The following table of contents also serves as a brief summary outline of this chapter, and a list of headings to jot down when answering one of the ubiquitous thrombocytopenia SAQs. Here is a link to an article with a diagnostic approach to thrombocytopenia. The well-resourced candidate will also draw on UpToDate: Approach to the adult patient with thrombocytopenia. A diagnostic approach to thrombocytopenia has come up in numerous past SAQs. The questions either ask for a broad list of differentials to explain thrombocytopenia, or for a diagnostic workup of thrombocytopenia, or both.

  • Question 3.1 from the second paper of 2023 (thrombocytopenia on VV ECMO)
  • Question 27 from the second paper of 2015 ( broad list of differentials; diagnostic workup; management)
  • Question 23 from the second paper of 2012 (broad list of differentials; management)
  • Question 11.3 from the first paper of 2012 (broad list of differentials)
  • Question 4 from the second paper of 2001 ( broad list of differentials; diagnostic workup; management)

Causes of thrombocytopenia:


  • The sample was improperly anticoagulated, and there is platelet clumping on microscopy of the blood film. Send a citrated tube instead- often the EDTA is to blame.
  • Abciximab can cause this, as it is an antibody to the GP IIb/IIIa receptor.

Dilution of platelets

  • Massive transfusion
  • Massive fluid resuscitation


  • Hypersplenism
  • Accessory spleens or splenunculi
  • Hepatic sequestration
  • Extremes of hypothermia

Decreased platelet production: Bone marrow suppression

  • Alcohol toxicity
  • Drugs: linezolid, Bactrim, etc
  • Chemotherapy
  • Congential causes, eg. Fanconi anaemia
  • Myelofibrosis or aplastic anaemia
  • Neoplasm, eg. leukaemia or lymphoma
  • Viral infection, eg. HIV, EBV, Hep C, parvovirus, mumps, rubella, varicella...
  • Nutritional deficiency: B12 and folate deficiency
  • Liver disease - decreased production of thrombopoietin (TPO)

Increased platelet destruction

  • SLE
  • ITP
  • DIC
  • Drugs:  Quinine, Heparin (HITTS), Valproate
  • Post-transfusion thrombocytopenia
  • Microangiopathic haemolytic anaemia
  • Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS)
  • Antiphospholipid syndrome
  • HELLP syndrome in pregnancy
  • Physical destruction in the cardiopulmonary bypass apparatus or circuit

Diagnostic workup for thrombocytopenia

This list of investigations has been modelled largely on the college answer to Question 27 from the second paper of 2015. The college answer to the very similar Question 4 from the second paper of 2001  leaves much to be desired. The workup starts with cheap basic things. History and examination will rapidly exclude hypersplenism, drug toxicity, pregnancy-related problems, liver disease and mechanical haemolysis in various extracorporeal circuits.

Peripheral blood smear, and a repeat platelet count in a citrated tube

This will establish whether there is platelet clumping. It may also reveal pancytopenia, which then makes one wonder what might be the cause of the death of all three lineages.

If there is platelet clumping, the cytometer will get confused. The clumps will not count towards the total platelet population. The outcome will be pseudothrombocytopenia. The solution is to run a citrated tube (an ionised calcium of less than 0.30 mmol/L should prevent the formation of clumps). But, one might ask - does EDTA not act in the same way? Why does it matetr how you chelate the calcium?

Well. The EDTA causes an immunoglobulin-associated platelet clumping, which is caused by agglutinating antibodies that recognise cytoadhesive receptors on platelet gpIIb-IIIa (Casonato et al, 1994). Citrate does not. Ergo, the citrated sample will yield a true platelet count when yolu run it thtough th cytometer.

So, the peripheral blood smear will reveal the presence of clumps. It will also reveal the absence of clumps, accompanied by broken fragmented red cells (schistocytes), which might suggest that the thrombocytopenia is caused by a microangiopathic haemolytic anaemia (MAHA).

DIC screen: coagulation tests, D-dimers and fibrinogen

These tests are a screen for consumptive coagulopathy of any sort. One needs to exclude this in the critical care environment, particularly if there are risk factors for DIC. The college will usually give you some of these, eg. in Question 27 from the second paper of 2015 the patient is in severe septic shock and MOSF.

Vitamin B12 level and full blood count

This will exclude causes such as B12 deficiency and alcoholism (which produces macrocytosis). 

HITTS screen: anti-platelet factor 4 antibody and platelet aggregation tests

The specific screen investigates the possibility of HITTS type 2, the nasty one where plateelt count may drop to nil and which is related to the generation fo an antibody to the complex of platelet factor 4 and heparin.  When the HIT antibody binds to this complex, it causes platelet activation and aggregation, and so there is a tendency towards clotting (because all the platelets are activates) as well as a simultaneous tendency towards bleeding (as there is a destruction of antibody-coated platelets in the reticuloendothelial system. This combined clotty-bleedy derangement of haemostasis is precisely what is described in Question 27 from the second paper of 2015, where the patient is horribly thrombocytopenic and yet keeps clagging the CRRT filters.

