6-Mercaptopurine, still valuable for the palliative treatment of acute myeloid leukaemia

Although 6-mercaptopurine (6-MP) is frequently used in the treatment of acute myeloid leukaemia (AML), its effect on disease progression has not been studied systematically. In a small retrospective analysis, we found that 6-MP could induce marked haematological improvement in a considerable number of AML patients who were not treated with intensive remission induction courses. Due to the inherent limitations of retrospective analyses, we then investigated prospectively in 51 consecutive patients over a 3-year period in a single centre, to what extent, oral 6-MP 250 mg twice a week could be beneficial to AML patients who were not-or no longer-eligible for intensive chemotherapy. Clinical response was scored according to changes in blood cell counts and dependency on blood transfusions. Thirteen patients (25%) were considered responders since they showed an increased platelet count from the first month after initiation of 6-MP onwards and they became independent of blood transfusions after 3 months. This effect lasted for 13 (range 7-30+) months. Median overall survival of this subgroup was 16.5 (6-33+) months. Ten patients (20%) had a shorter or incomplete response and a survival of 12 (6-30) months. Seven patients were lost to follow-up. Twenty-one (41%) failed to respond and survived for 4 (1.5-17) months. The response seemed not to be affected by previous chemotherapy, history of myelodysplasia, or karyotype abnormalities, but high leukocyte count initially was unfavourable. 6-MP thus can induce marked improvement of blood cell counts in a considerable proportion of AML patients who are not eligible for intensive chemotherapy, leading to good quality of life and a significant prolongation of survival.</p

Effects of red blood cells on hemostasis

BACKGROUND: Currently there is no sensitive laboratory test to establish the influence of red blood cells (RBCs) on hemostasis. As thromboelastography (TEG) measures hemostasis in whole blood, taking into account the interactions of all cellular elements, we used this instrument to investigate the role that RBCs play in hemostasis. STUDY DESIGN AND METHODS: In 29 patients with chemotherapy-induced anemia we studied the effect of progressive anemia on the coagulation profile. In 24 patients with chronic anemia we studied the effect of transfusion of RBCs on coagulation. Finally, in 18 patients we evaluated whether storage time of RBCs has additional effects on hemostasis. RESULTS: We observed a significant negative correlation between hemoglobin and TEG variables related to both clot strength and elasticity (p <0.05). Moreover, anemia was associated with a delay in the initiation of the coagulation cascade. Correction of anemia by RBC transfusion resulted in significant shortening of this initiation phase with now the opposite effect on clot strength and elasticity. The negative effects on clot quality were significantly worse when fresh RBCs were transfused compared to longer-stored RBCs. Furthermore, in contrast to the longer-stored RBCs, fresh RBCs did not enhance initial fibrin formation. CONCLUSIONS: In this study we found that anemia was associated with a delay in the initiation of the coagulation cascade with a finally formed clot with superior strength and viscoelastic properties. Transfusion of RBCs was associated with impaired clot quality, with even worse effects on the initial fibrin build-up and clot quality by fresh RBCs

Thrombocytopenia affects plasmatic coagulation as measured by thrombelastography

Thrombelastography (TEG) is used as a point-of-care test of hemostasis. Different components of the test tracing are considered to reflect various parts of the hemostatic system and to distinguish low platelet count, platelet dysfunction or both from lack of plasmatic coagulation factors. To analyze the influence of one single element of the coagulation system, namely the platelet count, we used TEG serially in patients with well documented transient thrombocytopenia. A total of 189 TEG analyses were performed from 16 patients with a hematological malignancy in remission, receiving consolidation courses of chemotherapy. TEG outcomes using unmanipulated and citrated blood samples at a median of 11 times (range 1 - 17) in the same patients during the decrease of platelet count in response to chemotherapy were compared with outcomes in 120 healthy adults from various age categories. We found a correlation (r = 0.7, P <0.001) between TEG clot strength (maximum amplitude) and platelet count. Moreover, platelet count was correlated respectively with the initial rate of clot formation (reaction time and clotting time), the rate of clot growth (alpha angle), and also with maximum thrombus generation, time to maximum thrombus generation and total thrombus generation. We conclude that platelet count not only affects the strength of clot formation, as was expected, but also all other phases of plasmatic coagulation. Citration of the blood sample, aiming at easy storage of the material, masked some of the important biological parameters of coagulation. Blood Coagul Fibrinolysis 21:389-397 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins

Loss of quiescence and impaired function of CD34(+)/CD38(low) cells one year following autologous stem cell transplantation

<p>Patients who have undergone autologous stem cell transplantation are subsequently more susceptible to chemotherapy-induced bone marrow toxicity. In the present study, bone marrow primitive progenitor cells were examined one year after autologous stem cell transplantation and compared with normal bone marrow and mobilized peripheral blood stem cells. Post-transplantation bone marrow contained a significantly lower percentage of quiescent cells in the CD34(+)/CD38(low) fraction compared to normal bone marrow. In addition, we observed a strong decrease in stem cell/primitive progenitor frequency in post-transplantation CD34(+) cells as defined by long-term culture assays. Measurement of the levels of reactive oxygen species by flow cytometry revealed comparable levels in post-transplantation and normal bone marrow CD34(+)/CD38(low) cells, while significantly higher levels of reactive oxygen species were observed in CD34(+)/CD38(high) cells following autologous stem cell transplantation compared to normal bone marrow. Moreover, post-transplantation CD34(+) bone marrow cells demonstrated an increased sensitivity to buthionine sulfoximine, a trigger for endogenous production of reactive oxygen species. Gene expression analysis on CD34(+) cells revealed a set of 195 genes, including HMOX1, EGR1, FOS and SIRPA that are persistently down-regulated in mobilized peripheral blood cells and post-transplantation bone marrow compared to normal bone marrow. In conclusion, our data indicate that the diminished regenerative capacity of bone marrow following autologous stem cell transplantation is possibly related to a loss of quiescence and a reduced tolerability to oxidative stress.</p>

