Itp: a patient bleeding repeatedly

Setting

This case is from a district hospital in Ibenga, Zambia. The hospital has an outpatient clinic and 4 wards with a total capacity of 100 beds. It has basic diagnostic facilities, such as a laboratory, ultrasound and X-ray. There is an operating theatre. The hospital is run by Franciscan sisters. Currently the medical staff consists of 2 Zambian doctors and 2 Dutch tropical doctors.

Background of thrombocytopenia

Thrombocyte physiology

Normal platelet count is 150-400*109/L and mean platelet volume (MPV) is 7-11 fL. Younger platelets, as seen in ITP, are larger and more active. Platelets have a lifespan of 8-10 days. (1)

Differential diagnosis

Thrombocytopenia is defined as a platelet count <150*109/L. It can be caused by either platelet destruction or impaired platelet production. (2) The former includes immune-mediated destruction (ITP, drug-induced), platelet activation/consumption (haemolytic uremic syndrome (HUS), disseminated intravascular coagulation (DIC)), mechanical platelet destruction (due to extracorporeal therapies, including haemodialysis) and platelet sequestration (hypersplenism, e.g. due to malaria). The latter includes a defect in megakaryocyte development and bone marrow suppression or failure (leukaemia, infection (HIV), chemotherapy, radiation, nutritional deficiencies (folate, vitamin B12, iron)). Evaluation should therefore include a history of bleeding symptoms, systemic symptoms, prodromal illness, medication, underlying disease, family, travel and diet.

Background of itp

Pathophysiology

ITP is caused by auto-antibodies against platelet membrane antigens. (3) The antibodies have two effects. First, antibody-coated platelets are cleared by macrophages and therefore have a shortened half-life; second, antibodies may inhibit platelet production. ITP can occur after a viral illness or vaccination (particularly measles, mumps and rubella). (3,4)

Epidemiology

ITP is common, with an incidence of 1 to 6.4 per 100,000 children. There is a peak incidence between 2 and 6 years of age, and another peak in adolescence. (3,4)

Clinical features

ITP can be asymptomatic or present with mucosal bleeding (nasal, gingival, gastrointestinal and genitourinary) or cutaneous bleeding (petechiae, purpura, ecchymoses). (3) Spontaneous bleeding occurs when platelet count falls below 20109/L and surgical bleeding with thrombocytopenia below 50109/L. (1) Severe bleeding complications, including intracranial haemorrhage, is rare. (4) In some cases, splenomegaly is seen. Typically, there are no systemic signs (e.g. fever, anorexia, bone pain, weight loss, lymphadenopathy, hepatosplenomegaly); these symptoms suggest a different diagnosis.

Diagnosis

ITP is characterized by an isolated thrombocytopenia (platelet count of < 100*109/L), (4) and a mildly elevated MPV. Manual platelet count should be performed, as automated methods lead to underestimation. (5) The diagnosis is one of exclusion and can be verified by a platelet response to standard therapy (i.e. corticosteroids). Standard tests include complete blood count and examination of peripheral blood smear. (6) Testing for antibodies is not recommended. (4) Bone marrow examination is not routinely necessary, but can be used to exclude other causes of thrombocytopenia. In ITP, it may reveal normal erythroid and myeloid precursors and large or immature megakaryocytes. (3)

Treatment

In some cases of ITP, treatment is not required and an observational approach may be appropriate. In adults, this is the case for asymptomatic patients with a platelet count of 20-30 x 109/L without risk factors (e.g. occupation, participation in sports, need for antithrombotic therapy). In children, due to their low bleeding risk, watchful waiting may suffice irrespective of platelet count. (5) It is also important to consider the self-limiting nature of ITP.

Treatment involves rescue therapy and maintenance therapy. The former focuses on promptly increasing platelet count with less concern for durability, safety and tolerability. The latter aims to achieve longstanding platelet response and minimal toxicity. (5)

Rescue therapy consists of corticosteroids, intravenous immunoglobulin, anti-D and platelet transfusion. (6) For maintenance therapy, splenectomy and/or medication are applied. First choice options include low dose prednisone (<5 mg/day), the monoclonal antibody rituximab, and thrombopoietin receptor agonists. (5)

Prognosis

ITP is a benign disease and can be self-limiting in 50-70% of children. Initially, 70-80% of patients respond to corticosteroids, with 10-30% reaching remission. (6) Following splenectomy, 70-80% of patients show initial response, with 50-60% demonstrating a stable response. (7) Splenectomized patients are at an increased risk of (mostly encapsulated) bacteria, warranting pneumococcal, meningococcal and influenza vaccinations. (8) As the spleen removes parasitized red blood cells from the circulation, malaria prophylaxis is also indicated.

References

1. Yee DL. Clinical manifestations and evaluation of thrombocytopenia in children. UpToDate, 2015.
2. Yee DL. Causes of thrombocytopenia in children. UpToDate, 2015.
3. Bussel JB. Immune thrombocytopenia (ITP) in children: Clinical features and diagnosis. UpToDate, 2016.
4. Bansal D, Rajendran A, Singhi S. Newly diagnosed immune thrombocytopenia: update on diagnosis and management. Indian J Pediatr 2014;81(10):1033-1041.
5. Cuker A, Neunert CE. How I treat refractory immune thrombocytopenia. Blood 2016;22;128(12):1547-1554.
6. Nomura S. Advances in Diagnosis and Treatments for Immune Thrombocytopenia. Clin Med Insights Blood Disord. 2016;17(9):15-22.
7. Ahmed R, Devasia AJ, Viswabandya A et al. Long-term outcome following splenectomy for chronic and persistent immune thrombocytopenia (ITP) in adults and children: Splenectomy in ITP. Ann Hematol 2016;95(9):1429-1434.
8. Newland A, Provan D, Myint S. Preventing severe infection after splenectomy: Patients should know the risks, be immunised, and take prophylactic antibiotics. BMJ 2005;331(7514):417-8.