Thrombocytopenia

Published on 03/04/2015 by admin

Filed under Hematology, Oncology and Palliative Medicine

Last modified 22/04/2025

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Thrombocytopenia

Thrombocytopenia can be simply defined as a blood platelet count of below 150 × 10⁹/L. With the routine measurement of platelet number by automated cell counters it is a relatively common laboratory finding. Before initiating further investigations it is important to confirm that a low platelet count is genuine by careful inspection of the blood sample and film. Either a small clot in the sample or platelet clumping (Fig 34.1) can cause artefactual thrombocytopenia.

Fig 34.1 Blood film showing clumping of platelets.
This phenomenon causes an artefactual thrombocytopenia in the automated blood count.

Causes

Major causes of thrombocytopenia are listed in Table 34.1. Many of the diseases and syndromes are discussed elsewhere.

Table 34.1

Causes of thrombocytopenia

Pathogenesis	Disease examples
Failure of production	Leukaemia, myelodysplasia, aplastic anaemia, megaloblastic anaemia, myelofibrosis, malignant infiltration, infection, drugs¹
Shortened lifespan
Immune	ITP, drugs¹, connective tissue disorders, antiphospholipid antibody syndrome, infection, post-transfusion purpura, neonatal alloimmune thrombocytopenia
Non-immune	DIC, thrombotic thrombocytopenic purpura
Sequestration	Hypersplenism, cardiopulmonary bypass surgery
Dilution	Massive blood transfusion

ITP, immune thrombocytopenia; DIC, disseminated intravascular coagulation.

¹ See Table 34.3.

In general terms there are four possible processes leading to thrombocytopenia:

Failure of marrow production. The bone marrow failure of haematological disease (e.g. aplastic anaemia, leukaemia) usually causes pancytopenia. However, thrombocytopenia may be the only sign of intrinsic marrow disease or marrow suppression associated with infection or chemotherapy.

Shortened lifespan. Platelets can be destroyed in the circulation. The most common mechanism is an immunological reaction in clinical syndromes such as immune thrombocytopenia.

Sequestration. Splenomegaly can cause low platelet counts because of pooling in the enlarged organ. The spleen is not necessarily massively enlarged.

Dilution. Normal platelets are diluted by massive blood transfusion.

Clinical presentation

Patients with thrombocytopenia are particularly prone to bleeding from mucous membranes. It should be emphasised that spontaneous bleeding is usually only seen with platelet counts of less than 10–20 × 10⁹/L, although patients with associated platelet dysfunction may bleed at higher counts. Conjunctival haemorrhage, nose and gum bleeding and menorrhagia are all relatively common, with haematuria and melaena less frequent. Intracranial bleeding is of serious import but, thankfully, is rare. Possible examination findings include purpura and more extensive petechial haemorrhages involving the skin and mucous membranes (Fig 34.2). The retina should be routinely inspected for haemorrhages.

Fig 34.2 Purpuric rash in a patient with acute ITP.

Clinical syndromes

Immune thrombocytopenia (ITP)

ITP is a disease characterised by immune thrombocytopenia mediated by platelet antibodies that accelerate platelet destruction and inhibit their production. It is a heterogeneous disorder but it is conventional to divide it into two discrete entities: acute ITP and chronic ITP (Table 34.2). This division is convenient for discussion of pathogenesis and apt for most patients, but in ‘real life’ there is overlap between the two syndromes.

Table 34.2

Comparison of classic acute and chronic ITP

Characteristic	Acute ITP	Chronic ITP
Age	Childhood	Adult life
Previous viral infection	Frequent	Unusual
Platelet count (µ 10⁹/L)	Often <20	Variable
Onset	Sudden	Insidious
Duration	Few weeks	Years/lifelong
Spontaneous remission	Around 90%	Rare

ITP, immune thrombocytopenia.

Acute ITP

The acute form of the disease is usually seen in childhood. It typically has an abrupt onset a week or so following a trivial viral illness. It is likely that in post-viral cases IgG antibody attaches to viral antigen absorbed onto the platelet surface. The resultant sudden fall in platelet count (often to below 20 × 10⁹/L) can lead to all the symptoms and signs quoted above. Despite this, serious complications such as intracranial bleeding are very rare and the disease is self-limiting in around 90% of cases. Often only observation is required, but where the bleeding tendency is unusually severe, oral corticosteroids or intravenous immunoglobulin can be given as in chronic ITP (see below). A few children go on to develop chronic thrombocytopenia, but even here the disease is relatively benign and may eventually spontaneously remit.

Chronic ITP

There has been recent change in our understanding of the pathophysiology of chronic ITP. Antibodies that mediate platelet destruction also impact platelet production by damaging megakaryocytes and/or blocking the release of proplatelets. A few cases may not be antibody-mediated and will not respond to standard immunosuppressive therapies.

Chronic ITP is most common in adult life. Patients may be asymptomatic or have insidious onset of bleeding problems. Serious spontaneous bleeding is generally limited to platelet counts below 10 × 10⁹/L and even then it is unusual. Fatigue is common. Paradoxically, it appears that the disorder may have a pro-thrombotic element where platelet counts are restored to normal. A palpable spleen suggests a diagnosis other than ITP.

The blood film confirms thrombocytopenia; often the platelets are increased in size (Fig 34.3). There is no single specific test for ITP. A bone marrow aspirate and trephine biopsy will show increased megakaryocytes but it is often not necessary if other features are typical. Further investigations are designed to exclude other causes of isolated thrombocytopenia such as connective tissue disorders and antiphospholipid antibody syndrome. Apparent ‘primary’ ITP may be secondary to subclinical viral infections such as hepatitis C, cytomegalovirus, HIV and Helicobacter pylori. In younger patients congenital thrombocytopenias may be confused with ITP. A thorough drug history is essential.

Fig 34.3 Blood film in ITP.
The platelets are reduced in number and increased in size.

Patients with asymptomatic mild thrombocytopenia can be merely observed. It is difficult to state a platelet count below which treatment is mandatory. In practice, serious bleeding is rare even at lower platelet counts and drug side-effects are common so treatment should generally be reserved for patients who have symptoms or signs. The normal first-line treatment is prednisolone (1 mg/kg body weight). About two-thirds of patients have a significant increase in platelet count within weeks but subsequent dose reduction often leads to relapse. Where there is no response to steroids, immunoglobulin (IVIg) can be efficacious. Platelet transfusions are seldom indicated as the platelets are rapidly destroyed but they may be considered in severe haemorrhage.

If the platelet count cannot be adequately maintained on non-toxic doses of corticosteroid then splenectomy is considered. About two-thirds of patients have a good response. The management of severe/symptomatic thrombocytopenia post-splenectomy is improving as new agents are introduced. The monoclonal antibody rituximab may give durable responses. Second-generation thrombopoietin receptor (TPO-R) agonists stimulate platelet production via megakaryocyte proliferation and maturation. Two TPO-R agonists in current use are romiplostim and eltrombopag. There remains a need for other approaches including relatively non-toxic doses of corticosteroids (e.g. prednisolone 10 mg), pulsed high dose corticosteroids, intermittent IVIg, danazol, vinca alkaloids, ciclosporin, azathioprine and mycophenolate. All give some responses reflecting the heterogeneity of the disease.

Drug-induced thrombocytopenia

Many drugs have been linked with isolated thrombocytopenia (Table 34.3). The mechanism is usually the formation of antiplatelet antibodies. General management is withdrawal of the offending drug and platelet transfusion for significant bleeding.

Table 34.3

Some drugs associated with thrombocytopenia