Thrombotic Microangiopathy

A 32 year old male patient, previously well, presented with a 6 week course of generalised malaise, nausea, vomiting, anorexia, with 5 days of increasing fatigue and blurring of vision. His fundi photos are shown below. 

+ What are the fundoscopic changes asscociated with hypertension (and found here?)

  • Papilloedema (increased ICP)
  • Flame Haemorrhages (damaged vessels)
  • Cotton Wool Spots (dammaged axons and micro-infarcts)
  • Constricted and tortuose arterioles
  • Hard exudates

In ED he was found to have a blood pressure of 240/160 mmHg, with an otherwise normal cardio-respiratory exam.

His initial bloods are below:

The blood film showed numerous red cell fragments on film, undetectable haptoglobin, consistent with microangiopathy.

+ What are the main differentials, based on the clinical presentation and pathology results so far?

  • Malignant Hypertension
  • Haemolytic uraemic syndrome (HUS)
  • Atypical Haemolytic Uraemic Syndrome (aHUS)
  • Thrombotic Thrombocytopenia (TTP)

Thrombotic microangiopathy (TMA) is a pathological process involving thrombocytopenia, microangiopathic haemolytic anaemia and microvascular occlusion. TMA is common to haemolytic uraemic syndrome (HUS) associated with shiga toxin or invasive pneumococcal infection, atypical HUS (aHUS), thrombotic thrombocytopenic purpura (TTP) and other disorders including malignant hypertension. HUS complicating infection with shiga toxin-producing Escherichia coli (STEC) is a significant cause of acute renal failure in children worldwide, occurring sporadically or in epidemics. Studies in aHUS have revealed genetic and acquired factors leading to dysregulation of the alternative complement pathway. TTP has been linked to reduced activity of the ADAMTS13 cleaving protease (typically with an autoantibody to ADAMTS13) with consequent disruption of von Willebrand factor multimer processing. However, the convergence of pathogenic pathways and clinical overlap create diagnostic uncertainty, especially at initial presentation.

+ How would you treat his hypertension initially?

This is malignant hypertension, (severe hypertension with retinal haemorrhages, exudates, and papilloedema).
The aim of therapy is to lower the BP slowly, over 48 hours.
Suitable short acting oral agents include

  • Nifedipine 5-10mg
  • Captopril 6.25-25mg
  • Methyldopa 250-500mg

Suitable longer acting oral agents include:

  • Irbesartan 75-300mg
  • Perindopril 1-4mg
  • Amlodipine 2.5-10mg
  • Atenolol 25-50mg

Intravenous agents include

  • Sodium Nitroprusside
  • Labetolol
  • Hydralazine

+ What is the further management and disposition for this patient?

An empirical treatment strategy is required in most patients presenting with microangiopathic haemolytic anaemia, thrombocytopenia and renal and / or neurological dysfunction.
Given that it takes time for the ADAMTS13 test to come back, it is sensible to intitiate plasma exchange early, given the high risk of preventable early deaths related to TTP.

It may be difficult to distinguish a patient with TTP and renal failure with severe hypertension from someone with severe hypertension, secondary renal failure with microangipathic haemolytic anaemia.

It is worth bearing in mind that malignant hypertension is rarely associated with severe thrombocytopenia (< 20x10(9)/L) and TTP is rarely associated with severe hypertension (diastolic BP >130mmHg).

The disposition is ICU for consideration of plasma exchange, renal replacement therapy, and ongoing management of blood pressure. Consults required from renal, and haematology teams.