Combination chemotherapy in refractory immune thrombocytopenic purpura

BACKGROUND: Chronic idiopathic thrombocytopenic purpura is a destructive thrombocytopenia caused by an autoantibody. About 80 percent of patients with chronic idiopathic thrombocytopenic purpura have remissions after either corticosteroid therapy or splenectomy. Some patients with resistant disease respond to other agents, but a substantial group are refractory to therapy. METHODS: We used combination chemotherapy to treat 10 patients with refractory immune thrombocytopenia. An average of 6.8 (range, 3 to 10) previous therapies, including corticosteroids and splenectomy, had been unsuccessful in these patients. The patients received from three to eight cycles of therapy consisting of cyclophosphamide and prednisone combined with either vincristine (one patient), vincristine and procarbazine (four patients), or etoposide (six patients, including one patient who received four cycles each containing procarbazine and etoposide). RESULTS: Among the 10 patients, 6 had complete responses (platelet count, > 180,000 per cubic millimeter); of these, 4 patients had responses that persisted for more than 11, 30, 54, or 126 months, 1 had a relapse 9 months after therapy but had a remission with further therapy and remained in remission for 48 months before dying of an unrelated illness, and another relapsed just before her fifth course of therapy. Two patients had partial responses (platelet count, > 50,000 per cubic millimeter); the platelet counts in one remained stable for more than nine months after the end of therapy, and the other patient relapsed. The remaining two patients had no response. Complete responses were associated with a disappearance or marked decrease in the level of platelet-associated autoantibody. CONCLUSIONS: Combination chemotherapy is beneficial in some patients in whom immune thrombocytopenia is refractory to corticosteroids and splenectomy.     

Laparoscopic splenectomy for immune thrombocytopenic purpura

A very unusual case of traumatic tricuspid regurgitation is reported, with severe symptoms of right ventricular failure, extreme dilatation of the right heart, echocardiographic and angiographic criteria of major tricuspid regurgitation, and severe right ventricular systolic dysfunction. The patient was referred for heart transplantation, on the assumption that conventional surgery was not possible. After careful evaluation, as the patient had normal pulmonary artery pressure and resistance, a tricuspid valve was replaced with good surgical outcome.     

Coronary artery bypass grafting in immune thrombocytopenic purpura

BACKGROUND: Reports of patients with idiopathic thrombocytopenic purpura undergoing cardiac operations are scarce and no recommendations exist regarding their management. We report 3 patients with idiopathic thrombocytopenic purpura and severe coronary artery disease who underwent uncomplicated coronary bypass grafting. METHODS: The case history of each patient with idiopathic thrombocytopenic purpura who underwent coronary artery bypass grafting and the literature were reviewed. RESULTS: All 3 patients underwent uncomplicated coronary artery bypass grafting after preoperative treatment with intravenous immunoglobulin and intraoperative platelet transfusions if needed. Prophylactic splenectomy was not performed. There was no increased incidence of bleeding complications. CONCLUSIONS: Coronary artery bypass grafting can be safely performed in patients with idiopathic thrombocytopenic purpura using conventional conduits after pretreating with immunoglobulin G and avoiding splenectomy.     

Characterization of platelet-reactive antibodies in children with varicella-associated acute immune thrombocytopenic purpura (ITP)

Urinary excretion of trypsin inhibitor increased after injection of a carcinogen, N-nitrosobis(2-oxopropyl)amine, into Syrian hamsters. Two inhibitors were purified to apparent homogeneity from urine collected during the course of the carcinogenesis experiment. Their complete amino acid sequences were determined by Edman degradation of the intact proteins and partially degraded fragments. One corresponded to a hamster liver cDNA clone that hybridized with human bikunin probe [Ide et al, (1994) Biochim, Biophys. Acta 1209, 286-292], except that the protein sequence lacked C-terminal serine and the other was trypstatin, the C-terminal half of the bikunin molecule. Three proteins containing covalently linked bikunin were also identified in pooled blood plasma. They were all dissociated into heavy and light chains by treatment with chondroitinase ABC or 50 mM NaOH, but not by heating at 100 degrees C in the presence of sodium dodecyl sulfate and dithiothreitol, N-terminal amino acid sequence analyses of the native chains and partially degraded fragments thereof revealed that these proteins are (i) human-type inter-alpha-trypsin inhibitor, consisting of heavy chains 1 and 2 and bikunin, (ii) bovine-type inter-alpha-trypsin inhibitor, consisting of heavy chains 2 and 3 and bikunin, and (iii) pre-alpha-trypsin inhibitor, consisting of heavy chain 3 and bikunin. Heterodimer of bikunin/heavy chain 1 or bikunin/heavy chain 2 was not detected. These results suggest that the composition, and hence function, of the inter-alpha-trypsin inhibitor family differs considerably from species to species.     

