Assessment of the HScore for reactive haemophagocytic syndrome in patients with rheumatic diseases.

OBJECTIVES: Reactive haemophagocytic syndrome (RHS) is a hyperinflammatory disorder often occurring in the background of several disorders such as infections, malignancies, and rheumatic diseases. Recently, a score known as the HScore was developed for the diagnosis of RHS. In the original study, most of the patients had underlying haematological malignancy or infection and the best cut-off value for the HScore was 169 (sensitivity 93%; specificity 86%). In this study we aimed to analyse the performance of the HScore in rheumatic disease-related RHS. METHOD: The patients with rheumatic disorders evaluated in the Departments of Rheumatology and Paediatric Rheumatology at Hacettepe University, Ankara, Turkey between 2002 and 2014 were reviewed retrospectively. The first group (n = 30) consisted of patients with RHS; the control group (n = 64) included patients with active rheumatic diseases without RHS. RESULTS: In the RHS group, 14 (46.7%) had adult-onset Still's disease (AOSD), 10 (33.3%) systemic juvenile idiopathic arthritis (SJIA), and six (20%) systemic lupus erythematosus (SLE). The control group (n = 64) consisted of 32 (50%) AOSD, 13 (20.3%) SJIA, and 19 (29.7%) SLE patients. Applying the HScore to the RHS patients, the best cut-off value was 190.5 with a sensitivity of 96.7% and specificity of 98.4%. When we excluded the patients from the control group who had not had bone marrow aspiration (n = 23), the same cut-off (190.5) performed best (sensitivity 96.7%; specificity 97.6%). Applying the 2004 haemophagocytic lymphohistiocytosis (HLH-2004) criteria gave a sensitivity of 56.6% and a specificity of 100% in the whole study group. CONCLUSIONS: In our study, a cut-off value for the HScore different from the original study performed better. Further studies are warranted to determine optimum cut-off values in different studies.

Aspirin resistance in systemic lupus erythematosus. A pilot study.

Systemic lupus erythematosus (SLE) patients are at increased risk of thrombosis and cardiovascular diseases. Aspirin is an effective treatment option for these patients. The aim of this study was to investigate the presence of aspirin resistance in SLE patients. We studied aspirin resistance in 33 SLE patients and nine healthy controls by using a Multiplate® impedance aggregometer (Dynabyte GmbH, Munich, Germany). Twenty-six SLE patients were on regular aspirin treatment. Aspirin resistance was found in five (19.2%) out of 26 patients who were on aspirin treatment. When the tests were repeated by adding acetylsalicylic acid in the medium, all of these patients became responsive to the aspirin. SLE disease activity, body mass index, smoking status, and the presence of anticardiolipin antibodies or positive lupus anticoagulant test results were no different in patients with or without aspirin resistance. (p>0.05 for all). Our results suggest that there may be a considerable number of SLE patients with aspirin resistance.

Pre-operative flexion contracture determines the functional outcome of haemophilic arthropathy treated with total knee arthroplasty.

End-stage haemophiliac arthropathy can be successfully treated with total knee arthroplasty. However, the functional results may not be as good as anticipated and certain pre-op knee characteristics may alter the functional results. The purpose of this study was to evaluate the functional outcome of TKA in haemophilic patients with specific attention to final range of motion and residual flexion contracture of the joint. Twenty-one consecutive patients were retrospectively reviewed. The average age was 34 years with an average follow-up of 5.7 years. Functional status was evaluated with Hospital for Special Surgery Knee Score. Receiving Operating Characteristics analysis was used to determine the threshold of pre-operative flexion contracture degree to avoid residual knee contracture. The range of motion was increased in 16 joints and unchanged in three joints and decreased in the remaining two. Preoperative average range of motion was 37.6°, improved to 57.1° post-operatively. The average knee score increased from 27.85 (15-30) points pre-operatively to 79.42 (12-94) points at the last follow-up. The degree of pre-operative flexion contracture was found to be a good predictor for residual flexion contracture. (Specificity: 85.7%, sensitivity: 100%, cut-off: 27.5°). Total knee replacement improves the quality of life in patients with advanced haemophilic arthropathy. Statistical analysis revealed that pre-op flexion contracture of 27.5° is an important threshold. Patients should be operated before that stage to gain maximum benefit with minimal gait abnormalities.

