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MikkoKeränen

Thrombocytopenia

Essentials

  • The cause of thrombocytopenia should be clarified.
  • In an acutely ill patient, thrombocytopenia is most commonly associated with an infection.
  • Mild thrombocytopenia found incidentally in an asymptomatic patient may be due to, for example, idiopathic thrombocytopenic purpura (ITP), a viral infection, liver disease, other chronic disease, alcohol consumption or sometimes a bone marrow disease or its precursor. If platelet levels remain stable when checked, and there is nothing suggesting an underlying disease, regular follow-up is unnecessary.
  • The risk of bleeding depends on the cause of thrombocytopenia and does not necessarily correlate with platelet levels.
  • Pay attention to any medication affecting blood coagulation in a patient with thrombocytopenia.
  • If the thrombocytopenic patient has symptoms of bleeding, treatment should take place in a hospital.

Basic rules

  • Classification of the severity of thrombocytopenia
    • Blood platelet levels 100-149 × 109 /l: mild
    • Blood platelet levels 50-99 × 109 /l: moderate
    • Blood platelet levels < 50 × 109 /l: severe
  • When blood platelet levels < 100 × 109 /l is detected for the first time, pseudothrombocytopenia should be excluded as locally agreed by, for example, examining a blood smear Peripheral Blood Smear or taking a sample in a citrate tube.

Symptoms and bleeding tendency

  • Typical manifestations of thrombocytopenia are skin bruising and petechiae Easy Bruising, Petechiae and Ecchymoses and mucous membrane bleeding.
    • In particular, gum and nasal bleeding is common. Bleeding may also take place in the gastrointestinal and urinary tracts after surgery of the prostate gland or urinary tract.
    • Heavy menstrual bleeding (menorrhagia) Abnormal Menstrual Bleeding is common in patients with thrombocytopenia.
  • Patients with mild or moderate thrombocytopenia usually have no abnormal bleeding tendency.
  • The risk of bleeding depends not only on platelet levels but also on any coagulation system disorder, platelet function and any concomitant anaemia.
  • The risk of bleeding is increased particularly if the patient has a history of bleeding or if there is haematuria or mucosal bleeding (‘wet purpura', with blood-filled blisters on the mucosa).
  • Platelet levels of 10-50 × 109 /l are frequently associated with spontaneous bleeding, and spontaneous bleeding may be severe with platelet counts of < 10 × 109 /l.
    • However, the risk of bleeding depends on the cause of thrombocytopenia. For example, in patients with ITP, the risk of bleeding is lower (at the same platelet levels) than in patients with no or impaired platelet production in the bone marrow.
    • Bleeding tendency is also increased by platelet-inhibiting medication (ASA, and ADP receptor blockers, such as clopidogrel, prasugrel and ticagrelor), platelet dysfunction, coagulation disorders (or anticoagulant treatment), and liver and kidney diseases.
  • Patients with thrombocytopenia may also have a risk of thrombosis. Conditions such as heparin-induced thrombocytopenia (HIT), antiphospholipid syndrome, disseminated intravascular coagulopathy, thrombotic microangiopathies, and paroxysmal nocturnal haemoglobinuria involve such a risk.

Anticoagulant therapy and other medication in patients with thrombocytopenia

  • In patients with platelet levels > 100 × 109 /l without bleeding symptoms, basically all drugs can be safely used. Platelet levels of 50 × 109 /l is generally considered the lower limit for using antithrombotic agents or anticoagulants. It should be noted that such limits are not based on strong scientific evidence.
  • At platelet levels < 50 × 109 /l, platelet transfusion should be considered to implement safe anticoagulant therapy. It should be kept in mind that thrombocytopenia will not protect against thrombosis, and the opposite is often true.
  • If there is a strong indication for using platelet inhibitors, anticoagulants or other medication that increases bleeding tendency, a coagulation disorder unit or haematologist (depending on local practice) should be consulted about safe implementation of such treatment.
  • Sufficient platelet levels vary for various procedures, and the person conducting the operation should decide on the appropriate level.

Causes of thrombocytopenia

Decreased production

Increased consumption

  • Inborn causes
    • Non-immunological (haemolytic disease of the newborn, prematurity, maternal pre-eclampsia, infections)
    • Immunological (alloimmune neonatal thrombocytopenia, maternal ITP)
  • Acquired causes
    • ITP here
    • Antibody-mediated thrombocytopenia can be caused by various drugs, such as antimicrobials (sulphonamides, ampicillin, piperacillin, vancomycin) and antiepileptic drugs (carbamazepine, phenytoin). Withdrawing the drug will often reverse thrombocytopenia within a week.
    • Other immunological cause (following blood transfusion; platelet or HLA antibodies in patients with a history of platelet transfusion)
    • Non-immunological causes (infections, disseminated intravascular coagulation (DIC), thrombotic thrombocytopenic purpura, haemolytic-uraemic syndrome, thrombosis, surgical intervention)

Dilution

  • Significant fluid administration
  • Gestational thrombocytopenia

Platelet sequestration

  • Hypersplenism (of various causes)

Loss of platelets

  • Acute haemorrhage
  • Haemoperfusion
  • Treatment with ECMO or heart-lung machine

Workup

Emergency investigation indicated

  • Severe thrombocytopenia (platelet levels < 50 × 109 /l) as a new finding. Consult a haematologist for further investigations.
  • If the thrombocytopenic patient has symptoms of bleeding, treatment should take place in a hospital.

