Jack Kutti

Vascular and Neoplastic Risk in a Large Cohort of Patients With Polycythemia Vera

PURPOSE The clinical course of polycythemia vera is often complicated by thrombosis as well as by the possible transition to myeloid metaplasia with myelofibrosis or acute myeloid leukemia. The aim of this study was to assess the rate of these complications in subjects receiving currently recommended treatments. PATIENTS AND METHODS Overall, 1,638 patients from 12 countries were enrolled onto a large, prospective multicenter project aimed at describing the clinical history of polycythemia vera for the following outcomes: survival, the cumulative rate of cardiovascular death and thrombosis, the cumulative rate of leukemia, myelodysplasia, and myelofibrosis. The mean duration of the disease at entry and the duration of the follow-up were 4.9 and 2.7 years, respectively. RESULTS The overall mortality rate of 3.7 deaths per 100 persons per year resulted from a moderate risk of cardiovascular death and a high risk of death from noncardiovascular causes (mainly hematologic transformations). Age older than 65 years and a positive history of thrombosis were the most important predictors of cardiovascular events. Antiplatelet therapy, but not cytoreductive treatment, was significantly associated with a lower risk of cardiovascular events. We found a consistent association between age and risk of leukemia, and between duration of the disease with risk of myelofibrosis. CONCLUSION The European Collaboration on Low-Dose Aspirin in Polycythemia Vera study documents that large international collaborative studies are feasible in this field, in which few epidemiologic data are available. The persistently high mortality rate from hematologic malignancies characterizes the unmet therapeutic need of polycythemic patients and suggests a priority for future studies in this disease.

Clinical Experience with Recombinant Factor VIla in Patients with Thrombocytopenia

Platelets play a central role in primary hemostasis. The role of the coagulation mechanism during early stages of hemostasis is less clear, although increasing evidence is emerging indicating the ultimate importance of the factor VII (FVII)-tissue factor-dependent coagulation system in providing the first thrombin molecules necessary for the platelet activation to occur. Supporting this, early fibrin formation has been reported to occur within the bleeding time wound and infusion of recombinant FVIIa (rFIIa) has been shown to shorten the bleeding time in rabbits. We have investigated whether infusion of rFVIIa would enhance fibrin formation in bleeding time wounds in patients with thrombocytopenia as reflected by a shortening of the bleeding time. A reduction of the bleeding time was found in 55/105 cases (52%). The decrease was significantly more pronounced when the platelet count exceeded 20 x 10(9)/l. With the exception of an anaphylactoid reaction in 1 patient, no major adverse reactions related to the study drug were observed. Nine infusions of rFVIIa were given to 8 thrombocytopenic patients with overt bleeding. One patient received two infusions. Bleeding decreased in all patients and stopped in 6 patients.

Platelet survival and platelet production in idiopathic thrombocytopenic purpura (ITP).

Summary. Platelet mean life span (MLS) and platelet production were measured in 3–5 patients with idiopathic thrombocytopenic purpura (ITP) and in 21 healthy subjects.

Endothelial cell seeding reduces thrombogenicity of Dacron grafts in humans

Vascular prostheses in humans do not endothelialize spontaneously. In the present study we explored the feasibility of seeding autologous endothelial cells into prostheses implanted in patients undergoing reconstruction of the infrarenal aorta. In 22 patients one limb of an aortic Dacron bifurcation prosthesis was seeded with autologous endothelial cells harvested from the distal portion of the saphenous vein. The other limb was sham-seeded with culture medium only. The effect of seeding was studied by use of indium 111 radiolabeled platelets and external gamma camera scanning at 1, 4, and 12 months after surgery. No complications ascribable to the seeding procedure were seen. During the first year after surgery a gradual decrease in platelet accumulation occurred over the whole vascular prosthesis. At all time points studied the seeded graft limbs exhibited significantly less deposition of radiolabeled platelets than did control limbs. The observed difference in platelet accumulation on autologous endothelial seeding-treated graft segments merits further investigation of this technique in humans.

An elevated venous haemoglobin concentration cannot be used as a surrogate marker for absolute erythrocytosis: a study of patients with polycythaemia vera and apparent polycythaemia.

The diagnosis of polycythaemia vera (PV) has been established upon sets of clinical criteria, which require the presence of absolute erythrocytosis (AE). The most recent clinical criteria for PV, published by the World Health Organization (WHO) in 2001, also required AE, and stated that the measured red cell mass (RCM) could be replaced by a surrogate marker for AE; a haemoglobin (Hb) value of >18·5 g/dl in males and >16·5 g/dl in females. The present study evaluated the potential of venous haematocrit (Hct) and Hb values as possible surrogate markers for AE in a series of 77 consecutive patients with PV and 66 patients with apparent polycythaemia (AP), in all of whom the RCM had been previously determined. In only 35% of the male PV patients would Hb values >18·5 g/dl indicate the presence of AE. Conversely, 14% of male AP patients would be misdiagnosed as having AE. A Hb > 16·5 g/dl would predict the presence of AE in 63% of the female PV patients, but 35% of female AP cases would be misdiagnosed as having AE. However, when the Hct was ≥0·60 an AE was always present, and this was true for both male and female subjects.

