Aetiology
Thrombocytopenia may be congenital or acquired. It may be due to marrow-based disorders, increased platelet clearance, sequestration, pseudothrombocytopenia, or dilutional causes.[5] More than one mechanism can contribute to thrombocytopenia.
Marrow-based disorders
The bone marrow is the site of platelet production. Megakaryocytes shed proplatelets from their surface.[6] Once platelets are formed by the bone marrow, they migrate to the peripheral circulation. Conditions affecting the bone marrow include:
Malignancy
Platelet production may be interrupted by a malignant process such as leukaemia, lymphoma, myeloma, or metastatic disease. Multiple myeloma may present with pancytopenia.[7]
Viral infections
May cause bone marrow suppression, include infectious mononucleosis, HIV/AIDS, cytomegalovirus, parvovirus.
The cause of thrombocytopenia in patients with dengue virus infection is incompletely understood, but is thought to involve both bone marrow suppression and increased platelet clearance.[8][9]
Severe thrombocytopenia is a rare feature of Zika virus infection.[10]
Drugs/toxins
Chemotherapy and heavy alcohol consumption may affect the marrow.
Miliary tuberculosis
Can cause caseating granulomas in the marrow, with resultant pancytopenia.
Bone marrow fibrosis
May be seen in patients with autoimmune or inflammatory conditions. This can cause pancytopenia, although some individuals with marrow fibrosis can have leukocytosis or thrombocytosis.
There is a subset of individuals with marrow fibrosis who develop a severe immune thrombocytopenia, which can respond to immune thrombocytopenia treatments.
Nutritional deficiencies
Vitamin B12 or folate deficiency leads to impaired DNA synthesis and megaloblastic changes in megakaryocytes. Platelet production is reduced.
Aplastic anaemia
Marrow failure and low megakaryocyte numbers result in a low platelet count.
Paroxysmal nocturnal haemoglobinuria (PNH)
Patients have a clonal stem cell defect leading to maturation defects in megakaryocytes.
This defect is in the phosphatidylinositol glycan class A (PIG-A) gene, an X-linked gene that codes for a protein involved with the phosphatidylinositol anchor.
Increased platelet clearance
Platelets may also be destroyed in the bloodstream faster than the rate of production. Causes include:
Immune thrombocytopenia (ITP)
A common illness and a diagnosis of exclusion.
In patients with immunological destruction of platelets, antiplatelet antibodies bind to platelets and are cleared via Fc receptors on macrophages in the reticuloendothelial system. This process mostly occurs in the spleen.
There is some evidence that patients with ITP may also underproduce platelets. However, bone marrow biopsies typically show an exceedingly high number of megakaryocytes.[11]
A completely normal peripheral smear, except for a low platelet count is typical. Microcytic hypochromic anaemia of iron deficiency due to excessive bleeding may occur.
Medication
Many drugs cause thrombocytopenia.[12] Common culprit drugs include heparin; antibiotics, especially sulfur-containing drugs and penicillins; quinine; and antiepileptic medicine such as valproic acid and carbamazepine.
Drugs may cause an increased clearance of platelets, either as the drug interacts with the platelet itself or as the drug alters an epitope conformation on the platelet, leading to antibody-mediated destruction.[12]
Heparin-induced thrombocytopenia (HIT) occurs due to a paradoxical thrombotic tendency when platelet counts decline secondary to endothelial damage.[13][14]
Disseminated intravascular coagulation (DIC)
DIC is associated with endotoxins, obstetric complications such as abruptio placentae, snake bites, malignancies (e.g., acute promyelocytic leukaemia), or tissue trauma (e.g., surgery).
Consumption of platelets and clotting factors leads to bleeding and formation of small microthrombi. These can lead to occlusive disease of microcirculation and digital ischaemia.
Symptoms can include epistaxis, gingival bleeding, cough, dyspnoea, fever, and confusion. Physical exam may reveal petechiae, ecchymosis, gangrene, tachycardia, hypotension, pleural friction rub, and gastrointestinal or genitourinary bleeding.
Laboratory results show prolongation of the prothrombin time (PT) and activated partial thromboplastin time (PTT) and decreased fibrinogen.
Usually, the platelet count will rise as there is a successful treatment of the underlying pathology.
Thrombotic thrombocytopenic purpura (TTP)
In children, this disease may present as haemolytic-uraemic syndrome (HUS). A Shiga toxin-producing strain of Escherichia coli leads to platelet clumping in the microcirculation.
In adults, a deficiency of ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), or an immunoglobulin against ADAMTS13 may lead to the inability to cleave high-molecular von Willebrand factors; platelets then clump in the microcirculation.[15]
The pentad of thrombocytopenia, microangiopathic haemolytic anaemia, fever, renal abnormalities, and neurological abnormalities results.
Clotting factor levels remain normal, and the PT and activated PTT stay normal, as does fibrinogen. This differs from DIC, in which PT and activated PTT are elevated and the fibrinogen is below normal.
Certain drugs may cause a TTP-like state, particularly ciclosporin, tacrolimus, clopidogrel, and quinine.
Intravascular trauma
Cardiopulmonary bypass may cause platelet count reductions of 50%.
Haemolysis, elevated enzymes, and low platelets (HELLP) syndrome
May occur in pregnant women with pre-eclampsia or eclampsia.
Typically diagnosed in the third trimester.
Sepsis
Temperature elevation to 38.3°C (101°F) can lead to cytokine derangement, resulting in pronounced thrombocytopenia.
Vaccinations
Measles, mumps, and rubella vaccination has been reported to cause thrombocytopenia.
