Effects of imatinib mesylate on renin-angiotensin system (RAS) activity during the clinical course of chronic myeloid leukaemia.

The renin-angiotensin system (RAS) is involved in cell growth, proliferation and differentiation in bone marrow in an autocrine-paracrine manner, and it modulates normal and neoplastic haematopoietic cell proliferation. This study aimed to assess expressions of the RAS components, renin, angiotensinogen and angiotensin-converting enzyme (ACE), during imatinib mesylate treatment of patients with chronic myeloid leukaemia (CML). Expressions of RAS components were studied in patients with CML at the time of diagnosis (n = 83) and at 3, 6 and 12 months after diagnosis (n = 35) by quantitative real-time polymerase chain reaction. De novo CML patients had increased ACE, angiotensinogen and renin mRNA levels and these expression levels decreased following administration of imatinib. The RAS activities were significantly different among Sokal risk groups of CML, highlighting the altered biological activity of RAS in neoplastic disorders. The results of this study confirm that haematopoietic RAS affects neoplastic cell production, which may be altered via administration of tyrosine kinase inhibitors such as imatinib mesylate.

Successful treatment of myelodysplastic syndrome-induced pyoderma gangrenosum.

We report successful treatment of a refractory myelodysplastic syndrome-associated pyoderma gangrenosum with the combination of thalidomide and interferon-alpha2a in a single patient. A non-healing wound developed on a 40-year-old woman's left thumb after minor trauma. Massive ulcerovegetative lesions developed after reconstruction surgery. Histopathological examination of the bone marrow and cytogenetic studies revealed an atypical myeloproliferative/myelodysplastic syndrome. The skin lesions resolved dramatically after two months of thalidomide and interferon-alpha2a combination therapy and the haematological status improved.

Predicting chronic leukaemias from assessment of complete peripheral blood counts.

The chronic leukaemias include two distinct chronic neoplastic disease states, namely chronic myelogenous leukaemia (CML) and chronic lymphocytic leukaemia (CLL). The aim of this study was to assess the utility of leucocyte count, neutrophil percentage and absolute lymphocyte count from differential complete blood count analyses as indicators of the possible presence of CML and CLL. Blood counts from 102 patients with histopathologically confirmed CML and CLL were compared with counts for 858 cancer-free control subjects. Optimal cut-off values were identified by selecting values with the highest sensitivity-specificity combination for each blood count parameter for the two diseases. The results indicated that any individual with mature-appearing lymphocytes at a level > 6.65 x 10(9)/l in the peripheral blood should be examined further for CLL, and that any individual with a leucocyte count > 18.0 x 10(9)/l or a neutrophil proportion > 72.6% should be investigated for CML.

Overt gastrointestinal bleeding in haematologic neoplasms.

BACKGROUND AND AIM: Patients with acute leukaemia suffer from various haemorrhages, most frequently due to thrombocytopenia. We could not reach any information regarding the frequency of gastrointestinal bleeding in acute leukaemia and decided to search this complication in patients with acute and chronic leukaemias and myeloproliferative disorders, retrospectively. PATIENTS AND METHODS: During a 6-year period, 291 patients with acute leukaemia, 52 patients with chronic leukaemia and 108 patients with myeloproliferative disorders had been followed. Thirty-two cases of overt gastrointestinal haemorrhage episodes (25 upper, 7 lower) were observed during the mentioned period. RESULTS: The frequency of bleeding episodes was 7.1% (32/451) in haematologic malignancies as a whole, 5.8% (17/291) for acute leukaemia, 1.9% (1/52) for chronic leukaemia and 13% (14/108) for myeloproliferative disorders. If the patients with myeloproliferative disorders in blastic phase were analysed separately, the ratio was 30% (6/20). Oesophagogastroduodenoscopy, which could be performed in 8 of 25 upper gastrointestinal haemorrhage episodes, revealed erosive gastritis in five patients and duodenal ulcers in three patients. Neutropenic enterocolitis was the underlying cause in all of the seven patients with lower gastrointestinal haemorhage. Five out of the seven patients had acute leukaemia. In 7 bleeding attacks, out of 32, the ultimate result was death. Generally, the haemorrhage was only a contributing cause of mortality. All of the mortality cases were patients with acute leukaemia. CONCLUSION: Especially, the patients with myeloproliferative disorders are prone to develop gastrointestinal haemorrhage. The manifestation is generally as upper gastrointestinal bleeding due to gastric erosions and duodenal ulcers. Lower gastrointestinal bleeding is frequently a problem of the patients with acute leukaemia. It is commonly a sign of neutropenic enterocolitis.

