the Management of Bleeding in Pediatric Patients with Isolated Thrombocytopenia
- Introduction
Thrombocytopenia was defined as a platelet count of less than 150 000 per microliter and can be acquired or inherited.8 However, platelet counts between 100 and 150 × 109/L do not necessarily indicate disease if they have been stable,9 and a cutoff value of 100 ×109/L may be more appropriate to identify a pathologic condition.10 Isolated thrombocytopenia is defined as a low platelet count in the absence of abnormalities of RBC and WBC lineages and no signs or symptoms of systemic illness. The most prevalent etiologies are ITP and drug-induced ITP (DITP).11
Establishing the cause of thrombocytopenia has obvious clinical repercussions but is sometimes quite challenging. We aimed to describe the different etiologies, clinical presentation, clues for diagnosis and management of primary immune thrombocytopenic purpura (ITP) and non-immune thrombocytopenia (non-IT).
An individual with newly diagnosed thrombocytopenia is more likely to have an acquired disorder rather than an inherited genetic mutation. The myriad causes of acquired thrombocytopenia include autoimmune diseases, increased platelet consumption, splenomegaly, marrow suppression, and bone marrow failure. Two important clinical characteristics for recognizing inherited thrombocytopenia syndromes are the age of presentation and the chronicity/duration of symptoms. In the event of severe thrombocytopenia or profound platelet dysfunction, thrombocytopenia is usually recognized during the perinatal period. Milder disorders are noted sporadically at times of hemostatic stress (onset of menses).12
Depending on the patient’s age of onset, the causes of thrombocytopenia will vary. In newborn, a prevalence of thrombocytopenia reaching 22–35% of all admissions neonatal intensive care units has been reported, 13, 14 particularly in very low birth weight preterm neonates in which a prevalence of 70–80% has been reported. 15, 16 A recent meta-analysis reported a prevalence of 24 % across 21 studies.
In preterm neonates, early-onset thrombocytopenia (<72 h) is usually secondary to antenatal causes, has a characteristic pattern and resolves without complications or the need for treatment. By contrast, late-onset thrombocytopenia in preterm neonates (>72 h) is nearly always due to post-natal acquired bacterial infection and/or necrotizing enterocolitis, which rapidly leads to severe thrombocytopenia (platelet count < 50 x 109/l). Thrombocytopenia is much less common in term neonates and the most important cause is neonatal alloimmune thrombocytopenia (NAIT).17
Immune thrombocytopenia (ITP) is relatively common in childhood, with an annual incidence of 1.9–6.4 per 100,000 children.18 Diagnosis is made when isolated thrombocytopenia occurs in the absence of identifiable and specific precipitants.19 Guidelines have recommended a minimum evaluative process to look for secondary causes of thrombocytopenia before the diagnosis of ITP.20 Differential diagnosis includes infectious, immune, hematologic, endocrine, and neoplastic causes of thrombocytopenia. 21-25
Diagnosis of ITP in children is essentially one of exclusion. To differentiate it from other conditions, medical history should include type and severity of bleeding, systemic symptoms, history of respiratory infections, recent live viral vaccine, medications, presence of bone pain, and family history of bleeding disorders. Clinical examination should include observation for any dysmorphic features, especially skeletal anomalies, and the presence or absence of hepatosplenomegaly and/ or lymphadenopathy.26
Khalifa et al. reported in a large Egyptian study a 30% rate of chronic ITP, matching the international reports.27 There was no gender preference in most acute ITP studies; however, chronic ITP was more frequent in females in Egypt.28 A retrospective report from Lebanon indicated a much lower chronicity rate of 10%.29
Secondary ITP and non-IT are rare and sometimes difficult to recognize. Moreover, other manifestations of the underlying disease may emerge only during the follow-up period.30 Red flags that raise the suspicion of secondary ITP and other non-immune causes of thrombocytopenia include positive family history, older age (adolescence), chronic course, platelet size either above or below the normal range, moderate (instead of severe) thrombocytopenia at first presentation, nonresponse to first-line treatments, and new symptoms or laboratory abnormalities during the disease course.31
Patients with thrombocytopenia typically experience mucocutaneous bleeding. The presence of joint or extensive soft tissue bleeding suggests coagulation abnormalities. Ischemic limb of skin necrosis should raise suspicion of heparin-induced thrombocytopenia.32
There is no single hematologic or biochemical test that is conclusive for a given mechanism of thrombocytopenia.33 If a decision is made to observe the child, even in typical cases, a CBC and blood smear should be repeated periodically to exclude the evolution of a serious bone marrow or other hematologic disorder until the diagnosis is clear or recovery has occurred.7
From registry data, 0% to 4% of children with newly diagnosed ITP have severe bleeding requiring immediate intervention34 with incidence of ICH from; 0% to 1%.35 Risk factors for ICH include low platelet count, non-steroidal anti-inflammatory drugs (NSAIDs) and arteriovenous malformation. Consensus favors consideration of multiple factors when deciding to treat or not, including bleeding symptoms, platelet count, recent trauma, existence of headache, recent medication use, psychosocial and lifestyle issues.7
In children, the symptoms of ITP are of greater impact in treatment decisions than platelet count. The ITP IWG recommends a treatment goal of a safe platelet count in the absence of bleeding, not a normal platelet count.10 Most children do not require therapy “Expectant watch-and-wait policy”.7
The most recent updated consensus report on the investigations and management of primary ITP stated the following: 1) Treatment goals should be individualized to the patient and the phase of the disease, 2) Treatment should prevent severe bleeding episodes, 3) treatment should maintain a target platelet level of 20-30 x 109 at least for symptomatic patients (because risk of major bleeding increases below this level), 4) treatment should be with minimal toxicity, 4) treatment should optimize health related quality of life (HRQoL).7
Although there are numerous publications on the diagnosis and treatment of ITP, knowledge gaps remain, and up-to-date expert opinion and experience are key elements for management of cases.
The aim of this adapted clinical practice guideline (CPG) is to provide evidence-based recommendations for the diagnosis and managment of thrombocytopenia in the paediatric age group. These recommendations were adapted from the relevant CPGs using a formal methodology for CPG adaptation: the Adapted-ADAPTE.
➡️Purpose and Scope
These guidelines have been developed to standardize the delivery of services and to implement the guidance on the prevention, diagnosis and management of bleeding in pediatric patients with isolated thrombocytopenia.
It provides guidance to primary health care physicians at Ministry of Health (MOH), general practitioners, family medicine specialists and pediatricians.
This guideline focuses on the diagnosis, treatment and prevention of thrombocytopenia in pediatrics. It provides an evidence-based document for how to prevent mortality and morbidity from bleeding, prevent sequelae and disabilities, and prevent further episodes.
This version of the guideline includes recommendations and good practice statements for the diagnosis, management and prevention of bleeding in the pediatric age group with special focus on thrombocytopenia.