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.

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.

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).

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.

Vasculitis of breast in Behçet's disease--a case report.

This is the case report of a thirty-one-year-old woman who presented with a large skin lesion on a breast that was first thought to be a malignant or inflammatory process. After a biopsy, the lesion was diagnosed as nonspecific vasculitis. No similar case has been found in a review of the literature.

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.

Familial cases of Behcet's disease.

Seven families with Behcet's disease are presented. HLA-B5 tissue type was shown in the three families in whom lymphocyte microcytotoxicity tests were carried out. Genetic factors appear to be important in the pathogenesis of Behcet's disease.

The role of natural anticoagulant deficiencies and factor V Leiden in the development of idiopathic portal vein thrombosis.

One of the causes of portal hypertension is portal vein thrombosis (PVT). The aim of this study was to determine whether natural anticoagulant deficiencies, activated protein C resistance (APCR), and factor V Leiden play a role in the development of PVT, leading to cavernous transformation of the portal vein (CTPV). Twenty-three patients with idiopathic CTPV (group 1) seen at Hacettepe University Hospital during the past 12 years were identified and prospectively studied. These 23 patients underwent a detailed hematological evaluation including measurement of protein S, protein C, antithrombin III, activated protein C resistance (APCR), and factor V Leiden gene mutation. Additionally, all patients were tested for anticardiolipin antibodies (ACA), IgG, IgM, and lupus anticoagulant (LA). Natural anticoagulants and APCR were measured using available commercial kits, and factor V Leiden mutation (R506Q) was detected by Mnl I digestion of an amplified factor V DNA fragment. All parameters were measured at least 6 months after the diagnosis of CTPV was established. No patient was on anticoagulant or antiaggregant treatment while tested. The findings in these 23 patients were compared with those in 20 healthy control subjects (group 2), in whom all tests mentioned above were also performed. In 23 patients (group 1), who had no recognizable factor for portal vein thrombosis, considerably natural anticoagulant deficiencies and factor V Leiden mutation positivity were found when we compare them to those healthy controls (group 2). The protein C levels of six patients (26%), the protein S levels of 10 patients (43.5%), and the antithrombin III levels of five patients (26%) were lower than in control subjects. Two patients were found to have combined protein S and antithrombin III deficiency, and one had combined protein S and C deficiency and APCR. APCR was detected in seven of the 23 patients, and six of these seven patients were found to have R506Q factor V Leiden mutations. In group 1, ACA IgG levels were higher in four patients (17%) and ACA IgM level was higher in one (4%) compared with the control group. LA was positive in only one patient in group 1. Natural anticoagulant deficiencies and factor V Leiden mutation are strongly associated with PVT. The natural anticoagulant deficiencies and APCR (almost totally caused by R506Q mutation) produce a favorable medium for thrombus generation. PVT seems to be related to the natural anticoagulant deficiencies and factor V Leiden R506Q mutation. A combination of these defects increases the incidence of PVT and these factors should be evaluated carefully in patients with idiopathic CTPV.

Thrombopoietin, interleukin-6, and P-selectin at diagnosis and during post-steroid recovery period of patients with autoimmune thrombocytopenic purpura.

Plasma concentrations of the most potent megakaryocytopoietic cytokines, thrombopoietin (TPO) and interleukin-6 (IL-6), and the platelet activation marker P-selectin were evaluated in 24 patients with autoimmune thrombocytopenic purpura (ATP) who responded to conventional steroid treatment, at diagnosis and after steroid-induced recovery. Baseline TPO concentration (median [interquartile range]=0 [17.52] pg/ml) was significantly decreased and IL-6 (38 [19.75] pg/ml) and P-selectin (485 [393.75] ng/ml) were significantly elevated compared with healthy subjects (100 [68] pg/ml, 8 [7] pg/ml and 166 [69] ng/ml, respectively). Following steroid treatment, all values approached normal, i.e., TPO (20 [18.75] pg/ml) was increased and IL-6 (19.5 [13] pg/ml) and P-selectin (248 [172.5] ng/ml) were decreased, significantly. The decrease of TPO in ATP is suggested to occur due to increased megakaryocyte mass and, consequently, TPO clearance. The non-lineage-specific cytokine IL-6 may be elevated to compensate for megakaryocytopoiesis/thrombopoiesis. The elevation of P-selectin may reflect compensatory platelet hyperactivation; however, this molecule also might be a marker of platelet destruction.

