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Microangiopathic haemolytic anaemia



Thrombotic thrombocytopenic purpura

§        3.7 per million


Clinical features

§        Pentad

§        Thrombocytopenia

§        MAHA

§        Neurology

§        Coma = poor prognostic sign

§        Renal impairment

§        Fever

§        Insidious onset

§        Associations

§        GI ischaemia

§        Serous retinal detachment



§        Platelet microvascular thrombi

§        Renal and cerebral circulations are primarily affected

§        ULVWF are NOT a normal constituent of circulating plasma

§        Undergo proteolytic degradation to smaller multimeric forms

§        Metalloproteinase = ADAMTS13

§        Deficiency of ADAMTS13 is associated with acquired and congenital TTP

§        Secondary TTP may occur in the presence of normal protease levels



§        Congenital

§        Acquired

§        Idiopathic

§        Secondary

§        Drugs

§        OCP, cyclosporine, mitomycin C

§        Post BMT

§        SLE

§        Malignancy

§        Pregnancy

§        Infection

§        HIV, E coli 0157

§        Intermittent



§        Metalloproteinase

§        Congenital – constitutional deficiency, presentation may be delayed until adulthood

§        Found to have high diagnostic value in initial studies but this was subsequently challenged

§        Levels <10% unequivocal indicate a diagnosis of inherited or acquired TTP (but as few as 18% of patients had levels this low in one study cf 94% in the earlier studies).

§        Also predictive of relapse (PPV28% cf NPV95% if levels not severely reduced)

§        Levels of 10-40% may be associated with acquired TTP (more commonly than inherited TTP)

§        Levels also reduced in cirrhosis, uraemia, acute inflammation, DIC, neonates, post op and malignancy (only in the 10-40% range).

§        In addition low levels of ADAMTS 13 do not correlate with disease activity in inherited TTP

§        Siblings may have very different patterns of disease despite similar levels of ADAMTS13

§        Half life of 4-5 days and infusions every 2-3 weeks of FFP keeping trough levels >10% appear to be sufficient to prevent recurrence

§        Role of serial monitoring to gauge response to treatment is currently unclear

§        Studies to date do not provide convincing evidence that real-time ADAMTS13 levels help to improve management of TTP.


§        Anti-ADAMTS13 antibodies

§        Low titre commonly found

§        High titre may be associated with more severe disease and slower response to plasma exchange

§        As good as severely reduced ADAMTS13 as a predictor of relapse



§        FBC and Film

§        Fragments may be absent in the first 24-48 hours

§        Clotting screen usually normal

§        Silent increases in D-dimers, FDPs

§        Secondary DIC may arise from prolonged tissue ischaemia

§        Abnormal VWF multimers

§        ULVWF during remission has been associated with intermittent TTP

§        Liver function tests

§        Raised bilirubin

§        Raised transaminase level secondary to hepatic ischaemia

§        Renal

§        Normal in the majority

§        If unable to distinguish from HUS, assume TTP and initiate treatment

§        Renal biopsy

§        Stains strongly for platelets and vWF in contrast to DIC which stains strongly for fibrin and fibrinogen

§        LDH

§        DAT

§        Urinalysis

§        Proteinuria

§        Virology

§        HIV – strong association

§        Hep B/C – donor exposure during treatment



§        Plasma exchange

§        Mortality rates from 90 to 10-30%

§        Single volume daily exchange within 24 hours of presentation

§        Average number for remission is 16 (in one study)

§        Continues for a minimum of 2 days after CR obtained

§        CR = normal neurology, platelet and LDH with rising Hb

§        Accepted practice is to taper frequency of exchanges

§        Solvent detergent FFP or cryosupernatant are preferred

§        Lack the large VWF multimers

§        Corticosteroids

§        Adjunctive treatment

§        To minimise long-term side effects

§        Methylpred 1g for 3 days

§        Little evidence of efficacy

§        Anti-platelet agents

§        Ticlopidine and clopidogrel have been associated with TTP and therefore NOT recommended

§        75mg aspirin is recommended when platelet count rises >50

§        Supportive therapy

§        Folic acid supplements

§        Red cell transfusions

§        Hepatitis B vaccination

§        Phenytoin as secondary prohpylaxis for seizures can be considered


Refractory disease

§        Persistent thrombocytopenia or LDH elevation after 7 exchanges

§        Manipulate plasma exchange

§        Alternative plasma product

§        SD FFP or cryosupernatant if using FFP

§        MB-FFP like FFP both have large VWF multimers

§        Intensify frequency

§        Vincristine

§        1mg every 3-4 days for a total of four doses

§        Cyclophosphamide

§        Used for relapses

§        Daily or pulsed

§        Cyclosporin

§        Has been used successfully in refactory, intermittent, post-auto transplant TTP


