Comparison of relapse rates in Behçet's disease with venous involvement on different doses of azathioprine therapy, a retrospective observational study.

AIM: The aim of this study was to investigate relapse rates in azathioprine (AZA) maintenance therapy at different doses in Behçet's disease (BD) with venous involvement. METHOD: Clinical records of patients who met the diagnostic criteria of International Study Group (ISG) for BD, were diagnosed with venous involvement of BD for at least 6 months and sustained clinical remission with AZA for at least 3 months were analyzed retrospectively. The analysis cohort was divided into 2 groups based on AZA dose (Group A: ≥ 2 mg/kg/d and Group B: <2 mg/kg/d). Relapse was defined as requiring another antirheumatic/immunosuppressive drug or more than dose of 10 mg/d of prednisolone. RESULTS: Of 78 patients who were included into the study, there was no significant difference between the 2 groups in terms of age, gender and clinical characteristics. Mean relapse-free survival time was found to be higher in group A compared to group B (111.6 ± 11.2, 95% CI 89.5 ± 133.8 versus 51.5 ± 6.1, 95% CI 39.5 ± 63.4 months). CONCLUSION: Relapse-free survival rate was less in the group receiving low-dose AZA and shows the importance of effective dose of AZA in maintenance therapy.

INDEXES OF CYTOKINE PROFILE OF BLOOD IN PATIENTS WITH COMPLICATED ERYSIPELAS.

The cytokine blood profile in patients with complicated erysipelas was investigated. It was found that in patients with complications of erysipelas (gangrene, phlegmon, abscess, thrombophlebitis of the subcutaneous veins of the shin) levels of pro-inflammatory cytokines IL-1ß, TNF-α, IL-2, IL-6 in serum significantly increase and level of anti-inflammatory cytokine IL-4 increases slightly, as well as was found a significant increase in coefficients reflecting the ratio of pro-inflammatory and anti-inflammatory cytokines, which indicates the prevalence in the blood of examined patients with complications of erysipelas an anti-inflammatory properties. A more significant increase in pro-inflammatory cytokines serum levels is typical for patients with destructive forms of erysipelas - phlegmonous and gangrenous, a slight increase - for patients without purulent-necrotic component of complication (thrombophlebitis of the subcutaneous veins of the shin). In the future we plan to study pharmacological correction of shifts in cytokine blood profile with drugs with immunomodulating properties in patients with complicated erysipelas.

Trichosporon asahii septic thrombophlebitis following lower extremity amputation in an immunocompetent host.

A 59-year-old man with a history of peripheral vascular disease status post femoral popliteal bypass presented with critical limb ischaemia of the left leg. An arterial Doppler ultrasound showed an occluded graft requiring an above knee amputation. Five days after surgery, the patient developed fever, leucocytosis, significant stump swelling and pain, and serosanguinous discharge from his wound. Wound swab cultures from the stump grew Trichosporon asahii A venous Doppler ultrasound revealed extensive thrombosis of the left lower extremity. Biopsy of the left thigh muscle showed necrotic thrombus with fungal hyphae in the clotted blood vessel. The left femoral vein was subsequently resected, and the excised venous tissue also grew T. asahii The patient was successfully treated with voriconazole based on antifungal susceptibilities. This case describes an invasive fungal infection in the absence of typical immunosuppressive conditions commonly associated with Trichosporon spp. It also illustrates the role of a combination of antimicrobial and surgical management in achieving cure.

Superficial thrombophlebitis: A new clinical manifestation of the immune reconstitution inflammatory syndrome in a patient with HIV infection.

Skin manifestations of immune reconstitution inflammatory syndrome in response to highly active antiretroviral therapy may account for up to 50% of the clinical presentations in this syndrome. Viable or dying infective antigens, host antigens, tumoral antigens, and others may target immune reconstitution inflammatory syndrome, resulting in a wide spectrum of clinical manifestations. We describe a 26-year-old HIV-infected man who had started highly active antiretroviral therapy a few months earlier. He developed multiple linear nodules following the superficial veins in both legs. Histopathologic examination demonstrated a mostly septal panniculitis with features of superficial thrombophlebitis. We propose that superficial thrombophlebitis should be added to the list of clinical manifestations of this newly observed immune restoration disease.

Effects of acute global venous obstruction and unfractionated heparin on muscle cytokine synthesis.

