Thrombotic Microangiopathies

Family of microvascular diseases characterised by systemic platelet aggregation and formation of microthrombi with subsequent microvasculature occlusion and endothelial injury:

Defined by triad of:
- MAHA
- Thrombocytopaenia
- Organ dysfunction
Divided into:
- TTP
  Caused by severe deficiency in the ADAMTS13 protein. This may be:
  - Life-threatening
  - Inherited or acquired
- HUS
  Further divided into:
  - Typical HUS
    Caused by infection with Shiga toxin-producing bacteria
    - Predominantly infective diarrhoea
      Classically E. coli O157:H7. Other organisms include:
      - Shigella dysenteriae
      - Citrobacter freundii
    - More common in children
    - AKI is the distinguishing feature
  - Atypical HUS
    Uncontrolled activation of alternative complement pathway.

Although the pathophysiology of each differs substantially, subtypes may be indistinguishable on clinical grounds.

HELLP syndrome also causes microangiopathic thrombosis and is covered under Hypertensive Diseases of Pregnancy.

Epidemiology and Risk Factors

Pathophysiology

TTP:

Large vWF multimers are produced by endothelial cells
Circulating ADAMTS13 cleaves large vWF multimers into more sensibly-sized proteins
Absence of ADAMTS13 results in persisting large vWF multimers, which attract and bind circulating platelets
Platelet clumping around vWF results in microvascular occlusion, with subsequent:
- Haemolysis
  Of erythrocytes passing through the obstructed microvascular space.
- Ischaemia
  Of the affected tissue bed.

Aetiology

Clinical Features

Cardiovascular symptoms
- Ischaemic chest pain
- ECG symptoms
Fever
Neurological manifestations
80% of cases.
- Coma
- Headache
- Focal deficit
- Visual changes
- Weakness
AKI
Rare in TTP.
Haemolytic anaemia
Mucocutaneous bleeding
Thrombocytopaenia
Gastrointestinal symptoms

Assessment

History:

Exam:

Investigations

Bedside:

Laboratory:

Blood
- FBE
  - Platelets
    Generally 20-50×10⁹/L.
- Blood smear
  - Evidence of haemolysis
  - Schistocytes
- Negative Coombs test
- ADAMTS13
  Normal in HUS.

ADAMTS13 is not required for diagnosis; haemolysis and thrombocytopaenia absent another cause is adequate.

Coombs test is:

Also known as antiglobulin testing
A test for autoantibodies against circulating erythrocytes
Diagnostic of autoimmune haemolytic anaemia
Also used in identifying transfusion-relevant antibody.
Performed either by:
- Direct antiglobulin testing
  - Detects antibodies bound to erythrocytes.
  - Patient blood washed in saline to remove plasma and unbound antibodies
  - Reagent added to detect bound IgG
- Indirect antibody testing
  - Patient plasma mixed with foreign erythocytes of known antigenicity
  - Reagent added to detect patient antibody bound to foreign cells

Haemolysis screen consists of:

Reticulocyte count
↑ Due to ↑ marrow turnover.
Blood film
- Schistocytes
  Mechanically fragmented erythrocyte, favours intravascular mechanical haemolysis.
LDH
Present in many cells and so not specific for haemolysis (as opoposed to other cellular destruction). Substantial ↑ (4-5× ULN) favours intravascular over extravascular haemolysis.
Haptoglobin
Binds free haemoglobin, and is non-specific for intravascular vs. extravascular haemolysis. Acute phase reactant and so result may be equivocal in inflammatory states.
Free Hb
↑ Due to cellular destruction.
Bilirubin
↑ Due to haemoglobin metabolism. Classically ↑ conjugated bilirubin, although unconjugated may ↑ in concurrent hepatic impairment.

Imaging:

Other:

Diagnostic Approach and DDx

Comparison of Microangiopathies
Characteristic	TTP	Typical HUS	Atypical HUS
Clinical	Lung almost never involved AKI rare at presentation Fever	Blood diarrhoea prodrome AKI common Neurological symptoms common	↑ Severity of organ involvement
Investigations	Profound thrombocytopaenia ADAMTS13 <10%	Positive stool culture for Shiga-toxin E. coli	Mild (or no) thrombocytopaenia

Differential diagnoses include:

C
- Hypertension
H
- DIC
I
- Vasculitis
- Autoimmune
  - APS
Infections
- Viral
- Severe bacterial or fungal infection
Drugs
- Simvastatin
- Calcineurin inhibitors
- Quinine
- Interferon
Obstetric
- Pre-eclampsia

Management

TTP:

Corticosteroids
Urgent plasmapheresis
Consider monoclonal antibody therapy

Resuscitation:

Specific therapy:

Pharmacological
- TTP
  - Corticosteroids
    - Methylprednisolone 1g/day for 3 days
    - Prednisolone 1mg/kg/day
  - PPI
    To ↓ gastric erosion.
  - Rituximab
    If neurological or cardiac involvement.
  - Folic acid 5mg/day
- Atypical HUS
  - Eculizumab
Procedural
- TTP
  - Plasma exchange
    - Removes precipitating antibody
    - Replaces ADAMTS13
Physical

Supportive care:

C
- Hypertension management
F
- RRT
  Required in majority of HUS patients.

Disposition:

Preventative:

Marginal and Ineffective Therapies

Anaesthetic Considerations

Complications

Prognosis

Untreated TTP may have mortality up to 90%
H
- Relapse
  - ~50% of patients relapse
  - Majority relapse within one year
  - May be ↓ after splenectomy

Key Studies

References

Bersten, A. D., & Handy, J. M. (2018). Oh’s Intensive Care Manual. Elsevier Gezondheidszorg.
Kappler S, Ronan-Bentle S, Graham A. Thrombotic Microangiopathies (TTP, HUS, HELLP). Emergency Medicine Clinics of North America. 2014;32(3):649-671. doi:10.1016/j.emc.2014.04.008
George JN. Thrombotic Thrombocytopenic Purpura. The new england journal of medicine. Published online 2006.