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Adding tiotropium to inhaled corticosteroids (ICS) appeared safe and well tolerated in preschool children with persistent asthmatic symptoms, reveals an exploratory, regulatory trial—suggesting that tiotropium may be a complementary strategy for managing this young population for whom treatment options are scarce.

Thrombocytopenia – A Clinical Review

Frances Yeap, MBBS (UK), MRCPCH/ MMED (Pediatrics) (UK/ SIN)
08 Mar 2018


Thrombocytopenia, defined as a platelet count of less than 150,000/microL, is clinically suspected when there is a history of increased bruising or bleeding, or when there is petechiae noted which is often referred to as a “rash”. Thrombocytopenia is usually asymptomatic until platelet counts fall below 50,000/microL, and may also be detected incidentally in a full blood count (FBC) during routine evaluation of an asymptomatic patient or during investigations performed for other reasons.1


Taking a detailed history and systemic physical examination is important in establishing the diagnosis and evaluating the severity of thrombocytopenia. Aspects of particular relevance that would quickly narrow down the diagnosis include age of the patient, past medical history of any blood or autoimmune disorders, positive family history of thrombocytopenia, and recent medications, vaccinations, travel history, infections, or other comorbidities. In relation to bleeding history, it is important to gather information on the site and duration of bleeding, and also the amount of blood loss. Physical examination should focus on the location and severity of the bleed and other ab normalities that will aid in the diagnosis of lymphadenopathy and hepatosplenomegaly that may point towards bone marrow infiltration or infections, dysmorphism, and skeletal malformations that would suggest bone marrow failure syndromes, as well as genetic causes of thrombocytopenia. One should also look out for features such as pallor and that may point towards more than one cell line involvement.2


FBC to assess the degree of thrombocytopenia and other blood cell lineages. Peripheral blood film to look for morphological platelet abnormalities and abnormal features in other cell lineages. This is especially important in conditions where platelet numbers may be normal, but platelet size or granularity is abnormal. Special attention should also be paid to looking for red cell fragmentation that would suggest thrombotic microangiopathy and also to look for leukaemic blasts. Other investigations depending on the clinician’s suspicion could also include liver and renal function tests, coagulation screen, and other more specific tests such as bleeding time, platelet aggregation studies, and bone marrow aspirate and biopsy (Figures 1 and 2).2

Figure1_Examination of the peripheral blood film


Thrombocytopenia is a feature of bone marrow failure and is usually accompanied by pancytopenia. Its presence suggests general bone marrow dysfunction (eg, aplastic anaemia, Fanconi anaemia (FA), and chemotherapeutic agents) or infiltrative disease (eg, leukaemia or haemophagocytic lymphohistiocytosis). FA is one of the most common inherited bone marrow failure syndromes, others being dyskeratosis congenital, Shwachman-Diamond syndrome, and Diamond-Blackfan anaemia. FA is usually autosomal recessive, and individuals with FA are mostly short, have café au lait spots, skeletal abnormalities, and have a much higher risk of developing malignancies especially myelodysplasia/acute myeloid leukaemia. The hallmark of FA is a defective DNA repair that results in extreme sensitivity to DNA interstrand cross-linking agents. The screening laboratory test for this defect involves assessment of chromosomal breakage upon exposure of cells to diepoxybutane (DEB) or mitomycin C (MMC). Less commonly seen in paediatric patients is paroxysmal nocturnal haemoglobinuria (PNH), which is recognised by its unique triad of haemolytic anaemia and pancytopenia as well as thrombosis. Diagnosis of PNH is made using flow cytometry to detect the absence or reduced expression of both CD59 and CD55 or the lack of FLAER (fluorescently labeled inactive toxin aerolysin which binds GPI specifically) binding to granulocytes.10-11


Congenital thrombocytopenias with normal-sized platelets include congenital amegakaryocytic thrombocytopenia (CAMT), thrombocytopenia with absent radii (TAR) syndrome, amegakaryocytic thrombocytopenia with radioulnar synostosis, and familial platelet disorder with predisposition to myeloid malignancy. CAMT usually presents as isolated thrombocytopenia early in life but often progress to pancytopenia and leukaemic transformation later in life. TAR usually sees spontaneous recovery of platelets as opposed to amegakaryocytic thrombocytopenia with radioulnar synostosis which other than upper limb abnormalities also presents with hip dysplasia, sensorineural hearing loss, and the thrombocytopenia persists with age.1

