1. MAHA: diagnosis and management
Kathryn Boyd
Consultant haematologist
April 2016

2. Photo blood film

3. Patient P: presentation on 18/01/2015
LP, 47yr old lady
Hb 98g/l, WBC 4.1, plat 21 x 10 9/l, ,Retics 6%,
2 days vomiting, nose bleed, dyspnoea, orthopnoea, leg swelling
PH: breast cancer in 2005, metastatic since 2010, last chemo 18 Nov 2014 gemcitabine and carboplatin
OE: Tachycardia, Pleural effusions, peripheral oedema, hypertension
Creatinine 301mmol/l, eGFR 14ml/min, BNP

4. Photo blood film

5. Schistocytes are evidence of fragmentation haemolysis
Cardiac: prosthetic valves, patches, grafts, leaks around valves
Arteriovenous malformations: Kasabach-Merritt syndrome, malignant haemangioendotheliomas
Microangiopathy (MAHA): destruction of RBC’s in pathologically altered small blood vessels

6. MAHA: a clinical syndrome
Fragmentation haemolysis
main pathological lesions in microcirculation
- deposition of fibrin strands often with DIC
- platelet adherence and aggregation
- vasculitis
- tumour plugs in vessels
Vascular abnormalities may be generalized or confined to sites/organs

7. Thrombotic Micro-angiopathies
The Triad
Micro-angiopathic haemolytic anaemia (MAHA)
Thrombocytopenia
Clinical or histological effects of microvascular thrombosis
Classification
Thrombotic thrombocytopenic purpura : TTP
Haemolytic Uremic syndrome: HUS
Atypical haemolytic uremic syndrome: aHUS
Other Thrombotic microangiopathies: TMA’s
DIC, Malignant hypertension
HELLP, Preeclampsia
Systemic malignancies Systemic infection
Autoimmune disorders

8. Patient P: Why develop TMA ?
Clinical history:
symptoms severe for 2 days but progressive over 3 months
metastatic breast cancer for 5 yrs
gemcitabine and carboplatin 3mths ago
Investigations:
Onset of uremia and cytopenias

12. Further investigations
LDH 1353
Haptoglobins absent
DC negative
PT 11, APTT 30, Fib 4.4, D dimer 2.2
Urine alb 1120mg, creat 5.36, ratio 209
CT pleural effusions, consolidation, ground glass shadows in lungs, patchy medullary pattern in rib cage, large liver with patchy left lobe
Bone marrow biopsy: Infiltrate?

14. Bone marrow

16. Summary of Patient P: 47 yr old lady
3 month history of progressive cytopenia and renal impairment since chemotherapy given 4mth ago for metastatic breast cancer.
Presents with nose bleed and severe fluid overload causing heart failure.
Micro-angiopathic Haemolytic anaemia, Thrombocytopenia and renal failure
Conclusion: TMA
What type: TTP, a HUS, TMA Assoc with Cancer or chemo

17. TTP ? Thrombotic thrombocyopenic purpura
Acute syndrome of MA haemolytic anaemia, thrombocytopenia and evidence for microthrombi:
Often Neurological or cardiac symptoms/signs
Usually mild proteinuria, mild renal impairment
Microthrombi are platelet and VWF rich
Deficiency of ADAMTS13, a metalloprotease, often due to autoantibodies or congenital

19. TTP: ADAMTS13 activity <10%
Metalloprotease which cleaves VWF
Deficiency leads to persistence of unusually large vWF multimers.
Acquired: Autoantibody to protease
Congenital: ADAMTS 13 gene mutation
FRET (Flourescent resonance energy transfer), ELISA assays available as kits
TEST for enzyme activity and Antibody presence

27. Importance of recognizing TTP early
Untreated TTP has 100% mortality, 50% occurring within 24hr of diagnosis
Plasma exchange (PEX), corticosteroids, and use of rituximab achieves >90% survival
NB avoid platelet transfusion as it can aggravate the disease

