CI 1.2-4.4; p = 0.01), and malignancy (odds ratio 2.4, 95% CI 1.1-4.9; p = 0.02) were confirmed to be independent risk factors. An increased treatment-related risk of bleeding was observed in patients treated with high doses of heparin, independent of the concomitant activated partial thromboplastin time ratios. Both bleeding risk scores had low diagnostic value for bleeding in this sample of mainly minor bleeders. CONCLUSIONS: A small body surface area and malignancy were associated with a higher frequency of bleeding. The bleeding risk scores merely offer the clinician a general estimation of the risk of bleeding. In patients with a small body surface area or in patients with malignancy, it may be of interest to study whether limited dose reduction of the anticoagulant drug may cause less bleeding without affecting efficacy.

Intermediate-dose melphalan (IDM) combined with G-CSF (filgrastim) is an effective and safe induction therapy for autologous stem cell transplantation in multiple myeloma.

Twenty-one previously untreated multiple myeloma (MM) patients and 10 previously treated patients with refractory or relapsed disease received two or three cycles of intermediate-dose melphalan (70 mg/m2) (IDM), administered intravenously every 6 weeks. Seven previously untreated patients received three and all other patients received two courses of IDM. The objective of the study was to reduce the toxicity of high-dose melphalan (140 mg/m2) (HDM) while maintaining its cytotoxic efficacy and secondly to ensure the possibility of collecting sufficient numbers of peripheral blood stem cells (PBSC) for transplantation. 18 (85%) previously untreated patients responded, of whom four achieved CR (18%). In addition five out of 10 previously treated patients with refractory or relapsed disease responded although bone marrow toxicity in this category was a major drawback. Toxicity was moderate, consisting of alopecia and moderate bone marrow suppression: the granulocyte count dropped below 0.5 x 10(9)/l and platelets below 25 x 10(9)/l for a median of 8 and 6 d, respectively. No serious infections occurred and the majority of patients attended the out-patient clinic. In 12/14 previously untreated patients sufficient peripheral blood CD34+ cells for harvest were present in the repopulation phase after the first IDM. In nine patients peripheral blood stem cells were collected and eight patients have undergone successful transplantation. Repeated IDM followed by filgrastim is highly effective in untreated MM and may be safely administered to reduce tumour load prior to PBSC collection. Autologous stem cells harvested after repeated IDM have a full long-term repopulating capacity.

Comparing subcutaneous danaparoid with intravenous unfractionated heparin for the treatment of venous thromboembolism. A randomized controlled trial.

OBJECTIVE: To compare the efficacy and safety of two subcutaneous doses of danaparoid with that of continuous intravenous administration of unfractionated heparin in the treatment of venous thromboembolism. DESIGN: An open-label, randomized, multicenter clinical trial. SETTING: One university hospital and two university-affiliated hospitals. PATIENTS: 209 patients suspected to have venous thromboembolism. Of these, 188 had a confirmed diagnosis (by ventilation-perfusion lung scan and ultrasonography or contrast venography of the leg) and received study medication. INTERVENTIONS: Patients were randomly assigned to either low-dose danaparoid (intravenous loading dose of 1250 U followed by 1250 U administered subcutaneously twice daily [n = 65]); high-dose danaparoid (intravenous loading dose of 2000 U followed by 2000 U administered subcutaneously twice daily [n = 63]); or unfractionated heparin (intravenous loading dose of 2500 U followed by dose-adjusted continuous infusion [n = 60]). Treatment lasted at least 5 days and was continued until anticoagulation (achieved with acenocoumarol) was adequate. MEASUREMENTS: Efficacy determined clinically and by repeated imaging tests on treatment days 5 to 8; safety determined by daily assessment for bleeding. RESULTS: Two lung scans were done in each of 179 patients; ultrasonography or venography of the leg was done twice in each of 173 patients; and both repeated leg and lung tests were done in 166 patients. A significant reduction in recurrence or extension of venous thromboembolism was seen in patients receiving high-dose danaparoid (8 of 63 [13%]) compared with patients receiving intravenous unfractionated heparin (17 of 60 [28%]; relative risk, 0.45 [95% CI, 0.21 to 0.96]). Four of 61 patients receiving high-dose danaparoid (7%) and 14 of 58 patients receiving unfractionated heparin (24%) had recurrence of pulmonary embolism (relative risk, 0.27 [CI, 0.09 to 0.78]); 3 of 58 patients receiving high-dose danaparoid (5%) and 6 of 54 patients receiving unfractionated heparin (11%) had recurrence of deep venous thrombosis (relative risk, 0.47 [CI, 0.12 to 1.77]). Occurrence of major and minor bleeding was similar in the three groups; major bleeding occurred in 1 patient receiving low-dose danaparoid, 1 patient receiving high-dose danaparoid, and 2 patients receiving heparin. CONCLUSIONS: Our results suggest that high-dose danaparoid is safer and more effective than unfractionated heparin for the treatment of venous thromboembolism.

