Abnormal platelet function and arachidonate metabolism in chronic idiopathic thrombocytopenic purpura

We observed several patients with chronic idiopathic thrombocytopenic purpura (ITP) whose bleeding times were more prolonged than would have been expected from their platelet counts. To investigate this further, we performed in vivo and in vitro platelet function studies, assessed arachidonate metabolism, and measured platelet-associated IgG (PAIGG) in seven patients with chronic ITP. The bleeding times of three of the patients were prolonged for greater than 7 min, and all of these patients had impaired platelet aggregation and abnormal platelet arachidonic acid metabolism as reflected by increased production of the lipoxygenase product HETE and a concomitant decrease in cyclooxygenase products, TXB2 and HHT (p less than 0.001). The abnormalities noted were not due to concomitant drug ingestion, since they were present on repeated evaluation. There was no relationship between the platelet count and the bleeding time; however, there was a significant inverse correlation between the bleeding time and TXB2 production in all patients evaluated (r = 0.81; p less than 0.05). There was no relationship between the level of platelet-associated IgG and any parameter of platelet aggregation or arachidonate metabolism. The abnormalities noted should be looked for in the individual patient with chronic ITP, since the bleeding tendency is exacerbated by the superimposed impairment of platelet function even at platelet counts of greater than 50,000/cu mm, levels generally regarded as "safe."     

The platelet resistance in idiopathic thrombocytopenic purpura

Summary 29 cases of idiopathic thrombocytopenic purpure were studied by the test of mechanical resistance of platelets. Under these conditions platelets are much more fragile than normal. Furthermore, their resistance increases to normal values in cases showing favourable response to splenectomy.

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Zusammefassung 29 Fälle von Werlhofscher Krankheit wurden mittels des mechanischen Resistenztestes von Thrombozyten untersucht. Unter diesen Umständen sind die Thrombozyten viel schwächer als normal. Weiterhin steigt ihre Resistenz in Fällen mit günstiger Reaktion auf Milzexstirpation auf normale Werte.

     

Helicobacter pylori eradication can induce platelet recovery in chronic idiopathic thrombocytopenic purpura

We prospectively investigated the prevalence of Helicobacter pylori (H. pylori) infection in a cohort of 54 adult Serbian patients with chronic idiopathic thrombocytopenic purpura (ITP), and examined the effects of its eradication on their platelet counts. H. pylori infection was diagnosed in 39/54 (72.2%) patients, using the 14C-urea breath test; and was significantly higher than in the healthy Serbian population (55% P < 0.05). H. pylori-positive patients were significantly older than H. pylori-negative patients (P = 0.006), though there were no significant differences regarding gender, disease duration, mean platelet counts, previous therapies and spleen status between H. pylori-positive and H. pylori-negative patients. Successful eradication was confirmed in 23/30 (77%) treated patients. Stable platelet recovery was registered in 6/23 eradicated patients (26.1%) and maintained for 18 months. Complete and partial remissions were achieved in two and four patients, respectively, including one highly refractory patient. A significant mean platelet recovery was seen 6 months after successful H. pylori eradication in the group of 23 patients (P < 0.05). No platelet recovery was registered in either H. pylori-negative (n = 15), untreated H. pylori-positive patients (n = 9) or H. pylori-positive non-eradicated patients (n = 7). Even though the pathogenetic mechanisms of H. pylori-induced thrombocytopenia remain obscure, the results of this small prospective study support the use of H. pylori eradication as an effective non-immunosuppressive treatment for chronic ITP.     

Platelet antigens in chronic idiopathic thrombocytopenic purpura

IgG produced by splenic cells from five patients with chronic immune thrombocytopenic purpura (ITP) and from four control subjects was radiolabelled and incubated with target platelets. Eluates from these platelets were incubated with solubilized proteins from the same platelets immobilized on nitrocellulose paper. After washing, putative antigens were localized by autoradiography. Positive results were obtained in three of the five ITP patients; in two patients three radiolabelled bands of high molecular weight were noted (greater than 200 000) and in the third patient two different bands (molecular weight 140 000 and 105 000) were seen. Control studies were negative. These studies show that patients with chronic ITP produce antibody reactive with antigens associated with human platelet proteins and that the antigenic pattern differs between patients.     