The plasma levels of prostanoids and plasminogen activator inhibitor-1 in primary and secondary thrombocytosis.

An elevated platelet count is a common finding in both hospitalized and ambulatory patients. Thrombosis and bleeding complications are more frequently observed in patients with clonal thrombocytosis than secondary thrombocytosis. The aim of this study was to investigate the behaviors of plasminogen activator inhibitor type 1 (PAI-1), the inhibitor of fibrinolysis; and thromboxane A2 and 6-keto-PGF1 alpha, the products of endoperoxides, in 16 patients affected with clonal thrombocytemia as compared with 16 patients with reactive thrombocytosis and 15 normal controls. In the clonal thrombocytemia group, plasma levels of PAI-1 antigen and activity were significantly higher than both reactive thrombocytosis and control group. Plasma levels of 6-keto-PGF1alpha were significantly higher in the clonal thrombocytemia group than the other two groups and also higher in the reactive thrombocytosis group than the control group, which was also significant. This study confirms that arachidonate metabolism is frequently deranged in patients with thrombocytosis and hypofibrinolysis due to increased PAI-1 plasma levels as shown in the clonal thrombocytosis group. This may explain the thrombotic tendency in myeloproliferative disorders.

Non-Hodgkin's lymphoma complicating pregnancy: a case report.

A 40-year-old, gravida 3, para 2 woman was initially referred to our department at 31 weeks' gestation complaining of fever, night sweats, malaise in association with jaundice and pancytopenia. Cesarean section with excisional iliac lymph node biopsy was carried out following a period of expectant management. An 1,840 g healthy male infant with an Apgar score of 9 at 34 weeks of gestation was delivered. Histologic examination of the excised lymph node revealed non-Hodgkin's lymphoma (Histiocyte and T cell predominant B cell lymphoma). The patient was evaluated to have Stage II B disease. A chemotherapy regimen of CHOP/Rituximab was instituted with successful maternal-fetal prognosis.

Enhanced expression of the local haematopoietic bone marrow renin-angiotensin system in polycythemia rubra vera.

Local bone marrow (BM) renin-angiotensin system (RAS) affects physiological and pathological haematopoiesis, including erythropoiesis. In this study, quantitative expression of the messenger RNAs of the major RAS components--angiotensin-converting enzyme (CD143), renin and angiotensinogen--were measured in BM samples by quantitative real-time polymerase chain reaction, to evaluate the activity of local BM RAS in polycythemia rubra vera (PV) in comparison with normal erythropoiesis. The presence of CD143 was also investigated in the same BM samples by flow cytometry. Increased local synthesis of the major RAS components has been identified by demonstrating corresponding mRNAs in the BM of the patients with PV. Our findings indicate up-regulation of local BM RAS, together with down-regulation of the cell surface angiotensin-converting enzyme receptors, in the autonomous neoplastic clonal erythropoiesis of PV.

Neutropenic enterocolitis in adult leukemias.

Neutropenic enterocolitis is a frequent autopsy finding in adult patients with acute leukemias. The predisposing factors other than neutropenia are not clear. There are also contradictions about treatment. Therefore, this entity still presents a diagnostic and therapeutic dilemma for clinicians. This retrospective study was performed to determine the incidence of neutropenic enterocolitis in adult leukemic patients, to examine the possible risk factors, clinical characteristics and treatment outcome. The pathogenesis is also discussed considering clinical and laboratory findings of the patients. The incidence of neutropenic enterocolitis was 6.5% for acute myeloid leukemia and 4.6% for acute lymphoblastic leukemia. The mean absolute neutrophil count at diagnosis was 48/mm3 (median: 0/mm3). The median duration of severe neutropenia (absolute neutrophil count < or = 500/mm3) on follow-up before the diagnosis was 32 days. Thirteen out of 20 patients had received antineoplastic drugs within the last 12 days, but 2 had not. Fourteen patients had signs of peritoneal irritation and 3 of them underwent surgery. The others received supportive measures, i.e. bowel rest, intravenous fluids, combinations of wide spectrum antibiotics, transfusions, hemodynamic supports and nasogastric decompression, if necessary. All 3 patients who underwent surgery survived, whereas only 1 of the 11 who received other treatments did. Six patients without signs of peritonitis were treated with antibiotics and the mentioned supportive measures. Four survived, but the others died due to sepsis. In conclusion, considering some recent reports that stated good outcome with conservative measures in the presence or absence of peritonitis, there is still debate regarding the optimal choice of treatment. The importance of early diagnosis cannot be overemphasized. Signs of peritoneal irritation indicate a life threatening condition. Surgery can be performed successfully in such patients. Long duration of neutropenia may be an important risk for neutropenic enterocolitis.

