ADAMTS-13 may not predict disease or outcome in patients with Thrombotic Thrombocytopenic Purpura.

BACKGROUND: The pathophysiology of Thrombotic Thrombocytopenia Purpura (TTP) has been questioned since described in 1924. In 1998, Tsai [1] and Furlan [2] demonstrated a relationship of low levels of ADAMTS-13 with an IgG inhibitor in acquired idiopathic TTP. This study reports on a series of TTP patients treated with solvent/detergent plasma (SDP) or cryosupernatant plasma (CSP) and focuses on the correlation of their presentation, clinical response and outcome with the levels of ADAMTS-13, the inhibitor and VWF multimers. METHODS: Plasma exchange was carried out in patients with the clinical diagnosis of acquired idiopathic TTP. ADAMTS-13 enzyme activity and inhibitor levels, VWF multimers and platelet count were analyzed in correlation with patient outcome. This RCT was intended to compare outcome in 280 patients treated either with cryosupernatant or solvent-detergent heated plasmas. The primary end point was survival at six months. RESULTS: Data on 61 TTP patients were obtained from 16 centres across Canada. The study was then closed prematurely due to removal of one of the interventional products from the market. ADAMTS-13 enzyme activity and inhibitor levels varied considerably among study participants. At baseline, only 12/49 (24.5%) had ≤10% enzyme activity and 20/49 (41%) had levels ≥80%; whereas 16/49 had ≥80% inhibitors; 19/49 had ≤10% inhibitors 18/49 (37%) had no inhibitors. No unusually large VWF multimers were identified in any of the patients at presentation. The 6-month, all-cause mortality rates for patients randomized to receive CSP vs. SDP were 3/34 (9%; 95% CI: 3%, 23%) and 1/27 (4%; 95% CI: 1%, 18%), respectively, with a difference of 5% (95% CI: -11%, 20%). CONCLUSION: Although this study was underpowered to compare solvent/detergent vs. cryosupernatant plasma, our data suggest that ADAMTS-13 activity and inhibitor level at baseline cannot differentiate TTP response to plasma exchange therapy.

Laparoscopic vs open splenectomy.

HYPOTHESIS: Laparoscopic splenectomy (LS) provides health benefits to patients compared with open splenectomy (OS) in terms of perioperative morbidity, complications, and patient recuperation. DESIGN: Prospective operative and outcome data of LS patients were compared with those of OS patients (historical controls). SETTING: Data were gathered, and patients were evaluated and treated at 2 McMaster University teaching hospitals in Hamilton, Ontario, and at the University of Kentucky Chandler Medical Center, Lexington, also a teaching hospital. PATIENTS: From January 1, 1994, through October 31, 1998, a total of 210 patients were studied. Of them, 147 patients from 3 university teaching hospitals underwent LS. These patients were matched with 63 OS patients according to age, sex, spleen weight, indication for splenectomy, and preoperative morbidity score. INTERVENTIONS: A total of 147 patients evaluated for elective splenectomy underwent LS. MAIN OUTCOME MEASURES: Spleen weight, operative time, intraoperative blood loss, postoperative hospital stay, perioperative complications, and cost. RESULTS: No significant difference in mean spleen weight was found between groups. Mean operative time was significantly longer for LS, but intraoperative blood loss was significantly lower. Mean postoperative hospital stay was significantly lower and perioperative complications significantly fewer for LS patients. Mean cost for LS with no complications was slightly lower than for OS. CONCLUSIONS: Compared with OS, the lateral approach to LS takes longer to perform but results in reduced blood loss, shorter postoperative stay, and fewer complications. Mean weighted cost of LS is lower than OS at the study institutions. A prospective, randomized, controlled trial comparing these techniques is planned.

Protecting the health and safety of working teenagers.

More than one third of high school students work during the school year, and many more are employed during the summer months. Teenage workers face a variety of health and safety hazards. Occupational injury and illness are largely preventable, and family physicians can play a crucial role in this prevention effort by advising adolescents about common workplace dangers. Physicians who sign work permits and provide ongoing health care to teenagers should counsel them and their parents or guardians about the benefits and risks of work and discuss the regulations governing jobs that are prohibited for adolescents, work hours, protective measures and workers' compensation benefits.

Evaluation and initial management of patients with ascites.

