Her hemogram and other investigations were as follows. Hb 11.3gm% TLC 6800/mm3 Platelet count 30 x 109/L .Direct Coumbs test was negative. Bone marrow was normocellular, slightly increased megakaryocytes with no atypical cells. ANA & anti ds DNA negative. HIV negative. She was treated with intravenous immune globulin (IV Ig) 1g/kg/d for 2 days from 25th May. The platelet count on 27/05/11 & 29/05/11 were 70 x 109/L and 100 x 109/L respectively. On 3/06/11 the platelet count rose to 175 x 109/L and she underwent debridement of surgical area and flap reconstruction surgery thereafter.
Immune thrombocytopenia or immune thrombocytopenic purpura (ITP) comprises a group of disorders characterized by autoimmune-mediated platelet destruction and impairment of thrombopoiesis. ITP may occur in the absence of an evident predisposing etiology (primary ITP) or secondary to other associated conditions (secondary ITP). The international working group also recommends that a platelet count below 100 x 109/L to fulfill the diagnostic criteria. ITP can occur in children and in adults.
The traditional goal of therapy is to achieve a hemostatic platelet count of 30 x 109/L or above for most patients while maintaining the quality of life. Recently it has been shown that aggressive therapy at the time of diagnosis can alter the natural history of ITP.
Etiology and pathogenesis
The underlying defects leading to autoantibody production are mainly unknown. A Th1/Th0 cytokine profile, a decrease in suppressor T-regulatory cells and an increase in B-cell-activating factor may predispose to emergence of autoantibodies in response to exogenous antigens. Molecular mimicry appears to play a role in the formation of self-reactive platelet antibodies after vaccination and in certain infections like HIV, hepatitis C virus, and Helicobacter pylori .
In almost all patients there is antibody-mediated clearance of platelets by tissue macrophages. Immune-mediated suppression of megakaryocyte and megakaryocyte apoptosis are also playing a part in the pathogenesis of many patients.
Primary ITP is a diagnosis of exclusion from both non-autoimmune causes and secondary causes of thrombocytopenia.
The non-autoimmune causes of thrombocytopenia consist of congenital thrombocytopenia, ethanol toxicity, Vitamin B12-folate deficiency, certain viral infections, myelosuppressive chemotherapy or radiation, bone marrow disorders (MDS, myelofibrosis, lymphoma, leukemia),certain drug history(heparin,quinidine), alloimmune thrombocytopenia ( post transfusion), DIC, thrombotic thrombocytopenic purpura etc. Splenic sequestration due to portal hypertension and infiltrative diseases of spleen can also lead to thrombocytopenia.
Treatment of ITP should be individualized. A hemostatic platelet count of 30 x 109/L or more is adequate for most patients. But this may be suboptimal for those like sportspeople, those who are taking other medications predisposing to bleeding and for pre-operative and post operative patients ( like the patient in this article) . Bleeding risk is higher in older patients and those with a prior history of bleeding. A major surgery requires a minimum platelet count of 80 x 109/L while a minor surgery requires a minimum platelet count of 50 x 109/L.
Corticosteroids, supplemented with either intravenous immune globulin or anti-Rh(D) are used to stop bleeding and increase the platelet count to above 30 to 50 x 109/L in newly diagnosed patients. In one recent trial by Zaja F et al , patients randomized to an intravenous anti-CD20 antibody (rituximab) and dexamethasone as an initial treatment showed higher response rates and duration than those treated with a single course of dexamethasone.
Once a response with first-line steroid therapy occurs, minimizing toxicities of chronic steroid exposure is a priority. Very few patients can be maintained on low levels of corticosteroids. Danazol, either alone or in combination with azathioprine, and dapsone have been used as steroid-sparing agents. But most of the patients require splenectomy, rituximab, or TRA therapy.
Fewer hemato-oncologists now recommend splenectomy as the initial second-line form of management. Atherosclerosis, pulmonary hypertension, and defects in immunity are known late complications of splenectomy. But splenectomy offers the highest chance for remission and remains cost-effective . Patient should be preferably immunized with polyvalent pneumoccocal, H influenzae type b, and quadrivalent meningococcal polysaccharide vaccines at least 2 weeks prior to splenectomy.After splenectomy two-thirds of patients attain a durable long-term remission, and others attain a partial response that allows for a reduction in the use of rescue therapy
A single course of rituximab (375 mg/m2 weekly for 4 weeks) induces a complete remission in approximately 40% of patients at 1 year, 15% to 20% at 5 years. An initial rise in platelet count often occurs within 1 to 2 weeks. Relapse after initial complete response, responds to retreatment. Rituximab is contraindicated in patients with active hepatitis B.
Thrombopoietin receptor agonists (TRAs)
Two TRAs, romiplostim and eltrombopag, have been approved for use in patients with primary ITP who require treatment after an initial course of corticosteroids.
Romiplostim is administered weekly as a subcutaneous injection (110 g/kg). In two placebo-controlled, double-blind randomized phase III trials, romiplostim was given to 63 splenectomized and 62 non-splenectomized patients for 6 months. A platelet count of 50 x 109/L or above in the absence of rescue therapy, was achieved in 61% of non-splenectomized patients and in 38% of splenectomized individuals receiving romiplostim. In an ongoing open-label extension study, most patients on romiplostim, have sustained their platelet response even after more than 5 years .
Eltrombopag is administered orally at a dose of 25 to 75 mg/d. It must be taken 1 h before or 2 h after a meal. An initial 50% dose reduction is made in south-east Asians. Responses around 60% are obtained in phase III studies.
These TRAs might slightly increase the risk of thromboembolic complications. Hepatobiliary laboratory abnormalities were detected in 13% of eltrombopag-treated patients.
Vinca alkaloids, azathioprine, cyclophosphamide, mycophenylate mofetil, and cyclosporine are the drugs mainly reserved for patients unresponsive to or ineligible for the first- and second-line treatment options. Hematopoietic stem-cell transplantation is reserved for extreme circumstances.