British Journal of Haematology

Rao, P. Nagesh; Flejter, Wendy L.; Rahi, Sonya; Li, Hong; Pettenati, Mark J.

doi: 10.1111/j.1365-2141.1999.image.xpmid: 10050698

Smith, O. P.; White, B.

doi: 10.1046/j.1365-2141.1999.01186.xpmid: 10050699

Bevan, David H.

doi: 10.1046/j.1365-2141.1999.01182.xpmid: 10050700

Kowalska, M. Anna; Ratajczak, Janina; Hoxie, James; Brass, Lawrence F.; Gewirtz, Alan; Poncz, Mortimer; Ratajczak, Mariusz Z.

doi: 10.1046/j.1365-2141.1999.01169.xpmid: 10050701

Thrombocytopenia is a late complication of human immunodeficiency virus (HIV) infection. The chemokine receptor CXCR4 has been shown to be a co‐receptor for lymphocyte‐tropic HIV‐1 strains. CXCR4 is also a natural receptor for the chemokine SDF‐1. We have previously shown that CXCR1 and CXCR2 are present on megakaryocytes and platelets. Although interleukin‐8 (IL‐8) and other chemokines that bind to these two receptors do not activate platelets, they are able to inhibit megakaryocytopoiesis, presumably through these receptors. We therefore examined whether CXCR4 is present on developing and mature megakaryocytes and on platelets. Reverse transcription‐polymerase chain reaction (RT‐PCR) demonstrated the presence of CXCR4 message. Immature and mature αIIbβ3+ megakaryocytes, and platelets were also positive for CXCR4 by flow cytometric studies using a CXCR4‐specific antibody. We then tested whether SDF‐1 can affect the biology of these cells. CD34+ cells and immature αIIbβ3+ cells responded to SDF‐1 as indicated by Ca2+ mobilization and chemotaxis. However, mature megakaryocytes failed to demonstrate either of these responses, in spite of their continued ability to bind 125I‐SDF‐1. Further, SDF‐1 failed to inhibit megakaryocyte colony growth. Platelets bound 125I‐SDF‐1 with a KD similar to the affinity seen for CXCR4 on other cells, yet SDF‐1 did not aggregate washed platelets nor augment aggregation by low‐dose ADP or thrombin. SDF‐1 also failed to stimulate Ca2+ mobilization, granular release or expression of P‐selectin in platelets. Accordingly, although our studies demonstrate that CD34+ precursors, megakaryocytes and platelets all express CXCR4 and bind SDF‐1, biological effects were only demonstrable of SDF‐1 on CD34+ precursors. The potential biological implications of CXCR4 expression on maturing megakaryocytes and platelets in normal individuals and following HIV infection are discussed.

Bara, Lucienne; Planes, André; Samama, Meyer‐Michel

doi: 10.1046/j.1365-2141.1999.01153.xpmid: 10050702

Studies in experimental animal models and in patients receiving low molecular weight heparin (LMWH) to prevent thromboembolic events after surgery have not demonstrated a clear relationship between anti‐Xa and anti‐IIa activities in plasma and either bleeding or prevention of thrombosis. The relationship between these clinical outcomes and ex vivo anti‐Xa and anti‐IIa activities, activated partial thromboplastin time (APTT) and D‐dimers were evaluated in 440 patients undergoing total hip replacement and given prophylaxis once daily with a LMWH (tinzaparin or enoxaparin) in a multicentre double‐blind randomized study. 221 patients received 4500 anti‐Xa IU of tinzaparin; 219 patients received 40 mg (4000 anti‐Xa IU) of enoxaparin. Both regimens were administered subcutaneously once daily. Blood samples for anti‐IIa, anti‐Xa, D‐dimers levels and APTT were taken at baseline, on day 1, day 5 and on the day of discharge (days 8–14) and clinical assessments were performed daily until day 14. All patients had bilateral venography between days 8 and 14. All coagulation tests were performed in central laboratories. A significant correlation was observed between anti‐IIa activity and anti‐Xa activity and the dose of each LMWH injected. The anti‐Xa activity was significantly higher with enoxaparin and the anti‐IIa activity was significantly higher with tinzaparin. No clear relationship between these two activities and the clinical outcomes was observed. This was also true with regards to APTT. Before and after surgery, D‐dimers were significantly higher in patients with deep vein thrombosis (DVT) than in those without DVT but had no predictive value. Interestingly, a significant post‐operative increase of D‐dimers persisted in both groups of patients during the whole observation period, possibly suggesting that a longer duration of prophylactic treatment may be appropriate.

Penning‐van Beest, F. J. A.; Rosendaal, F. R.; Grobbee, D. E.; Van Meegen, E.; Stricker, B. H. Ch.

doi: 10.1046/j.1365-2141.1999.01196.xpmid: 10050703

Oral vitamin K1 is used for the treatment of excessive anticoagulation. Detailed information on changes in the International Normalized Ratio (INR) in response to vitamin K1 is not available. We therefore measured the INR for the first 7 d following the oral intake of 1–5 mg of vitamin K1 in 24 patients routinely treated with phenprocoumon who had an INR 6.0 at presentation. On the first 2 d after administration of vitamin K1, the mean INR decreased by 40% and 23% respectively. After day 2, the day‐to‐day proportional change in the mean INR depended on the dose of vitamin K1 and varied from a decrease of 12% to an increase of 21%. On day 7 the mean INR was higher than on day 2 in three out of five treatment groups. Between day 2 and day 7, in general, 32% of the patients had an INR value within the target zone, 25% had an INR value 6.0 and 8% had an INR value <2.0. These findings suggest that our routine treatment of overanticoagulation in patients on phenprocoumon should be intensified to improve its efficacy.