The acute effect of smoking on platelet and endothelial release reaction is suppressed in chronic smokers.

Whilst increased plasma beta-thromboglobulin (beta TG), platelet factor 4 and thrombospondin levels are regarded as reflecting the release reaction of platelets, tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) levels represent endothelial release reaction and/or damage. In this study including 12 smokers and 9 nonsmokers, we investigated the acute and chronic effect of smoking on these parameters and antithrombin III, protein S and fibrinogen, as well. Nonsmokers were found to have somewhat higher plasma levels of beta TG, t-PA and PAI-1 than chronic smokers, and 30 minutes after smoking two cigarettes, these levels and protein S levels of nonsmokers showed more prominent increases than of chronic smokers. It is speculated that chronic exposure to cigarette smoke may cause "exhaustion" or "receptor down-regulation" of platelets and endothelial cells, resulting with diminished release reaction of platelets and endothelium in response to acute smoking.

Evidence for the role of dialysis hypoxemia in the pathogenesis of hemodialysis-induced rise in tissue-type plasminogen activator.

It is well known that hemodialysis (HD) causes a rise in plasma tissue-type plasminogen activator (t-PA). Although there have been several suggested mechanisms responsible for this effect of HD, the precise cause has not been well understood yet. Another complication of HD, when performed with acetate-containing dialysate, is hypoxemia, which is commonly observed during the first hour of the session. The purpose of this study was to investigate the relationship between dialysis hypoxemia and HD-induced t-PA changes during the first two hours of HD. HD caused significant increase in plasma t-PA antigen levels. When individual t-PA profiles versus time were examined, two patterns were observed. Whilst ten subjects (%56) experienced minimal or no increase, t-PA antigen level of the remaining eight subjects began to rise at 30 minutes and continued at that level up to 90 minutes, when the last samples were drawn. The courses of pO2 were also different; whilst the former group had "early-onset and short-term" hypoxemia, the latter had "late-onset and prolonged" hypoxemia. The amount of increase in t-PA antigen and the amount of decrease in pO2 were correlated at 60 and 90 minutes of the HD session. Thus, it is concluded that dialysis hypoxemia may contribute to HD-induced rise in plasma t-PA levels. Further studies comparing different dialysates and dialyser membranes are required to confirm this hypothesis.

Is activated factor VII associated with retinal vein occlusion?

AIM: To determine whether a newly identified thrombophilia factor, activated factor VII (FVIIa), is associated with retinal vein occlusion (RVO). METHODS: 54 consecutive cases with RVO seen between March and September 1999 were included in the study. 22 cases had central retinal vein occlusion (CRVO) and 32 had branch retinal vein occlusion (BRVO). Ophthalmoscopic examination with detailed medical history was followed by blood analyses for liver and renal functions, cholesterol, triglycerides, complete blood count, and coagulation factors including protein C activity, free protein S, antithrombin III, fibrinogen, and factor VIIa (FVIIa). Data were compared with those of the control group, composed of 19 cases under ophthalmological follow up for refractive errors, presbyopia, or senile cataract. RESULTS: Hypertension was highly prevalent in cases with BRVO. Complete blood count, and liver and kidney function tests were within normal limits in the study group. Two cases had low protein C activity, and one had low free protein S. FVIIa levels were significantly higher in the RVO group than in the control group (p=0.0004). There was no significant difference in FVIIa levels between the CRVO and BRVO groups (p=0.51). CONCLUSION: No haematological parameter except FVIIa differed significantly from that of the control group. Elevation of FVIIa level may play a part in the pathophysiology of both CRVO and BRVO.