Non-invasive detection of deep venous thrombosis: ultrasonography versus duplex scanning.

In a prospective study the diagnostic value of compression ultrasonography (CUS) versus Duplex scanning (DS) in the non-invasive detection of acute femoropopliteal deep venous thrombosis (DVT) was determined. In 114 eligible patients clinically suspected of DVT of the lower extremity, compression ultrasonography and Duplex scanning were performed within 24 hours by different assessors unaware of the outcome of the other test. In 109 patients concordant results of combined compression ultrasonography and Duplex scanning were obtained and considered as a proof of the absence or presence of deep venous thrombosis and no subsequent invasive investigations were performed. In five patients compression ultrasonography and Duplex scanning were discordant and contrast venography was performed. Femoropopliteal thrombosis was present in 47 legs (41%). The sensitivity, specificity and accuracy of compression ultrasonography were 93.6, 97.0 and 95.6%, respectively, and of Duplex scanning 100, 98.5 and 99.1%, respectively. We conclude that compression ultrasonography and Duplex scanning are methods with comparably high accuracy. Because of its availability, accuracy, cost-effectiveness and simplicity we recommend compression ultrasonography as the primary diagnostic test in the detection of deep venous thrombosis.

Comparison of plasma cell infiltration in bone marrow biopsies and aspirates in patients with multiple myeloma.

In 54 patients with multiple myeloma plasma cell infiltration was compared in bone marrow biopsies and aspirates. In 48% of cases plasma cell infiltration was comparable, in 48% infiltration in the aspirate was lower than in the biopsy. In only two cases more plasma cells were found in the aspirate. Eleven patients (20%) had less than 20% plasma cells in the aspirate and more than 50% in the biopsy. Underestimation of plasma cell load especially seems to occur in patients with a focal growth pattern of multiple myeloma or when strong fibrosis is present. 69% of patients with stage III, according to Durie & Salmon (1975), and 76% of patients with a high beta 2-microglobulin had more than 50% plasma cells in the biopsy, indicating that these parameters, which are based on tumour load, are influenced by other factors as well. The bone marrow biopsy is of superior value for direct estimation of the tumour load in multiple myeloma compared to bone marrow aspirates. A prospective study is needed to determine its prognostic significance.

High-risk multiple myeloma treated with high-dose melphalan.

PURPOSE: This study was undertaken to evaluate the efficacy and toxicity of high-dose melphalan (HDM) 140 mg/m2 in poor-risk multiple myeloma (MM). PATIENTS AND METHODS: Thirteen patients were previously untreated, and 13 had been pretreated with vincristine, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and dexamethasone (VAD) for refractory or relapsed MM. RESULTS: All 11 fully assessed, untreated patients responded, and six achieved a complete response. Remissions were of excellent quality, but response duration--a median of 16 months--was short. This was probably due to the high incidence of unfavorable prognostic signs, like a high beta 2-microglobulin (B2M) and/or a high plasma cell labeling index (LI). None of the nine pretreated patients with a measurable M component had more than 50% reduction of M component after HDM, indicating that intensive treatment has no effect on a residual tumor population. The relapse-free period after HDM in this group of patients (median, 9 months) was not better than in a historical control group of patients treated with VAD alone. The major complications due to the prolonged myelosuppression were severe infections. After primary HDM, median time to recovery to greater than 0.5 x 16(9) granulocytes was 30 days; in previously treated patients, the recovery period was even longer. There were three toxic deaths. Fulminant relapses with features of J-chain disease were frequently observed, indicating a dedifferentiated tumor, probably induced or selected by the HDM. CONCLUSIONS: HDM is an effective treatment resulting in good remissions for untreated MM. However, other therapy strategies should be explored first, focusing on the reduction of toxicity and prolongation of the relapse-free period, before HDM can be recommended as first-line treatment for the younger MM patient.

Duplex scanning in the diagnosis of acute deep vein thrombosis of the lower extremity.

In a prospective study the value of duplex scanning in the diagnosis of acute femoro-popliteal thrombosis was compared to conventional contrast venography (CV) as a gold standard. A total of 126 legs in 117 patients suspected of having deep vein thrombosis (DVT) or pulmonary embolism (PE) were examined with both methods. CV and duplex scanning were diagnostic in 98.5 and 97%, respectively. Femoro-popliteal thrombosis was present in 64 legs (prevalence 54%). The sensitivity and specificity of duplex scanning were 90.6% and 94.6%, respectively. A marked improvement in sensitivity from 83.3 to 97% and overall accuracy from 88.7 to 96% was noticed between the first and second half of the study period. Of the individual duplex criteria in the diagnosis of DVT, abnormal vessel wall compressibility was the most accurate. The Doppler measurements however allow evaluation of venous areas difficult to assess with B-mode and add discrimination between partial or total vein occlusion. Duplex scanning is more accurate compared to CV in grading the anatomical extent of thrombosis. Agreement between venography and duplex scanning was found in 75% of the vein segments, in about 20% CV suggested more thrombus formation compared to duplex scanning. Thrombus in the deep femoral vein was documented by duplex scanning in 24 patients including two cases of isolated deep femoral vein thrombosis. Venography failed to visualise the deep femoral vein with sufficient diagnostic accuracy in 88% of the patients vs. 8.5% with duplex scanning. Duplex scanning is an accurate non-invasive test in the diagnosis of acute femoro-popliteal thrombosis and superior to CV in the detection of non-occlusive and deep femoral vein thrombosis.