28. Suspect TTP: Urgent referral for plasma exchange
TTP must be considered in all patients presenting with thrombotic MA
TTP is life threatening with 50% deaths within 24hr of diagnosis
Diagnosis based on clinical history, examination and blood film.
ADAMTS 13 assay: activity or antibody assay, Not emergency tests, used to confirm and monitor TTP

29. How I treat TTP and HUS. Marie Scully and Tim Goodship. BJH Jan 2014

30. Atypical HUS ?
Triad of thrombocytopenia, MAHA and renal failure in 100% of cases
(HUS: diarrhoea positive syndrome due to Shiga-like toxin producing E coli )
Excessive complement activation on the surface of the renal microvacsulature
Sporadic and familial
60% have inherited or acquired abnormality of complement system including mutations

31. aHUS diagnostic criteria
Exclusion
Shiga toxin assoc HUS
Secondary causes
Drugs,
Cobalamin deficiency
Infection, HIV, Strep p
Transplantation
SLE, APLs, scleroderma
ADAMTS13 Antibodies or deficiency
Inclusion
Renal biopsy showing a TMA
And /or
Classic triad of MAHA, Thrombocytopenia and renal failure

32. Plan for Patient P Urgent referral for discussion of PEX
TTP: not acute, renal failure,
HUS : no diarrhoea, not acute, not oliguric
aHUS: triad present, but not acute and underlying metastatic cancer
PEX not useful in malignancy /chemo related MAHA
PEX not indicated immediately given clinical history
Give FFP immediately: to provide ADAMTS 13,
Check ADAMTS 13 assay
Heart failure and BP management

33. Diagnosis for Patient P: TMA
Not TTP: ADAMTS13 activity is >10%
Not HUS: no diarrhoea
Not aHUS: underlying metastatic malignancy and gemcitabine chemotherapy
Secondary TMA
Management
manage fluid overload causing heart failure,
Unfractionated heparin by IV infusion to provide inhibition of complement pathway.

34. Progress of Patient P
Improved fluid balance and slow rise in platelets,
At 2 weeks fit for discharge :Std Heparin 5000 units sc bd
At 4 weeks fluid overload causing more SOB,
At 5 mths (5/5/2015): well, enjoying life
Hb 94, wbc 5, plat 171,
Creatinine 259, eGFR19,
Darbepoietin alpha renal dose
Enoxparin 20mg daily
Frusemide 40mg daily

38. TMA: malignancy or drug related
LP: general well
MAHA secondary to metastatic malignancy less likely.
MAHA secondary to chemo more likely and reported after Gemcitabine, also carboplatin and mitomycin c.

39. Gemcitabine and MAHA 0.02 – 2.2 % of patients treated
Renal failure, hypertension, fluid overload and anaemia described in case reports
Mechanism uncertain: direct damage to endothelial cells ?
Therapy: stop chemo, steroids no benefit and PEX no use.
Eculizumab a MoAb that inhibits C5, licensed for atypical HUS and in report, 3 of 4 Gem related MAHA cases showed response. Ustwani OA et al JGastro oncol 2014,5 (1).

40. How I treat TTP and HUS. Marie Scully and Tim Goodship. BJH Jan 2014

41. Patient P’s progress Anaemia resolved with Darbepoietin Alpha
Thrombocytopenia resolved: enoxaparin prophylaxis substituted and then stopped.
LP remained well until Oct 2015: pain in left hypochrondrium: liver mets enlarged
Over next 3 months progressive liver decompensation, femoral DVT,
No recurrence of TMA
Died Feb 2016: metastatic breast cancer

42. Thank you

43. How I treat patients with TTP. James George
BLOOD, 18 NOVEMBER VOLUME 116, NUMBER 20

44. How I treat refractory thrombotic thrombocytopenic purpura.
Farzana A. Sayani and Charles S. Abrams
Blood March 2015