Malignant evolution of Schnitzler's syndrome--chronic urticaria and IgM monoclonal gammopathy: report of a new case and review of the literature.

Schnitzler's syndrome, initially described in 1974 is an uncommon condition defined by chronic urticaria and monoclonal IgM gammopathy. Additional features include fever of unknown origin, elevated ESR, bone pain and frequently a benign clinical course. We conducted a literature search of Medline, EMBASE and Cancerlit and found 56 cases of Schnitzler's syndrome reported to date. The absence of lymphoproliferative disease in this condition is typical, but nine patients have progressed to develop lymphoplasmacytic neoplasias, particularly Waldenstrom's macroglobulinemia (WM). Malignant evolution of Schnitzler's syndrome is a rare complication, but emphasizes the importance of long term follow-up and the need for these patients to undergo periodic assessment of the bone marrow and lymph nodes. Treatment of this condition is difficult, with varying response to corticosteroids and largely unsuccessful results with standard chemotherapy used for WM. We describe a case of Schnitzler's syndrome in a 50-year old man with lymphocytic aggregates in the bone marrow after 9 years of chronic urticaria, fever, arthralgias and bone pain. We review the clinical features and treatment, with emphasis on the hematologic aspects of this unusual condition.

Therapeutic plasma exchange: an update from the Canadian Apheresis Group.

In 1997, the Canadian Apheresis Group reviewed data on 103,416 plasma exchange procedures that had been collected since 1980. Although the number of plasma exchanges gradually increased (from 3189 to 8208 per year), the pattern changed. In 1981, the five most frequent indications for plasma exchange resulted in 55% of all such procedures; by 1997, the five most frequent indications for plasma exchange resulted in 81.1% of all such procedures. During this period, three conditions that were originally among the most frequent indications for plasma exchange became among the least frequent. This paper reviews the published evidence that supports or refutes the use of plasma exchange in the category of the five most frequent indications from 1981 to 1997: thrombotic thrombocytopenic purpura, myasthenia gravis, chronic inflammatory demyelinating polyneuropathy, Waldenstrom macroglobulinemia, the Guillain-Barre syndrome, rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis. For most disorders, use of plasma exchange procedures is correlated with published evidence, and the changing patterns of plasma exchange use by members of the Canadian Apheresis Group reflect published evidence. Annual center-by-center reviews of use of plasma exchange may also have influenced practice patterns.

Laboratory abnormalities in thrombotic thrombocytopenic purpura. Canadian Apheresis Group.

Thrombotic thrombocytopenic purpura is an uncommon disorder that requires prompt recognition and intervention to prevent death. To date, information regarding the classic laboratory abnormalities in the disease has been derived from small numbers of patients whose laboratory tests have been done at many different sites. We report the laboratory findings in 135 patients who presented with thrombotic thrombocytopenic purpura to 17 Canadian centres. 50 men and 85 women had a mean platelet count of 25.3+/-19.4x10(9)/l. The initial platelet count correlated with mortality; 32% of patients with a platelet count of 20x10(9)/l or less died compared with 18% of patients with a platelet count >20x10(9)/l (P=0.058). The platelet-associated IgG was elevated in 88% at presentation whereas the indirect platelet suspension immunofluorescence test was positive in only 18%, 93% of the sera showed reactivity against platelets following protein blotting. All sera tested also showed reactivity against endothelial cells. Immune complexes were seen in all patients, whereas the platelet aggregating factor was detected in 59%. Although the von Willebrand factor was elevated in the majority of patients at entry, the multimer pattern was variable and showed no predictive pattern. Renal dysfunction was common (18%).

Cryosupernatant as replacement fluid for plasma exchange in thrombotic thrombocytopenic purpura. Members of the Canadian Apheresis Group.

The current established treatment of thrombotic thrombocytopenic purpura (TTP) is plasma exchange with fresh frozen plasma (FEP). With this treatment, there is a 49% response after seven exchanges and a 78% survival at 1 month. Although the exact cause of TTP is unknown, the presence of von Willebrand factor (VWF) multimers has been implicated in the disease. Accordingly, it has been suggested that cryosupernatant (plasma from which cryoprecipitate has been removed), which is relatively deficient in VWF multimers, might be an effective replacement fluid during plasma exchange. Patients from six centers were treated by plasma exchange with cryosupernatant. 18 patients who had failed a first course (average 7.7 exchanges) of plasma exchange with FFP. received a further seven exchanges with cryosupernatant. Subsequently, 40 previously untreated patients were exchanged with cryosupernatant. Of the 18 previously treated patients, 11 responded (defined as an increase in platelet count to > 150 x 10(9) /1 and no neurological events) after seven exchanges and 15 (83%) of the patients were alive at 1 month. The response rate in the 40 previously untreated patients was 75% at the end of seven exchanges and 95% of the patients were alive at 1 month. These values are significantly different (P < 0.05) from those reported in our earlier study and in other patients concurrently treated at the same centres with FFP when cryosupernatant was not available. Some patients who have failed to respond to plasma exchange with FFP replacement will respond to further exchange with cryosupernatant. Cryosupernatant replacement may be more effective as first-line treatment of TTP than FFP.