Increased QT dispersion in the absence of QT prolongation in patients with Behcet's disease and ventricular arrhythmias.

In Behcet's disease, prominent clinical manifestations include involvement of mucocutaneous, ocular, gastrointestinal, respiratory, neurologic, urogenital, articular and cardiovascular systems. Patients with Behcet's disease have higher incidence of ventricular arrhythmia than healthy subjects. However there is a little information about the mechanism of ventricular arrhythmias in Behcet's disease. The aim of the study was to investigate whether dispersion of ventricular repolarisation was an arrhythmogenic mechanism. QT dispersion parameters were measured in 73 Behcet patients and QT dispersion was defined as the difference between the maximum and minimum QT interval in any of the 12 leads of surface electrocardiogram. Corrected QT dispersion for heart rate was calculated by Bazett's formula. The results were compared with the data from 51 matched controls without a history of cardiac disease. We found QT dispersion was greater in Behcet patients (58+/-12 vs. 37+/-8 ms, P=0.001) as was corrected QT dispersion (81+/-14 vs. 52+/-11 ms, P=0.001). There was no significant difference in minimum or maximum QT intervals between Behcet patients and controls (P>0.05). We found a correlation between QT dispersion and grade of premature ventricular complexes (r=0.7, P=0.002). Our findings suggest that increased dispersion of repolarisation may account for the development of ventricular arrhythmias in Behcet's disease.

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.

Increased systemic coagulation activity in patients with rheumatic mitral stenosis: assessment of the clinical and echocardiographic determinants.

In this study, we aimed to determine systemic coagulation activity in patients with rheumatic mitral stenosis and to define determinants of a possible prethrombotic state. Peripheral venous plasma level of thrombin-antithrombin III complex was measured in 84 consecutive patients with rheumatic mitral stenosis who had no left atrial thrombus by transesophageal echocardiography. The patients had significantly higher thrombin-antithrombin III complex values (mean +/- SD = 9.6+/-15.9 ng/ ml) compared with the healthy subjects (2.1+/-1.8 ng/ml) (P<0.001). Among many clinical and echocardiographic variables, severe mitral regurgitation (odds ratio = 6.7, P<0.001) and left atrial spontaneous echo contrast (odds ratio = 22.8, P<0.001) appeared as significant predictors of the increased systemic coagulation activity in multivariate logistic regression analysis. In conclusion, systemic coagulation activity is increased in the patients with rheumatic mitral stenosis, and coexistence of severe mitral regurgitation and presence of left atrial spontaneous echo contrast are determinants of this increment.

Efficacy of sulbactam-ampicillin for the treatment of severe diabetic foot infections.

Diabetic foot infections, a frequent and serious cause of morbidity in patients with diabetes mellitus, are caused by anaerobic and aerobic bacteria. Given the fact that seriously impaired host defense factors are almost always present in these patients, bactericidal agents with a broad spectrum of antimicrobial activity are required for their treatment. Seventy-four patients with diabetic foot infections were treated with parenteral sulbactam-ampicillin (1.5 g, q.i.d.). All patients were followed-up prospectively in order to determine the efficacy and safety of sulbactam-ampicillin. The mean duration (+/- SD) of treatment in patients with osteomyelitis (n = 49) and soft tissue infections (n = 25) was 41 +/- 5 and 14 +/- 3 days, respectively. Infected limbs were amputated at various levels in 14 patients (19%). Clinical cure rates were 86% and 100% in patients with osteomyelitis and with soft tissue infection, respectively. The most frequent side effect was diarrhea and observed in 10 patients (14%). The results of the present study indicate that sulbactam-ampicillin is safe and effective in the treatment of diabetic foot infections.

The predictability of factor V Leiden (FV:Q(506)) gene mutation via clotting-based diagnosis of activated protein C resistance.