Laparoscopic splenectomy in chronic idiopathic thrombocytopenic purpura

Splenectomy remains the definitive treatment for idiopathic thrombocytopenic purpura (ITP). Issues related to timing of splenectomy, perioperative management of platelet count, deep vein thrombosis prophylaxis, and preoperative vaccination are not standardized. Predicting the outcome of splenectomy is desirable but, again, consistent evidence for a particular approach is lacking. Laparoscopic splenectomy, first introduced in 1991, has removed some of the barriers to acceptance of splenectomy and may well change its place in the various treatment algorithms. This article reviews current knowledge with respect to laparoscopic splenectomy and provides an analysis of current evidence regarding issues of safety, efficacy, and cost effectiveness. Surgical technique is briefly reviewed. The information is drawn from a comprehensive analysis of the literature, as well as my own large experience with laparoscopic splenectomy, the majority of which has been focused on laparoscopic splenectomy for ITP.     

Immunosuppressive therapy of chronic idiopathic thrombocytopenic purpura

The results of 17 courses of immunosuppressive therapy in 12 adult patients with chronic idiopathic thrombocytopenic purpura were compared to those reported in 94 patients in the literature. About 50 per cent of the reported patients with chronic idiopathic thrombocytopenic purpura treated with immunosuppressive drugs have had a successful response. In most of these, however, the idiopathic thrombocytopenic purpura was of short duration which suggests that many of the responses were spontaneous. The probability of response to immunosuppressive agents is much greater in the splenectomized patient than in the nonsplenectomized patient.Azathioprine and cyclophosphamide are the drugs of choice for the immunosuppressive therapy of chronic idiopathic thrombocytopenic purpura. The immunosuppressive effects of cyclophosphamide probably are better, but the potential complications of this drug in patients with chronic idiopathic thrombocytopenic purpura are more serious. Nonsteroidal immunosuppressive therapy should be used as the primary form of treatment only in patients with serious disease who fail to respond to corticosteroid therapy and who are poor risks for splenectomy. One or more courses of nonsteroidal immunosuppressive therapy may be indicated in patients with chronic refractory idiopathic thrombocytopenic purpura with life-threatening disease. It is expected that from 15 to 35 per cent of adults and probably more children with chronic refractory idiopathic thrombocytopenic purpura will have a successful response.The use of nonsteroidal immunosuppressive drugs in patients with chronic idiopathic thrombocytopenic purpura remains experimental and involves uncertain risks to the patient.     

Dapsone for refractory chronic idiopathic thrombocytopenic purpura

Summary. Fifteen patients with refractory chronic idiopathic thrombocytopenic purpura (ITP) were treated with dapsone (lOOmg/d) for 1-31 months. The overall response rate to dapsone was 40%. Five patients responded in 1 month and one patient in 2 months. No pretreatment characteristics -sex, age, platelet count or duration of ITP - were correlated with response to dapsone. Treatment was well tolerated. The most frequent adverse effect was dose-related haemolytic anaemia. In our experience, dapsone provides an inexpensive and well-tolerated alternative for patients with ITP who had inadequate reponses to conventional therapy.     

Effect of Helicobacter pylori eradication on platelet recovery in Japanese patients with chronic idiopathic thrombocytopenic purpura and secondary autoimmune thrombocytopenic purpura

The prevalence of Helicobacter pylori infection and the effect of its eradication on platelet count in 48 Japanese patients with autoimmune thrombocytopenic purpura (AITP), including 40 chronic idiopathic thrombocytopenic purpura (ITP) and eight secondary AITP, were investigated. H. pylori infection was found in 25 ITP patients (62.5%) and in two secondary AITP (25%). H.pylori eradication was obtained in 19 of 19 infected ITP patients (100%), who were not in remission (platelets < 100 x 109/l) at the time of infection assessment. During follow-up (median 14.8 months), 12 of 19 H. pylori-eradicated patients (63.2%) showed a significant increase in platelet count accompanied by a significant decrease of platelet-associated immunoglobulin G (IgG). This response was maintained in all responding patients throughout the follow-up period. However, two infected patients with secondary AITP did not show platelet increase after eradication. The assessment of H. pylori infection and its eradication should be attempted in ITP as this approach could be an effective strategy, at least for some of these patients.     

