Nilgun Sayinalp

Effects of interferon-α2a treatment on serum levels of tumor necrosis factor-α, tumor necrosis factor-α2 receptor, interleukin-2, interleukin-2 receptor, and E-selectin in Behçet's disease

Abstract This study was performed to investigate serum levels of various cytokines and E-selectin in patients with Behçets disease (BD) before and after treatment with interferon-α2a (IFN-α). The study population consisted of 22 patients with active BD; 15 age- and sex-matched healthy adults served as the control group. IFN-α (3 million units subcutaneously) was given to all patients twice a week for 3 months. Twenty of twenty-two patients experienced clinical improvement with this therapy. Pre- and post-treatment serum levels of tumor necrosis factor-α (TNF-α), TNF-α2-receptor (TNFα2R), interleukin-2 (IL-2), IL-2 receptor (IL-2R), and E-selectin were measured by sandwich-type enzyme immunoassay. Baseline E-selectin, TNF-α, and TNF-α2R levels of the patients were increased in comparison with the control group and post-treatment values. However, IL-2 and IL-2R levels did not change either with treatment or compared with the control group levels. In conclusion, these results confirm the previously described efficacy of IFN-α in the treatment of BD. Serum levels of TNF-α, TNF-α2R, and E-selectin are prominently increased during active stage of the disease, indicating presence of immune system activation and endothelial injury/activation. Improvement of the pathological cytokinemia and endothelial disturbance accompany interferon-α-induced disease remission.

Over-expression of angiotensin-converting enzyme (CD 143) on leukemic blasts as a clue for the activated local bone marrow RAS in AML

Local bone marrow renin-angiotensin system (RAS) is an autocrine-paracrine system affecting hematopoiesis. Angiotensin II type 1a (AT1a) receptors are present on the CD34+ hematopoietic stem cells. Angiotensin II stimulates the proliferation of bone marrow and umbilical cord blood hematopoietic progenitors. There are preliminary data that local RAS might also be involved in leukemogenesis. ACE hyper-function may lead to the acceleration of negative hematopoietic regulator peptide, AcSDKP, metabolism, which in turn lowers its level in the bone marrow micro-environment, finally removing the anti-proliferative effect of AcSDKP on the hematopoietic cells and blasts. Renin expression could have a role on the leukemia development and angiotensin may act as an autocrine growth factor for acute myeloid leukemia (AML) cells. The aim of this study is to search ACE (CD 143) surface antigen by flow-cytometric analyses on the leukemic blast cells taken from the bone marrow of the patients with AML. Bone marrow aspiration materials and peripheral blood samples were obtained from 11 patients with AML (eight males, three females; aged 46 (range 26–67) years) and six patients with non-malignant hematological disorders (four males, two females; aged 56 (range 22–71) years). ACE (CD 143) surface antigen was shown to be over-expressed in leukemic myeloid blast cells. ACE is positively correlated with bone marrow blast count. Elucidation of the pathological activity of the local RAS-mediated regulation of the leukemogenesis is both pathobiologically and clinically important, since the angiotensin peptides represent a molecular target in the disease management.

Megakaryocyte-Related Interleukins in Reactive Thrombocytosis versus Autonomous Thrombocythemia

The primary thrombocytosis (thrombocythemia) associated with myeloproliferative disorders is believed to be due to autonomous platelet production. Secondary or reactive thrombocytosis can be observed in a number of clinical circumstances, and may be related to persistent overproduction of some thrombocytopoietic factors acting on megakaryocytes. Several cytokines, including IL-6, IL-1 and IL-4 have been shown to act alone or in concert, to affect various cellular stages of megakaryocytopoiesis in humans. The aim of this study is to assess the serum concentrations of these cytokines in myeloproliferative disorders (MPD) with thrombocythemia and in rheumatoid arthritis (RA) with marked reactive thrombocytosis. Twenty-two patients (14 men, 8 women) with MPD and thrombocythemia (platelet counts > 500 x 10(9)/1; range 507-996 x 10(9)/1), 33 RA patients (28 women, 5 men) with marked thrombocytosis (platelet counts > 500 x 10(9)/1; range 500-745 x 10(9)/ 1), 27 RA patients (24 women, 3 men) with normal platelet counts (range 168-399 x 10(9)/1) and 15 healthy volunteers (8 women, 7 men) with normal platelet counts (range 161-385 x 10(9)/1) enrolled in the study. Serum IL-1 alpha, IL-1 beta, IL-4 and IL-6 concentrations were measured in these four groups. Of the 22 patients with MPD, 10 had chronic myelogenous leukemia, 5 had polycythemia vera, 6 had essential thrombocytosis and 1 had osteomyelofibrosis. Serum interleukin concentrations in patients with MPD and thrombocythemia were either suppressed or similar to those of normal subjects, whereas IL-6, IL-1 beta and IL-4 levels were increased in RA patients with reactive thrombocytosis. We conclude that thrombocythemia associated with MPD is an autonomous phenomenon, and is not regulated by cytokines which affect megakaryocytopoiesis.

