5. Microangiopathic haemolytic anaemias (TTP, HUS)

The term thrombotic microangiopathy refers to any condition where microthrombi, consisting of mostly platelets, are formed in small blood vessels. In almost all cases these microthrombi cause mechanical damage to the RBCs, causing microangiopathic haemolytic anaemia. It’s an umbrella term which includes four diseases:

  • Thrombotic thrombocytopaenic purpura
  • Haemolytic uraemic syndrome
  • Disseminated intravascular coagulation (DIC)
  • HELLP syndrome

The first two are the most important types.

Thrombotic thrombocytopaenic purpura

Thrombotic thrombocytopaenic purpura (TTP) is the first thrombotic microangiopathy. It’s similar to haemolytic uraemic syndrome and in some cases it’s difficult to separate the two in a patient.

Epidemiology:

TTP occurs mainly in adult patients around 40 years old. It affects around 3 people per million. TTP patients are typically previously healthy adults.

Etiology:

TTP can be precipitated by drugs, cancer, HIV, SLE, infections, bone marrow transplant, etc. It is inherited in 5% of cases.

Pathophysiology:

TTP is characterised by the lack of function of a protein called ADAMTS13. This occurs because of autoantibody formation against ADAMTS13 in 95% of cases. The remaining 5% occur because of inherited genetic mutations of the ADAMTS13 gene.

The function of ADAMTS13 is to inactivate von Willebrand Factor. When ADAMTS13 is deficient will vWF accumulate on endothelial cell surfaces, causing platelets to adhere to the endothelium. This causes the formation of microthrombi.

These microthrombi mechanically damage RBCs, causing haemolytic anaemia. They also block arterioles and capillaries, causing ischaemia. This occurs especially in the brain and kidneys.

Clinical features:

TTP is characterised by five clinical findings:

  • Fever
  • Neurological symptoms
    • Altered mental status
    • Stroke
  • Thrombocytopaenia
    • Petechiae
    • Purpura
  • Haemolytic anaemia
  • Impaired renal function
    • Rarely severe
    • Haematuria
    • Proteinuria

Only a minority of patients present with all five findings.

Diagnosis:

  • Laboratory
    • Thrombocytopaenia
    • Haemolytic anaemia
    • Increased urea/BUN and creatinine
  • Negative Coombs test
  • Peripheral blood smear
    • Schistocytes – fragmented RBCs

Diagnosis is made by an ADAMTS13 activity assay. However, this test can take days, but treatment should begin immediately if there is clinical suspicion of TTP, as TTP can be a medical emergency.

Treatment:

Therapeutic plasma exchange should be initiated in anyone with clinical suspicion of TTP. Plasma exchange refers to the process when the patient’s blood is passed through a machine which separates the patient’s plasma and the blood cells. The patient’s plasma is discarded, and the blood cells are reinfused to the patient along with plasma from a healthy donor.

Additional therapies include glucocorticoids and monoclonal antibodies like rituximab.

Haemolytic uraemic syndrome

Haemolytic uraemic syndrome (HUS) is the second thrombotic microangiopathy.

Epidemiology:

Unlike TTP, HUS occurs more commonly in children < 5 years old.

Etiology:

> 90% of cases of HUS occurs due to infection by Shiga toxin-producing bacteria like EHEC. 10% of children with EHEC infection develop HUS.

The remaining cases are caused by gene mutations or pneumococcal infection.

Classification:

  • Primary HUS – previously called atypical HUS
    • Those cases caused by genetic mutations
  • Secondary HUS – previously called typical HUS
    • Those cases caused by infections
    • Shiga toxin HUS
      • EHEC – O157:H7
      • Shigella dysenteriae
    • Pneumococcal HUS

Pathophysiology:

Only the pathophysiology of Shiga toxin HUS is important.

Shiga toxin enters the systemic circulation, directly injuring endothelium in blood vessels by binding to a cell surface-bound molecule called Gb3. The glomeruli are especially damaged. The injured endothelium produces cytokines which promote vasoconstriction and platelet microthrombus formation. Like in TTP, the microthrombi damage RBCs and cause ischaemia of organs. Especially the kidney is affected.

Clinical features:

Shiga toxin HUS is usually preceded by diarrhoea, usually bloody, in the past 5 – 10 days. HUS presents with the following three clinical features, all of which are also features of TTP:

  • Thrombocytopaenia
    • Petechiae
    • Purpura
  • Microangiopathic haemolytic anaemia
  • Impaired renal function
    • Oliguria

Renal symptoms are more severe in HUS than in TTP.

Diagnosis:

  • Laboratory
    • Thrombocytopaenia
    • Haemolytic anaemia
    • Increased urea/BUN and creatinine
  • Negative Coombs test
  • Peripheral blood smear
    • Schistocytes – fragmented RBCs

In case of secondary HUS stool can be cultured for EHEC or Shigella.

Treatment:

EHEC should not be treated with antibiotics or antimotility agents as they increase the risk for HUS to develop. HUS is treated with supportive therapy and dialysis if acute kidney injury occurs.


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4. Haemolytic anaemias (inherited and acquired)

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13. Aggressive non-Hodgkin’s lymphomas

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