Laparoscopic versus open splenectomy for immune thrombocytopenic purpura

Erythrokeratodermia variabilis (EKV, OMIM 133200) is an autosomal dominant genodermatosis with considerable intra- and interfamilial variability. It has a disfiguring phenotype characterized by the independent occurrence of two morphologic features: transient figurate red patches and localized or generalized hyperkeratosis. Both features can be triggered by external factors such as trauma to the skin. After initial linkage to the RH locus on 1p, EKV was mapped to an interval of 2.6 cM on 1p34-p35, and a candidate gene (GJA4) encoding the gap junction protein alpha-4 (connexin 31, Cx31) was excluded by sequence analysis. Evidence in mouse suggesting that the EKV region harbours a cluster of epidermally expressed connexin genes led us to characterize the human homologues of GJB3 (encoding Cx31) and GJB5 (encoding Cx31.1). GJB3, GJB5 and GJA4 were localized to a 1.1-Mb YAC in the candidate interval. We detected heterozygous missense mutations in GJB3 in four EKV families leading to substitution of a conserved glycine by charged residues (G12R and G12D), or change of a cysteine (C86S). These mutations are predicted to interfere with normal Cx31 structure and function, possibly due to a dominant inhibitory effect. Our results implicate Cx31 in the pathogenesis of EKV, and provide evidence that intercellular communication mediated by Cx31 is crucial for epidermal differentiation and response to external factors.     

Percutaneous umbilical blood sampling in the management of immune thrombocytopenic purpura during pregnancy

Severe neonatal thrombocytopenia occurs in about 15% of deliveries from women with immune thrombocytopenic purpura (ITP). Conflicting data exist about the real usefulness of percutaneous umbilical blood sampling (PUBS) in evaluating the fetal platelet count. We report successful experience, using PUBS, in the management of 12 pregnant women with ITP.     

Gastric carcinoma and thrombotic thrombocytopenic purpura: association with plasma immune complex concentrations

A patient with metastatic adenocarcinoma of the stomach developed microangiopathic haemolytic anaemia, thrombocytopenia, renal insufficiency, and fluctuating neurological abnormalities in association with appreciably raised plasma concentrations of immune complexes. This syndrome, similar to thrombotic thrombocytopenic purpura, occurred while the tumour was in sustained objective remission after successful treatment with fluorouracil, doxorubicin, and mitomycin. Reversal of the syndrome was achieved with plasmapheresis, azathioprine, corticosteroids, and antiplatelet treatment; this response was paralleled by a reduction in immune complex concentration, suggesting an immune aetiology for the syndrome. Antibodies eluted from the immune complexes reacted with 50% of cells from the gastric cancer but less than 10% of cells from normal gastric mucosa. There was no reactivity with either carcinoembryonic antigen or mitomycin. A 17S immune complex reacted with a glycoprotein from the patient's autologous platelets and produced platelet aggregation. It is postulated that reducing the tumour and the pre-existing state of antigen excess by chemotherapy allowed soluble antigen-antibody complexes to form and the syndrome to develop.     