Patients hospitalized for other reasons

  • Thrombocytopenia is a common finding in acutely ill patients.
  • Possible causes
    • Sepsis
    • Other infections
    • Liver diseases and hypersplenism
    • Medication
    • Disseminated intravascular coagulopathy (DIC)
    • Preceding surgical procedure (postoperative thrombocytopenia)
    • Rarer causes, such as thrombotic microangiopathies or cancer
  • Investigations depend on the cause of hospitalization. In acutely ill patients in particular (with fever, need for intensive care or treatment in a surveillance unit, bleeding symptoms), thrombotic microangiopathy, acute leukaemia and haemophagocytic lymphohistiocytosis should be kept in mind.

Symptomless patient with mild or moderate thrombocytopenia

  • Family history
    • If the patient has a family history of thrombocytopenia or other blood dyscrasias, they should be referred to an outpatient haematology clinic.
  • History of infections or vaccination
    • Thrombocytopenia may be a transient phenomenon during viral or bacterial infections and should in such cases be reversed after recovery.
    • Thrombocytopenia can be caused by HIV, hepatitis, Helicobacter, CMV, EBV, parvovirus or SARS-CoV-2 virus, for example.
    • Transient or long-standing thrombocytopenia may appear after MPR, VZV, influenza, HBV, HPV or COVID-19 vaccination.
  • Symptoms or signs suggestive of systemic disease
    • Thrombocytopenia may appear in association with autoimmune diseases, inflammatory bowel diseases, acute or chronic blood dyscrasias, malignant diseases, liver diseases or uraemia.
    • There may be other causes, such as a prosthetic heart valve, history of radiotherapy or large spleen (hypersplenism).
  • Dietary causes
    • Vitamin B12, folate or copper deficiency
    • Heavy alcohol consumption
  • Medication
    • Thrombocytopenia may be caused by drugs such as heparin, many antimicrobial drugs (such as penicillins, vancomycin, sulfa drugs or trimethoprim), quinidine, chloroquine, salicylates, allopurinol, phenytoin, carbamazepine, NSAIDs, cytostatic drugs, diuretics (furosemide or thiazides), gold, antidepressants or antipsychotic drugs (such as olanzapine or quetiapine) and several biological agents.
  • Investigations may be performed in primary health care over several weeks, simultaneously checking the blood count for any changes. Medication should be reduced, as far as possible.
    • If no underlying disease or progression appears and the patient has no symptoms, further investigations or regular follow-up are unnecessary particularly in the case of mild thrombocytopenia.
  • If thrombocytopenia progresses, the patient has symptoms, or there are changes in other cell lines in the blood count, a haematologist should be consulted regarding need for bone marrow examination.

Treatment

  • As thrombocytopenia is often a symptom of some other disease or caused by medication, treatment should focus on the cause.
  • Patients with severe thrombocytopenia (B-Trom < 50 × 109 /l) should refrain from contact sports (martial arts and ice hockey, at least).
  • Platelet transfusion can be considered in patients with bleeding or to prevent bleeding. In palliative treatment, platelet transfusion is normally only used for bleeding symptoms.

Idiopathic thrombocytopenic purpura (ITP)

  • ITP is a diagnosis of exclusion, and the treatment should be outlined by a haematologist or a specialist in internal medicine. The diagnosis of ITP should include the above diagnostic investigations.
  • In adults, 40 mg/day dexamethasone for 4 days is the first-line therapy. Prednisone and prednisolone are equally effective alternatives. The starting dose is 1 mg/kg/day orally.
    • With a glucocorticoid, it often takes 1-4 weeks to achieve a response to treatment. A partial response to treatment is achieved in 70-90% of cases, but a good one in only about 30-50% of patients.
    • After a response is observed, the drug should be tapered to the lowest dose possible; the objective is a platelet count > 50 × 109 /l, with no symptoms of bleeding.
  • Mucosal bleeding (menstruation, severe epistaxis, gastrointestinal or urinary tract bleeding) can be controlled by antifibrinolytic agents (tranexamic acid). Massive bleeding should be compensated with red cells, fresh-frozen plasma and platelets.
  • Further follow-up of patients with ITP should be carried out at an outpatient clinic for internal diseases or haematology.
  • Patients with ITP who are in remission (without continuous medication) do not need regular follow-up but they should recognize the symptoms of ITP and seek emergency treatment if such symptoms occur.

    References

    • Fuentes S, Chrétien B, Dolladille C, et al. An updated list of drugs suspected to be associated with immune thrombocytopenia based on the WHO pharmacovigilance database. Blood 2022;140(8):922-927 [PubMed]
    • Gauer RL, Whitaker DJ. Thrombocytopenia: Evaluation and Management. Am Fam Physician 2022;106(3):288-298 [PubMed]
    • Swain F, Bird R. How I approach new onset thrombocytopenia. Platelets 2020;31(3):285-290 [PubMed]
    • Provan D, Arnold DM, Bussel JB, et al. Updated international consensus report on the investigation and management of primary immune thrombocytopenia. Blood Adv 2019;3(22):3780-3817 [PubMed]
    • Greinacher A, Selleng S. How I evaluate and treat thrombocytopenia in the intensive care unit patient. Blood 2016;128(26):3032-3042 [PubMed]