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