Phlegmasia cerulea dolens is a devastating complication of massive deep venous thrombosis, which is clinically characterized by massive lower extremity tissue edema and subsequent arterial insufficiency. These experiments evaluated the local tissue effects of acute global venous obstruction combined with partial arterial ischemia. Experiments were performed to assess the effects of heparin on the cytokine response to simultaneous venous and partial arterial obstruction. Murine hind limbs were subjected to conditions of unilateral venous occlusion and partial tourniquet limb ischemia, which was confirmed by laser Doppler imaging (LDI). Mice underwent either hind limb venous obstruction with intravenous unfractionated heparin (200IU/kg) or intravenous saline 5min before venous occlusion. Sham-treated mice were subjected to anesthesia alone without venous occlusion. After 3hr, the mice were killed and tissue was harvested for measurement of edema (wet to dry weight ratio, W/D), muscle viability, indices of local thrombosis (thrombin-antithrombin complex [TAT]), and cytokine analysis for growth-related oncogene-1 (GRO-1) and interleukin-6 (IL-6, protein via enzyme-linked immunoassay and mRNA via reverse transcriptase polymerase chain reaction). Bleeding time and volume were documented in saline- and heparin-treated mice to confirm systemic anticoagulation. Administration of intravenous heparin resulted in a marked increase in bleeding time and volume. LDI confirmed venous obstruction and ongoing arterial inflow. Venous obstruction resulted in severe visible edema that correlated with a significantly higher W/D ratio but was not associated with a significant decrease in muscle viability. GRO-1 and IL-6 protein and mRNA levels were significantly elevated in the venous occlusion group compared to sham. Heparin therapy significantly decreased TAT3 levels but did not alter the profile of GRO-1 or IL-6 protein levels seen with venous occlusion. Venous occlusion with partial ischemia induces a unique and potent local cytokine expression. Heparin therapy did not ameliorate the cytokine response. These data indicate that heparin therapy does not modulate the cytokine response to venous obstruction.

An antifibrinolytic effect associated with an anti-factor V antibody in a patient with severe thrombophilia.

BACKGROUND AND OBJECTIVES: The case of a patient with thrombotic manifestations and severe activated protein C resistance due to an anti-factor V antibody has recently been described. Since activated protein C (APC) is also profibrinolytic we wanted to determine whether the presence of antibodies interfering with the anticoagulant activity of APC also inhibits its profibrinolytic effect. DESIGN AND METHODS: Plasma clots were formed in the presence of tissue plasminogen activator, thrombin, phospholipids, Ca++, and various concentrations of APC, and the rate of lysis was monitored over time by the reduction in turbidity. Generation of endogenous thrombin and activation of thrombin activatable fibrinolysis inhibitor (TAFI) were also determined during fibrinolysis by clotting and spectrophotometric assays, respectively. RESULTS: Addition of APC to the patient's plasma failed to stimulate fibrinolysis even at a concentration 4 times higher than that needed to produce the maximal effect in control plasma. Removal of IgG from the patient's plasma fully restored the fibrinolytic response to APC. Accordingly, addition of the patient's IgG to control plasma caused a concentration-dependent inhibition of APC-dependent fibrinolysis. The patient's IgG did not, however, inhibit the profibrinolytic effect of heparin. Determination of thrombin and activated TAFI generation during clot lysis showed that APC inhibited the generation of these enzymes by less than 20% in plasma supplemented with the patient's IgG as opposed to >80% in a control sample. INTERPRETATION AND CONCLUSIONS: Our data suggest that the anti-factor V antibody inhibits fibrinolysis by antagonizing the anticoagulant effect of APC thereby favoring thrombin generation and TAFI activation. Impaired fibrinolysis may represent an additional mechanism contributing to thrombosis in patients with severe APC resistance phenotype.

Association of class I HLA antigens with the clinical manifestations of Turkish patients with Behçet's disease.