Congenital thrombocytopenias with giant platelet disorders are differentiated by their distinct genetic defects and structural abnormalities, such as platelet glycoprotein abnormalities (eg, Bernard-Soulier syndrome), defects of platelet alpha granules (eg, gray platelet syndrome and Paris-Trousseau syndrome), abnormal neutrophil inclusions (eg, MYH9-related disorders), and abnormal erythrocyte morphology (eg, X-linked thrombocytopenia (XLT) with dyserythropoiesis/thalassaemia).1

Lastly, Wiskott-Aldrich syndrome (WAS) and its related XLT are characterised by small platelets. It is important to recognise and have WAS as a differential as patients with WAS are prone to infections due to the associated immunodeficiency.


Autoantibodies, alloantibodies, and/or drug-dependent antibodies can destroy platelet through platelet antigen interaction, and also formation of immune complexes which then binds to Fc receptors on reticuloendothelial cells which removes platelets from the circulation. Autoimmune causes of thrombocytopenia are a lot more common than alloimmune thrombocytopenia. The most common of which is immune-mediated thrombocytopenia that typically occurs post vaccination, viral infections, or even spontaneously. Measles, mumps, and rubella (MMR) vaccine is the most common cause of vaccine-associated thrombocytopenia. A systemic review of thrombocytopenia post-MMR vaccination was published in 2010, which revealed that based on 12 studies, the incidence of MMR-associated idiopathic thrombocytopenic purpura (ITP) was very rare and ranged from 0.087–4 (median 2.6) cases per 100,000 vaccine doses. Severe bleeding manifestations were rare, and MMR-associated thrombocytopenia resolved within 6 months from diagnosis in 93% of the children. Revaccination did not lead to a recurrence of ITP and hence children with vaccine-induced ITP should still receive the recommended vaccine schedule.13 Occasionally, other immune cytopenias develop concurrently eg, Evans syndrome (ITP, autoimmune haemolytic anaemia, and/or autoimmune neutropenia). Evans syndrome tends to have a more chronic course and patients are likely to have other features of systemic autoimmunity. Neonatal alloimmune thrombocytopenia (NAIT) is caused by maternal antibodies raised against alloantigens carried on foetal platelets, of which almost 80% of antigens are human platelet antigen (HPA)-1a. The foetal response to NAIT is variable and may include compensatory extramedullary haematopoiesis. Although many cases are mild, NAIT is a significant cause of morbidity and mortality in newborns and is the most common cause of intracranial haemorrhage in full-term infants.14


Thrombotic thrombocytopenic purpura (TTP, hereditary or acquired), haemolytic-uraemic syndrome (HUS, usually Shigella toxin-mediated), drug-induced, or complement-mediated thrombotic microangiopathies (TMA) are the main causes of primary TMA. Disorders of metabolism (eg, vitamin B12) and hereditary deficiencies of proteins involved in coagulation can cause TMA. Other systemic disorders that can present with microangiopathic haemolytic anaemia and thrombocytopenia include pregnancy-associated syndromes (eg, severe pre-eclampsia/HELLP syndrome), severe hypertension, systemic infections and malignancies, autoimmune disorders, and complications of hematopoietic stem cell or organ transplantation.

Clinical features for distinguishing the various causes would include age of patient, rate of progression of symptoms, presence of neurological signs, and kidney injury. Management of the patient would be dependent on the cause of TMA and other than supportive measures and platelet transfusion if patient is acutely bleeding would be to treat the underlying cause and also consider plasma exchange and use of eculizumab especially in complement mediated haemolysis (Table 1).12

Table1_Causes of Thrombocytopenia


A suggested algorithm for the management of thrombocytopenia is shown above (Figure 3). Symptomatic patients require immediate evaluation. A platelet count greater than 50x109/L is adequate for haemostasis and patient is usually asymptomatic. Patients with platelet count above 50x109/L can generally participate in most activities but should avoid contact sports. More caution should be taken when thrombocytopenia occurs in the neonatal period due to risk of intraventricular haemorrhage as well as in toddlers and the elderly as they are more prone to falls. Even with a platelet count of 10-20x109/L, simple packing or application of pressure will stop most bleeds such as nose bleeding, gum bleeding, etc. This would mean that most patients can be managed in the outpatient setting without aggressive management strategies as long as they are asymptomatic with stable, albeit low, platelet counts.

