MAHA 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
Pathogenesis § 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
Subtypes § Congenital § Acquired § Idiopathic § Secondary § Drugs § OCP, cyclosporine, mitomycin C § Post BMT § SLE § Malignancy § Pregnancy § Infection § HIV, E coli 0157 § Intermittent
ADMATS 13 § 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
Investigations § 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
Management § 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
Relapse § 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
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
Subtypes § 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)
Management D+ § 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
D- § 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
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