High-dose dexamethasone therapy in chronic idiopathic thrombocytopenic purpura

 A high-dose pulse of dexamethasone has been described as a current option for the treatment of refractory idiopathic thrombocytopenic purpura (ITP), but the results are controversial. Here we describe the use of a high dose of dexamethasone (40 mg per day for 4 days every month) in 18 patients with chronic ITP. The median age of the patients was 42.5 years (range, 16–77 years); 13 were female and five male. The duration of the disease ranged from 5 to 480 months, and splenectomy was carried out in six of the 18 patients.The overall results obtained revealed a satisfactory response (platelet counts higher than 50×10⁹/l) in eight of the 18 patients. However, a long-term remisson was achieved in only three of the eight patients with a follow up of 7–16 months. We were not able to identify any clinical or laboratory prognostic parameters or previous treatment which would allow one to predict a successful outcome of this treatment. These results suggest that a high dose of dexamethasone may provide an alternative, be it a poor one, for the treatment of refractory IPT, in which the use of a low-cost drug with limited side effects is an important consideration. Received: 18 March 1996 / Accepted: 2 July 1996     

Intravenous gammaglobulin treatment of chronic idiopathic thrombocytopenic purpura

High-dose intravenous gammaglobulin (IVIgG) was given to 12 children and adults with chronic idiopathic thrombocytopenic purpura (ITP) to avoid splenectomy or because they either failed to respond to or required maintenance with high doses of steroids and/or immunosuppressives. The average platelet count increase to initial therapy was 239,500/microliters (range 23,000-790,000). A concomitant IgG Fc receptor blockade, measured by IgG-sensitized 51Cr-labeled autologous erythrocytes, was seen in 11 of 11 patients tested, both splenectomized and not splenectomized, lasting 3-4 wk. Six or more months after treatment, 2 children are in remission, 2 children and 2 adults are stable requiring no therapy with platelet counts of approximately 50,000 and 30,000, respectively, 3 children require maintenance IVIgG therapy at 2-10-wk intervals, and 1 child and 2 adults have become refractory to further IVIgG. Splenectomy was not performed in 4 children. Two adults were able to discontinue daily prednisone. The 3 patients who became unresponsive to Swiss Red Cross gamma-globulin (IgSRK) therapy did so in conjunction with a markedly elevated platelet-associated IgG and IgM. Serum IgM increased an average of 103 mg/dl after the IVIgG infusions. No significant side effects were seen.     

Effect of Helicobacter pylori eradication on platelet recovery in patients with chronic idiopathic thrombocytopenic purpura

BACKGROUND: A relationship between Helicobacter pylori infection and idiopathic thrombocytopenic purpura (ITP) has previously been reported. We determined the prevalence of H pylori infection in Japanese patients with chronic ITP and the effect of its eradication on platelet count. METHODS: The study population comprised 53 Japanese adults with chronic ITP and a platelet count of less than 100 x 10(3)/ micro L. A (13)C-urea breath test was performed to determine H pylori infection status. Those patients who were H pylori positive gave written informed consent and received eradication therapy. The effect of H pylori eradication on platelet count was evaluated up to 6 months after therapy. Clinical parameters were compared between responders to the therapy (increase in platelet count) and nonresponders, as well as between H pylori-positive and -negative patients. RESULTS: Of the 53 patients with chronic ITP in the study, 39 (74%) were H pylori positive. Of the 32 infected patients who received treatment, H pylori was successfully eradicated in 27 patients (84%). In 10 (37%) of these patients, this resulted in a favorable platelet response. A partial response was seen in 5 additional patients (19%). A significant (P<.001) increase in platelet count was demonstrated in patients in whom H pylori was successfully eradicated but not in patients who were unsuccessfully treated or in untreated patients. Current corticosteroid therapy was reported more often in nonresponders than in responders. CONCLUSION: Eradication of H pylori may prove effective in increasing platelet count in H pylori-positive patients with chronic ITP.     

Pharmacological characterization of cepharanthin in chronic idiopathic thrombocytopenic purpura