Figure3_Algorithm to approach thrombocytopenia

Most surgical and invasive procedures can be performed in patients with platelet counts greater than 50x109/L. Procedures such as bone marrow biopsy, bronchoscopy, etc, can generally be safely done in patients with platelet counts above 20x109/L as long as there are no other bleeding abnormalities or coagulation defects, however this is also dependent on institution guidelines.

Unlike other blood components, platelets must be stored at room temperature, limiting the shelf life of platelet units to only 5 days because of the risk for bacterial growth during storage. Therefore, maintaining hospital platelet inventories is logistically difficult and highly resource-intensive. Platelet transfusion is associated with several risks to the recipient, including allergic reactions and febrile nonhaemolytic reactions. Sepsis from a bacterially contaminated platelet unit represents the most frequent infectious complication from any blood product today. In any situation where platelet transfusion is being considered, these risks must be balanced against the potential clinical benefits.5

In the management of acute life-threatening haemorrhage, stabilization of the patient’s haemodynamics is of utmost importance. This includes the use of crystalloid/colloidal fluid, blood products (packed cells to restore blood volume and platelets), and of course cryoprecipitate and Factor VII, VIII, and IX, if there is a specific coagulation defect. If there is an offending agent or drug, that will also need to be stopped immediately. If there is disseminated intravascular coagulation secondary to sepsis or bone marrow infiltration by malignant cells, then the thrombocytopenia will persist and worsen unless the cause is treated.

Another agent that is often used is tranexamic acid which acts by binding to plasminogen or plasmin and preventing its degradation of fibrin, which has been used successfully in patients with bleeding manifestations both prophylactically and as a treatment option. It has been particularly useful in dental procedures, tonsillectomy, and prostate surgery as well as in menorrhagia. However, it is contraindicated in the setting of urinary tract bleed due to the risk of clot formation and urinary obstruction.

In patients with an immune-mediated thrombocytopenia, depending on the specific cause of the thrombocytopenia and its severity, various different immunosuppressive/immunomodulating agents have been used. This includes corticosteroids, immunoglobulins, rituximab, anti-D, azathioprine, and also less frequently danazol, mycophenolate mofetil, cyclophosphamide, and cyclosporine. In severe cases, plasma exchange to remove platelet directed antibodies and eculizumab for complement-mediated platelet destruction has also been tried. Eculizumab is a recombinant humanized monoclonal IgG2/4 antibody that specifically binds to the terminal complement component 5 or C5, which acts at a late stage in the complement cascade. Eculizumab inhibits the cleavage of C5 to C5a and C5b by C5 convertase, which prevents the generation of the terminal complement complex C5b-9. However, other than reducing the pro-inflammatory and prothrombotic responses associated with complements, it also results in patients being more vulnerable to infection with encapsulated organisms (Table 2).6-8

Table2_Drugs Commonly Used in the Management of Childhood ITP

In 2008, the US FDA also approved eltrombopag for the treatment of immune (idiopathic) thrombocytopenic purpura in patients who have had an insufficient response to corticosteroids, immunoglobulin therapy, or splenectomy. It is a small molecule agonist of the c-mpl (TpoR) receptor, which is the physiological target of the hormone thrombopoietin. It has also been used for patients with aplastic anaemia who have failed immunotherapy and has been shown to improve haematopoiesis across all three cell lines. It has been safely used in clinical trials with no major side effects, except that of transaminitis requiring cessation of the medication.3-4 Finally, splenectomy is indicated when medical therapy fails or its side effects outweighs that of a splenectomy and its associated problems such as more frequent infections mainly by Streptococcus, Neisseria, and Haemophilus, and also thrombotic tendencies that tend to occur in the cerebrovascular, pulmonary, and hepatic portal circulation.

