Treatment of childhood idiopathic thrombocytopenic purpura with Rhesus antibodies (anti-D).

We have recently reported that a rise of platelet numbers in ITP can be induced by blockade of the RES with antibody-coated red blood cells. We now present a collaborative study in which 15 Rhesus-positive children with ITP (nine boys and six girls aged 1-15 years) were treated with low-dose anti-D. Ten patients had chronic ITP (duration 6-47 months), five had acute ITP. Doses of 28-50 micrograms anti-D/kg bodyweight per course were given intravenously. In all patients clinical signs of bleeding ceased and platelet counts were elevated. An excellent, good or fair response with platelet increments of greater than 100, 50-100, or 20-50 X 10(9)/l, respectively, was observed in 19, 7, and 12 out of 45 courses in chronic ITP, and in 4, 1, and 2 out of 8 courses in acute ITP. The platelet increase (greater than 40 X 10(9)/l) persisted for 10 to over 360 days in chronic ITP. There were no untoward side reactions. Haemoglobin values remained stable in all patients but laboratory signs of mild, compensated haemolysis ensued. The direct antiglobulin test became positive in all cases due to anti-D IgG. Previous therapy of patients with chronic ITP included high-dose immunoglobulins and prednisone. These regimens were both effective but remissions were short. We conclude that anti-D therapy is an effective and safe form of treatment in childhood ITP.

Immunogenicity of and immune response to the human platelet antigen Zwa is strongly associated with HLA-B8 and DR3.

In a prospective study the immunogenicity of the Zwa antigen during gestation was investigated. Twenty-six out of 1,211 pregnant women were Zwa negative (2.15%). In 2 out of 23 Zwa negative mothers who delivered Zwa positive children, an antibody to Zwa was detected. To determine the relationship between the immune response of pregnant women towards Zwa and the MHC, the phenotype frequencies of HLA-A, B, C, DR, and complement BF, C2, C4A, C4B allotypes of "non-responders" without detectable Zwa antibodies (N = 20) were compared with a group of "responders", i.e. Zwa negative mothers giving birth to Zwa positive children with typical neonatal alloimmune thrombocytopenia (NAIT; N = 39) and with a normal control population. When compared to the normal control group, "non-responders" showed a significant increase of the DRw6 frequency, whereas in the "responders" group HLA-A1, B8, DR3, and C4A*QO were significantly elevated. If "non-responders" and "responders" were directly compared, only B8 and DR3 remained significantly different. The strongest association with a hypothetical immune response gene appeared to exist with DR3.

Fatal outcome of acute thrombocytopenic purpura associated with a viral infection in an 11-year-old child.

A case of fatal intracranial hemorrhage is reported in an eleven year old girl with acute idiopathic thrombocytopenic purpura following a viral infection. The patient was randomized to the IgG-arm of the ITP therapy study. Immunoglobulin administration was not followed by a raise of the thrombocyte count. Neither the IgG therapy nor intensive therapeutic measurements were able to prevent the fatal course of cerebral hemorrhage in this case. Pathological and immunological findings indicate that our patient suffered from a fulminant ITP which must be considered as a part of a still active viral disease.

Treatment of idiopathic thrombocytic purpura in pregnancy by high-dose intravenous immunoglobulin.

ITP in pregnancy may lead to fetal thrombocytopenia caused by the transplacental passage of maternal antiplatelet antibody. The most hazardous complication in the infant is intracranial hemorrhage. In addition ITP in pregnancy is reported to be associated with an increased abortion rate and an elevated fetal morbidity and mortality. Therefore obstetric management must aim at increasing maternal and fetal platelets. Several therapeutic approaches to the treatment of ITP in pregnancy are evaluated. Two cases of ITP in pregnancy are reported. Administration of high-dose intravenous immunoglobulin is introduced as a new therapy for ITP in pregnancy. The rapid reversal of thrombocytopenia following immunoglobulin G administration suggests that it is useful especially as emergency treatment for ITP in pregnancy.

[The syndrome of post-transfusion purpura]. / Das Syndrom der posttransfusionellen Purpura.

