Management of Immune Thrombocytopenic Purpura: An UpdateA View From the Classroom. Laura Michaelis interviews Drs. Keel reviews work that expands our idiopathic thrombocytopenic purpura corticosteroid therapy of the inherited genetic underpinnings of marrow failure and hematologic malignancy predisposition. High-dose dexamethasone vs prednisone for treatment of adult immune thrombocytopenia: Corticosteroids have been used for more than 30 years as a first-line treatment for adult immune thrombocytopenia ITP. Patients were considered to have achieved an initial response if they met the corresponding milestones on or before day 10 in the HD-DXM arm and day 28 in the prednisone arm.
Initial Treatment of Immune Thrombocytopenic Purpura with High-Dose Dexamethasone | NEJM
Rapid strides have been made in the field of hematology, and advances in immune thrombocytopenic purpura ITP management are no exception. From idiopathic to immune, the changed nomenclature is itself a testimonial to the growing awareness and improvements in the management of ITP. We discuss the pathophysiology, clinical presentation, and current management of this common pediatric disorder and summarize current guidelines for ITP treatment.
All pediatricians encounter cases of immune thrombocytopenia ITP , especially in these days of Coulter counters and automated platelet counts. ITP is reported in approximately 5 per , children and 2 per , adults. ITP follows a benign course in most children but has the potential to be life threatening.
The risk of primary intracranial bleeding and soft tissue and mucosal bleeding secondary to trauma can cause morbidity and mortality.
The lack of evidence-based management protocols is a potential cause for poor management of ITP because no evidence clearly demonstrates that treatment alters the final outcome in any way.
At present, our understanding of the pathophysiology of ITP leads us to 2 central mechanisms: Harrington et al 3 first highlighted the role of immunity in the destruction of platelets in ITP patients. In an unusual experiment, Harrington injected himself and other test subjects with blood from ITP patients.
To everyone's surprise, he found a rapid decline in circulating platelet quantities in the test subjects. Opsonized platelets are finally phagocytosed by macrophages. T cells, at the same time, stimulate B cells to produce more antiplatelet antibodies, and new research shows that some cryptic epitopes from platelet antigens stimulate platelet-specific T cells. Reduced platelet production is another important mechanism that explains the pathophysiology of ITP in some patients.
The recent discovery of thrombopoietin TPO and its role in thrombopoiesis helped us understand the role of reduced thrombopoiesis in ITP.
Most ITP cases are self-limiting and require no treatment because most often the event responsible for antiplatelet antibody production is a viral illness. At present, most treatment protocols concentrate on the reduction of platelet destruction, and the drugs used are usually immunosuppressives. However, other drugs may be used in the near future if the TPO mimetic proves safe and effective in the various trials currently in progress.
As depicted in Figure 1 , the spectrum of disease fluctuates from an asymptomatic state to intracranial hemorrhage. One-fourth of children present with epistaxis, although hematuria is less frequent. Clinical manifestations of immune thrombocytopenic purpura in increasing order of severity. A diagnosis of ITP is confirmed by a finding of thrombocytopenia in a blood smear. Bone marrow examination is not routinely performed in children unless atypical clinical or laboratory findings are present.
General pediatricians often obtain a marrow test to be interpreted by pathologists to exclude the possibility of acute leukemia, which could enter a temporary remission with steroid treatment, with disastrous results. Tests for retic count, erythrocyte sedimentation rate, antinuclear antibodies, blood group, Coombs, and Epstein-Barr virus may be needed in selected cases depending on associated symptoms. Close and continued monitoring of clinical status and hematologic status is the most important step in managing ITP.
Obtaining an accurate history combined with a complete blood count and a thorough evaluation of the blood smear is the first and most important step. Acute onset of bruising and petechiae in an otherwise healthy child—often with a recent history of viral infection—associated with isolated thrombocytopenia and large platelets in the smear suggests acute ITP. Prolonged fever, weight loss, bone pain, significant lymphadenopathy, and organomegaly are unusual and warrant careful examination to exclude leukemia, aplastic anemia, or other more serious illnesses.
Pseudothrombocytopenia is the result of platelets clumping in the presence of ethylenediaminetetraacetic acid. A smear must be evaluated to rule out a false count and to determine the morphology of red blood cells RBCs , white blood cells WBCs , and platelets themselves.
Clinicians can exclude the common causes of secondary thrombocytopenia by investigating for Epstein-Barr virus, systemic lupus erythematosus, hepatitis C, and human immunodeficiency virus based on history and clinical examination findings. The inherited thrombocytopenias are classified on the basis of platelet size and gene mutations. A sound understanding of pathophysiology is essential for the appropriate management of ITP in children. Rapid strides in pharmacotherapy have added to the preexisting predicament of when to treat and how to treat.
Clinicians must clearly understand that no study has shown that any form of treatment decreases mortality or alters the risk of the disease process becoming chronic. Personalization of treatment based on platelet count, age, clinical picture, duration, lifestyle issues, economic considerations, and parental, patient, or physician concerns is the best approach.
A standard treatment protocol for all ITPs would be a step backward. Treatment of ITP can be divided into medical and surgical management. Medical management is further divided into first-line and second-line pharmacotherapy. Supportive therapy by a team experienced in the variable course and outcome of ITP is crucial. Education of the patient, teachers, siblings, parents, and primary care physician of the need for close monitoring for any acute bleed, especially intracranial or intraabdominal, can significantly decrease mortality and morbidity.
The child and family also require psychosocial support and trauma prevention advice, including a strong warning about participating in contact sports.
