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.     

Aberrant increase in the immature platelet fraction in patients with myelodysplastic syndrome: a marker of karyotypic abnormalities associated with poor prognosis

Objectives: Some patients with myelodysplastic syndrome (MDS) show a marked increase in the percentage of immature platelet fraction (IPF%) despite the absence of severe thrombocytopenia. To determine the significance of such an unbalanced increase in the IPF%, we investigated the IPF% and other laboratory findings of 51 patients recently diagnosed with MDS. Method: Subjects consisted of 80 healthy males, 90 healthy females, and 51 patients with MDS and 20 patients with idiopathic thrombocytopenic purpura (ITP). The IPF and IPF% were determined using a Sysmex XE‐2100 system loaded with IPF Master software (XE IPF Master, Sysmex). Platelet counts were measured simultaneously. Results: IPF% and platelet counts of these patients ranged from 1.1% to 25.1% (median, 5.3%) and from 6 to 260 × 10⁹/L (median, 71 × 10⁹/L), respectively. Twelve patients showed platelet counts more than 50 × 10⁹/L with 10% or more IPF%. All of the 12 patients had chromosome abnormalities including monosomy 7 and complex abnormalities involving 7 or 5q. In the other 39 patients who did not show the aberrant IPF% increase, chromosomal abnormalities were seen only in seven patients and none of them had chromosome 7 abnormalities. The IPF% of two patients increased to more than 10% in association with the appearance of monosomy 7. Conclusions: These findings suggest that a high IPF% in MDS patient may be a marker for karyotypic abnormalities with a poor prognosis, including chromosome 7 abnormalities.     

Persistent remission of adult chronic autoimmune thrombocytopenic purpura after treatment with high-dose intravenous immunoglobulin

Transient efficacy of high-dose intravenous immunoglobulin infusions (HDI) is widely demonstrated in autoimmune thrombocytopenic purpura (AITP). A trial involving repeated injections of HDI was conducted in two adult patients with chronic AITP in order to evaluate their long-term efficacy in refractory forms and their ability to obviate splenectomy. Both patients received 2 g/kg body weight of polyvalent intact intravenous immunoglobulin followed by seven and eight boosters (0.8 to 1.2 g/kg body weight) when the platelet count decreased. It was found that the injections could be spaced progressively. The platelet count remained normal 200 and 800 days after the end of the treatment. The demonstration of the possible long-term efficacy of repeated injections of intravenous immunoglobulin encourages us to recommend this safe therapy for patients with chronic AITP.     

Dapsone for chronic autoimmune thrombocytopenic purpura: a report of 66 cases

Sixty-six adults with chronic autoimmune thrombocytopenic purpura AITP and platelet count <50 ×10⁹ l were treated with dapsone (75–100 mg orally). A response was observed in 33 patients. The median duration of treatment required to obtain a response was 21 d (range 8–90). The median maximal platelet count on treatment was 130 × 10⁹ l (range 71–355). Dapsone was continued in 20/33 responders for a median of 12.5 months (range 1–48) and the response persisted in 19. Treatment was intentionally withdrawn in the other 13 responders and thrombocytopenia immediately recurred in 12. Reversible side-effects required cessation of treatment in seven patients. These results demonstrate that dapsone is an effective, inexpensive, and well-tolerated treatment for chronic AITP.     

Immature platelet fraction measurement in patients with chronic liver disease: a convenient marker for evaluating cirrhotic change

Platelet number is often used as an indicator of the severity of liver disease. Although inadequate thrombopoietin production and decreased platelet production have been proposed as major causes of cirrhotic thrombocytopenia, the underlying mechanism has not yet been fully clarified. We examined whether the measurement of the immature platelet fraction (IPF) in thrombocytopenic patients with liver dysfunction is useful as a rapid and noninvasive method for the differential diagnosis of chronic liver diseases. We examined 20 liver cirrhosis patients, 56 patients with chronic hepatitis, 9 patients with fatty liver, and 86 patients without liver disease. The percentage value of IPF (IPF%) was measured using an XE-2100 multiparameter automatic hematology analyzer. Using a receiver operating characteristic curve, we found diagnostic significance of the absolute platelet count and the absolute number of the IPF between cirrhotic patients and noncirrhotic patients, and developed a powerful multivariate discriminant analysis (MDA) function based on the platelet count and the IPF%. The diagnostic accuracy obtained by the MDA function was superior to that obtained by the absolute number of platelets and the IPF. We therefore propose our IPF% measurement for the diagnosis of liver cirrhosis.     