Cepharanthin, a bisbenzylisoquinoline (biscolaurine) alkaloid drug, has been reported to improve the symptoms of intractable or steroid-resistant chronic idiopathic thrombocytopenic purpura (ITP). To clarify the mechanism by which the cepharanthin is beneficial to ITP, we examined the effects of cepharanthin on thrombocytopenia in (NZW 2 BXSB) F1 (W/B F1) mice and on the formation of colony forming unit of megakaryocyte (CFU-MK) derived from human CD34-positive progenitor cells. The decrease in platelet numbers in W/B F1 was diminished by the administration of 5 mg/kg cepharanthin for 6 weeks as well as by 2 mg/kg prednisolone. Furthermore, the administration of over 0.2 mg/kg cepharanthin enhanced the therapeutic effect of prednisolone. From the data in this animal model, it is suggested that cepharanthin may prolong the platelet lifespan. The treatment of CD34-positive progenitor cells isolated from cord blood with cepharanthin (over 5 2 10 -10 g/ml) caused an increase in the formation of CFU-MK induced by the cocktail of thrombopoietin, interleukin (IL)-6 and IL-3. The addition of 0.1% normal human serum dramatically increased the number of CFU-MK. In contrast, the serum isolated from patients with ITP at the same concentration decreased the number of CFU-MK. However, the simultaneous addition of 5 2 10 -8 g/ml cepharanthin recovered the number of CFU-MK to the level induced by normal serum. These findings indicate that cepharanthin has the potent therapeutic activity not only on the platelet destruction process, but also on the platelet production process of thrombocytopenia in chronic ITP.     

Pharmacological characterization of cepharanthin in chronic idiopathic thrombocytopenic purpura

Cepharanthin, a bisbenzylisoquinoline (biscolaurine) alkaloid drug, has been reported to improve the symptoms of intractable or steroid-resistant chronic idiopathic thrombocytopenic purpura (ITP). To clarify the mechanism by which the cepharanthin is beneficial to ITP, we examined the effects of cepharanthin on thrombocytopenia in (NZW x BXSB) F1 (W/B F1) mice and on the formation of colony forming unit of megakaryocyte (CFU-MK) derived from human CD34-positive progenitor cells. The decrease in platelet numbers in W/B F1 was diminished by the administration of 5 mg/kg cepharanthin for 6 weeks as well as by 2 mg/kg prednisolone. Furthermore, the administration of over 0.2 mg/kg cepharanthin enhanced the therapeutic effect of prednisolone. From the data in this animal model, it is suggested that cepharanthin may prolong the platelet lifespan. The treatment of CD34-positive progenitor cells isolated from cord blood with cepharanthin (over 5 x 10(-10)g/ml) caused an increase in the formation of CFU-MK induced by the cocktail of thrombopoietin, interleukin (IL)-6 and IL-3. The addition of 0.1% normal human serum dramatically increased the number of CFU-MK. In contrast, the serum isolated from patients with ITP at the same concentration decreased the number of CFU-MK. However, the simultaneous addition of 5 x 10(-8)g/ml cepharanthin recovered the number of CFU-MK to the level induced by normal serum. These findings indicate that cepharanthin has the potent therapeutic activity not only on the platelet destruction process, but also on the platelet production process of thrombocytopenia in chronic ITP.     

Pathophysiology of platelet destruction in immune (idiopathic) thrombocytopenic purpura

The mechanism of platelet destruction in immune (idiopathic) thrombocytopenic purpura (ITP) is thought to involve production of autoantibody to platelet surface antigens. Once coated with antibody, circulating platelets undergo sequestration via interaction with Fc receptors of macrophages in the reticuloendothelial system. A number of questions remain about the mechanism of platelet destruction in this disease: 1) What is the nature of the stimulus to the immune system that generates antiplatelet antibodies? 2) What is the role of interactions between T-helper lymphocytes and antigen-presenting cells in ITP? 3) What role, if any, is played by the targeting of single or multiple platelet surface glycoproteins by the autoimmune response? 4) Is the site of platelet destruction, intravascular or extravascular, or the state of activation of platelets important in the destruction of platelets?     

Analysis of anti-platelet antibody and platelet volume in idiopathic thrombocytopenic purpura

We investigated platelets and plasma from patients with idiopathic thrombocytopenic purpura (ITP) to elucidate the antigenic determinants at which their autoantibodies are directed, and studied the relationship between anti-platelet antibody and platelet volume. We used flow cytometry to detect platelet-associated IgG (PAIgG), C3 (PAC3), IgM (PAIgM) and platelet volume, and also to determine the binding rate of monoclonal anti-platelet antibodies in patients with ITP. The following results were obtained. 1. Both anti-GPIIb/IIIa autoantibodies (21 of 71 patients) and anti-GPIb autoantibodies (3 of 71 patients) were found in ITP. 2. The decrease in platelet count in patients without anti-GPIIb/IIIa autoantibodies was significant. 3. The increase in platelet volume was found more frequently in patients with a platelet count less than 50,000 and in untreated patients. 4. There was a positive correlation between the platelet volume and PAIgM in patients with a platelet count less than 30,000 and high levels of PAIgM.