Rational use of the PFA-100 device for screening of platelet function disorders and von Willebrand disease.

Two hundred and five patients referred for evaluation of platelet functions and 126 healthy controls were tested with the PFA-100 instrument. A cut-off value of 150 s for collagen/epinephrine (CEPI) closure time (CT) produced most acceptable sensitivity (90%), specificity (85.2%), and positive (82.6%) and negative (91.6%) predictivity values for screening of platelet function disorders and von Willebrand disease (vWD). All patients with vWD and Glanzmann thrombasthenia could be detected by PFA-100. Both CEPI and collagen/adenosine diphosphate (CADP) CTs were elevated in all of these cases. Sensitivity of the device was 81.6% for patients with platelet secretion defects. CADP CT was normal in 63.9% of the patients in this subgroup. Specificity (47%) and positive predictivity (57%) of the instrument were diminished in patients with low hemoglobin concentrations. Depending on the results, an algorithm was developed for screening of platelet function disorders and vWD with PFA-100.

Perianal infections in patients with leukemia

PURPOSE: This study was performed to evaluate relations among neutrophil count (including its course), type of lesion, treatment, and prognosis in patients with leukemia and perianal infection. METHODS: Medical records of patients with acute and chronic leukemia who were followed during the last five years were reviewed retrospectively. RESULTS: The incidence of perianal infections was found to be 7.3 percent in 259 patients with acute leukemia. Only 1 of 108 patients with chronic leukemia suffered from this problem. Twenty percent of all patients with this complication died as a result of sepsis. Perianal abscess was the sole and obligatory indication for surgical treatment in our patients. There were ten patients in each treatment group. The operative group had better results (9 cures, 1 complicationvs. 3 cures, 7 complications). However, median neutrophil count at diagnosis was notably higher in the operative group 1,280/mm3vs. 96/mm3;P=0.075). Also, significantly more frequent abscess formations and, consequently, operative treatments were performed in patients with a period of normal neutrophil counts during the infection compared with continuously neutropenic patients (9 operative, 4 nonoperativevs. 1 operative, 6 nonoperative;P=0.057). Ten cures, three complicationsvs. two cures, five complications (3 mortalities) were present in patients with and without normal neutrophil counts, respectively (P=0.062). When only severely neutropenic patients were considered, four patients in the surgery group had normal neutrophil counts before or shortly after surgery. However, only two of eight patients with perianal cellulitis had normal counts during full-course infection (P=0.06). CONCLUSIONS: The course of the neutrophil count during infection was an important factor affecting the perianal lesion, and indirectly, choice of treatment and prognosis. A period of normal counts during infection usually led to well bordered and fluctuant lesions, and the prognosis was acceptable with operative treatment. However, continuously neutropenic patients developed nonfluctuating indurations. We found disappointing results with nonoperative treatment of such patients. In all studies, regarding treatment of perianal infections in neutropenic patients, the course of the neutrophil count and indications for surgery should be clarified to get reliable results.

Local umbilical cord blood renin–angiotensin system

Local bone marrow (BM) renin–angiotensin system (RAS) is an autocrine-paracrine system affecting normal and neoplastic hematopoiesis. Angiotensin II type 1a (AT1a) receptors are present on the CD34+ hematopoietic stem cells (HSC). Angiotensin II stimulates the proliferation and differentiation of the HSC populations through the activation of AT1 receptors on HSC. Umbilical cord blood (UCB) is a rich source of HSC. The existence of a complete local UCB RAS has not been previously investigated. In this study, local synthesis of the major RAS components, namely, angiotensin-converting enzyme (ACE), renin, and angiotensinogen, was identified by demonstrating their corresponding mRNAs using quantitative reverse transcriptase polymerase chain reaction (RT-PCR) in human UCB. Local RAS could regulate cellular growth in a variety of tissues including the BM. Major RAS peptides can exert significant effects on primitive pluripotential HSC populations. Further studies should focus on the interactions between possible autocrine, paracrine, endocrine, and intracrine actions of the local UCB RAS and growth, engraftment, differentiation, and plasticity functions of HSC of UCB origin.