Patterns of platelet response in idiopathic TTP/HUS: frequency of declining platelet counts with plasma exchange and the recognition and significance of a pseudo refractory state

For thrombotic thrombocytopenic purpura (TTP), daily plasma exchange (TPE) is typically discontinued when the platelet count normalizes (>150 x 10(9)/L). We observed a decline in platelet count during TPE and in patients who appeared pseudo-refractory because of a platelet count plateau (100-150 10(9)/L range). In the present study, we evaluated platelet count trends in TTP patients. Retrospective review of TTP patients from 01/1999 to 12/2004 was completed. Patients were categorized based on platelet count trends: Group I, counts rose then decreased to levels <100 x 10(9)/L; Group II, counts declined following TPE initiation; Group III, counts rose continuously; Group IV, counts decreased after the count was >100 x 10(9)/L. Additionally, we identified pseudo-refractory patients caused by a platelet count plateau (>100 x 10(9)/L but <150 x 10(9)/L). We identified 60 TTP patients. Within Group I (17 patients/17 series/19.1% of total), the mean decrease in platelet count was 67.3% +/- 22.1% following initial rise. Within Group II (24 patients/25 series/28.1% of total), the mean decrease was 28% +/- 5.3% following presentation. Group III included 31 patients/39 series (43.8% of the total). Within Group IV (seven patients/eight series/9.0% of total), the mean decrease was 17.4% +/- 12.6% following a sustained rise >100 x 10(9)/L. With a declining platelet count and daily TPE, it is generally sufficient to stay the course and the decline will reverse. Our limited experience with pseudo-refractory patients supports discontinuing TPE when counts plateau between 100 and 150 x 10(9)/L when a therapy goal is a platelet count of 150 x 10(9)/L. Recognition of this pseudo-refractory state can minimize the risks of prolonged TPE and the risks of adjunct interventions.     

Does cryosupernatant plasma improve outcome in thrombotic thrombocytopenic purpura? No answer yet

A randomized prospective trial compared cryosupernatant plasma (CSP) to fresh frozen plasma (FFP) for treatment of thrombotic thrombocytopenic purpura (TTP). A total of 236 patients were required: 28 patients were treated with CSP and 24 with FFP within 30 months. There were no differences in survival at 1 month. By day 9, 17 of 26 patients with CSP and 18 of 24 with FFP had a platelet count >100 x 10(9)/l. At entry, von Willebrand factor (VWF) multimers were normal in all patients (range 1.1-3.95 IU/ml). ADAMTS-13 levels showed large variations ranging from 10% to 100% activity. At entry, no individual had <5% VWF cleaving protease. By day 9 (end of cycle), 89% (FFP) and 67% (CSP) had levels >50% of the controls. At 6 months some patients showed inhibitors to the enzyme in spite of adequate or normal platelet counts. The data from this study do not show an apparent advantage to the use of CSP in TTP. A large number of patients will be required to determine appropriate replacement therapy. We were not able to find a statistically significant relationship between the low level of protease activity at presentation of TTP and response.     

Thrombotic thrombocytopenic purpura precipitated by acute pancreatitis: a report of seven cases from a regional UK TTP registry

Thrombotic thrombocytopenic purpura (TTP) may be idiopathic or secondary. We report seven TTP cases precipitated by pancreatitis. The patients were admitted with acute pancreatitis and at that time had no clinical or laboratory features of TTP. The median time to develop TTP after pancreatitis was 3 d. The patients had moderately reduced ADAMTS13 activity (mean activity 49%; normal range 66–126%) with no evidence of anti-ADAMTS13 inhibitory autoantibodies. The median number of plasma exchanges to remission was 10 (range 7–14) and no additional treatment with immunosuppression was required to maintain remission. There have been no relapses to date.     

Complement activation on platelets correlates with a decrease in circulating immature platelets in patients with immune thrombocytopenic purpura

The role of the complement system in immune thrombocytopenic purpura (ITP) is not well defined. We examined plasma from 79 patients with ITP, 50 healthy volunteers, and 25 patients with non‐immune mediated thrombocytopenia, to investigate their complement activation/fixation capacity (CAC) on immobilized heterologous platelets. Enhanced CAC was found in 46 plasma samples (59%) from patients with ITP, but no samples from patients with non‐immune mediated thrombocytopenia. Plasma from healthy volunteers was used for comparison. In patients with ITP, an enhanced plasma CAC was associated with a decreased circulating absolute immature platelet fraction (A‐IPF) (<15 × 10⁹/l) (P = 0·027) and thrombocytopenia (platelet count < 100 × 10⁹/l) (P = 0·024). The positive predictive value of an enhanced CAC for a low A‐IPF was 93%, with a specificity of 77%. The specificity and positive predictive values increased to 100% when plasma CAC was defined strictly by enhanced C1q and/or C4d deposition on test platelets. Although no statistically significant correlation emerged between CAC and response to different pharmacological therapies, an enhanced response to splenectomy was noted (P < 0·063). Thus, complement fixation may contribute to the thrombocytopenia of ITP by enhancing clearance of opsonized platelets from the circulation, and/or directly damaging platelets and megakaryocytes.     