Regarding the specific HITTS tests, one may find more details in the article by Arepally et al (2006). In summary, an ELISA for anti-PF4 is the initial test of choice. This immunoassay has a sensitivity close to 100% but a specificity closer to 75-80%. The college also mention "platelet aggregation tests" which are apparently "more specific but more technically difficult"- they involve the mixing of patient blood samples with heparin to demonstrate platelet aggregation. The specificity of the two-point test (where samples are mixed with two different heparin doses) are close to 100%, as they represent a true demonstration of heparin-induced platelet aggregation (Chong et al, 1993). Still, these are not the gold standard: apparently that crown belongs to the 14C-labelled serotonin release assay, which is not widely available.

Autoimmune screen, including tests for SLE and other vasculitic diseases

At this point in the process of investigation, one might have come up to needing to exclude such causes of thrombocytopenia as antiphospholipid syndrome and MAHA. The specifict tests to run would depend on other clinical features, or at least one should write this in the exam. Realistically, one tends to order an ESR, ANA, ENA, double stranded DNA, anticardiolipin antibodies, rheumatoid factor and  antiCCP, ANCA, cryoglobulins and complement levels. This expensive battery rarely turns up anything of use. An immunology consult is frequently the outcome. If one wishes to know more about such tests, one is invited to read the brief but informative introduction by Castro and Gourley (2010).

ADAMTS13 screening for TTP

TTP is dealt with elsewhere, and it requires a lot of attention (because so far about eight past paper SAQs have asked about TTP). In brief, ADAMTS13 is normally responsible for destroying  von Willebrand factor, and in the absence of ADAMTS13 massive quantities of vWF accumulate. The result is a systemic prothrombotic state. In short, low ADAMTS13 = TTP.

Bone marrow biopsy

This is the last stage, as befits the most invasive test. It may also yield nothing (a completely acellular marrow is actually quite unhelpful) but will in any case be of prognostic interest.

Management of thrombocytopenia

Most of the previous SAQs expect the candidates to come up with a management plan for thrombocytopenia, without knowing its cause.  This is frequently silly, because management would depend on the cause of thrombocytopenia, and would frequently consists of dramatically different and highly invasive options (eg. steroids for MAHA, plasmapheresis for TTP, bone marrow transplant for aplastic anaemia, splenectomy for massive hypersplenism). A generic answer which is not specific to the cause of thrombocytopenia would have to be full of examiner-pleasing keywords. In my opinion, it might resemble the following word salad:

Minimise platelet destruction

  • Withhold heparin and rationalise the indications for heparin, eg.:
    • Use alternative anticoagulants for the extracorporeal circuit (citrate comes to mind but there are numerous others
    • Use mechanical thromboprophylaxis or LMWH
    • Rationalise the use of dialysis
  • Manage the sepsis with appropriate antibiotics and resuscitation (as sepsis improves, DIC will resolve)
  • Address specific destructive aetiologies with appropriately targeted therapies, eg.:
    • Plasmapheresis for TTP
    • High dose methylprednisone for MAHA
    • Delivery for HELLP

Maximise platelet production

  • Ensure supply of haematinics is uninterrupted
  • Optimise nutrition, focusing on vitamins and trace elements
  • Withhold or rationalise any drugs which are bone marrow toxins
  • Correct the correctable causes of bone marrow failure and liver disease
  • Think about thrombopoietin receptor agonists (eg. eltrombopag) - some promising results have come from the RAISE trial (Cheng et al, 2010)

Protect the patient from complications of thrombocytopenia

  • Cancel or postpone all nonessential invasive procedures
  • Cover unavoidable procedures with transfusion of pooled platelets (up to a level of 50)
  • For neurosurgical procedures (or lumbar puncture, etc) aim for a level above 100
  • Otherwise, keep the level above 20
    (the above numbers derived from recommendations made by Van der Linden et al, 2012)


Stasi, Roberto. "How to approach thrombocytopenia." ASH Education Program Book 2012.1 (2012): 191-197.

UpToDate: Approach to the adult patient with thrombocytopenia.

Casonato, A., et al. "EDTA dependent pseudothrombocytopenia caused by antibodies against the cytoadhesive receptor of platelet gpIIB-IIIA." Journal of clinical pathology 47.7 (1994): 625-630.

Castro, Christine, and Mark Gourley. "Diagnostic testing and interpretation of tests for autoimmunity." Journal of Allergy and Clinical Immunology 125.2 (2010): S238-S247.

Arepally, Gowthami M., and Thomas L. Ortel. "Heparin-induced thrombocytopenia." New England Journal of Medicine 355.8 (2006): 809-817.

Chong, B. H., J. Burgess, and F. Ismail. "The clinical usefulness of the platelet aggregation test for the diagnosis of heparin-induced thrombocytopenia." Thrombosis and haemostasis 69.4 (1993): 344-350.

Van der Linden, Thierry, et al. "Management of thrombocytopenia in the ICU (pregnancy excluded)." Annals of intensive care 2.1 (2012): 1-6.

Cheng, Gregory, et al. "Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study." The Lancet 377.9763 (2011): 393-402.