Genetic factors appear to be important in the pathogenesis of Behçet's disease. Although it is known to be strongly associated with HLA-B 51, the association of HLA class I antigens with specific clinical findings of the disease has not been studied extensively and the few studies are conflicting. The aim of this study was to investigate the association of HLA class I alleles with the manifestations of Behçet's disease in Turkish patients. Eighty-five patients with Behçet's disease were typed for HLA-A, B, and C antigens with the serologic, standard microlymphocytotoxicity technique. Possible associations of the HLA complex with clinical findings of Behçet's disease were examined. Statistically significant findings are as follows (P < 0.05): increased HLA-B 51 and decreased HLA-B35 frequency in patients with thrombophlebitis, increased HLA-A29 and decreased HLA-Bw6 frequency in patients with ocular involvement, decreased HLA-Cw2 frequency in patients with erythema nodosum, and decreased HLA-Cw 7 frequency in patients with genital ulceration. Of particular note, the results of this study suggest that the presence of HLA-B 51 and the absence of HLA-B35 can be regarded as laboratory risk factors of venous thrombosis in patients with Behçet's disease.

Superficial thrombophlebitis and anticardiolipin antibodies--report of association.

The aim of this study was to determine a possible association between recidivist superficial thrombophlebitis and anticardiolipin antibodies. Forty-five patients with two or more episodes of superficial thrombophlebitis in lower limbs (33 women and 12 men with ages ranging from 17 to 60 years, average: 39.8) were studied. The control group was formed by 100 voluntary donors from the blood bank (83 men and 17 women, age range: 21 to 59 years, average: 35.4). Anticardiolipin antibody concentrations were determined by enzyme-linked immunosorbent assay (ELISA). For semiquantitative detection in human sera with use of QUANTA Lite ACA IgG/IgM--INOVA Diagnostic, Inc., and positive values were considered as 15 GPL units/mL and 12.5 MPL units/mL for immunoglobulin G (IgG) and IgM, respectively, as recommended by the test. The Odds Ratio method was chosen for statistical analysis with a confidence interval (CI) of 95%. In 15 patients (33.3%) anticardiolipin antibody positivity was detected, whereas in 12 patients (26.7%) it occurred as immunoglobulin M (IgM) anticardiolipin and in 3 (6.7%) as immunoglobulin G anticardiolipin. In the control group, positivity was found in 7 patients (7%) for those antibodies. Furthermore, the Odds Ratio = 6.64 with CI = 95% and values ranging from 2.48 to 17.82 (p < 0.05) were significant, as well as for IgM/IgG anticardiolipin proportion with Odds Ratio = 5.09, C = 95% and values varying from 1.33 to 19.54 (p < 0.05). The authors conclude that there is a correlation between the presence of anticardiolipin antibodies and recurrent superficial thrombophlebitis.

Chlamydia pneumoniae IgG seropositivity and risk of deep-vein thrombosis.

In a population-based case-control study of 474 patients with a first episode of deep-vein thrombosis and 474 age-matched and sex-matched controls, we found no effect of Chlamydia pneumoniae infection on the occurrence of deep-vein thrombosis.

[Atypical heparin-induced thrombocytopenia (HIT)--"heparin allergy" with thrombocytosis]. / Atypische heparininduzierte Thrombocytopenie (HIT)--"Heparinallergie" mit Thrombocytose.

We report a truck driver with severe soft tissue contusion of both legs who developed atypical heparin-induced thrombocytopenia (HIT) after a thrombosis prophylaxis with unfractionated heparin; despite a thrombosis the patient showed a systemic allergic reaction to heparin in combination with elevation of thrombocytes and positive heparin-dependent antibodies. Six days after the initial trauma deep vein thrombosis of the left lower leg was diagnosed and fasciotomy was performed, preventing an imminent compartment syndrome. Another 5 days later the patient developed exanthema of the trunk and upper extremities and urticaria on his face, as well as severe headache. His platelet count increased from 134,000/microliter to 258,000/microliter. After exclusion of other causes for these symptoms, a reaction to heparin-dependent antibodies (heparin-platelet-factor 4 complex) was demonstrated 2 days later. Thrombosis prophylaxis was changed to hirudin (Refludan) and elevation of thrombocytes to 445,000/microliter was noted. Shortly after rinsing of an intravenous line with less than 50 IE unfractionated heparin at day 36 after trauma the patient developed an anaphylactic shock, which could be managed with cortisone. We suggest that in HIT the thrombocytopenia may represent only one form of an allergic reaction to heparin. The cause of the thromboembolic event is an antigen-antibody reaction to heparin taking place on the surface of the thrombocyte. This is similar in all forms of systemic reaction to heparin application, even though the symptoms may vary. As thrombocytopenia may not be the main symptom of a heparin-induced antibody reaction--in our hospital only 5 of 10 patients with HIT--the disease should rather be named "heparin allergy". We suggest a new classification of different pattern of heparin allergy types I-IV. The new types I and II are similar to HIT types I and II. Type III is the reaction of antibodies without decrease of thrombocytes, and type IV the reaction of antibodies associated with systemic allergic symptoms.