Thrombocytopenic purpura occurred in two women aged 67 and 77 years, who earlier on had been pregnant, six and twelve days after blood transfusions. The platelet deficient phase lasted 16 and more than 50 days. Differentiation from other causes of thrombocytopenic haemorrhage was based on immunohaematologic findings. Both patients were negative for the platelet specific antigen PlA1 (Zwa). The platelet specific antibody (anti-PlA1) responsible for the purpura could be demonstrated and characterised immunologically.

High-dose methotrexate for osteosarcoma: toxicity and clinical results.

9 patients with osteosarcoma were treated with a total of 122 infusions of high-dose methotrexate (MTX; 140-350 mg/kg) followed by leucovorin rescue. Plasma kinetics of MTX and 7-hydroxymethotrexate (7-OH-MTX) has been routinely monitored. Due to inadequate hydration and alkalinization, 1 of the 122 high-dose MTX infusions was followed by delayed disappearance of MTX and 7-OH-MTX from plasma with subsequent development of severe mucositis. Serious hepatotoxicity repeatedly developed in another patient with inconspicuous MTX kinetics. The benefit of monotherapy with high-dose MTX for adjuvant treatment of osteosarcoma remains questionable, since 6 of 8 patients with primary osteosarcoma developed pulmonary metastases within 4-12 months (median 5 months), 2 have been disease-free and alive for 25 and 53 months.

Pharmacokinetics of methotrexate and 7-hydroxymethotrexate following infusions of high-dose methotrexate.

The pharmacokinetics of methotrexate (MXT) and 7-hydroxymethotrexate (7-OH-MTX) has been studied in seven patients treated for osteosarcoma with up to 27 cycles of MTX at doses of 140-350 mg/kg of body weight. The distribution volume of MTX was 0.186 +/- 0.062 liter/kg. Peak plasma levels ranged from 540 to 1700 microM for MTX and from 12 to 560 mu M for 7-OH-MTX. The MTX metabolite 2,4-diamino-N10-methylpteroic acid was occasionally detectable in plasma and urine at a level of 10(-7)M. Plasma disappearance of MTX was biphasic, with a terminal half-life of 2.1 +/- 0.6 hours (mean +/- SE). Plasma decay of 7-OH-MTX was mainly monoexponential, with a half-life of 23.8 +/- 15.2 hours. The renal clearance of MTX (0.0623 +/- 0.0232 liter/kg/hour) accounted for about 84% of the total clearance of MTX (0.0742 +/- 0.0288 liter/kg/hour). In urine, 70%-94% of the dose was recovered as MTX and 0.4%-11% as 7-OH-MTX. The renal clearance of 7-OH-MTX was in the range of 0.0173 +/- 0.0149 liter/kg/hour. The pharmacokinetics of MTX and 7-OH-MTX was influenced by orally coadministered activated charcoal, presumably by inhibition of enteral reabsorption of MTX and 7-OH-MTX.

Platelet associated IgG, platelet survival, and platelet sequestration in thrombocytopenic states.

Platelet-associated IgG (PAIgG), platelet mean life span (MLS), and platelet sequestration sites were studied in 69 patients with immune (ITP) and presumed nonimmune thrombocytopenias (NTP). A shortened MLS was associated with elevated PAIgG (N = 46), and with normal PAIgG (N = 15). Four patients had a normal MLS, but elevated PAIgG, four patients were normal for both parameters. The highest PAIgG values occurred in ITP patients with a very short MLS. Nine NTP patients had also elevated PAIgG, but a normal or slightly shortened MLS. There was a significant double log correlation between PAIgG and MLS for ITP, but not for NTP patients. Judged from the coefficient of determination, only 10% of PAIgG were directly related to a shortened MLS. 70% of patients (N = 63) had exclusively splenic and 30% hepatosplenic sequestration. PAIgG was elevated in 29/44 patients with splenic (66%) and in 16/19 patients with hepatosplenic sequestration (84%). In ITP, PAIgG-positive cases were observed in 69% of splenic v 82% of hepatosplenic sequestration, while in NTP the corresponding figures were 6/11 and 2/2. No significant correlation between PAIgG and either sequestration type was demonstrable. We conclude that in immunologically mediated thrombocytopenia only a small portion of PAIgG accounts for a decreased MLS, and that the concentration of PAIgG per se does not determine the platelet sequestration type.