Viva 1

A 75-year-old male has been in your ICU for 4 days following a mitral valve replacement and coronary artery grafts, ventilated and shocked, requiring significant ongoing cardiovascular support. Over this time, his platelet count, (normal range 150 – 450 x 109 /L), has fallen, as per the table below:

Pre-op

Post CPB

Day 1

Day 3

Day 5

386

109

151

142

61

What are the likely causes for the thrombocytopaenia in this situation?

Causes of thrombocytopenia, in a broader sense, include:

Pseudothrombocytopenia

  • 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

Sequestration

  • 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

 
How will you investigate this thrombocytopenia?
  • Peripheral blood smear, and a repeat platelet count in a citrated tube
  • DIC screen: coagulation tests, D-dimers and fibrinogen
  • Vitamin B12 level and full blood count
  • HITTS screen: anti-platelet factor 4 antibody and platelet aggregation tests
  • Autoimmune screen, including tests for SLE and other vasculitic diseases
  • ADAMTS13 screening for TTP
  • Bone marrow biopsy
     
Your registrar raises the concern that this may be HIT. What scoring systems are you aware of to determine the risk of HIT?
  • the 4T score: Thrombocytopenia, Timing, Thrombosis and "other causes of thrombocytopenia" 
    4T score from Greinacher, 2015

    The maximum score of 8 was associated with "real" laboratory-confirmed HIT 100% of the time;  a score of less than 4 has a negative predictive value of 97-99%.   The UpToDate authors have recommended that a low score should discourage one from pursuing any sort of formal laboratory testing.
What are the "classical" features you might expect from history?

Onset usually is within 5-10 days of heparin commencement. However:

  • Major surgery can "reset the clock" - even patients chronically exposed to heparin can develop HIT 5-10 days after major surgery
  • Rapid-onset HIT can occur within 90 days of heparin exposure, upon re-exposure
  • HIT can continue getting worse after heparin has been discontinued
What specific tests are you aware of, which look for HIT?

Two major tests:

  • antibodies to PF4 (ELISA)
  • functional platelet activation assay to measures the ability of patient serum to activate test platelets in the presence of heparin.
Which of these tests is the gold standard?
  • A negative functional assay excludes HIT and is the gold standard, but is difficult to run, takes several days and requires a specialised laboratory. The anti-PF4 ELISA immunoassay is faster, but ore useless. The detection of a low level of anti-PF4 antibodies will be interpreted as a positive test, but the patient will not have clinically significant disease. 
What types of HIT are you aware of?

HIT Type I

  • Mild transient thrombocytopenia, platelet count above 100
  • Totally reversed by heparin cessation
  • Occurs in up to 10% of patents
  • NOT associated with an increased risk of thrombosis
  • Probably not even immune in origin (likely it is some sort of pre-aggregatory effect on the platelets)

HIT Type II

  • Nasty severe thrombocytopenia, platelet count might drop to nil
  • Occurs in something like 1% of patents
  • Associated with thrombosis in 30% of cases
  • Requires anticoagulation

HIT Type II can be further split into several recognisable varieties:

  • latent: antibodies without thrombocytopenia;
  • HIT: antibodies with thrombocytopenia; and
  • HITT: antibodies with thrombocytopenia and thrombosis.
What are the options for the management of HIT in this patient?

These patients need to be anticoagulated. ASH (2018) recommend the following options to consider:

  • argatroban
  • bivalirudin
  • danaparoid
  • fondaparinux
  •  direct oral anticoagulants
What is the pathophysiology of HIT?
  • It is IgG mediated
  • The antibodies form rapidly (within days)
  • These antibodies are directed against PF4 complexed with heparin (PF4 is "Platelet Factor 4", a little cytokine which is normally released from platalet α-granules and which is meant to control the influence of various natural heparin-like molecules on platelet aggregation)
  • When anti-PF4 antibodies bind to PF4 it  activating more platelets and triggers the release of more PF4, providing more substrate for antibody binding in a positive feedback loop
  • The IgG-coated platelets are then removed by macrophages in the reticuloendothelial system. Thrombocytopenia ensues.
  • The fact that anti-PF4 antibodies can activate platelets also leads to thrombosis (both arterial and venous); a second mechanism is the consumption of platelets in thrombi. The actual mechanism of this prothrombotic tendency is apparently unknown. 

Disclaimer: the viva stem above may be an original CICM stem, acquired from their publicly available past papers. Or, perhaps it is a slightly altered version of the original CICM stem. Or, it is a completely original viva stem, concocted by the monstrously amoral author of Deranged Physiology for nothing more than his own personal amusement. In either case, because the college do not make the main viva text or marking criteria available, almost everything here has been confabulated. It might sound like a plausible viva and it could be used for the purpose of practice, but all should be aware that it does not represent the "true" canonical CICM viva station.