Late relapses in patients successfully treated for thrombotic thrombocytopenic purpura. Canadian Apheresis Group.

OBJECTIVE: To determine the incidence and timing of relapses in patients who have recovered from an acute episode of thrombotic thrombocytopenic purpura. DESIGN: Clinical follow-up for 3 to 10 years. SETTING: General community outpatient study; patients who had relapse were hospitalized. PARTICIPANTS: 63 of 72 surviving patients who had participated in a randomized study that compared plasma exchange and plasma infusion as treatments for thrombotic thrombocytopenic purpura and for whom continued clinical follow-up was obtained. OUTCOME MEASURES: Recurrence of thrombotic thrombocytopenic purpura as defined by a decrease in platelet count to less than 100 x 10(9)/L and by the onset of microangiopathic hemolytic anemia as identified by erythrocyte fragmentation in a peripheral blood film. RESULTS: 37 of the 63 patients have not had recurrence of thrombotic thrombocytopenic purpura and have remained completely well; 6 patients have not had recurrence but have developed other medical problems; 3 patients have not had recurrence but have residual neurologic defects from the original episode; and 17 patients have had one or more recurrences, occurring 7 months to 8 years after the original episode. As determined by Kaplan-Meier analysis, the projected recurrence rate after 10 years in all surviving patients is 36% (95% CI, 23% to 59%). CONCLUSIONS: More than one third of patients who survive an acute episode of thrombotic thrombocytopenic purpura will have at least one relapse during the following 10 years.

Polylactosamines are not obligate receptors for invasion of Plasmodium falciparum malaria as shown in HEMPAS variant II-gal- erythrocytes.

A HEMPAS (hereditary erythroblastic multinuclearity with positive acidified serum test) erythrocyte, atypical Variant II (referred to herein as Variant II-gal-), lacking long-chain polylactosamine on both glycoproteins (Band 3 and 4.5) and glycosphingolipids, was characterized by the carbohydrate profile of the erythrocyte membrane according to Fukuda et al. (Blood, 73, 1331-1339, 1989). Two laboratories previously reported that polylactosamine isolated from the erythrocyte protein Band 3 inhibited invasion of red blood cells by Plasmodium falciparum in malarial culture, suggesting a role for this carbohydrate in adhesion of the parasite. Therefore, HEMPAS erythrocyte Variant II-gal- presented a unique opportunity to further examine this premise. Freshly drawn blood samples (normal and HEMPAS Variant II-gal-) were separately incubated with P. falciparum from mannitol-synchronized cultures. The parasite was found to invade HEMPAS Variant II-gal- erythrocytes at a 30% lower rate through two life cycles, as shown by microscopic evaluation of invasion and by [3H]hypoxanthine incorporation into parasite. This observation, along with the published fact that glycophorin-deficient MkMk cells are also infectable, but at a lower rate, indicates that neither sialoglycoproteins nor polylactosamines are an obligate adhesive ligand for P. falciparum, although the possibility remains that either may still contribute to adhesive events during infection.

Treatment outcomes in patients with adult thrombotic thrombocytopenic purpura-hemolytic uremic syndrome.

BACKGROUND: Plasma treatment has improved the outcomes in adults with thrombotic thrombocytopenic purpura (TTP)-hemolytic uremic syndrome (HUS). We reviewed our experience in treating unselected patients to determine the clinical outcomes and to evaluate the treatments given in addition to plasma. METHODS: A chart review of all cases of TTP and HUS in adults treated at the Toronto (Ontario) Hospital, the largest treatment center for adults with TTP-HUS in the province of Ontario, was conducted. RESULTS: Sixty-seven episodes of TTP-HUS in 52 consecutive adult patients were treated during a 12-year period. Plasma was the primary form of therapy, and most patients received plasma exchange. A complete hematologic remission was achieved in 65 of 67 episodes; however, two patients in remission were brain-dead. The time to complete remission varied from 3 to 58 days (median, 13 days). The death rate during the acute illness was 8%. Long-term sequelae included relapses, persisting renal impairment, hepatitis, and transfusion-associated acquired immunodeficiency syndrome. Relapses occurred in 21% of patients during a median follow-up of 1.1 years (range, 0.1 to 18 years). Analyses of the treatment given in addition to plasma did not demonstrate a significant benefit in terms of reducing the illness duration, mortality, or long-term sequelae. CONCLUSION: While most patients recovered from TTP-HUS, deaths still occurred and many patients suffered long-term complications. The role of the treatments given in addition to plasma is uncertain.

Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. Canadian Apheresis Study Group.

BACKGROUND: Thrombotic thrombocytopenic purpura is an uncommon disease with a high mortality rate even with current treatment. The cause of the syndrome and its optimal treatment are unknown. Although both plasma exchange and plasma infusion have been useful treatments, it is not clear which is superior. In this report we describe a prospective randomized trial comparing plasma exchange with plasma infusion for the treatment of thrombotic thrombocytopenic purpura. METHODS: One hundred two patients with thrombotic thrombocytopenic purpura were randomly assigned to receive either plasma exchange or plasma infusion with fresh-frozen plasma on seven of the first nine days after entry into the trial. The total volume of plasma received by patients undergoing plasma exchange was three times that received by patients undergoing plasma infusion. All the patients also received aspirin and dipyridamole. The outcomes in the two groups were compared at the end of the first treatment cycle (day 9) and after six months. RESULTS: At the end of the first treatment cycle patients receiving plasma exchange had a higher rate of response as defined by an increase in the platelet count (24 of 51 patients) than those who received plasma infusion (13 of 51, P = 0.025). Of the 51 patients treated with plasma exchange, 2 died, whereas 8 of the 51 patients who received plasma infusion died (P = 0.035). After six months the outcome in the plasma-exchange group was still superior, with a response observed in 40 of 51 patients, whereas 25 of 51 patients in the plasma-infusion group responded (P = 0.002). Eleven patients in the plasma-exchange group died, as did 19 patients in the plasma-infusion group (P = 0.036). The overall mortality was 29 percent. CONCLUSIONS: Plasma exchange is more effective than plasma infusion in the treatment of thrombotic thrombocytopenic purpura.

Long-term use of antecubital veins for plasma exchange. The Canadian Cooperative Multiple Sclerosis Study Group.

True or sham plasma exchange was done weekly for 20 weeks in patients in two of the randomization groups in a prospective, blind clinical trial of experimental treatments for multiple sclerosis. Because patients could be randomized to receive sham plasma exchange and placebo medications, it was decided when the trial was designed that the use of fistulae, arteriovenous shunts, venous cutdowns, or other aggressive forms of venous access would not be permitted for any patient. Accordingly, patients judged to have inadequate superficial antecubital veins were ineligible for the trial. To date, only 13 (4.4%) of 294 patients considered for entry into the trial have been rejected on these grounds. In only 4 of the 93 patients undergoing exchange was it necessary to discontinue plasma exchange because of inadequate venous access. In 79.3 percent of the 1207 exchanges done in these patients, there were no problems of any kind with venous access. In 5.4 percent of these 1207 exchanges, it was necessary to terminate the procedure prematurely because of difficulties with patients' veins. Thus, the great majority of patients free of serious systemic illness (other than chronic progressive multiple sclerosis) can undergo weekly plasma exchange for up to 20 weeks using superficial antecubital veins without the need to resort to more invasive methods of venous access.

Toronto General Hospital controlled trial data plasma exchange therapy in Guillain-Barré' syndrome.

The mechanism by which plasma exchange (PE) may benefit patients with acute Guillain-Barre' syndrome (AGBS) is unclear. It is possible, therefore, that the response of patients with AGBS is influenced by the choice of replacement solution (whole plasma vs. albumin or similar protein-containing solution). This report compares the outcome in 57 patients with AGBS treated at the Toronto General Hospital (TGH) using conventional therapy (27), PE with plasma replacement (15) and PE with albumin replacement (15). Fifteen patients (5 treated conventionally, 8 by PE with plasma replacement, 2 by PE with albumin replacement) were treated before the Baltimore coordinated multicenter trial. Forty-two patients (22 treated conventionally, 7 by PE with plasma replacement and 13 by PE with albumin replacement) were then entered at the TGH into the multicenter trial. The best outcome was observed in those patients (9) in whom PE was started within 14 days of the first neuropathic symptoms and plasma was used as replacement. The mean improvements in clinical grade in this subgroup of patients of 1.11 at four weeks after starting treatment and 1.71 at six weeks were significantly better than the corresponding improvements in the conventionally treated group of 0.35 (p less than 0.01) and 0.94 (p less than 0.05). The response of patients (9) exchanged within 14 days of onset, but replaced with albumin (grade change of 0.67 at four weeks and 0.86 at six weeks), was not significantly different from that of the conventionally treated patients. These data support the need for a randomized trial to compare PE using plasma replacement and PE using albumin replacement in patients with AGBS.(ABSTRACT TRUNCATED AT 250 WORDS)

Transferrin receptors on human reticulocytes: variation in site number in hematologic disorders.

