Making Sense…

1. Making Sense… Thrombotic Microangiopathies ‘TTP & AHUS’ Tina Dutt Roald Dahl Haemostasis &Thrombosis Centre Royal Liverpool University Hospital

2. The Thrombosis –Complement Crossroads

3. Complement and Coagulation Common ancestry Pro-coagulant complications Platelets Inflammation Partners in attack and defence The clot thickens.. NETosis, complement, and coagulation: a new triangular relationship De Bont et al, Nature 2018

4. Making sense..?

5. Thrombotic MicroangiopathiesTTP & AHUS • What we knew? • Rare • Complex pathophysiology • Significant Morbidity and Mortality • Difficult to diagnose and treat well • What we know? • Increasing awareness of rare disease • Better understanding of underlying pathology • Novel Targeted therapies available • Impact of Specialist care on patient outcomes

6. Thrombotic Microangiopathies

7. Common Endpoint • Microvascular thrombosis • Haemolytic anaemia • Thrombocytopaenia

8. Untreated

9. TTP Case • 48 yr old female, carer, no PMHx • 12pm: A&E Minors • 3 day Hxof red urine, abdo pain, tired, sick, unwell • 14.30:Seen by Junior doctor • Plan: blood tests, antibiotics, home and refer to haematuria OPD • Patient awaits antibiotic prescription in the waiting area

10. 16.00 Haematology Lab: • Abnormal FBC result flagged • Hb 11 (11.5-15.5) (15) • Platelets 10(150-450) (250) • Creatinine 120 (70-100) (60) • Blood film: multiple fragmented red blood cells

12. 16.15:A&E • Haematology Consultant Review - Patient moved toRESUSfor close monitoring • Referral for urgentPlasma Exchange made • Critical CareOutreach Team informed about patient – ‘call us if you need us’ • Patient Early Warning Score 0

13. 21.00: Plasma Exchange commenced on Haematology Ward • 23.00 Patient R.I.P. • ADAMTS 13 < 5%

14. Treatment for TTP –Therapeutic Apheresis X

15. ?TTP

16. TTP IS A MEDICAL EMERGENCY It is due to a deficiency of the VWF cleaving protein, ADAMTS 13, leading to spontaneous platelet aggregation in the microvasculature Suspect if LOW PLATELETS + MAHA* *MAHA = micro-angiopathic haemolytic anaemia = falling Hb with fragmentation and micro-spherocytes on blood film REFERRAL CRITERIA LABORATORY TESTING Platelets median 10-30 Hb median 8-10, fragmentation on film Haemolysis screen +ve retics, haptoglobins, LDH , bilirubin eGFR Clotting screen normal CLINICAL FEATURES Bruising, bleeding Neurological symptoms e.g. headache, confusion, seizures Fever History of TTP IF YOUR PATIENT HAS ALL OR A COMBINATION OF THE ABOVE CALL ROYAL LIVERPOOL UNIVERSITY HOSPITAL HAEMOSTASIS CONSULTANT ON CALL

17. AHUS Case • 21 year old primip • Uneventful pregnancy, NVD • Unwell 1 day post partum • Hb 64, Plts 23, WCC 12 • Blood Film – ‘fragments’ • Urea 22, Creat 411, poor urine output, SOB • Diagnosis? • Management?

18. TTP IS A MEDICAL EMERGENCY It is due to a deficiency of the VWF cleaving protein, ADAMTS 13, leading to spontaneous platelet aggregation in the microvasculature Suspect if LOW PLATELETS + MAHA* *MAHA = micro-angiopathic haemolytic anaemia = falling Hb with fragmentation and micro-spherocytes on blood film REFERRAL CRITERIA LABORATORY TESTING Platelets median 10-30 Hb median 8-10, fragmentation on film Haemolysis screen +ve retics, haptoglobins, LDH , bilirubin eGFR Clotting screen normal CLINICAL FEATURES Bruising, bleeding Neurological symptoms e.g. headache, confusion, seizures Fever History of TTP IF YOUR PATIENT HAS ALL OR A COMBINATION OF THE ABOVE CALL ROYAL LIVERPOOL UNIVERSITY HOSPITAL HAEMOSTASIS CONSULTANT ON CALL

19. AHUS • ADAMTS 13 normal! • STEC Negative • Renal Impairment predominant • with suboptimal response to PEX • Often require haemodialysis • Consider renal biopsy

20. Features of aHUS • Familial occurrence observed • Affects adult and paediatric populations • Predisposing genetic mutations (vs. causative) in up to 50% cases, disease initiation factors e.g. infection, additional mutation • Multi organ involvement, ~40% neuro involvement • 20-30% cases present with diarrhoea • High mortality ~ 50%, ~ 50% relapse, > 1/3 require long term dialysis • Role of PEX unclear

21. aHUS Coppo and Veyradier, 2009

22. aHUS and Eculizumab

23. THROMBOCYTOPENIA and MAHA ∆∆ TTP/HUS/aHUS URGENT REFERRAL TO HAEM/ RENAL SEND ADAMTS 13 & STEC TESTS COMMENCE PEX ADAMTS 13 > 5% ? aHUS ADAMTS 13 < 5% TTP STEC +VE HUS CONSERVATIVE TX CONTINUE PEX REFER FOR ECULIZUMAB SEND GENETICS CONTINUE PEX N.B. if ADAMTS not available pre-PEX, consider aHUS if poor response to PEX DISCONTINUE PEX AFTER 1ST ECULIZUMAB

24. Making sense..?

25. When a diagnosis of an acute TMA has been made, suggesting TTP or aHUS, it is imperative that patients are transferred to Specialist Centres for treatment as soon as possible. Scully and Goodship, BJH 2014 Implementing a network of Specialist TTP Centres should drive a higher quality patient service where continuous improvement will be fuelled by volume and experience. Dutt and Scully BJH, 2015

26. TTP Specialist Centres • NHSE HSS Commissioning by 2019 • Blue Light Transfer agreement – NWAS now national • 4-8 hour ‘door to needle’ – time to PEX • 24/7 PEX provision • Specialist led care, critical care input • Trust board approved formalised care pathways • ADAMTS 13 assay provision and use for monitoring • National AHUS Service, Newcastle • NHSE Approved Eculuzimab • Genetic couselling • Patient Support • National AHUS Service

28. Rare but Reversible..

29. Thank you for your attention

30. The ‘clot’ thickens… NETosis, complement, and coagulation: a new triangular relationship Activated complement proteins can stimulate NET formation, and NETs, in turn, can serve as a platform for complement activation. NETs can act as a scaffold for thrombus formation during coagulation. NETosisappears to be a third important player in the coagulation complement cross talk consortium to protecting host against pathogen effects De Bont et al, Nature 2018