Hyperprolactinemia of pregnancy is not associated with increased in vivo platelet activity and shortened in vitro bleeding times.

The aim of the study is to investigate whether platelet activity is increased by hyperprolactinemia during pregnancy as reflected by beta-thromboglobulin level. Forty-eight healthy, pregnant, and 30 healthy, non-pregnant women were investigated with respect to platelet count, collagen/ADP and collagen/epinephrine closure times, beta-thromboglobulin and prolactin levels. The comparison of the variables between the two groups was made by Mann-Whitney U test. The correlation analyses were performed by Spearman's rank correlation test. Our results revealed that platelet counts, collagen/ADP and collagen/epinephrine closure times and beta-thromboglobulin showed no statistically significant differences between pregnant and non-pregnant women. We found no significant correlation between prolactin and collagen/ADP closure time (r = 0.175), between prolactin and collagen/epinephrine closure time (r = -0.112) and between prolactin and beta-thromboglobulin (r = 0.220) in pregnant women. Our findings suggest that platelet activity is comparable during pregnant and non-pregnant states and there is no significant effect of prolactin on platelet function in vivo as reflected by beta-thromboglobulin level.

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.

High cystine in platelets from patients with nephropathic cystinosis: a chemical, ultrastructural, and functional evaluation.

AIM: To investigate the morphology and function of platelets in nephropathic cystinosis (NC). METHODS: Seven patients (mean age, 6.5 years; SD, 20 months) with NC were investigated. Their platelets were examined by transmission electron microscopy (TEM) and the characteristics of the dense granules (DGs) were determined by mepacrine labelling and the uranaffin reaction. Bleeding time, turbidometric aggregation, and luminescence aggregation were studied and intraplatelet cystine was measured. RESULTS: Increased intraplatelet cystine, primary and secondary aggregation defects, and the absence of ATP release were demonstrated. TEM revealed DGs of various shapes and sizes and lamellary or amorphous cytoplasmic inclusions. Viscous material had been released into the vacuolar spaces and enlarged open canalicular system. Mepacrine labelling revealed that the numbers of DGs/platelet were comparable between the patients and the controls (mean, 2.9 (SD, 0.22) v 3.32 (0.18); p = 0.34). The uranaffin reaction revealed that the numbers of type 1, 3, and 4 DGs were comparable between the patients and the controls, but that there were fewer type 2 DGs in the patients (mean, 8.5 (SD, 1.95) v 17.22 (1.58); p = 0.01). TEM for platelet aggregation revealed a lack of induction and/or defective execution and/or delayed transmission. The patients' intraplatelet cystine concentrations were higher than the controls (mean, 1.56 (SD, 0.84) v 0.08 (0.01) nmol/mg protein; p = 0.009). CONCLUSIONS: This is the first report to demonstrate raised intraplatelet cystine, abnormal platelet ultrastructural findings, and defective aggregation in NC.

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.

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.

Activation of blood coagulation in patients with mitral stenosis and sinus rhythm.

The aim of this study was to assess whether there is blood coagulation activation in patients with mitral stenosis (MS) and sinus rhythm (SR) and to investigate the value of left atrial spontaneous echo contrast (LASEC) as a predictive sign of increased coagulation activity. Using thrombin-antithrombin III complexes and prothrombin fragment 1+2 as in vivo hemostatic markers, we concluded that there is a hypercoagulable state in patients with MS and SR when LASEC is present.

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.

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.

Internal carotid artery occlusion in a patient with malignant peritoneal mesothelioma: is it a sign of malignancy-related thrombosis?