Chronic relapsing thrombotic thrombocytopenic purpura: three case reports and update of the pathogenesis and therapeutic modalities

Chronic relapsing thrombotic thrombocytopenic purpura (CRTTP) is the rarest type of TTP, usually presenting in childhood. The aetiology is still not fully explained. The disorder is associated with the presence in plasma of unusually large von Willebrand factor (UlvWF) multimers that are especially prominent between episodes. CRTTP can be prevented by periodic plasma transfusions. We report three children with congenital CRTTP who have been successfully treated and maintained in prolonged remission by the prophylactic use of fresh frozen plasma without concurrent plasmapheresis. Two of the patients are sibs.     

Thrombotic thrombocytopenic purpura in 13 Dutch centres: treatment and longterm follow-up

OBJECTIVE: Analysis of the incidence, treatment modalities and disease course of thrombotic thrombocytopenic purpura (TTP) in the Netherlands. DESIGN: Retrospective follow-up study. SETTING: 13 centres in the Netherlands. METHODS: Regarding all patients admitted between 1-1-1979 and 1-1-1992 to one of 13 Dutch haematological centres, in whom the diagnosis of TTP was made for the first time, information was gathered from the medical records and from the patients own physicians on patient characteristics at presentation and the occurrence of relapse or death. The follow-up period tended on 1-4-1995. RESULTS: A total of 65 patients with newly diagnosed TTP were identified: 0.34 per 1,000,000 persons a year (95% confidence interval (95%-CI): 0.26-0.45), increasing to 0.83 in the last year of the study. Forty-six (95%) patients were treated with fresh frozen plasma: 18 (28%) by plasma infusion and 44 (68%) by plasma exchange; 48 (74%) (additionally) received corticosteroids. All 52 patients (80%) who survived the first four weeks after admission reached complete remission. Twelve patients with relapsing TTP underwent splenectomy in remission. The 5-year survival rate was 77% (95% CI: 66-87) and the 5-year relapse-free survival rate 38% (95% CI: 25-52). Cardiac symptoms, severe thrombocytopenia and a high serum LDH were risk factors for acute mortality, but no risk factors for relapse or late-occurring death could be identified. CONCLUSION: TTP is a rare disease which is increasingly being recognized. Plasma exchange and corticosteroids are the most frequently used therapies. The disease has a high mortality rate in the acute phase of the disease.     

Pregnancy and labor in idiopathic thrombocytopenic purpura

Clinical data from eight pregnant women with idiopathic thrombocytopenic purpura (ITP) were retrospectively analyses. The mean age of the women was 28.2 years. Five women underwent splenectomy during childhood. The lowest maternal platelet count observed ranged from 8000 to 88000/mm3. Genital bleeding occurred in only one case. Treatment was based on administration of corticosteroids with or without human-pooled immunoglobulins. Caesarian section was performed in all cases. Six newborns were healthy and had a successful subsequent course. Two infants died, one in utero because of abruptio placentae and the other one 1 month post partum because of a cerebral haematoma. After a mean follow-up of eighteen months, thrombocytopenia is still present in two women, despite the continuous treatment. In conclusion, ITP rather rarely coincides with pregnancy. Treatment is usually successful for the mother but the risk for the fetus remains considerably high.     

Pseudo-Glanzmann thrombasthenia in the course of autoimmune thrombocytopenic purpura

INTRODUCTION: Auto-immune thrombocytopenic purpura is associated with platelet anti-glycoprotein antibodies, particularly with anti-GPIIb/IIIa complex. Persistence of these antibodies sometimes leads to acquired auto-immune thrombopathy. EXEGESIS: We report the case of a woman treated by splenectomy for auto-immune thrombocytopenic purpura, who developed 5 years later an ecchymotic syndrome despite normal platelet count. High bleeding time and platelet aggregation defect in vitro were evidenced. Following the initial thrombocytopenia, anti-glycoproteins GPIIb/IIIa with lupus anticoagulant and benign monoclonal gammapathy were noticed. Platelet controls showed that hypoaggregant activity was secondary to the persistence of anti-GPIIb/IIa antibodies. CONCLUSION: This acquired auto-immune thrombopathy simulating Glanzmann's thrombasthenia was secondary to the persistence of platelet anti-glycoproteins GPIIb/IIIa.