Evaluation of the Haemostatic System during Ketoacidotic Deterioration of Diabetes mellitus

Clinical observations have indicated the frequent development of thrombotic complications during diabetic ketoacidosis (DKA). This study aimed to examine whether haemostatic changes that could lead to a thrombotic tendency occur during ketoacidosis. Plasma levels of in vivo haemostatic markers reflecting activation degrees of the coagulation system, fibrinolytic system, platelets and endothelium were assayed in 34 patients with DKA, both at diagnosis and 1 week after recovery. We found coagulation system and platelet activation and endothelial injury/activation in the patients at diagnosis of DKA. Although significant improvements were observed after recovery, only platelet activity was completely normalized. Fibrinolytic activity was also increased, both at diagnosis and after recovery, compared to the control group. However, although coagulation activity was prominently increased at diagnosis compared to the recovery period, there was no change in fibrinolytic activity in the same periods; on the contrary, the fibrinolytic capacity of the endothelium was diminished at diagnosis of DKA compared to the recovery period, suggesting the presence of relative hypofibrinolysis during DKA. Indications for a role of hyperglycaemia in the emergence of haemostatic disturbances during DKA were observed.

Unchanged global fibrinolytic capacity despite increased factor VIIa activity in Behçet's disease: evidence of a prethrombotic state

Abstract.The aim of this study was to evaluate coagulation and fibrinolytic systems in Behçets disease (BD). Accordingly, various parameters of the coagulation and fibrinolytic systems were investigated in 39 patients with BD and 31 age- and sex-matched healthy volunteers as the control group. Seven of these patients with BD had histories of thrombotic complication. Three were found to have decreased protein S activity, and one patient had diminished protein C activity. Each of those patients had experienced a thromboembolic event. Activated protein C resistance was present in two patients, one of whom had had a thromboembolic episode. Activated FVII (FVIIa), fibrinogen, and cholesterol levels were significantly higher in patients with BD than in the control group. In the patient group, plasma FVIIa level was inversely correlated with age. Plasma global fibrinolytic capacity (GFC) did not differ between the patients and control group. No statistically significant difference was found in the GFC and FVIIa levels between patients with and without histories of thrombosis. Although the coagulation system was activated in vivo in patients with BD, there was no reactive activation in the fibrinolytic system to counteract the activated coagulation system. These findings suggest a relative hypofibrinolytic state in BD.

EUTOS CML prognostic scoring system predicts ELN-based ‘event-free survival’ better than Euro/Hasford and Sokal systems in CML patients receiving front-line imatinib mesylate

Abstract Objectives The validity of the three currently used chronic myeloid leukemia (CML) scoring systems (Sokal CML prognostic scoring system, Euro/Hasford CML scoring system, and the EUTOS CML prognostic scoring system) were compared in the CML patients receiving frontline imatinib mesylate. Patients and methods One hundred and fourty-three chronic phase CML patients (71 males, 72 females) taking imatinib as frontline treatment were included in the study. The median age was 44 (16–82) years. Median total and on-imatinib follow-up durations were 29 (3.8–130) months and 25 (3–125) months, respectively. Results The complete hematological response (CHR) rate at 3 months was 95%. The best cumulative complete cytogenetic response (CCyR) rate at 24 months was 79.6%. Euro/Hasford scoring system was well-correlated with both Sokal and EUTOS scores (r = 0.6, P < 0.001 and r = 0.455, P < 0.001). However, there was only a weak correlation between Sokal and EUTOS scores (r = 0.2, P = 0.03). The 5-year median estimated event-free survival for low and high EUTOS risk patients were 62.6 (25.7–99.5) and 15.3 (7.4–23.2) months, respectively (P < 0.001). This performance was better than Sokal (P = 0.3) and Euro/Hasford (P = 0.04) scoring systems. Overall survival and CCyR rates were also better predicted by the EUTOS score. Discussion EUTOS CML prognostic scoring system, which is the only prognostic system developed during the imatinib era, predicts European LeukemiaNet (ELN)-based event-free survival better than Euro/Hasford and Sokal systems in CML patients receiving frontline imatinib mesylate. This observation might have important clinical implications.

Paget-Schroetter Syndrome Associated with FV:Q506 and Prothrombin 20210A A Case Report

Effort thrombosis of the axillary-subclavian vein (Paget-Schroetter syndrome) develops usually secondary to heavy arm exertion. An underlying chronic venous compressive anomaly at the thoracic outlet or intimal damage of the axillary vein following forceful hyperabduction, external rotation of the shoulder joint has been proposed to explain the pathophysiology of this thrombosis. This condition is usually not attributed to an under lying hypercoagulability such as deficiency of natural coagulation inhibitors. Here, the authors present a case with thrombosis of the axillary-subclavian vein following an effort, with factor V Leiden and prothrombin 20210A mutations. Both factor V Leiden and the genetic variant in the prothrombin gene have been shown to confer an increased risk for venous thrombosis. Although rare, effort thrombosis may develop in a patient with hereditary thrombophilia, so laboratory evaluation should include the common causes of thrombosis.