Rheumatological disorders
Systemic lupus erythematosus (SLE), rheumatoid arthritis, or sarcoidosis may cause peripheral destruction of platelets via secondary immune thrombocytopenia.
Typically labelled as an autoimmune thrombocytopenia associated with a rheumatological syndrome, as opposed to pure ITP.[4]
Antiphospholipid syndrome
Patients with a lupus anticoagulant (an antibody directed against cardiolipin or other platelet epitopes) may have thrombocytopenia and a paradoxical prothrombotic state.
Cyclical thrombocytopenia
Episodic bleeding every 21 to 35 days; may be associated with menstruation.
Sequestration
Cirrhosis
Splenic enlargement may result from liver disease (typically cirrhosis) with portal hypertension.
Lysosomal storage disease
Gaucher's disease causes thrombocytopenia via 2 mechanisms: splenic enlargement with glucocerebroside-laden macrophages filling the spleen, along with marrow Gaucher's cells causing a decrease in platelet production.
Malaria
Patients may have splenomegaly with accompanying thrombocytopenia.
Splenomegaly associated with haematological malignancy
Splenic lymphoma or enlarged spleen due to extramedullary haematopoiesis, as seen in advanced phase myeloproliferative neoplasms of bone marrow, can present with thrombocytopenia as platelets are sequestered in the enlarged spleen.
Pseudothrombocytopenia
Some patients have thrombocytopenia as a laboratory artifact; circulating ethylene diamine tetra acetic acid (EDTA)-dependent antibodies result in pseudothrombocytopenia in <0.1% of the population.[16][17] These individuals have no history of bleeding and have normal circulating counts. However, platelets clump upon drawing blood into an EDTA-containing glass tube. The platelet count is read by the laboratory as below normal because the clumps are not recognised by modern blood counters as platelets. In this circumstance, it is important to do one of the following:
Perform a fingerstick peripheral smear
Draw the blood into a different type of tube, most commonly one coated with heparin or citrate
Manually count on a sample diluted without anticoagulants.
Dilutional
After a blood transfusion, a dilution of the normal number of platelets into a larger RBC volume occurs. This may occur after receiving as few as 1 or 2 units of blood. The platelet count may decline by half after 2 units of RBCs are given to an anaemic patient. Typically, for every 6 units of blood given, a unit of exogenous platelets must be transfused to maintain the platelet count near the normal range. The severity of bleeding in these patients generally correlates with the degree of the thrombocytopenia.
Genetic
MYH9-related disorders, including May-Hegglin disorder
Autosomal dominant transmission.
The peripheral smear demonstrates Döhle bodies (grey-blue leukocyte inclusions) in neutrophils.
Platelets may appear large.
Mutations of the MYH9 gene are seen in these patients.
Bernard-Soulier syndrome
Autosomal recessive bleeding disorder.
Platelets are large, and there are low levels of glycoprotein IB/IX on the platelet surface.
Wiskott-Aldrich syndrome
Rare paediatric entity.
An X-linked disorder characterised by small platelets, with thrombocytopenia, along with eczema and an immunocompromised state.
These children have mutations of the Wiskott-Aldrich syndrome protein (WASP) gene (located on the short arm of the X chromosome).
Gaucher's disease
A lysosomal storage disease caused by an inherited deficiency of beta glucocerebrosidase.
Causes thrombocytopenia via 2 mechanisms: splenic enlargement with glucocerebroside-laden macrophages filling the spleen, along with marrow Gaucher's cells causing a decrease in platelet production.
Familial platelet disorder with germline RUNX1 mutation
An autosomal dominant syndrome characterised by thrombocytopenia and a predisposition to myeloid neoplasms.
Mild to moderate bleeding tendency.
Normal platelet morphology, but evidence of platelet dysfunction (impaired platelet aggregation studies with collagen and adrenaline; dense granule storage pool deficiency).
Thrombocytopenia due to germline ANKRD26 mutation
An autosomal dominant syndrome characterised by thrombocytopenia and a predisposition to myeloid neoplasms.
Moderate thrombocytopenia with normal platelet morphology.
Normal platelet aggregation studies.
Thrombocytopenia due to germline ETV6 mutation
An autosomal dominant syndrome characterised by thrombocytopenia and a predisposition to malignancy (most commonly paediatric B-lymphoblastic leukaemia/lymphoma).
Mild to moderate bleeding tendency.
Normal platelet morphology and normal platelet aggregation studies.
Other
This category includes diverse mechanisms of thrombocytopenias.
Endocrine
Some inflammatory endocrine disorders, such as Hashimoto's thyroiditis, can be characterised by thrombocytopenia. The mechanism of thrombocytopenia is unclear, but may be similar to ITP.
Gestational thrombocytopenia
Occurs in 4.4% to 11.6% of pregnant women.[18]
Plasma volume expands in pregnancy, so the platelet count can fall due to dilutional effect.
It is also thought that the placenta releases factors that promote shortened platelet survival and accelerated clearance.[18][19]
Critically ill patients
Thrombocytopenia is very common in these patients and is poorly understood. It is likely multifactorial due to serious organ dysfunction, including development of intravascular coagulopathy.[20]
Thrombocytopenia in patients with coronavirus, including COVID-19, is frequent and is associated with increased risk of severe disease and mortality.[21]
Many critically ill patients satisfy at least some criteria for haemophagocytic syndrome (also known as haemophagocytic lymphohistiocytosis, or macrophage activation syndrome). Anaemia and thrombocytopenia are present in >80% of these patients.[22]
Patients are often treated with multiple medications which may cause thrombocytopenia.
Patients may develop post-transfusion purpura (low platelet count 7-10 days post-transfusion).
Those with multiple catheters have a nidus for platelet deposition and clot development.
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