Serum cardiolipin antibodies in cancer patients with thromboembolic events.

This study was undertaken to investigate a possible association of anticardiolipin antibodies (ACLAs) in cancer patients with thromboembolic events. Twenty-five patients with solid tumors complicated with acute thrombosis, 36 cancer patients without any thrombotic events, and a group of 20 healthy volunteers without thrombosis or malignancy were included. The mean age of the cancer patients with and without thrombosis and healthy subjects were 50 years (range 20-75), 45 years (range 23-66), and 40 years (range 20-68), respectively. Deep venous thrombosis (n = 16) and thrombosis of the central venous port-catheter systems (n = 9) were confirmed by Doppler sonography in all patients. IgG and IgM isotypes of ACLAs were quantitated by enzyme-linked immunosorbent assay with normal levels of < 23 GPL and < 11 MPL, respectively. Mean values of IgG ACLAs were found similar in cancer patients with acute thrombosis (13.8 +/- 4.9 GPL), without thrombosis (12.8 +/- 5.4 GPL) or in healthy subjects (14.8 +/- 5.5 GPL). Although the mean values of IgM ACLAs were within normal limits in all groups, cancer patients with thrombotic events had higher levels of IgM ACLAs (mean = 10.5 +/- 2.2 MPL) than cancer patients without thrombosis (mean = 4.6 +/- 2.4 MPL) (p = .01). Healthy subjects also had lower levels of IgM ACLAs (mean = 7.1 +/- 3.2 MPL) than cancer patients with thrombosis (p = .16). In addition, a higher percentage of cancer patients with or without thrombosis had IgM and IgG ACLA levels above normal limits compared with healthy controls. In conclusion, our study suggests an association between ACLAs or IgG and particularly IgM isotypes and venous thrombosis in malignancy. Identification of cancer patients who are at higher risk for developing thromboembolic events might lead to a better selection of patients for prophylactic anticoagulant therapy.

Ulcer bed infection. Report of a case of enlarging venous leg ulcer colonized by Pseudomonas aeruginosa.

We report a case of ulcer bed infection in an enlarging venous leg ulcer without clinical signs of cellulitis in the surrounding tissues. Signs of infection in the leg ulcer were: 1) cocci-like structures and bacteria-like rods around vessel walls in the viable ulcer bed, 2) vasculitis-like inflammation of deeply situated vessels of the viable tissue, 3) Pseudomonas aeruginosa-specific antibodies in the serum (other than against exotoxin A), 4) extensive epidermolysis of normal human skin by the wound exudate in vitro, and 5) P. aeruginosa exotoxin A in the wound exudate (23 ng/ml). In an in vitro cell assay, the wound exudate was cytotoxic and rabbit antibodies to exotoxin A, but not a serine proteinase inhibitor, inhibited this cytotoxicity. P. aeruginosa exotoxin A might contribute to the pathogenesis of the ulcer enlargement. The ulcer improved after the third skin graft, probably mainly due to effective treatment with a long-stretch compression bandage.

IL-10 regulates thrombus-induced vein wall inflammation and thrombosis.

Vein wall inflammation associated with venous thrombosis is mediated by an imbalance in proinflammatory as compared with antiinflammatory molecules. We hypothesize that IL-10 is an important antiinflammatory cytokine that influences vein wall inflammation and thrombus propagation during venous thrombosis. To test this hypothesis a model of inferior vena caval thrombosis was used. Studies were performed at sacrifice 2 days after thrombus induction and included leukocyte morphometrics, myeloperoxidase activity, vein wall permeability, thrombus weight, and IL-10 ELISA analysis from the vein wall. IL-10 was elevated in the vein wall during venous thrombosis. Neutralization of IL-10 increased inflammation, while supplementation with rIL-10 demonstrated a dose- and time-dependent decrease in inflammation. Interestingly, a low 2.5-microg rIL-10 dose given at time of initiation of thrombosis most significantly decreased inflammation. Thrombus weight was importantly diminished by reconstitution of IL-10. These studies support an important role for IL-10 in the regulation of thrombus-associated inflammation and thrombosis and suggest that IL-10 could be used as a therapeutic agent in the treatment of venous thrombosis.