Agranulocytosis, plasmacytosis, and thrombocytosis followed by a leukemoid reaction due to acute acetaminophen toxicity.

OBJECTIVE: To describe a patient who developed hepatotoxicity, reactive plasmacytosis with thrombocytosis and life-threatening agranulocytosis, followed by a leukemoid reaction, apparently caused by acute acetaminophen toxicity. SETTING: University-affiliated hospital. CASE SUMMARY: A 19-year old white women who took an overdose of acetaminophen developed hepatotoxicity and reactive plasmacytosis with thrombocytosis and life-threatening agranulocytosis, followed by a leukemoid reaction. Symptoms, signs, and laboratory findings regressed with symptomatic therapy during the follow-up period. CONCLUSIONS: We believe that acute acetaminophen toxicity was responsible for these hematologic abnormalities. This profile of hematologic adverse effects associated with acetaminophen toxicity has not been reported previously.

Impaired haemostatic kinetics and endothelial function in Behçet's disease.

OBJECTIVES: This study was planned to explore the alterations of endothelial functions in the prethrombotic state of Behçet's disease (BD) patients. DESIGN: Plasma levels of endothelial secretory markers, in vivo molecular haemostatic and fibrinolytic parameters were cross-sectionally determined in the study group. SETTING AND SUBJECTS: In our tertiary referral centre, 30 (13 men, 17 women) BD patients, mean age 31 +/- 7 years, and 15 (eight men, seven women) healthy volunteers, mean age 26 +/- 9 years, were eligible for inclusion in the study after obtaining their written consents. INTERVENTIONS: All plasma samples for the assays of haemostatic parameters were obtained before and after an endothelial stimulant, desmopressin acetate (DDAVP). RESULTS: We have shown that in the procoagulant phase of BD patients: (1) basal thrombomodulin concentrations are increased and could not be provoked by DDAVP infusion; (2) both thromboxane B2 and 6-keto prostaglandin F1 alpha increments occur concurrently; (3) in vivo coagulation markers are elevated and raised plasmin-alpha 2 antiplasmin complex indicates a subclinical concomitant fibrinolysis; (4) the fibrinolytic process is conveyed in a somewhat complex manner in which plasminogen activator binding kinetics might be also altered. CONCLUSIONS: Endothelial cell injury, augmented thrombotic risk with compensatory excessive fibrinolysis and alterations in endothelial cell receptor-fibrinolytic marker relations might take place in the pathogenesis and thereby modulate the natural course of haemostatic processes of BD.

Serum L-selectin and P-selectin levels in lymphomas.

The migration of normal and malignant lymphoid cells is governed by specific adhesion molecules. Selectins comprise a family of adhesion receptors expressed by leukocytes, platelets and endothelial cells. In this study, the serum levels of soluble L-selectin and P-selectin were measured in patients with non-Hodgkin's lymphoma and Hodgkin's disease and found to be significantly elevated in both patient groups compared to healthy controls. This result provides evidence that alterations in the expression and function of adhesion molecules may play an important role in the progression of lymphomas. Further studies are awaited to establish the exact roles of these adhesion molecules in distinct patterns of growth and spread of lymphomas.

Selectin adhesion molecules in Behçet's disease.

OBJECTIVES: The pathogenesis of Behçet's disease (BD) is closely related to endothelial cells, leucocyte functions and autoimmunity. The aim of this study was to investigate circulating selectin adhesion molecules, which are known to play a significant part in the immune response especially by regulating interactions of the leucocytes with endothelium, in BD. METHODS: Plasma E-, L-, and P-selectin concentrations were evaluated in 11 patients with widespread BD (group I), 10 cases with merely mucocutaneous involvement (group II) and 15 age and sex matched healthy control subjects. The patients were newly or previously diagnosed cases not taking any drug for BD. RESULTS: Plasma concentrations of all selectins were significantly higher in group I compared with group II. E-selectin and P-selectin were significantly increased in each subgroup of patients compared with the healthy controls. L-selectin concentrations were higher than the controls only in group I. CONCLUSIONS: Increases in the selectins in BD may be a direct consequence of the leucocyte, endothelium and platelet activations observed during the disease process. However, abnormal/increased selectin expression to various triggers should also be considered. More prominent increases in patients with extensive disease suggest that circulating selectin concentrations are related to disease severity.