Large amounts of ascitic fluid may cause distention, weight gain, anorexia and nausea. Smaller accumulations may be asymptomatic and difficult to detect clinically. In addition to signs associated with the cause of ascites, the physical examination may reveal shifting dullness, a fluid wave and peripheral edema. Ultrasound examination is useful in establishing the diagnosis and in locating the optimal site for paracentesis. Calculation of the serum-ascites albumin gradient provides useful diagnostic information. High gradients usually indicate portal hypertension, while low gradients may indicate infection or carcinomatosis. Management is directed toward alleviating the underlying cause of ascites and reducing symptoms. Initially, restriction of salt intake to 2 g per day is usually advised. Most patients require diuretic therapy. Spironolactone, the usual first-choice agent, may be combined with furosemide in selected patients. If diuretic therapy is unsuccessful, large-volume paracentesis, peritoneovenous portosystemic shunting, transjugular intrahepatic shunting or liver transplantation may be required.

Plasma exchange in chronic inflammatory demyelinating polyneuropathies.

Chronic Inflammatory Demyelinating Polyneuropathies (CIDP) are characterized by demyelination of peripheral nerves with mononuclear cell infiltrates, electrical conduction slowing or block and elevated cerebrospinal fluid protein with no cells. An immune mediated pathogenesis has been suggested. Immune suppressive therapy, as well as plasmapheresis and intravenous immunoglobulins have been used with variable success. Our objective was to review our results of plasma exchange in this disease in 20 patients with very different underlying diseases, none of them eligible for the Canadian CIDP plasmapheresis study, and define certain guidelines of predictability for the effectiveness of plasma exchange. Five patients had monoclonal gammopathies of unknown significance, two had lung cancer, one breast cancer, one hairy cell leukemia and later carcinoma of the pancreas; two had hepato-splenomegaly and hemolytic anemia; nine were idiopathic (two with autoimmune markers). Plasmapheresis varied from 4 to 31 plasma volumes and procedures with a median of 12, always with 5% albumin. Two excellent responses, one very good, two moderate transient and 12 had no change in clinical or conduction status. Best response occurred in paraproteinemias. Thus immune modulation with plasma exchange may be useful in CIDPs with paraproteinemias and autoimmune manifestations.

Randomized phase II comparison of standard CHOP with weekly CHOP in elderly patients with non-Hodgkin's lymphoma.

PURPOSE: To determine whether modifying the standard regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) from full doses given every 3 weeks to one-third doses given weekly (chop) increases the received chemotherapy dose-intensity in elderly patients with advanced-stage intermediate-grade lymphoma. PATIENTS AND METHODS: Consenting patients, age > or = 65 years who had acceptable cardiac, renal, and liver function and an Eastern Cooperative Oncology Group (ECOG) performance status less than 4, were stratified by bone marrow and performance status and randomized to receive standard CHOP or weekly chop. Drug doses were attenuated or escalated according to a defined dose-modification schedule. The primary outcome was average relative received dose-intensity. Secondary outcomes included response, progression-free and overall survival, toxicity, and performance status. RESULTS: Nineteen patients were allocated to each group. No difference in received dose-intensity was seen. When dose-intensity was calculated for the first six cycles of therapy, average relative received dose-intensity was .92 with CHOP versus .89 with weekly chop (P = .5); when calculated for the first 18 weeks of therapy, values were .88 with CHOP versus .89 with weekly chop (P = .8). The complete response rate was 68% with CHOP versus 74% with weekly chop (P = .9). At 2 years, the progression-free survival rate was 57% with CHOP versus 46% with weekly chop (P = .16) and the survival rate was 74% with CHOP versus 51% with weekly chop (p = .05). More myelotoxicity was seen with CHOP. CONCLUSION: We conclude that CHOP can be given in sufficient doses to elderly patients and that weekly chop does not increase received dose-intensity. Progression-free and overall survival are unlikely to be superior with weekly chop, and may be worse. CHOP should remain the standard against which new therapies for elderly patients with intermediate-grade lymphoma are compared.

Measurement of factor Xa-antithrombin III in plasma: relationship to prothrombin activation in vivo.