Assays of binding of 125iodine-labeled (125I) human transferrin were used to study transferrin receptor sites on reticulocytes from 15 normal subjects and from 66 patients with various hematologic disorders. In normal subjects, few or no transferrin receptors were detected whereas the average number of receptors per reticulocyte varied greatly from patient to patient, ranging from 0 to 67,700 in samples, from 35 patients, on which Scatchard analysis of binding of [125I]-transferrin was done. Marked heterogeneity in the number of reticulocyte transferrin receptors in different hematologic disorders was also found in assays with [125I]-OKT9 (monoclonal antibody to the human transferrin receptor). The number of receptors was not correlated with either the reticulocyte count or the hemoglobin.

An antigen shared by human granulocytes, monocytes, marrow granulocyte precursors and leukemic blasts.

An antibody to human granulocytes was raised in rabbits by immunization with granulocytes pretreated with rabbit antibody to contaminating antigens. The antibody reacted not only with granulocytes but also with monocytes and bone marrow granulocyte precursors including colony-forming units in culture (CFU-C). In tests with leukemic cells, the antibody reacted with blasts from most (8 of 9) patients with acute myelomonoblastic leukemia and from some patients with acute myeloblastic leukemia, morphologically undifferentiated acute leukemia and chronic myelogenous leukemia in blast crisis. The antibody did not react with blasts from patients with acute lymphoblastic leukemia nor with leukemic cells from patients with chronic lymphocytic leukemia.

Myeloblastic and lymphoblastic markers in acute undifferentiated leukemia and chronic myelogenous leukemia in blast crisis.

Blast cells were obtained from 17 patients with acute undifferentiated leukemia and 13 patients with chronic myelogenous leukemia in blast crisis. The blasts were tested with anti-i serum in cytotoxicity tests and with antisera to myeloblastic leukemia-associated antigens in immunofluorescence tests. The terminal deoxynucleotidyl transferase (TDT) content of the blasts was also measured. Lymphoblasts react strongly with anti-i, do not react with anti-myeloblast serum, and have high levels of TDT; myeloblasts react weakly with anti-i, do not react with anti-myeloblast serum, and have very low levels of TDT. Of the 17 patients with acute undifferentiated leukemia, there were six with blasts which reacted like lymphoblasts, six with blasts which reacted like myeloblasts, and five with blasts bearing different combinations of these lymphoblastic and myeloblastic markers. Eight of the 11 patients with lymphoblastic or mixed lymphoblastic-myeloblastic markers, but only one of the six with myeloblastic markers, achieved complete or partial remission in response to therapy. Thus, in acute undifferentiated leukemia, classification of blasts with these markers may be of prognostic value. Of the 13 patients with chronic myelogenous leukemia in blast crises, the markers were concordant (for myeloblasts) in only two cases. Three of the 13 patients had TDT-positive blasts, but the reactions of these cells with anti-i and with anti-myeloblast serum differed from those seen with lymphoblasts from patients with acute lymphoblastic leukemia. Although the cell involved in "lymphoid" blast crisis of chronic myelogenous leukemia is similar in many respects to that involved in acute lymphoblastic leukemia, these cells are not identical.

Diagnosis of haematological disease using anti-i. II. Distinction between acute myeloblastic and acute lymphoblastic leukaemia.

Leukaemic blast cells were obtained from the blood of six patients with acute lymphoblastic leukaemia (ALL) and 15 patients with acute myeloblastic leukaemia (AML). The blasts were compared with lymphocytes from normal subjects in cytotoxicity and 125I-labelled antibody binding tests using several examples of anti-i. As much i antigen was detected on ALL blasts as on normal lymphocytes; much less i antigen was detected on AML blasts. Studies of three patients with morphologically undifferentiated acute leukaemia suggest that, in tests with anti-i, blasts from such patients react either like lymphoblasts or myeloblasts despite the absence of the corresponding morphological features.

Diagnosis of haematological disease using anti-i. I. Disorders with lymphocytosis.

Using cytotoxicity and antibody-binding tests, the i antigen was measured on the blood lymphocytes of normal subjects and of patients in whom a diagnosis of chronic lymphocytic leukemia (CLL) was considered because of a slight lymphocytosis in the blood and bone marrow. Among 25 patients, 15 had a normal amount of i antigen; in 10 there was a marked reduction in i antigen, such as is found in typical CLL. Similar studies were done on lymphocytes from 15 patients with clinical and morphological findings usually associated with lymphosarcoma cell leukemia (LSL). Nine had a normal amount of i antigen; in six there was a marked reduction of i antigen, suggesting a diagnosis of CLL. A study of the subsequent clinical course and final diagnosis in these patients suggests that the reduction in lymphocyte i antigen characteristic of typical CLL occurs in patients with early CLL who have only slight lymphocytosis, but not in patients with slight lymphocytosis from other causes. Similarly, a reduction in lymphocyte i antigen is found in patients with morphologically atypical CLL but not in patients with LSL.