Evaluation of 143 Cases of Immune Thrombocytopenic Purpura With Regards to Clinical Course and Response to Treatment

Objective: Immune thrombocytopenic purpura (ITP) is also known as idiopathic thrombocytopenic purpura. Increased platelet destruction and insuffi cient platelet production are both responsible for its etiopathogenesis. ITP can be diagnosed after excluding other possible causes of thrombocytopenia. Materials and Methods: One hundred forty-three cases of chronic ITP that were monitored in a hematology clinic were retrospectively evaluated. All cases received fi rst line treatment of 1 mg/kg/day prednisolone. Corticosteroid nonresponsive (CN) cases and corticosteroid-dependent (CD) cases underwent splenectomies. Results: The rate of CN/CD cases was found to be 53% (n=76). Sixtysix percent of these cases (n=50) underwent splenectomies. The ratio of non-responsive cases to relapse cases after splenectomy (SN/SR) was 30% (n=15). The total number of cases was 41, including those without splenectomy (n=26) and with SY/SR (n=15). Helicobacter pylori (Hp) eradication, immunosuppressive agents and danazol treatments were administered to patients (n=10, n=14 and n=4, respectively). Currently, 13 patients are being monitored without treatment. Fifteen patients who were non-responsive to Hp eradication treatment, immunosuppressive treatment or danazol treatment are still being monitored without any treatment. Conclusion: Optimal treatment is not available for splenectomy-resistant cases of ITP. The response rates for Hp eradication treatment, immunosuppressive treatments and anabolic agents are low. Therefore, larger studies with more patients are required using new agents, such as thrombopoietin (TPO) receptor agonists and anti-CD20 monoclonal antibodies.


Introduction
Immune thrombocytopenic purpura (ITP) is also known as idiopathic thrombocytopenic purpura [1].No specific criteria are available for the diagnosis of ITP.ITP can be diagnosed after the exclusion of other diseases causing thrombocytopenia.Therefore, ITP is currently described as a primary immune thrombocytopenia [2,3].The clinical course of ITP is usually chronic in adults.In cases of chronic ITP, serious bleeding is not expected even with significant thrombocytopenia.The mortality rate due to bleeding secondary to ITP is less than 1% [4].Corticosteroids are given as the first line of therapy in ITP cases with serious thrombocytopenia.Splenectomy is the standard care for cases that are non-responsive to corticosteroids.The rate of complete remission is 66% [5].No consensus is currently available regarding the appropriate treatment of patients with serious thrombocytopenia who require treatment following the splenectomy [6].Various post-splenectomy treatments have been administered to refractory patients.Azathioprine, vinka alkaloids, danazol, cyclophosphamide, high dose dexamethasone, rituximab, interferon, and cyclosporine have been used.The treatment of chronic refractory ITP is difficult because response to treatment is variable.Treatment-related serious side effects may be observed [7].Thrombopoietin (TPO) receptor antagonists and anti-CD20 monoclonal antibodies are new treatment approaches with different mechanisms of action [8,9].

Materials and Methods
Age, gender, baseline clinical symptoms, platelet count, administered treatment, treatment response, complications and relapse rates of 143 chronic ITP patients admitted to hematology clinics were retrospectively evaluated.The general patient characteristics are summarized in Table 1.

Statistical analyses
Data were analyzed with Statistical Software Package Program (SPSS) 11.5 for Windows.Continuous variables were used for descriptive statistics and means±standard deviations or medians (min-max) were used for categorical variables.