The M(r) of the complexes formed when factor Xa reacts with antithrombin III (ATIII) in plasma were estimated by gel filtration and SDS-polyacrylamide electrophoresis. The predominant species of factor Xa-ATIII detected after plasma and plasma to which factor Xa had been added were gel filtered on Sephadex G-200 and Sepharose 4B had apparent M(r) > 200,000, in which factor Xa-ATIII was associated with vitronectin. Addition of factor Xa-ATIII to ATIII-depleted plasma also resulted in the formation of factor Xa-ATIII-vitronectin complexes with M(r) > 200,000. Using polyclonal antibodies to human factor Xa-ATIII and ATIII as the capture and detector antibodies, respectively, a sensitive and specific enzyme-linked immunosorbent assay was developed to quantify factor Xa-ATIII in plasma. The relationship between factor Xa-ATIII production and prothrombinase activity in vivo was investigated by quantifying factor Xa-ATIII and prothrombin fragment 1 + 2 endogenous to the plasmas of blood donors and patients with Hodgkin's and non-Hodgkin's lymphoma. Whereas the concentrations of prothrombin fragment 1 + 2 in the 84 normal plasmas increased with age, those of factor Xa-ATIII (mean +/- SD of 34.7 +/- 13.8 pM) did not, and no correlation existed between the concentrations of the two parameters in normal plasmas. In contrast, a highly significant correlation between the concentrations of these two parameters was found in the plasmas of the cancer patients which coincidentally also had higher concentrations of both factor Xa-ATIII and prothrombin fragment 1 + 2 than the normal plasmas. Thus, ATIII may differentially influence prothrombinase formation and activity in normal individuals and cancer patients.

Replication and cytopathology of human parvovirus B19 in human umbilical cord blood erythroid progenitor cells.

Human parvovirus B19 productively infected erythroid progenitor (EP) cells from umbilical cord blood, in vitro as shown by an increase of viral DNA in supernatant fluid assayed by dot blot hybridization and liquid scintillation counting. Progeny virus was released into the supernatant fluid of CD34+ EP cells which had been purified by immunomagnetic separation. This supernatant fluid was infectious for bone marrow cells. Erythroid bursts infected with virus showed characteristic cytopathic effect by electron microscopy consisting of cytoplasmic vacuolization, marginated chromatin, and nuclear inclusions of lattice or crystalline arrays. Cultures of umbilical cord blood EP cells may be useful for the propagation of parvovirus B19 serological testing reagents and the study of virus-host cell interactions.

Repeat plateletpheresis: the effects on the donor and the yield.

Requirements for HLA ot otherwise matched single-donor platelets may sometimes require repeat plateletpheresis of an individual donor. AABB standards permit the repeat collection of platelets by plateletpheresis of a single donor at 48-hour intervals, whereas recent recommendations from England state that a donor should not donate platelets more often than 12 times a year. To assess the effects of repeat plateletpheresis on the donor, we have studied the hematological indices and the product yields following every other day plateletpheresis of 13 normal donors who gave a total of 10 times during 22 days. The platelet count decreased in every case, with the lowest values reached at the third donation (day 5). The pre-donation count averaged 225 +/- 53 x 10(9)/l decreasing to 174 +/- 27 x 10(9)/l at the time of the 3rd donation then increasing by the 6th donation to 198 +/- 46 x 10(9)/l. The yield in the product decreased from 3.2 +/- 1.3 x 10(11) on day 1 to 2.6 +/- 0.8 x 10(11) for the third donation, returning thereafter to higher values. In spite of the expected and apparent stimulation of platelet production through feedback, the counts did not rebound above starting levels indicating a basic homeostatic mechanism. The donor WBC showed minimal changes during the study period, however there was a significant increase in the total number of lymphocytes by the 3rd procedure; this was corrected by the fifth procedure. The absolute number and ratio of T4 (helper) and T8 (suppressor) lymphocytes did not change.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult Still's disease: manifestations, disease course, and outcome in 62 patients.

Clinical and laboratory manifestations, disease course, outcome, and HLA associations were studied in an inception cohort of 62 subjects with adult Still's disease (ASD) from 5 Canadian universities. Twenty-eight patients (45%) were female and the median age at disease onset was 24 years. In general, the clinical features observed in our patients were identical to those in other published series. However, significantly higher frequencies of sore throat (92%), weight loss (76%), lymphadenopathy (74%), pleuritis (53%), pneumonitis (27%), and abdominal pain (48%) were noted in our patients compared to those in a recent literature review. Liver involvement with hepatomegaly (44%) or abnormal liver function tests (LFTs) (76%) was common and was responsible for the 2 deaths attributed to Still's disease in our series. Severe liver failure always occurred in conjunction with aspirin or NSAID therapy. Therefore, whether or not aspirin or other NSAIDs are used, we recommend close monitoring of LFTs in patients with ASD, especially early in the disease course. Laboratory manifestations were similar to those already reported. Leukocytosis (greater than or equal to 15,000/mm3) was present in 50 patients (81%), a normochromic, normocytic anemia (hemoglobin less than or equal to 10 g/dl) in 42 (68%), and an elevated ESR in all. The mean follow-up of the 62 patients was 70 months (range, 2-163). Twenty-one patients (34%) had a self-limited disease course, 15 (24%) an intermittent course, and 22 (36%) a chronic disease course. Four patients (6%) died, and 2 of these deaths were attributed to Still's disease. For those patients who experienced a recurrence of ASD, the flares were usually of shorter duration and milder in severity than the initial episode. No initiating factor for disease exacerbation was identified in our patients. Although 22 of 62 patients (36%) had a chronic disease course, 52 (90%) were in ARA Functional Class I, and only 4 and 2 patients were in ARA Functional Class II and III, respectively. Patients with Still's disease had higher scores than the controls on the Pain (P less than 0.01) and Physical Disability (P less than 0.05) subscales of Arthritis Impact Measurement Scales health status questionnaire. Joint radiographs performed at the follow-up evaluation disclosed typical carpometacarpal and intercarpal involvement in 16 of 39 patients. In our series, HLA-B17, B18, B35, and DR2 were significantly associated with ASD. Three significant predictors of an unfavorable outcome, either a chronic disease course or a longer time to clinical remission, were identified.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult Still's disease in only one of identical twins.