Characterization of platelet glycoproteins and platelet/endothelial cell antibodies in patients with thrombotic thrombocytopenic purpura

Platelets and sera from 12 patients with thrombotic thrombocytopenic purpura (TTP) and 12 healthy normal control subjects were examined. As determined by quantitative flow cytometry, prior to plasma exchange therapy platelet surface glycoprotein (GP) Ib levels were similar in TTP patients and normal controls (mean 20 188 and 20 226 molecules/platelet, respectively). Platelets from patients with TTP did, however, have significantly reduced levels of GPIIb/IIIa prior to plasmapheresis (mean 36 348 v 52 505 molecules/platelet in controls; P = 0.0004) and of GPIV (mean 13 321 v 26 212 molecules/platelet in controls; P = 0.0002). An increase in activated platelets, as determined by CD62 expression, was observed in 82% of patients. Increased platelet-associated immunoglobulins and/or complement was also seen in approximately 60% of the patients. In general, with return of platelet counts to normal levels following seven plasmaphereses, the above abnormalities were reversed, although often not to normal levels. Western blot analysis indicated the presence of antibodies reactive to platelet GPIV (88 kD) in 70% of pretreatment sera from patients with TTP; a similar band was observed in 80% of patient sera against microvascular endothelial cells. Immunofluorescence microscopic examination indicated the presence of antibody in pretreatment sera from patients with TTP to microvascular (73%) and large vessel (36%) endothelial cells. As measured by an indirect flow cytometric assay, pretreatment sera from 55% of patients with TTP were reactive with large vessel endothelial cells and 100% reacted with microvascular endothelial cells; reactivity was significantly greater against the microvascular endothelial cells (P = 0.0048) and was reduced following plasma exchange therapy. These results indicate abnormalities in platelet glycoprotein expression in TTP and suggest that anti-platelet and anti-endothelial cell antibodies play a role in the thrombocytopenia and vasculitis characteristic of this disorder.     

Myelofibrosis and idiopathic thrombocytopenic purpura

 A case of idiopathic myelofibrosis (IMF) with concomitant autoimmune thrombocytopenic purpura (AITP) is reported. The literature on platelet antibodies in IMF is reviewed. Received: 25 March 1997 / Accepted: 11 July 1997     

Rituximab for the treatment of refractory idiopathic thrombocytopenic purpura (ITP) and thrombotic thrombocytopenic purpura (TTP): report of three cases

Three patients (one with idiopathic thrombocytopenic purpura [ITP] and two with thrombotic thrombocytopenic purpura [TTP]) were treated with rituximab (anti-CD20 chimeric antibody) at a dose of 325 mg/m2 administered weekly after they failed standard therapies. The patient with ITP who did not respond to steroids and anti-D antibody administration achieved augmentation of her platelet counts up to 180 x 10(3)/microL after four doses of rituximab. Six months later, when her counts started to decrease, she received maintenance therapy with an additional course of 4 standard doses of antibody that resulted in consolidation of her platelet counts around 100 x 10(3)/microL. One patient with TTP and concurrent idiopathic nephropathy who was previously treated with plasmapheresis, steroids, and vincristine improved only after 4 weekly administrations of the antibody. Moreover, his nephrotic-range proteinuria resolved after he received rituximab. The other patient with chronic TTP who still relapsed after splenectomy received 5 doses of rituximab with concomitant plasmapheresis. His thrombocytopenia improved slowly, and his platelet count stabilized at 300 x 10(3)/microL. All three patients showed evidence of response to anti-CD20 antibody with improvement in clinical outcome as well as augmentation of platelet counts to normal levels. We conclude that rituximab is a useful immunomodulating adjunct in the treatment of refractory ITP and TTP.     

Effectiveness of platelet transfusions after plasma exchange in adult thrombotic thrombocytopenic purpura: a report of two cases.