After the discovery of activated protein C resistance (APCR) due to factor V Leiden mutation and the causal relationship of the phenomenon with clinical thromboembolism, a wide variety of functional clotting-based assays were developed for testing of APCR in relation to the specific DNA-based analysis of FV:Q(506) Leiden. The aim of this study is to assess a clotting-based APCR assay using procoagulant crotalidae snake venom with respect to the sensitivity, specificity, and predictability for the presence of the factor V Leiden mutation. APCR testing and factor V DNA analyses have been performed concurrently on 319 patient specimens. APCR values of the patients with homozygous factor V Leiden mutation (70.4+/-13.5 s) were significantly lower (p<0.001) in comparison to the subjects with the heterozygous mutation (87.6+/-13.4 s). The assay is highly sensitive (98.7%) and specific (91.9%) for the screening of factor V Leiden mutation. The sensitivity and specificity of the APCR testing reached to 100% below the cut-off value of 120 s among the patients with homozygous factor V Leiden mutation. Therefore, this method could help the desired effective optimal screening strategy for the laboratory search of hereditary thrombophilia focusing on the diagnosis of APCR due to FV:Q(506).

Cytokines, endothelium, and adhesive molecules in pathologic thrombopoiesis.

Clonal thrombocytosis (CT) associated with myeloproliferative disorders (MPD) is believed to be secondary to autonomous unregulated platelet production. Secondary or reactive thrombocytosis (RT) can be observed in a number of clinical circumstances and may be related to persistent production of some thrombopoietic factors acting on megakaryocytes (MK). The goal of this study is to assess the serum concentrations of these cytokines in control subjects and patients with MPD associated with thrombocythemia, RT, and autoimmune thrombocytopenic purpura (ATP). Eleven patients with MPD, five with chronic myeloid leukemia (CML), three with polycythemia vera (PCV), two with essential thrombocythemia (ET), one with myelofibrosis, 15 with RT, eight with ATP, and 12 healthy volunteers were enrolled in the study. Serum interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha (TNF), fibronectin, intracellular adhesion molecule-1 (ICAM-1), and thrombomodulin (TM) were measured in these groups. Interleukin- 1beta, IL-6, and TNF levels were high in patients with RT and ATP, suggesting that these cytokines act on early uncommitted progenitors, promoting commitment along the MK lineage and leading to thrombocytosis or compensation for thrombocytopenia. TM was significantly increased in patients with MPD compared to all other groups, probably indicating the presence of subclinical endothelial damage. Fibronectin levels were high in MPD and RT patients. This finding can be secondary to high platelet turnover in these patients. We found that ICAM-1 levels were high in patients with clonal thrombocytosis. ICAM-1 can be one of the factors initiating the events ultimately leading to clonal thrombocytosis. Thrombocythemia associated with MPD is an autonomous phenomenon not regulated by cytokines.

Cardiac and great vessel thrombosis in Behçet's disease.

Behçet's disease (BD) is a chronic relapsing systemic vasculitis in which orogenital ulceration is a prominent feature. The disease affects many systems and causes hypercoagulability. We present a 27-year-old male patient who exhibited widespread great vessel thrombosis including right atrial and ventricular thrombi in the setting of right-sided infectious endocarditis and orogenital aphthous ulcerations and erythema nodosum due to BD. We reviewed the enigmatic prothrombotic state of BD, and discuss our prior experiences in this field.

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 underlying 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.

Protein C inhibitor and serum amyloid A in immune thrombocytopaenic purpura.

In immune thrombocytopaenic purpura (ITP), phagocytic cells prematurely destroy platelets opsonized by anti-platelet auto-antibodies, while residual platelets rescued from these autoimmune attacks are hyperfunctioning. The exact pathobiological basis of this phenomenon is unknown. Protein C inhibitor (PCI), a platelet alpha-granule pro-coagulant molecule, is released on activation of platelets. Serum amyloid A (SAA; an acute phase protein), however, inhibits platelet aggregation and modulates platelet adhesion. We aimed to assess circulating soluble plasma PCI and SAA concentrations in 17 patients with newly diagnosed ITP and ten healthy volunteers. Plasma PCI concentrations tended to be higher in ITP patients, despite absolute thrombocytopaenia, than in normal controls. SAA levels were significantly higher in ITP patients compared with the control group. We conclude that secretion of the alpha-granule PCI content of platelets could result from platelet activation, and that PCI may be the link between platelet microparticles and haemostatically active ITP platelets. Increased concentrations of SAA and PCI may interfere with the disordered and compensatory pro-coagulant mechanisms of ITP.