Case 142: summary

Pregnancy-associated TTP

Definition:

  • Rare but life-threatening thrombotic microangiopathy characterised by thrombocytopenia, MAHA and end organ damage due to microvascular thrombosis

Pathogenesis:

  • Severe ADAMTS13 deficiency (acquired or congenital)
    • ULVWF multimers lead to platelet adhesion resulting in platelet-rich microthrombi, red cell fragmentation (MAHA) and end organ damage
  • Acquired – autoantibody-mediated, more common
  • Congenital – genetic, less common
  • Pregnancy provoking factor for both acquired and congenital acute TTP episodes
    • Haemostatic changes: rising VWF levels, falling ADAMTS13 levels
    • Immunologic: changes in immune tolerance both during pregnancy and postpartum leading to autoimmunity
    • Often first provoking event in adult-onset congenital TTP

Presentation:

  • More common third trimester and postpartum
  • Microangiopathic haemolytic anaemia
    • Red cell fragments on blood smear
    • Features of non-immune haemolysis: raised LDH, raised reticulocytes, raised bilirubin, low haptoglobin, DAT negative
  • Severe thrombocytopenia can lead to bleeding complications although not usually severe/life-threatening
  • Usually normal coagulation
  • End organ damage
    • Gastrointestinal: abdominal pain and vomiting
    • Cardiac: chest pain, dyspnoea, raised troponin
    • Neurological: confusion, lethargy, seizures, focal deficits, coma
    • Renal: acute kidney injury (usually only mild-moderate)

Differential diagnosis (with differentiating features):

  • Pregnancy-specific
    • Pre-eclampsia with severe features (hypertension, proteinuria, peripheral oedema)
    • HELLP syndrome (LFTs more deranged than in TTP, often overlaps with pre-eclampsia)
  • Not pregnancy-specific
    • Acute DIC (deranged coagulation)
    • ST-HUS (acute diarrhoea from Shiga toxin, renal failure)
    • cHUS (renal failure)
    • Systemic vasculitis (acute nephritis, hypertension, positive ANCA)
    • CAPS (multiorgan failure with positive antiphospholipid antibodies)

Diagnosis:

  • Clinical diagnosis – MAHA and thrombocytopenia in the absence of other alternative cause (see differential diagnosis above)
  • Investigations
    • Haematology panel, including haemolysis screen and peripheral blood smear
      • Confirms MAHA and thrombocytopenia
    • LFTs, U/Es, coagulation, urinalysis, ANA, ANCA, anti-phospholipid antibodies, stool culture (if diarrhoea present), blood pressure measurement
      • Excludes differentials
    • Fetal ultrasound
      • Assess for intrauterine growth restriction
    • ADAMTS13 activity and anti-ADAMTS13 IgG
      • Confirms diagnosis and differentiates between acquired and congenital TTP
    • Troponins, CT brain (if neuro symptoms)
      • To assess for cardiac and neuro involvement

 Management (acute episode)

  • MDT approach: haematologists, obstetricians, nephrologists and intensivists
  • PEX and steroids as soon as clinical diagnosis is made (send ADAMTS13 assay off first)
  • Regular fetal monitoring for growth restriction
  • Confirmed aTTP = ADAMTS13 activity <10%, positive anti-ADAMTS13 IgG
    • Daily PEX and corticosteroids
    • Monitor response with platelet count, LDH, serial blood smears, clinical status
    • Stop PEX when platelets > 150 x 10^9/L for at least two days and monitor for recurrence
    • Gradual wean of steroids when in remission
    • Consider thromboprophylaxis and aspirin when platelets > 50 x 10^9/L
    • Normal obstetric indications for delivery of foetus
  • Confirmed cTTP = ADAMTS13 activity <10%, negative anti-ADAMTS13 IgG
    • Switch to plasma infusions – daily until remission
    • Ongoing management outside scope of this case but requires specialist tertiary care service with experience in managing this rare condition

Management (subsequent pregnancies)

  • Counselling re: risk of recurrence
  • Previous aTTP with persistently low ADAMTS13 activity
    • Pre-emptive treatment with rituximab to normalise ADAMTS13 activity
    • Avoid conception for at least 6 months after rituximab
  • Clinical and laboratory monitoring during pregnancy for relapse
    • ADAMTS13 activity normal – watchful waiting
    • ADAMTS13 activity borderline (10-20%) – low dose steroids
    • ADAMTS13 activity <10% – prophylactic PEX and low dose steroids
    • Overt acute TTP – see above management for acute episode

References

BSH guidelines: https://b-s-h.org.uk/guidelines/guidelines/diagnosis-and-management-of-thrombocytopenic-purpura-and-other-thrombotic-microangiopathies/

ISTH guidelines: https://www.isth.org/page/TTPGuidelines

Blood – “How I treat thrombotic thrombocytopenic purpura in pregnancy”: https://doi.org/10.1182/blood.2019000962

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