Plasma infusion (PI) and plasma exchange (PE) are the most efficient treatment of thrombotic thrombocytopenic purpura (TTP), allowing achievement of complete remission in 60 to 90% of cases. Life-threatening bleeding, related to severe thrombocytopenia, is one of the main complications of the disease. Thrombocytopenia may also preclude invasive procedures such as splenectomy, which may be required during the management of TTP. Platelet concentrates transfusions are usually thought to worsen the disease, especially if not associated with the appropriate treatment of this latter, and thus should be avoided. We report hereon 2 patients with TTP who experienced a surgical procedure i.e., a cholecystectomy for a cholecystitis, and a splenectomy for a refractory TTP. In both patients, the surgical procedure was preceded by a 60 mL/kg plasma exchange with solvent/detergent treated plasma as replacement fluid, followed by platelet transfusion, with a corrected count increment of 57.1% (Patient 1) and 69.3% (Patient 2). Using this sequential treatment, the patients did not experience any deterioration of their status. Both patients had a favorable outcome after surgery. However, until such a procedure will be validated on a larger series of patients, it should be restricted to patients presenting with a refractory life-threatening thrombocytopenia and/or requiring surgery or any kind of invasive procedure. Am. J. Hematol. 68:198-201, 2001. Published 2001 Wiley-Liss, Inc.     

Therapeutic plasma exchange in patients with grade 2-3 hematopoietic stem cell transplantation-associated thrombotic thrombocytopenic purpura: a ten-year experience

In the present retrospective study we report our 10-year experience with therapeutic plasma exchange (TPE) in 18 patients with grade 2-3 hematopoietic stem cell transplantation (HSCT)-associated thrombotic thrombocytopenic purpura (TTP). During TPE a mean total quantity of 26.5 +/- 15.1 L of plasma was exchanged. Five patients (27.7%) had a complete response eight patients (44.4%) had a partial response while five patients (27.7%) died during TPE treatment. Among the survivors, relapse of TTP occured in three patients (23%) and although these patients were treated again with TPE, all died. First-year survival rate was 41.2%. Our results indicate that TPE may be effective in the treatment of some patients with grade 2-3 HSCT-associated TTP.     

The role of splenectomy in the treatment of relapsing thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) is a serious disorder of unknown etiology. Clinical findings are the result of vascular occlusions by platelet aggregates. Treatment with plasma exchange, often used in combination with corticosteroids, vincristine, aspirin, and dipyridamole, has reduced mortality to 20%. Relapses may occur even after long disease-free intervals. In this report we describe our experience with splenectomy in patients with relapsing TTP. Between July 1978 and March 1994, 16 patients with TTP were treated in our hospital. Five of the 13 patients surviving the first episode of TTP had relapses. Most relapses were treated as the first episode of TTP with plasma exchange with fresh-frozen plasma, followed by plasma infusions, corticosteroids, and vincristine. Sometimes aspirin and dipyridamole were added. Splenectomy was performed after five relapses in the first two patients and after two and three relapses in the other patients. Before splenectomy the disease-free interval varied from 3 weeks to 27 months and the incidence rate of relapses was 1.5 relapse/patient/year. None of the patients had relapses after splenectomy. The mean follow-up after splenectomy is 39 months with a range of 9–62 months. We conclude that patients with relapsing TTP can benefit from splenectomy, since it seems to increase disease-free intervals. Further investigation is necessary to understand the role of the spleen in the pathogenesis of TTP.     

The response to high-dose intravenous immunoglobulin or steroids is not predictive of outcome after splenectomy in adults with autoimmune thrombocytopenic purpura

The response to high-dose intravenous immunoglobulin (IVIg) was recently reported to be predictive of outcome after splenectomy in patients with autoimmune thrombocytopenic purpura (AITP). We analysed the records of 75 adults with chronic AITP who received IVIg and subsequently underwent splenectomy. There was no significant difference in the response rate to splenectomy according to whether or not patients had responded to IVIg (81% v 67%, P = 0.36). Age, the time from diagnosis to splenectomy, and the response to steroids were also not significantly associated with outcome after splenectomy. These results indicate that the response to IVIg or steroids is not predictive of the efficacy of splenectomy.     