Woodward, Mark; Rumley, Ann; Tunstall‐Pedoe, Hugh; Lowe, Gordon D. O.

doi: 10.1046/j.1365-2141.1999.01158.xpmid: 10050704

Haemorheological variables (whole‐blood, plasma and relative blood viscosity, haematocrit, red cell aggregation, white cell count and fibrinogen) were measured in 753 men and 821 women aged 25–74 years, and related to cardiovascular risk factors and prevalent cardiovascular disease (CVD). Men had higher levels than women of blood viscosity, haematocrit, corrected viscosity and relative viscosity. Post‐menopausal women had higher levels than pre‐menopausal women of blood viscosity, haematocrit, corrected blood viscosity, plasma viscosity and fibrinogen: each of these differences was completely or partly abolished by use of hormone replacement therapy. Serum total cholesterol, triglycerides, diastolic blood pressure, body mass index and smoking markers showed positive associations with most rheological variables, whereas HDL‐cholesterol, plasma vitamin C and social class showed inverse associations. Rheological variables were associated with prevalent CVD after age‐adjustment. However, after multiple risk factor adjustment only plasma viscosity and red cell aggregation showed significant (P < 0.04) associations in both men and women (comparing top to bottom quarters). Plasma interleukin‐6 (measured in a 25% subsample of 196 men and 221 women) correlated significantly with age, fibrinogen, white cell count, plasma and blood viscosity, current smoking, and (in men) with low serum vitamin C levels; but not with other major risk factors or with prevalent cardiovascular disease.

Bianchi, Nicoletta; Osti, Fabio; Rutigliano, Cristina; Corradini, Federica Ginanni; Borsetti, Elena; Tomassetti, Marina; Mischiati, Carlo; Feriotto, Giordana; Gambari, Roberto

doi: 10.1046/j.1365-2141.1999.01173.xpmid: 10050705

Marsh, J. C. W.; Chowdry, J.; Parry‐Jones, N.; Ellis, S. W.; Muir, K. R.; Gordon‐Smith, E. C.; Tucker, G. T.

doi: 10.1046/j.1365-2141.1999.01190.xpmid: 10050706

A genetic susceptibility to drug or chemical toxicity may provide a basis for an increased risk of idiosyncratic aplastic anaemia (AA). The cytochrome P450 enzymes are responsible for the metabolism of many drugs, some of which have been linked to AA. Mutations in the cytochrome P450 CYP2D6 gene result in absent or impaired enzyme activity in about 7% of Caucasians, whereas a specific mutation in the 5′‐regulatory region of the CYP2E1 gene causes overexpression of the gene. We evaluated the frequency of allelic variants of CYP2D6 and CYP2E1 using allele‐specific PCR amplification and restriction enzyme analysis of blood mononuclear cell DNA among 54 Caucasian AA patients. CYP2D6 and CYP2E1 were chosen because of the link between AA and the antipsychotic drug remoxipride (CYP2D6 substrate) and benzene (CYP2E1 substrate), respectively. Results were compared with 53 controls matched for age, sex and ethnicity. The percentage of AA patients homozygous for the CYP2D6*3, CYP2D6*4 alleles (poor metabolizer phenotype) and the CYP2E1 mutant allele (overexpression) was 0%, 4% and 0%, respectively, and the percentage of heterozygotes was 2%, 28% and 15%, respectively. For normal controls the corresponding results for homozygous mutants were 0%, 4% and 0% and for heterozygotes 4%, 25% and 6%, respectively. We concluded that there were no major differences in the frequencies of the genetic polymorphisms between this series of AA patients and controls, but due to the low number of cases with the poor metabolizer phenotype and those with a history of drug exposure, the power of the study was too low to disprove an interaction.

Geary, C. G.; Harrison, C. J.; Philpott, N. J.; Hows, J. M.; Gordon‐Smith, E. C.; Marsh, J. C. W.

doi: 10.1046/j.1365-2141.1999.01187.xpmid: 10050707

We report the response to immunosuppressive therapy with antithymocyte globulin (ATG) and cyclosporin or oxymetholone in 13 cases of aplastic anaemia (AA) with an abnormal cytogenetic clone detected at or sometime after diagnosis. Blood and bone marrow examination showed no distinctive morphological features of myelodysplasia (MDS) at diagnosis. Haematological response occurred promptly in eight cases; the remainder responded after additional immunosuppression with or without oxymetholone. Three patients had a late relapse of AA, treated successfully by allogeneic bone marrow transplantation in one; the others responded to oxymetholone. Transformation to MDS or acute leukaemia was not observed after a median follow‐up of 4.1 years (range 1.2–11.2). In four patients the cytogenetic clone disappeared after treatment.