To our knowledge, the occlusion of arteries and platelet hyperaggregation have not been reported in patients with malignant mesothelioma. However, venous thromboembolism, especially in the pulmonary vasculature in association with thrombocytosis and hyperfibrinogenemia, are commonly noticed in this disorder. Furthermore, we detected enhanced platelet aggregation in a case of malignant peritoneal mesothelioma with internal carotid artery occlusion in whom there were postsplenectomy thrombocytosis and hyperfibrinogenemia. The possible mechanisms of ICA occlusion in this patient, including the role of MPM and postsplenectomy state, thrombocytosis, platelet functional changes, and other factors were investigated and discussed.

Influence of thrombolytic therapy on the incidence of left ventricular thrombi after acute anterior myocardial infarction: role of successful reperfusion.

BACKGROUND: Previous studies have reported controversial results regarding the effectiveness of systemic thrombolysis in preventing left ventricular (LV) thrombus after acute myocardial infarction (MI). HYPOTHESIS: This study was performed to evaluate the influences of thrombolysis, and particularly successful reperfusion, on the incidence of LV thrombus formation after acute anterior MI. METHODS: In all, 191 patients suffering from a first attack of acute anterior MI were prospectively evaluated by two-dimensional echocardiography and coronary angiography, performed at the end of the first week and within the first two weeks of MI, respectively. Of these, 98 who presented within 12 h of onset of symptoms received intravenous streptokinase (1.5 million IU), while the remaining 93 patients who, either because of contraindications or late admission, did not receive thrombolytic treatment served as control group. All patients received aspirin and full-dose anticoagulation with intravenous heparin. Successful reperfusion in the streptokinase group was assessed by enzymatic and electrocardiographic evidence. RESULTS: The overall incidence of LV thrombi was 24.6% (47/191). When all patients were evaluated, no statistically significant difference was found between the frequency of LV thrombi in the patients who had thrombolysis (22.4%) and those who did not (26.8%), despite a trend toward the formation of fewer thrombi in the initial group (p > 0.05). However, the patients who had successful reperfusion with streptokinase (n = 64) had significantly reduced incidence of LV thrombi compared with those who did not receive thrombolytic therapy (20 vs. 26.8%, p < 0.05). Stepwise multivariate analysis suggested that LV abnormal wall motion score (p = 0.01) and presence of LV aneurysm were independent predictors of LV thrombus formation in patients with acute anterior MI. CONCLUSION: Not all patients who received streptokinase for acute anterior MI, but only those with successful reperfusion had reduced incidence of LV thrombi. The favorable effects of thrombolysis on LV thrombus formation are probably due to the preservation of global LV systolic function.

Pregnancy complicated by Evan's syndrome.

Evan's syndrome was initially diagnosed in a 26-year-old pregnant patient. Following the introduction of high dose steroid therapy, the patient developed possible disseminated gonococcal infection which was followed by preterm labor and abruptio placentae. A cesarean delivery was performed at the 34th week of pregnancy following platelet infusion. While the infant survived, the mother had delayed postpartum hemorrhage.

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.

A unifying hypothesis for the renin-angiotensin system and hematopoiesis: sticking the pieces together with the JAK-STAT pathway.

JAK-STAT pathway is a recently encountered intracellular signal transduction system. The pathway is utilized by numerous cytokines, growth factors, and hormones for gene expression and a variety of biological activities. Hematopoiesis is regulated by many cytokines and growth factors that support the proliferation and differentiation of progenitor cells in the bone marrow. JAK-STAT pathway arises as the most common signalling cascade of a wide range of cytokines and/or growth factors in propagation of physiological and pathological/neoplastic hematopoiesis. On the other side, renin-angiotensin system (RAS) includes not only the classic circulating endocrine system controlling blood pressure and electrolyte homeostasis, but also tissue-specific RASs with autocrine and/or paracrine functions. Preliminary data suggest the involvement of the RAS components in normal and pathologic hematopoiesis, although the precise mechanism of action has not been elucidated yet. We have hypothesized, in this report, that JAK-STAT pathway serves as a point of crosstalk between the components of the locally present RAS in the bone marrow and hematopoiesis. Demonstration of a local RAS in the bone marrow with clarification of the postreceptor signalling events may play a consequential role not only for further clarification of normal hematopoiesis but also novel therapeutic approaches in pathologic/neoplastic conditions.

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.