Case 1

A 16-year-old Chinese girl presenting with thrombocytopenia with symptomatic epistaxis (severe) and occasional gum bleeding. The patient also had intermittent low-grade fever for 1 week which has been associated with fatigue and lethargy. Dengue duo was negative and coagulation profile was normal. FBC showed a platelet count of 23x10^9/L, mild lymphopenia of ALC 0.9 x10^9/L with 1+ left shift. The impression was that of viral-induced thrombocytopenia. There was also a significant positive family history with mother having Hashimoto’s and maternal aunt having Graves. In view of her age, thrombocytopenia, and mild lymphopenia, a systemic lupus erythematosus (SLE) panel, antinuclear antibody (ANA) test, and thyroid screen was sent. SLE panel returned negative and ANA was 1:160 (ref range <1:80 negative). Thyroid screen was normal. She was followed up regularly and over a 3-month period was found to have persistent symptomatic thrombocytopenia, weight loss of 4 kg, episodes of prolonged fever, fatigue, and nonspecific facial rash. This time a direct Coombs test was done which returned positive, and the ANA increased to 1:1640. In view of the above features, the diagnosis of systemic autoimmune disease was made, and she was started on prednisolone and hydroxychloroquine which resulted in normalization of her platelet counts and resolution of her fevers.

Case 2

Newborn male infant with early neonatal jaundice on day 1 of life. FBC done for neonatal jaundice workup and incidentally found to have thrombocytopenia (platelet count 13x103/uL). There was no bleeding, only petechiae and small haematomas over venipuncture sites. There was no family history of NAIT, SLE, or other autoimmune diseases. Congenital infection screen was negative and there was no suspicion of sepsis. Platelet transfusion was given initially but platelet counts soon dropped to <20x109/L. Impression was that of NAIT. Intravenous immunoglobulin was given with excellent response and platelet counts have remained normal since. Parents’ blood samples were sent to Australia for NAIT testing that did not detect HPA antibodies, but HPA antigen mismatch between parents and human leucocyte antigen antibodies were found, hence NAIT cannot be excluded.

Case 3

A 1-year-old boy presented with severe eczema and symptomatic thrombocytopenia with two episodes of haematemesis. Clinically, there was no evidence of hepatosplenomegaly or lymphadenopathy. There was also no dysmorphic features or skeletal abnormalities. There was no significant family history of any autoimmune conditions or bleeding disorders. The infant did not have any history of frequent infections, and other than thrombocytopenia, FBC was normal. Further workup included immunoglobulin levels which revealed low IgM and IgG levels. A bone marrow biopsy was per-formed, which showed erythroid hyperplasia and reduced megakaryocytes but otherwise no dysplastic cells. The patient was suspected to have a Wiskott-Aldrich syndrome, and molecular analysis of the WAS gene revealed a missense mutation in exon 10.


Thrombocytopenia is defined as a platelet count of less than 150,000/microL, and is usually brought to attention when a patient presents with bruising, petechiae, or bleeding. It may also present insidiously during a routine FBC. A detailed history focused on eliciting infections and other medical problems is important and the physical examination should also pay particular attention in looking for clues that would suggest malignancies, autoimmune conditions, and also syndromes that may be associated with thrombocytopenia. Treatment of thrombocytopenia depends on the underlying cause, and a haematology consult should be sought if the thrombocytopenia is severe or diagnosis is uncertain. Decision of treatment is dependent on the cause, risks vs benefits of therapy, and certainly parental preference.

About the author
Dr Frances Yeap is a Consultant in the Department of Paediatric Haematology-Oncology, Khoo Teck Puat-National University Children’s Medical Institute, National University Hospital, National University Health System, Singapore.
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Pearl Toh, 05 Apr 2018
Adding tiotropium to inhaled corticosteroids (ICS) appeared safe and well tolerated in preschool children with persistent asthmatic symptoms, reveals an exploratory, regulatory trial—suggesting that tiotropium may be a complementary strategy for managing this young population for whom treatment options are scarce.