Investigating an incidental finding of thrombocytopenia

What is the next investigation?Thrombocytopenia may result from impaired production of platelets (for example, as a result of marrow dysfunction), increased destruction (immune or non-immune), abnormal distribution, or a combination thereof. Table 1⇓ lists common causes and examples.View this table: In this window In a new window Table 1   Common causes of thrombocytopeniaIf isolated thrombocytopenia is picked up incidentally in an apparently asymptomatic patient with no relevant drug treatment and a normal blood film, the diagnosis is usually immune thrombocytopenia (ITP).1 2 No accurate data on the relative frequencies of different causes of thrombocytopenia are available in the literature, although there is now an international paediatric and adult registry.3 ITP is an acquired disorder characterised by an isolated thrombocytopenia of less than 100×109/L, and new evidence shows that this is the result of both increased platelet destruction and impaired production.4 Adult chronic ITP has an incidence of about 6 per 100 000 per year in the developed world, with an equal sex ratio, although it is more common in women in the age range 30-60 years. In children the incidence has been estimated at 2-6 per 100 000 per year. It is a diagnosis of exclusion, with no specific tests that can positively diagnose it. ITP may be primary or secondary to other conditions (such as systemic lupus erythematosus, lymphoproliferative disorders, HIV, and hepatitis C). Although the evidence base to guide investigation is limited, international consensus reports on the investigation and management of primary ITP have recently been published.1 2 5History and clinical examination can point to the underlying cause.HistoryAgeMyelodysplasia is more common in older patients and an important differential diagnosis in younger patients is congenital thrombocytopenia (for example, May-Hegglin anomaly and Bernard-Soulier syndrome). Incidental thrombocytopenia is also more likely to be immune than inherited in children, and ITP is usually short lived after a viral infection, with most children recovering spontaneously. By contrast, in adults it tends to develop insidiously and follow a more chronic course.Bruising or bleedingIf present, these symptoms suggest that the thrombocytopenia is genuine and should prompt screening for a more generalised coagulopathy. Specifically ask about epistaxis, haematuria, menorrhagia, and excessive bleeding with previous haemostatic challenges (such as surgery, dental extraction, and childbirth). A recent history (especially if previously normal counts are documented) suggests an acquired cause, whereas a lifelong history (with or without a family history) suggests a mild inherited cause.Constitutional symptomsSymptoms such as fevers, night sweats, and weight loss should prompt investigation for lymphoma, infection, or cancer. Patients with ITP are usually well and have no specific symptoms.Infection and immune historyOccasionally, thrombocytopenia is the first manifestation of HIV or hepatitis C infection in an otherwise well patient, and it is important to assess risk factors and not to overlook screening.6 Helicobacter pylori infection has also been associated with ITP and should be considered in patients with dyspepsia. The response to eradication treatment is variable.7 Other recent acute or chronic infections (viral, bacterial, or protozoan), some vaccinations (with live attenuated viruses), or a history of autoimmunity (for example, rashes or arthralgia) may also be relevant.Drug and alcohol historyConsider all recently started drugs (prescription or non-prescription) as potential causes. Some (such as cytotoxics) result in a predictable thrombocytopenia, whereas others result in idiosyncratic thrombocytopenia. Quinine consumption (tonic water) can result in profound thrombocytopenia through an immune mediated mechanism.8 An increasing number of patients are being discharged into the community with thromboprophylaxis. Consider heparin induced thrombocytopenia in patients recently started (<14 days) on heparin; these patients may or may not have thrombotic manifestations. Low molecular weight heparin is about 10 times less likely than unfractionated heparin to have this effect.9 Excessive alcohol intake is a common cause of modest thrombocytopenia (often with macrocytosis), with the platelet count usually at 75-100×109/L.CancerA history of cancer may cause thrombocytopenia by many mechanisms, including bone marrow infiltration and chronic microangiopathic haemolysis.PregnancyPregnancy broadens the differential diagnosis and should be considered in women of child bearing age. Gestational thrombocytopenia is mild (>80×109/L), common, occurs in the third trimester, and has no adverse clinical consequences. However, the hypertensive disorders (pre-eclampsia and HELLP (haemolysis, elevated liver enzymes, and low platelets) syndrome) may also occur in the third trimester and need urgent obstetric review. Disseminated intravascular coagulation may be precipitated by obstetric emergencies such as placental abruption, postpartum haemorrhage, amniotic fluid embolism, or sepsis. ITP may first present incidentally in pregnancy because women of this age group are commonly affected. The serious and rare associated condition, thrombotic thrombocytopenic purpura, can occur during any trimester.Clinical examinationClinical inspection for petechiae, bruising, mucosal bleeding, and fundal bleeding may help define the severity of thrombocytopenia and risk of bleeding.Lymphadenopathy or hepatosplenomegaly should prompt concern about lymphoproliferative disease, autoimmune disease, cancer, or infection.Features of chronic liver disease are relevant. Even in the absence of hypersplenism, liver disease can cause thrombocytopenia by many mechanisms, including impaired production of thrombopoietin.10Investigations in primary careWhen a low platelet count is picked up incidentally, the full blood count must be repeated and a blood smear performed. Comparison with previous results may show changes over time. Timing, degree of thrombocytopenia, clinical context, and the presence or absence of bleeding will help direct investigations and the need for referral.11 In all patients, a blood film is important to confirm whether thrombocytopenia is genuine or factitious (platelet clumping owing to EDTA antibodies or giant platelets failing to be counted by automated analysers; fig 1⇓). In the presence of platelet clumping, the full blood count will be more accurate if performed on a citrated sample. In ITP, red and white cells have normal morphology and platelets may be large but otherwise normal. Other abnormalities in the film may offer clues to the underlying cause of thrombocytopenia. Features of other conditions include dysplastic changes (in myelodysplasia), abnormal circulating cells (such as leukaemic blasts), and red cell fragments (suggesting microangiopathic haemolysis in cancer, disseminated intravascular coagulopathy, or thrombotic thrombocytopenic purpura). Red cell fragments and a raised lactate dehydrogenase should prompt urgent referral to haematology to exclude the potentially fatal diagnosis of thrombotic thrombocytopenic purpura, which requires prompt plasmapheresis. The other classic features of thrombotic thrombocytopenic purpura (neurological symptoms, fever, and renal dysfunction) are not always present.12 Table 2⇓ lists other suggested investigations.View larger version: In this window In a new window View this table: In this window In a new window Table 2 Suggested investigations in patients with thrombocytopenia