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

2. The Thrombosis –Complement Crossroads
For those of you familiar with this territory you will be aware that the relationship between coagulation and complement is historic but very much a work in progress and at the best of times not always an easy map to navigate!

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 Microangiopathies TTP & 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. Microvascular thrombosis
Common Endpoint
Microvascular thrombosis
Haemolytic anaemia
Thrombocytopaenia

8. Untreated Untreated patients will suffer devastating consequences.
The result of Thromboses in the small vessels feeding the skin and peripheries is shown here.
Renal failure is a common presenting symptom.
Patient will often have neurological symptoms such as mood changes, seizures or a stroke
And if the heart muscle is involved these cases are often fatal

9. TTP Case 48 yr old female, carer, no PMHx 12pm: A&E Minors
3 day Hx of 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
So to start with straight in to a case which I think really shaped my thinking in this area and dare I say the direction of travel in the UK

10. Abnormal FBC result flagged Hb 11 (11.5-15.5) (15)
16.00 Haematology Lab:
Abnormal FBC result flagged
Hb 11 ( ) (15)
Platelets 10( ) (250)
Creatinine 120 (70-100) (60)
Blood film: multiple fragmented red blood cells
The results are brought to the attention of the Hematology Consultant who based on the lab results strongly suspects a diagnosis of TTP

11. This shows a similar blood film to that which would have been found for this patient showing lots of broken red blood cells
Instead of a regular and round appearance of the red blood cells there are fragments representing broken down RBCs

12. Referral for urgent Plasma Exchange made
Haematology Consultant Review - Patient moved to RESUS for close monitoring
Referral for urgent Plasma Exchange made
Critical Care Outreach Team informed about patient – ‘call us if you need us’
Patient Early Warning Score 0
Within 10 minutes the Haematology team make their way to A and E where they find the patient mildly jaundiced, clutching a sick bowl awaiting her TTOs.
The patient complains of tiredness, headaches and feeling worse. She is informed that it is likely that she has a very serious condition which requires urgent tx and that she will need to stay in hospital. It is suggested that a next of kin is informed of admission however the patient is reluctant as she does not wish to worry her 80 year old mother with whom she lives.
The A and E sister is requested move the patient to a bed in resus and to keep the curtains open
MEWS CLINIAL SCORING SYSTEM

13. 21.00: Plasma Exchange commenced on Haematology Ward
23.00 Patient R.I.P.
ADAMTS 13 < 5%
Id like to now read out the account form the plasma exchange nurse who was with the patient form the time she arrived on the ward. p9

14. Treatment for TTP –Therapeutic ApheresisX
Plasma Exchange is the only treatment that has been shown to lower the mortality of TTP and the national guidelines recommend that patients should be treated within 4-8hours of presentation.
The treatment involves the patient being attached to an exchange machine as shown here and their blood volume being removed, the plasma filtered off and then the patients blood is returned with donor plasma which contains the missing ADAMTS 13 enzyme.
This is an intensive process requiring secure venous access and daily exchange for at least one week daily

15. ?TTP
Door to needle time as imp as MI, acute stroke etc

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
CLINICAL FEATURES
Bruising, bleeding
Neurological symptoms e.g. headache, confusion, seizures
Fever
History of TTP
LABORATORY TESTING
Platelets median 10-30
Hb median 8-10, fragmentation on film
Haemolysis screen +ve
retics, haptoglobins, LDH , bilirubin
eGFR
Clotting screen normal
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?
TMAs associated with pregnancy

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
CLINICAL FEATURES
Bruising, bleeding
Neurological symptoms e.g. headache, confusion, seizures
Fever
History of TTP
LABORATORY TESTING
Platelets median 10-30
Hb median 8-10, fragmentation on film
Haemolysis screen +ve
retics, haptoglobins, LDH , bilirubin
eGFR
Clotting screen normal
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%
TTP
ADAMTS 13 > 5%
? aHUS
STEC +VE
HUS
CONTINUE PEX
N.B. if ADAMTS not available pre-PEX,
consider aHUS if poor response to PEX
REFER FOR ECULIZUMAB
SEND GENETICS
CONSERVATIVE TX
DISCONTINUE PEX AFTER
1ST ECULIZUMAB
The specificity of
severe ADAMTS13 deficiency (<5%) in distinguishing acute
TTP from HUS is 90% (Bianchi et al, 2002; Zheng et al, 2004)

24. Making sense..?

25. Scully and Goodship, BJH 2014 Specialist TTP Centres
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. NETosis appears 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
NETosis is a regulated form of neutrophil cell death that contributes to the host defense against pathogens and was linked to various diseases soon after its first description in During NETosis, neutrophils release neutrophil extracellular traps (NETs), which can capture and kill bacteria and other pathogens to prevent them from spreading. Although substantial progress has been made in our understanding of NETosis, the precise mechanism underlying NETosis is still a matter of debate. Research continues to elucidate the molecular pathways involved in NETosis. In recent years, interactions with the complement and coagulation systems have become increasingly apparent. Activated complement proteins can stimulate NET formation, and NETs, in turn, can serve as a platform forcomplement activation. In addition, NETs can act as a scaffold for thrombus formation during coagulation. While crosstalk between thecoagulation and complement systems has been previously described, NETosis appears to be a third important player in this consortium to protect the host against pathogens. This review summarizes our current knowledge on the mutual interactions between NETosis, the complement system and the coagulation system, with an emerging description of their complex triangular relationship.