Findings
The most common complaints of patients admitted to the hospital were ecchymosis and epistaxis (Table 2).One hundred forty-three cases with a platelet count of 1.000-25.000/μIwere administered prednisolone as the first line of treatment.Eight cases who were admitted with gastrointestinal system (GIS) and subarachnoid bleeding were not included in this study.Complete response (CR) was considered the maintenance of a platelet count within normal ranges without treatment for three months following the discontinuation of prednisolone.A platelet count ≥30.000/ μI without treatment was considered a partial response (PR).A platelet count <30.000/μI, despite four-weeks of full dose treatment, was considered a non-response.A platelet count <30.000/μI with a reduced or discontinued used of steroids was considered steroid dependence.Forty-seven percent (n=67) of patients responded to treatment (CR 35%, PR 12%).Thirty-four patients (24%) were non-responsive to steroids and relapsed (31 patients non-responsive to steroids, and 3 patients relapsed).Forty-two patients (29%) were dependent on steroids.
Fifteen of the 143 cases were pregnant.Ten of the pregnant women achieved CR and PR.Two were non-responsive to steroids, and three were dependent on steroids.Splenectomy was performed in two steroid-dependent pregnant patients after delivery, and CR was achieved.
Splenectomy was performed in 66% of 76 cases (n=50) who were non-responsive and steroid dependent.Splenectomy indications were a platelet count <30.000/μI after 1 mg/kg prednisolone treatment for a period of four weeks or during the reduction or discontinuation of the steroid dosage.Regarding the preoperative preparation regimen for splenectomy, intravenous immunoglobulin G, steroids, platelet suspension and anti-D were administered to 5, 29, 13 and 3 patients, respectively.Thirty-five patients (70%) of 50 were respondent to splenectomy, but 15 (30%) patients were nonresponsive or relapsed.Eleven patients were non-responsive to splenectomy, and four cases relapsed.Splenectomies were either open or laparoscopic and were performed in 43 cases (86%) and 7 cases (14%), respectively.Forty-one cases did not have a splenectomy and relapse and/or lack of a response to splenectomy.Ten of 41 cases had a positive urea-breath  test, and Helicobacter pylori (Hp) eradication treatment was initiated.Immunosuppressive treatment was initiated for 14 patients whose platelet counts were <10.000.Danazol was given to 4 patients, and 13 cases (platelet counts in the range of 10.000-30.000 and without bleeding) were followed without any treatment.Fifteen cases that were non-responsive to Hp eradication treatment, immunosuppressive treatment or danazol continue to be followed without any treatment.Table 3 summarizes the treatments and results of patients who did not undergo splenectomies, who relapsed and who were non-responsive to splenectomy.Complications associated with treatment are summarized in Table 4.

Discussion
Typically, glucocorticoid treatment at a dose of 1 mg/kg is initiated for ITP cases with a platelet count <30.000.When the platelet count is >30.000,bleeding is not expected, and these cases are followed without any treatment.In patients non-responsive to glucocorticoids, splenectomy is the treatment choice, and 2/3 of cases respond.Mortality and morbidity associated with splenectomy are quite rare [10].
In accordance with the literature, the response rates for steroids and splenectomy were found to be 71% in our study of 143 ITP cases.No life-threatening complications have yet been observed due to the use of steroids or the splenectomy.Data about the immunosuppressive treatment responses were excluded because the number of patients non-responsive to steroids and splenectomy was low.However, no bleeding symptoms were observed in non-responsive and untreated patients.Therefore, long-term immunosuppressive treatment is unnecessary if the platelet count is over 10.000.Moreover, the rate of treatment-related mortality may be higher than the rate of bleeding-related mortality [11,12].In recent studies, treatment-free monitoring has been recommended for patients who are non-responsive to glucocorticoid treatment, have no symptoms of bleeding (or with minor purpura) and have a platelet count >20.000.Splenectomy is also recommended for patients who have bleeding symptoms with a platelet count <20.000.Following splenectomy, if the platelet level is between 10.000 and 20.000 and no bleeding symptoms are observed (or mild bleeding symptoms are present), monitoring is recommended.If bleeding symptoms are observed in these cases, other agents may be administered, such as rituximab (375 mg/m 2 ; once a week for four weeks), dexamethasone (10-40 mg/day; once every four weeks after a period of four days as needed), azathioprine, cyclophosphamide, danazol or cyclosporine.In cases that are non-responsive to immunosuppressive treatments, if bleeding symptoms are present and platelet counts are < 10.000-20.000,research protocols are recommended.In cases of serious bleeding, intravenous immunoglobulin (IVIG), highdose methylprednisolone, antifibrinolytic agents and platelet transfusion are recommended [2,5,13,14].
It has been shown that a 20% rate of complete remission can be achieved with 1-2 mg/kg/day of oral azathioprine in refractory ITP cases [7,15].In patients with refractory ITP, Hp eradication treatment has been shown to increase platelet levels [16].We also recommend eradication treatment for Hp (+) cases due to its proven efficacy in recent studies and the finding that it increased the platelet count in four of our ten cases.
In conclusion, no optimal treatment is currently available for patients with ITP who are resistant to splenectomy.The response rates of Hp eradication treatment, immunosuppressive treatment and anabolic agents are low.For this reason, larger studies evaluating TPO receptor agonists and anti-CD20 monoclonal antibodies with a large number of recruited subjects are needed.

Conflict of interest statement:
The authors declare that they have no conflict of interest to the publication of this article.

Table 3 . Treatment results of cases without splenectomy
*Helicobacter pylori