Diagnostic and Differential Criteria of Essential Thrombocythemia and Reactive Thrombocytosis

Among the chronic myeloproliferative disorders essential thrombocythemia (ET) is known to be a distinct clinical entity in which an excessive number of morphologically and functionally abnormal platelets are produced. The clonal nature of the disease is well established. Based on a review of the literature the present authors propose the following novel criteria for the diagnosis of ET: A1. Platelet count in excess of 600 x 10(9)/L. A2. No increase in red-cell mass (RCM) in the presence of stainable iron in the bone marrow or failure of iron trial (RCM < 36 mL/kg in males and < 32 mL/kg in females; or RCM < 25% above mean normal predicted value*). A3. No Philadelphia chromosome. A4. Megakaryocytic hyperplasia (= increased megakaryocyte number and size) in histological sections of bone marrow and/or increased megakaryocytic ploidy (two-color flow cytometry); no collagen fibrosis. B1. Splenomegaly on isotopic scan or echogram. B2. Unstimulated growth of BFU-E and/or CFU-Meg present. B3. Normal ESR/fibrinogen. The diagnosis of ET is considered to be established if A1 + A2 + A3 + A4 or A1 + A2 + A3 + two B-criteria are fulfilled. (* Br J Haematol 1995; 89:748-756.)

Trends in the incidence of chronic Philadelphia chromosome negative (Ph-) myeloproliferative disorders in the city of Göteborg, Sweden, during 1983-99.

Objective.  In the literature the incidence rates for the chronic Philadelphia chromosome negative (Ph‐) myeloproliferative disorders (MPD) are known to vary extensively; only a few studies have, however, been concerned with incidence trends over time. Therefore, the aim of the present work was to investigate possible trends as regards incidence rates over time for Ph‐MPD.

Reduction in deposition of indium 111-labeled platelets after autologous endothelial cell seeding of Dacron aortic bifurcation grafts in humans: a preliminary report.

Autologous endothelial seeding (AES) of vascular prostheses in dogs increases thrombus-free surface and improves prosthetic prostacyclin production, patency, and the ability to withstand hematogenous challenge with bacteria. No such information is available in human subjects. In the present study one limb of an aortic Dacron bifurcation prosthesis was seeded with autologous endothelial cells (ECs) harvested from the distal portion of the saphenous vein by enzymatic treatment. The deposition of indium 111-labeled platelets on the vascular prostheses was studied 1 and 4 months after operation. In seven of nine patients seeding resulted in decreased accumulation of radiolabeled platelets compared with sham-seeded control limbs (p less than 0.04), when studied 1 month after surgery. A decrease in platelet accumulation occurred over the whole prosthesis between 1 and 4 months, and no significant difference was noted at 4 months between seeded and nonseeded graft limbs. Although the seeding density was very low (440 ECs/cm2), the observed difference in platelet accumulation for AES-treated graft limbs in the early postoperative course merits further investigation of this technique in human beings.

Different outcome of allogeneic transplantation in myelofibrosis using conventional or reduced-intensity conditioning regimens

Allogeneic haematopoietic stem cell transplantation remains the only curative treatment of myelofibrosis with myeloid metaplasia (MMM). Previous reports have indicated significant treatment‐related mortality (TRM) for patients transplanted after myeloablative conditioning but superior survival has been reported after reduced‐intensity conditioning (RIC). We report the results of a survey of all allogeneic transplantations for MMM performed in Sweden at six transplant units between 1982 and 2004. Twenty‐seven patients were transplanted; 17 with a myeloablative conditioning regimen and 10 with RIC. The median age was 50 years (5–63 years) at transplantation. After a median follow up of 55 months, 20 patients are alive. TRM was 10% in the RIC group and 30% in the myeloablative group. There was no difference in survival for high or low‐risk patients according to Cervantes score or between sibling and unrelated donor transplantations.

Plasma erythropoietin by high‐detectability immunoradiometric assay in untreated and treated patients with polycythaemia vera and essential thrombocythaemia

Abstract: By using an immunoradiometric method with a stated detection limit of ≤1 IU/l (stated normal reference limit in adults 3.7–16 IU/l) we determined EDTA‐plasma erythropoietin (EPO) in 58 patients with polycythaemia vera (PV) and 49 patients with essential thrombocythaemia (ET). At the time of blood sampling, 20 of the PV patients were newly diagnosed and untreated, 23 were treated by phlebotomy only, and 30 also received myelosuppressive treatment (with 32P, hydroxyurea or alpha‐interferon). Of the ET patients 24 were untreated and 28 received myelosuppressive therapy. For comparison plasma EPO was also determined in 10 patients with pseudopolycythaemia (PP). In this latter group the results for plasma EPO agreed well with the cited normal reference limits. The majority of untreated PV patients (12/20) had undetectable plasma EPO concentration, and the remainder all had values below the lower normal reference limit. Plasma EPO in PV was not significantly influenced by phlebotomy therapy. Twelve of the 24 untreated ET patients (50%) had plasma EPO values below the reference interval (undetectable in 2 patients). The mean EPO concentration was significantly lower in PV patients receiving phlebotomy therapy than in patients with untreated ET. In the total material of PV and ET treated with myelosuppressive agents the PV patients showed significantly lower values for EPO concentration than did patients with ET. The present results support the view that EPO measurements by high‐detectability methods are diagnostically useful and should be included in the panel of new criteria for the diagnosis of PV.