This report describes the occurrence of adult Still's disease in only one of a pair of identical twins after 8 years of followup. This suggests that environmental factors may be important in the development of this rare syndrome in at least some patients.

Monocyte-macrophage (M-M) functions in asymptomatic hemophiliacs and supertransfused thalassemics.

Patients suffering from acquired immune deficiency syndrome (AIDS) succumb to opportunistic infections due to a generalized failure of their cell-mediated immune defenses. The monocyte-macrophage (M-M) system plays an important role in host defense against viruses, protozoa, mycobacteria, and tumours, all potentially involved in the terminal stages of AIDS. We studied M-M functions in 55 asymptomatic hemophiliacs, 20 supertransfused thalassemics, and 9 von Willebrand's syndrome patients over a period of 17 months to establish the part played by chronic repeated blood component transfusions on the macrophage defense system. We found a significant impairment of chemotaxis in 24 out of 55 hemophiliacs, 13 out of 20 thalassemics, and 4 out of 9 von Willebrand's patients. In contrast, Candida pseudotropicalis killing was markedly increased in all 3 patient groups, while Candida phagocytosis was most significantly diminished in thalassemics. Fc-receptor-dependent erythrophagocytosis showed wide variations in all patients, with a significant decrease only in thalassemics. Phorbol ester-activated nitroblue tetrazolium (NBT) reduction to formazan was normal in most cases, but background spontaneous NBT was often much higher than in the controls. Monocyte adhesion to plastic appeared impaired in hemophiliacs and von Willebrand's Syndrome patients, yet was of no statistical significance. It thus appears that continuous, repeated blood component transfusions cause an alteration of M-M functions. This may be either due to chronic, recurrent antigenic stimulation by foreign proteins transfused, or oncogenic and known immune suppressive viruses, like cytomegalovirus, Epstein-Barr virus, hepatitis, and human T cell lymphotropic virus III. This in turn may increase susceptibility to AIDS.

Hemolytic anemia following intravenous gamma globulin administration.

A young homosexual man with immune thrombocytopenia recently had transient intravascular hemolysis during intravenous gamma globulin treatment. The hemolysis, manifested by a sharp decrease in hemoglobin and by a direct Coombs' test with a positive result, was mediated by anti-A antibody present in the gamma globulin preparation. In view of the increasing use of intravenous gamma globulin in the treatment of patients with immune cytopenia, this problem may result in crossmatching difficulties and should be recognized as a potential complication of therapy.

Thrombotic and hemorrhagic complications in children with the lupus anticoagulant.

Endogenous circulating anticoagulants are unusual in children without a congenital factor deficiency. In particular, the lupus anticoagulant has only rarely been reported in children. Despite its functioning in vitro to prolong the partial thromboplastin time, patients more frequently have problems with thrombosis than bleeding, unless there is a coexistent prothrombin deficiency or thrombocytopenia. We report the cases of three children with the lupus anticoagulant. Two children had associated thromboses. One had a thrombosis of the iliofemoral system and the other had a partial Budd-Chiari syndrome, a thrombosis of the deep calf veins and ureteric obstruction. The third child had a concomitant prothrombin deficiency and bleeding after tooth extraction. Associated findings in these patients included a positive antinuclear antibody test in two, a positive anti-DNA antibody test in two, a false-positive VDRL test in two, and an antiphospholipid antibody test in two.