Multiple myeloma and acute megakaryoblast leukemia in spent phase polycythemia vera.

The spontaneous and simultaneous occurrence of multiple myeloma and megakaryoblast leukemia with myelodysplastic features in a case of spent phase polycythemia vera is well documented. In support of the morphologic characteristics of the bone marrow, immunocytologic studies show proliferation of monoclonal plasma cells and megakaryoblasts. The cytogenetic findings of 20q- and unbalanced t(1;7) are consistent with myelodysplastic and leukemic transformation of the bone marrow. These transformations expand observations on variable and spontaneous lineage commitments as the consequence of alterations of the hematopoietic stem cell clone. These data are in support of the changing insights in hematopoiesis as a process of ordered commitment of the stem cell with sequential lineage potentials.

Contrast venography: from gold standard to 'golden backup' in clinically suspected deep vein thrombosis.

In a series of 180 patients, clinically suspected of having deep venous thrombosis (DVT), contrast venography was compared with radionuclide phlebography, duplex ultrasonography and strain gauge plethysmography. In most patients lung scintigraphy was also performed to detect pulmonary embolism (PE). Venography was performed on a routine basis. All venograms were read by at least two observers (radiologists or radiologist/resident) and an inter-observer agreement was reached of 96% with a kappa value of 0.935. In six patients venography was technically impossible or inadequate, 58% of the patients actually had DVT and 26% developed pulmonary embolism (PE). Of the patients with proven DVT, 43% developed PE. Of the three other methods duplex scanning scored the best for the detection of proximal thrombosis, with 92%, 90% and 9.2, and strain gauge plethysmography the worst, with values of 72%, 78% and 3.2 for, respectively, sensitivity, specificity and positive likelihood ratio's. On the basis of the presented material and the current literature it is concluded that the choice for a screening test for proximal thrombosis could best be made on the basis of (local) availability, cost-effectiveness and patient comfort. Duplex ultra-sonography is tipped as the most promising method, accepting that distal thrombosis (calf veins) does not play an important role in PE. Contrast venography should be used as a 'golden backup' in any case of doubt.

A Dutch family with hereditary protein S deficiency.

Protein S, a vitamin K dependent factor, acts as a cofactor for activated protein C in preventing coagulation and stimulating fibrinolysis. Hereditary protein S deficiency has been reported to be an autosomal dominant disorder, associated with an increased risk for developing thrombosis in heterozygotes. Here we present a large Dutch family with familial thrombophilia based on hereditary protein S deficiency. Besides the proband, 27 individuals were tested. Of these, four had had complaints of thromboembolic events. Three of them had protein S levels below the limits of normal, and were considered to be heterozygous for protein S deficiency. Ten others who were also found to be heterozygotes had had no manifestations. Seven of them were under 15 years of age at the time of the investigation. It is uncommon for heterozygotes with protein S deficiency to develop thrombosis before that age, although there have been a few reports. Following these observations, some remarks are made on how to make the laboratory diagnosis of the deficiency, on when to perform family choice of analysis, and on the consequences for therapy.

VAD chemotherapy for refractory multiple myeloma.

Thirty-four patients with refractory multiple myeloma were treated with 4-d continuous infusions of vincristine and adriamycin in combination with 4-d pulsed high-dose dexamethasone (VAD). Of 31 evaluable patients, 16 entered a complete remission (50%) and three a partial remission (10%). No difference in response rate was observed between primary refractory and relapsed patients. The median response duration was 9 months and the median survival of the responding patients was 12 months versus 4 months for the non-responders. Ten patients have currently survived longer than 360 d, of which six are stable in complete remission without therapy. All responding patients showed a remarkable improvement of their performance status and 70% of these patients became pain-free. Bacterial infection was the major complication and was probably due to the intensive corticosteroid programme. Severe myelosuppression was rarely observed. Irrespective of the response to VAD, a high beta 2-microglobulin of 4 micrograms/ml or more was a bad prognostic parameter. As early relapses were seen especially in this group of patients, in the patients with a plasma-cell LI% of 3 or more, and in patients with previous anthracyclin treatment, early consolidation, with, for instance, high dose melphalan, might improve the prognosis for these patients.