Platelet production rate predicts the response to prednisone therapy in patients with idiopathic thrombocytopenic purpura

The predictive value of clinical and platelet kinetic parameters for treatment outcome in idiopathic thrombocytopenic purpura (ITP) was investigated in 75 patients with platelets 355x10(9)/day) in 33%, 48%, and 19% of patients, respectively. All patients started with prednisone at diagnosis (1 mg/kg/day). Initial complete and partial response (CR/PR) rate was 84% and a durable CR/PR (>= 6 months without treatment) was attained in 44% of the patients. Durable CR/PR was noticed in 64% of the patients with decreased PPR during a median follow-up time without treatment of 81 (range 18-92) months, compared to 34% of the patients with normal or increased PPR during a median follow-up time without treatment of 141 (range 10-284) months (p=0.03). Splenectomy was performed in 32% of patients with decreased PPR and in 62% of patients with normal or increased PPR (p=0.03). In conclusion, ITP patients with suppressed PPR have a significant higher durable CR/PR rate to prednisone therapy and are less frequently exposed to splenectomy than those with a normal or increased PPR

F-18 FLT PET:A Noninvasive Diagnostic Tool for Visualization of the Bone Marrow Compartment in Patients With Aplastic Anemia A Pilot Study

Rationale: A discordant relationship between bone marrow cellularity and peripheral blood findings is regularly noticed in patients with aplastic anemia (AA). Therefore, the feasibility of 3-F-18 fluoro-3-deoxy-L-thymidine (F-18 FLT PET was tested as a noninvasive tool to visualize the total distribution of the hematopoietic bone marrow compartment in AA at presentation or after treatment. Methods: In vivo scanning was performed with F-18 FLT PET in AA patients (n = 17), including patients upfront (n = 11) and following treatment (n = 6), in addition to peripheral blood cell counts and a bone marrow biopsy. Results: A striking abnormal F-18 FLT scan was observed in all patients upfront treatment, in particular a reduced uptake of the pelvis was shown, the area that is biopsied for the bone marrow biopsy. Following treatment, the number of solitary lesions with increased proliferative activity outside the pelvis was noticed in patients with partial response, whereas patients with a complete remission showed a homogenous uptake throughout the skeleton. Conclusion: This pilot study demonstrates that F-18 FLT scan provides a highly distinctive overview of the bone marrow compartment in AA that might be helpful for making a proper diagnosis and monitoring treatment response of AA patients

In Normal Controls, Both Age and Gender Affect Coagulability as Measured by Thrombelastography

BACKGROUND: Our objective was to analyze the effects of age, gender, and the use of oral contraceptives (OCs) on coagulation using thrombelastography (TEG (R)), a single test to analyze both plasma coagulation factors and cellular elements in whole blood. METHODS: TEG (R) variables were measured in native whole blood and in recalcified citrated blood from 120 healthy adults (60 men and 60 women) with various ages and in an additional 29 healthy women using OCs. RESULTS: We observed hypercoagulability in women compared with men and in women using OCs compared with age-matched nonusers. Moreover, we found hypercoagulability with aging. Using the method of Bland and Altman (Lancet 1986;1:307-10), we demonstrated no correlation between TEG (R) measurements in native and recalcified citrated blood. CONCLUSIONS: Aging, female gender, use of OCs, and low-normal hematocrit levels have significant procoagulant effects. TEG measurements in native and recalcified citrated blood are not interchangeable, as indicated by differences between the 2 measurements ranging from 20% in maximal amplitude to 246% in clotting time. Furthermore, the limits of agreement strongly exceeded clinical acceptability to conclude interchangeability. (Anesth Analg 2010;110:987-94

Quantifying the reduction in immunoglobulin use over time in patients with chronic immune thrombocytopenic purpura receiving romiplostim (AMG 531)

Patients with Immune thrombocytopenic purpura (ITP) often require immunoglobulin (Ig) therapy with intravenous 19 (IVIG) or anti-D to prevent or treat the serious bleeding events. Because the thrombopoietin (TPO) mimetic romiplostim (AMG 531; Nplate) elevates platelet counts in patients with chronic ITP, we quantified to what extent it reduced the incidence of Ig rescue therapy in two randomized (vs. placebo) trials of romiplostim for chronic ITP. Our analysis shows that significantly fewer romiplostim patients than placebo patients required Ig therapy over the course of 24 weeks (1-6% vs. 19-37%, respectively; P <0.05 for each 4-week interval), and romiplostim-treated patients were 5.31-fold less likely to receive Ig therapy (P <0.001)