Low serum vitamin B12 levels in chronic high-flux haemodialysis patients.

The occurrence of vitamin B12 (B12) deficiency in chronic haemodialysis patients and the need for its supplementation in these patients are still matters of debate. We measured serial predialysis serum B12 levels, at 3- to 6-month intervals, in 67 unselected patients on our high-flux haemodialysis programme. Over a 12-month period, there was a significant fall in serum B12 from 497 +/- 200 (SD) to 391 +/- 131 ng/l (p < 0.001). 22 patients developed subnormal serum B12 levels and were commenced on hydroxocobalamin supplements. We were unable to demonstrate B12 clearance during dialysis using blood side studies. Measurement of B12 in the dialysate showed that 0-4.5 microg B12 was cleared per dialysis. Using these B12 measurements, in vivo B12 clearance was estimated at 9.1 ml/min. Dietary studies on 24 unselected patients showed borderline or low B12 intake in 4 patients. Absorption studies by whole-body counting on 6 patients using 57Co and 58Co showed normal B12 absorption. The same radioisotope studies demonstrated no B12 adsorption to the dialyser membrane. This study demonstrates that low serum B12 levels occur in high-flux haemodialysis patients and that losses during dialysis and dietary deficiency may be contributing factors.

A randomized study of VAD therapy with either concurrent or maintenance interferon in patients with newly diagnosed multiple myeloma.

This randomized study was designed to determine whether response to VAD chemotherapy could be prolonged by using rh alpha-2b-interferon (IFN) at a dose of 3 mU three times per week, either concurrently with VAD (VIC) or as maintenance after completion of VAD (VIF). Maintenance IFN was given for 9 months in order for the duration of IFN therapy to be similar in both groups. 72 patients were randomized between December 1988 and August 1993. The majority of patients had poor prognostic features. The objective response rate was similar in each arm, 78% in VIF and 77% in VIC. Of the 56 responders, 33 have relapsed, three died in remission, and 18 proceeded to high-dose therapy, withdrew for other reasons or were lost to follow-up and were censored from analysis at the relevant time point. Only two patients remain in remission (both in partial remission). Median PFS was 15 months for both VIF and VIC, compared with 16.5 months for a historic control group treated with VAD alone (n.s.). The estimated median survival in VIF was 43 months and in VIC 22 months, compared with 45 months in the historic controls (n.s.). These findings indicate that neither maintenance nor concurrent IFN prolongs response to VAD.

Rearrangement of the breakpoint cluster region and expression of P210 BCR-ABL in a "masked" Philadelphia chromosome-positive acute myeloid leukemia.

The Philadelphia (Ph) translocation t(9;22)(q34;q11) occurs frequently in chronic myeloid leukemia (CML) but is less common in acute lymphoblastic leukemia (ALL) and rare in acute myeloid leukemia (AML). In most cases of CML and some cases of Ph+ ALL the protooncogene ABL from 9q34 is translocated to the breakpoint cluster region (bcr) of the BCR gene at 22q11 to form a chimeric gene encoding a novel 210-kd protein (P210 BCR-ABL) with enhanced tyrosine kinase activity. In other patients with Ph+ ALL and Ph+ AML, the breakpoint probably occurs in the first intron of the BCR gene; this results in a smaller chimeric gene which encodes a P190 BCR-ABL. We studied a patient with AML (FAB M6) arising de novo who had a "masked" Ph chromosome in association with extensive karyotypic changes. The leukemic cells initially showed rearrangement of the bcr, presence of a hybrid mRNA, and expression of the P210 BCR-ABL. These changes were absent in remission. These results support the concept that the BCR-ABL chimeric gene plays a crucial role in leukemogenesis but suggest that factors other than the position of the breakpoint in the BCR gene determine the lineage of the target cell for malignant transformation.

Relationship between ex vivo anti-proteinase (factor Xa and thrombin) assays and in vivo anticoagulant effect of very low molecular weight heparin, CY222.

There is uncertainty as to which activities of unfractionated heparin (UFH) and low MW heparin are responsible for their anticoagulant and antithrombotic properties. We have sought to answer this question by examining plasma samples taken during a recently conducted dose-finding study of the low MW heparin, CY222, in haemodialysis for chronic renal failure. In this study, in vivo anticoagulant effect was assessed by measurement of plasma FPA levels. UFH was administered as a dose of 5000 iu bolus + 1,500 iu/h maintenance infusion, while the effects of three doses of CY222 were studied (10,000, 15,000 and 20,000 Institute Choay anti-factor Xa u bolus, all with 1,500 Institute Choay anti-factor Xa u/h maintenance infusion). Anti-factor Xa levels were determined by chromogenic substrate assay. Anti-thrombin levels were determined by chromogenic substrate assay and by quantitation of catalysed thrombin-inhibitor complexes (using autoradiography). Analysis of the results indicate that plasma fibrinopeptide A (FPA) levels correlate with anti-factor Xa (r = -0.45) and anti-thrombin (substrate) (r = -0.63) levels of UFH, but only with the anti-factor Xa levels (r = -0.41) of CY222. These results suggest that the anti-factor Xa assay is currently the most suitable assay for monitoring low MW heparins such as CY222 in humans.

Equivalent effective doses of heparin and low molecular weight heparin(oid)s in haemodialysis for chronic renal failure.

In an attempt to provide an objective means of comparing the anticoagulant action of heparin with those of newly developed low MW heparin-like anticoagulants we have utilized the fibrinpeptide A assay as a method of determining fibrin formation during haemodialysis. In vivo suppression of FPA levels by increasing doses of administered anticoagulant enables equivalent effective doses of anticoagulants to be determined without making prior assumptions about which ex vivo activities of these compounds are responsible. In this communication we summarize results of studies with heparin and three low MW heparin(oid)s.