A 45-year-old woman presents with seizures, after having had a fluctuating level of consciousness and fever. Her admission tests revealed:

Test

Value

Normal range

Haemoglobin

100

115-160 g/L

White blood cells

6.9

4.0-11.0 x10^9/L

Platelets

64

140-400x10^12/L

International Normalised Ratio

1.1

0.8 – 1.3

APTT

38

24-35 seconds

Fibrinogen

3.6

2.0-5.0 g/L

Na

142

135-145 mmol/L

K

4.8

3.5-5.5 mmol/L

Glucose

6.8

3.6-7.7 mmol/L

Urea

18.9

2.5-8.3 mmol/L

Creatinine

0.21

0.05-0.11 mmol/L

Lactate  De-Hydrogenase

540

120-250 IU/L

What is the most likely diagnosis, and what other investigations would you order to help confirm the diagnosis? What do you expect the results of these investigations to show?

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College Answer

This woman has anaemia with an elevated LDH (suggestive of haemolysis), thrombocytopenia without evidence of DIC or other significant coagulation problems, renal insufficiency, fluctuating neurological abnormalities and fever. These are the “pentad” of features of the syndrome of Thrombotic Thrombocytopenic Purpura (also known as TTP-Haemolytic Uraemic Syndrome). Further tests are required to confirm the diagnosis (some by excluding significant negatives which require dramatically different treatment). Sepsis is less likely because of the normal white cell count and the presence of thrombocytopenia without evidence of DIC. Peripheral blood film should confirm a microangiopathic (i.e. red cell fragmentation) anaemia, confirm thrombocytopenia, and exclude a toxic appearance of the white cells (as they are normal in number). Haemolysis screen should demonstrate an elevated bilirubin and a reduced haptoglobin concentration, but a negative Coombs test. Urinalysis should be near normal and should exclude an active sediment. Microscopy and culture of appropriate samples (eg. urine and blood, and/or lumbar puncture to exclude meningitis) should exclude active infection. A CT scan of the head should also be performed to exclude intracranial pathology as the cause for the seizures.

Discussion

The abnormalities and characteristic historical features are:

  • anaemia
  • thrombocytopenia
  • uraemia
  • raised LDH
  • decreased level of consciousness
  • fever

The college correctly points out that these are the features of TTP. However, with the available test results, one cannot rule out other thrombotic microangiopathies.

What other investigations would you order to help confirm the diagnosis?

Well. A good article from 2013 offers a thorough discussion of the labratory features.

A systematic approach to the confirmation of the diagnosis of TTP would include the following:

  • ADAMTS-13
    • A severe functional deficiency of ADAMTS-13 is expected
  • Blood film
    • Schistocytes, fragments, and genuine thrombocytopenia (platelet aggregates which form in the blood tube tend to confuse the stupid FBC machine)
  • Conjugated/unconjugated bilirubin fraction
    • Genuine haemolysis should give rise to a disproportionately high fraction of unconjugated bilirubin
  • Direct Coombs test
    • This should be negative in TTP
  • Haptoglobin
    • This should be decreased in TTP
  • Reticulocyte count
    • This should be raised in TTP
  • Urinalysis
    • There should be proteinuria and haemoglobinuria
  • Additionally, the college wisely recommends that we exclude such things as intracranial catastrophe and sepsis. The picture they have given us is unlikely to represent DIC in sepsis, as the WCC is quite normal and there is no depletion of clotting factors. However, a CT head +/- LP cannot be left unmentioned when discussing the investigations of a febrile patient with a decreased level of consciousness.

References

References

George, James N. "Thrombotic thrombocytopenic purpura." New England Journal of Medicine 354.18 (2006): 1927-1935.

 

Peyvandi, Flora, et al. "von Willebrand factor cleaving protease (ADAMTS‐13) and ADAMTS‐13 neutralizing autoantibodies in 100 patients with thrombotic thrombocytopenic purpura." British journal of haematology 127.4 (2004): 433-439.

 

Tsai, Han-Mou. "Advances in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura." Journal of the American Society of Nephrology 14.4 (2003): 1072-1081.

 

Oh's Intensive Care manual:

Chapter 97 (pp. 993)  Therapeutic  plasma  exchange  and  intravenous  immunoglobulin  therapy  by Ian  Kerridge,  David  Collins  and  James  P  Isbister

 

Kakishita, Eizo. "Pathophysiology and treatment of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS)."International journal of hematology 71.4 (2000): 320-327.

 

Noris, Marina, and Giuseppe Remuzzi. "Hemolytic uremic syndrome." Journal of the American Society of Nephrology 16.4 (2005): 1035-1050.

 

Kappler, Shane, Sarah Ronan-Bentle, and Autumn Graham. "Thrombotic Microangiopathies (TTP, HUS, HELLP)." Emergency Medicine Clinics of North America (2014).

 

Veyradier, A., and D. Meyer. "Thrombotic thrombocytopenic purpura and its diagnosis." Journal of Thrombosis and Haemostasis 3.11 (2005): 2420-2427.

 

Beckford, M. D., and M. D. Shah. "Thrombotic Thrombocytopenic Purpura: A Review of the Disease Entity, its Clinical and Laboratory Features, and Management Strategies." The Medicine Forum. Vol. 12. No. 1. 2011.