Myocardial necrosis in patients with thrombotic thrombocytopenic purpura: pathophysiology and rationale for specific therapy

Myocardial necrosis is now recognized as a common feature of thrombotic thrombocytopenic purpura (TTP), usually due to platelet plugging in the microvasculature. Despite reports that TTP patients with myocardial damage have higher morbidity and mortality, there are no established guidelines for managing these high‐risk patients. The universal occurrence of thrombocytopenia and variable findings including renal dysfunction present unique challenges in this setting. Established therapies including plasma exchange and immunosuppression are the mainstay of therapy for all TTP patients. For the subset of patients with myocardial damage, therapy with more potent antiplatelet drugs, agents that enhance NO availability and alleviate vasospasm and drugs that suppress von Willebrand factor levels may have additional benefit. However, clinical trials are needed to optimize therapy for this subset of TTP patients.     

Serum thrombopoietin levels in thrombocytopenic and non-thrombocytopenic patients with human immunodeficiency virus (HIV-1) infection.

HIV-1 seropositive patients often exhibit thrombocytopenia, considered of multifactorial aetiology. Thrombopoietin (TPO), a recently isolated cytokine, is the main regulator of megakaryocyte and platelet production. The objective of this study was to analyse serum TPO levels in thrombocytopenic and non-thrombocytopenic HIV-1 infected patients. Serum TPO levels were measured by ELISA in 43 healthy individuals and in 88 HIV-1 infected patients: 68 thrombocytopenics and 20 non-thrombocytopenics. Thrombocytopenic HIV-1 infected patients showed higher TPO concentrations (263 +/- 342 pg/ml) than non-thrombocytopenics (191 +/- 86 pg/ml); levels in both groups were significantly higher than those of healthy controls (121 +/- 58 pg/ml). Two subgroups of thrombocytopenic patients, the autoimmune thrombocytopenic purpura (AITP) group and the mild thrombocytopenic group, presented TPO levels similar to those of non-thrombocytopenics. Patients exhibiting pancytopenia showed the highest TPO concentrations. However, there was no correlation between TPO levels and platelet counts in any group of HIV-1 infected patients. TPO levels in HIV-1 seropositive patients were slightly increased and the differences in TPO levels between thrombocytopenic and non-thrombocytopenic patients were generally small. The finding of mildly increased TPO levels along with the recently described recovery of thrombocytopenia following recombinant TPO administration confirms the implication of ineffective platelet production in the origin of HIV-associated thrombocytopenia.     

A simple method for detecting complement-fixation by autologous platelets in autoimmune thrombocytopenic purpura

Summary A new modification of the microtitre complement fixation test, (CFT), is described for the detection of platelet-bound antibodies (PBA). The test was positive in 12 out of 16 patients, (75%), with active autoimmune thrombocytopenic purpura (AITP). It was negative in four patients who were in remission of AITP when tested, in 10 patients with non-immune thrombocytopenia and in 51 normal blood donors. This is a semi-quantitative method in which suspensions of the patients' own platelets consume complement and therefore prevent the lysis of sensitised sheep red cells (SRBC). Sera from some of these cases were also tested for serum anti-platelet antibody (SPA) and immune complexes. The possible mechanisms and the relevance of positive results are discussed.     

Cyclosporin A as an Immunosuppressive Treatment Modality for Patients with Refractory Autoimmune Thrombocytopenic Purpura after Splenectomy Failure

The treatment of autoimmune thrombocytopenic purpura (AITP) remains unsatisfactory in patients refractory to first-line management such as corticosteroid therapy and/or splenectomy. Patients with refractory AITP usually require unacceptably high doses of corticosteroids to maintain a safe platelet count. Immunosuppressive treatment with cyclosporin A (CsA) is a relatively new treatment modality, and no large studies of this drug have been conducted. We used CsA in 6 patients with refractory AITP who had platelet counts of less than 20 x 10(9)/L without any therapy or who had evidence of subcutaneous and mucosal bleeding. All 6 patients had undergone splenectomy. When CsA therapy was begun, 5 of the patients were receiving methylprednisolone (MP) at a daily dose of 32 mg or greater. During the following months, the MP dosage was tapered, or the drug was withdrawn. Three patients achieved a complete remission (CR), whereupon CsA treatment was gradually discontinued. Two of these 3 patients later relapsed, but both responded to an additional course of CsA and achieved a second CR. The remaining 3 patients achieved a partial remission (PR). One patient, a woman with an AITP history of more than 30 years, obtained a stable PR with a platelet count substantially greater than 20 x 10(9)/L, which was successfully maintained by low doses of CsA and MP. The most frequent side effect of CsA therapy in our patients was a painful edema of the lower extremities. Our experience shows that CsA is a safe and effective treatment option for patients with refractory (chronic) AITP. It may be given at a low dose as maintenance therapy, and remissions may be sustained even after the drug has been discontinued.