Sartorius 15 in was the first to report the benefit of prednisolone in ITP. Another study by Buchanan and Holtkamp 16 in the same year reaffirmed that prednisolone boosts platelet counts by day 7 of treatment. A well-established consensus exists regarding the initial benefit from oral prednisolone. Corticosteroids act by impairing the clearance of opsonized platelets in bone marrow and peripheral organs and reducing autoantibody levels in the body.
Some of the common complications associated with corticosteroid treatment are avascular necrosis, diabetes, gastritis, ulcers, growth retardation, hypertension, insomnia, osteoporosis in adults , personality changes, and opportunistic infections. In fact, many doctors stop treatment after weeks regardless of the response.
Imbach et al 24 were the first to propose the role of IV IgG in the reversal of thrombocytopenia. Also, they found that single-dose IV IgG of 0. IV IgG, although more expensive than IV Rh anti-D, is definitely one of the safer options available and may shorten the length of the hospital stay because of the drug's rapid response, usually within hours.
Some common infusion-related side effects are headache, fever, chills, and nausea. Other worrisome but rare side effects include aseptic meningitis, renal impairment or failure, and thromboembolic events.
Salama et al 29 in reported an increase in platelet counts in ITP patients who were also positive for rhesus D antigen after the infusion of IV anti-D. Current wisdom favors the notion that IV anti-D coats the RBCs that are positive for D antigen, and these opsonized RBCs in turn compete with opsonized platelets in the spleen for sequestration. Some of the commonly encountered infusion-related side effects are fever, chills, nausea, and headache. Another important adverse effect is a fall in hemoglobin secondary to hemolysis.
Second-line pharmacotherapy mainly comprises immunosuppressants and rituximab. These drugs are used when first-line drugs have failed or patients have become intolerant.
Immunosuppressants primarily act at the level of T cells. Azathioprine, cyclophosphamide, and cyclosporine are the main drugs in use. Dapsone, mycophenolate mofetil, danazol, and vinca alkaloids are a few other second-line drugs with unproven efficacy, but these agents are used rarely in children at the physician's discretion. Rituximab is a human-murine monoclonal antibody against the CD20 antigen on B lymphocytes that is used to treat lymphoma.
It acts by reducing the number of B cells that produce autoantibodies. Results of a systemic review conducted by Arnold et al 35 from 19 studies were promising and instill hope for the efficacy of rituximab. Severe side effects after rituximab therapy are fortunately rare but include the potential for neutropenia and the reactivation of chronic infections such as tuberculosis. Presently, rituximab seems to be the most promising drug for treatment of refractory ITP.
Recent studies suggest a superior response rate if dexamethasone is given with rituximab. Also, some evidence favors rituximab being used before resorting to splenectomy in refractory ITP. The effects of the drug reportedly remain for a few months before relapse, which demands the continuation of therapy.
Few people believe that dapsone in addition to prednisone should be recommended for patients who require low-dose steroids to maintain a high platelet count.
Splenectomy is not a favored option for treating ITP in children, as reflected in various guidelines 38 that prefer medical treatment over surgical management. The few indications that justify splenectomy are severe menorrhagia, life-threatening hemorrhage, and relentless lifestyle limitation.
A major factor that deters most physicians from taking the surgical route is the risk of the patient developing overwhelming postsplenectomy sepsis and the lifetime risk of sepsis from encapsulated organisms.
If splenectomy is selected, a laparoscopic approach is preferred with efforts made to identify and remove the accessory spleen. Also, physicians must immunize the child against Haemophilus influenzae type b, pneumococcus, and meningococcus.
Some physicians recommend prophylactic penicillin in patients up to 5 years of age or even later ages because vaccines do not immunize against all pneumococcal serotypes. Education of the patient, parent, primary care physician, and emergency room physicians about the risk of sepsis is also essential.
The explanation given for relapse is that in patients with significant antibodies, the liver or macrophages will continue to destroy sensitized platelets and the defective production is unable to compensate for the sustained destruction.
A detailed clinical history and thorough physical examination are vital. The clinical history has important implications not only in diagnosing the disease but also for selecting the treatment regimen. Based on the clinical history, patients can be subclassified into the following groups: The goal of treatment is immediate cessation of bleeding that can be achieved by either platelet-directed interventions or ancillary interventions. Platelet infusions by themselves are of no use because of immediate antibody-mediated destruction.
Ancillary interventional options include the cessation of antiplatelet agents, antifibrinolytic therapy, and the use of recombinant factor VIIa. Emergency splenectomy under the cover of medical therapy may be very rarely indicated in extreme cases.
Those who believe in observation justify their judgment by the fact that severe hemorrhage is rare and drug therapy may not prevent severe hemorrhage. Medical treatment may add to the financial burden and expose the child to severe drug-associated side effects. Proponents of the early initiation of therapy argue that platelet count increases T cells faster than without treatment, thus decreasing the likelihood of severe bleeding.
Quality-of-life issues may decrease with a faster and better maintained response following drug treatment. Currently, there is no universally accepted regimen. For these patients, second-line pharmacotherapy can be considered a serious option. Azathioprine with or without prednisone, vincristine or vinblastine, cyclophosphamide, cyclosporin, dapsone, and combination chemotherapy are a few treatment options for chronic ITP. Patients with chronic ITP are also suitable candidates for splenectomy, as discussed before.
A conservative approach is still the first choice, with observation alone or a combination of drugs used when indicated. Any plans for immunosuppression or splenectomy in a child with chronic ITP should be carefully reviewed with experienced pediatric hematologists and then discussed at length with parents and the child.
ITP is a common hematological problem that pediatricians face.