Malignancy and post BMT associated TTP

§        Plasma exchange is rarely effective

§        In allo SCT, cyclosporine should be stopped

§        Protein A column immunoadsorption may be beneficial



§        Remission is attained in over 80%

§        Up to 36% relapse over 10 years

§        Presence of ULVWF during remission is associated with intermittent disease

§        Splenectomy may reduce risk of relapse

§        Urgent self-referral is advised


Congenital TTP

§        Classically presents during childhhod

§        Recurrent episodes of haemolysis and thrombocytopenia at predictable intervals (every 21-28 days)

§        Occasionally presents at a much later age

§        Precipitated by febrile illness

§        Typified by ULVWF during remission reflecting defective post-secretory VWF processing

§        Absolute deficiency of ADAMTS 13 (<5%)

§        Successfully treated with prophylactic FFP/ SD-FFP/ cryosupernatant  every 3-4 weeks

§        Prn plasma infusions for milder variants

§        Hepatitis vaccination


Haemolytic Uraemic Syndrome


Clinical features

§        MAHA

§        Thrombocytopenia

§        Renal failure


Epidemic form (D+)

§        Prodromal illness often with bloody diarrhoea

§        Verotoxin-producing organisms (Shiga toxin S1 or S2)

§        E.coli 0157:H7

§        Organisms bind to gut wall receptors and remain within gut lumen

§        Toxin targets organs with specific globotriosyl ceramide  (Gb) receptors in particular glomerular microvascular endothelial cells, via neutrophils

§        Toxin subsequently becomes internalised and disrupts peptide assembly and protein synthesis



§        Epidemic (D+)

§        Sporadic (D-)

§        Non VTEC infections

§        HIV, strep pneumoniae

§        Secondary

§        Post-transplant

§        Drugs

§        Pentostatin, cyclosporine, mitomycin C, heroin, interferon B, quinine

§        SLE

§        Malignancy

§        Pregnancy

§        Familial or defect in complement factor H


Poor prognostic features

§        High neutrophil count

§        Thrombocytopenia >10 days

§        Persistent proeinuria >1 year

§        High PAI-1 levels


§        Deficiency of ADAMTS 13 is not identified

§        Early stool culture

§        Serology is not useful in the acute phase (IgM)




§        Fluid and electrolyte balance

§        BP control

§        ACE-I

§        Renal dialysis

§        Anti-motility and antibiotics contraindicated

§        No conclusive evidence to support FFP or plasma exchange

§        Adjunctive treatment is not recommended


§        Low gastric acid is associated with worse outcome

§        Gastrectomy or PPI



§        Higher mortality than D+

§        Several family cases linked to a deficiency/ defect of complement factor H

§        Controls the alternative complement pathway

§        Failure to prevent excessive C3 activation resulting in endothelia cell injury

§        Detectable as reduced C3 levels

§        Should be treated in a tertiary renal unit

Thrombotic microangiopathy in pregnancy


Differential diagnosis

§        TTP

§        Post-partum HUS

§        Usually primips

§        Mean onset 26 days after delivery

§        Treatment is supportive, benefit of plasma exchange uncertain

§        Pre-eclampsia

§        4% of pregnancies

§        Nulliparous women or multiparous with new partners

§        New onset hypertension and proteinuria in second half of pregnancy +/-oedema

§        Classically regress after delivery

§        Eclampsia

§        Magnesium sulphate as seizure prophylaxis

§        HELLP

§        Haemolysis, elevated liver enzymes and thrombocytopenia

§        10% with severe pre-eclampsia

§        Exacerbations may occur post-partum or can present post-partum

§        Risk of recurrence 3%

§        Profound renal or hepatic failure are uncommon which help to distinguish from acute fatty liver of pregnancy


§        Treatment of pre-eclampsia, eclampsoa and HELLP is delivery of fetus and placenta

§        Usually followed by complete recovery within 24-48 hours

§        Persistent disease post partum may be indication for plasma exchange


§        Acute fatty liver of pregnancy

§        Liver failure

§        Thrombocytopenia is mild and haemolysis not a feature

§        SLE/ APLS

§        Renal flare may mimic HUS +/- pre-eclampsia

§        APLa associated with pre-eclampsia, TTP and HUS

§        DIC


Presnting features of thrombotic microangiopathy



Post-partum HUS


Pre-eclampsia/ eclampsia

Time of onset

< 24 weeks

Post partum

> 34 weeks

> 34 weeks


Platelet thrombi

Thrombi in renal glomeruli only

Hepatocyte necrosis & fibrin deposition in periportal sinusoids

Glomerular endothelial hypertrophy & occlusion of placental vessels















+/- (reduced levels of anti-thrombin cf. TTP)





















Effect on fetus

IUGR and mortality


Placental ischaemia, increased neonatal mortality

IUGR, occasional mortality

Effect of delivery



Recovery but may worsen transiently

Recovery, but may worsen transiently


Plasma exchange

Supportive +/- exchange

Supportive +/- plasma exchange

Supportive +/- plasma exchange