Case 146 – the beginning

You are about to see a new patient in the Haematology clinic.

She is a 58-year old lady with a background of hypertension. Ramipril is her only medication. She is otherwise fit and well.

She has been referred to you by a gastroenterology colleague. She presented to them with dyspepsia, and a gastric biopsy via oesophagogastroduodenoscopy (OGD) has been provisionally reported as showing lymphoma.

How would you proceed at this point and what further information would you like?

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Case 145 – continued

The critical care team inform you that while he was on LMWH prophylaxis whilst an inpatient for his acute appendicitis, he has not had any further heparin exposure in the last three weeks.

Further investigations are arranged with results as follows:

Blood film – a few red cell fragments (<1 per high power field) and polychromasia. Mild thrombocytopenia. No other diagnostic features.

ANCA – negative
ANA – weak positive with negative extractable nuclear antibodies
Anti-cardiolipin IgG 62 U/mL (0-10)
Anti-beta2-glycoprotein IgG 41 U/mL (0-7)

CT TAP has been requested to exclude underlying malignancy.

Given the degree of renal impairment and the require for invasive procedures (line insertions, etc.), you advise the critical care team to commence an unfractionated heparin infusion with anti-Xa monitoring due to the prolonged baseline aPTT.

What is the most likely diagnosis here?

What would you advise regarding the patient’s antiplatelet therapy – should this continue if starting UFH?

Given the most likely diagnosis, what treatment options are available and which ones would you initially recommend?

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Case 145 – the beginning

You are on-call for haematology and receive a call from the critical care team regarding a 36-year-old male with a complex medical history. With the exception of an episode of uncomplicated acute appendicitis 3 weeks ago which required a laparoscopic appendicectomy, he was otherwise previously fit and well. He was admitted to hospital 7 days ago with right hemiparesis and dysphasia – imaging demonstrated thrombus within the left middle cerebral artery. He received systemic thrombolysis with altepase with a good neurological response and was then commenced on aspirin 300 mg daily.

Three days into his admission while he was being worked up for the cause of his stroke, he developed central chest pain – troponin T was significantly elevated at 623 ng/L. Cardiology took him to the cath lab for a primary PCI; however, his coronary arteries appeared patent on angiography. ECG showed sinus rhythm and his echocardiogram was unremarkable with good LV function.

Over the next three days, he developed shallow skin ulcers affecting his shins and an acute kidney injury. He then deteriorated suddenly with features of acute respiratory distress syndrome and was transferred to intensive care where he was immediately intubated and ventilated. The admitting critical care doctor notices that his right leg is swollen and doppler ultrasound confirms a proximal DVT. CTPA did not demonstrate any associated large PE.

Prior to commencing anticoagulation, the critical care team note that his coagulation profile (below) is abnormal and call for advice both on the safety of anticoagulation and for advice on any further investigations for this very thrombotic patient.

What advice would you give them on anticoagulation? What would be your choice of anticoagulant in this patient and why?

What further investigations would you recommend?

Full blood count
Hb 102            (130-180)
MCV 99           (80-100)
Platelets 123   (150-450)
WCC 14.2        (4.0-11.0)
Lymph 2.1       (0.5-3.5)
Neut 10.8        (2.0-8.0)
Eosin 0.3         (0.1-0.5)
Baso 0.1          (0.0-0.1)
Mono 1.0        (0.2-1.2)
Retic 120         (20-80)

Coagulation
PT 15               (11-15)
APTT 61           (25-35)
Fibrinogen 6.7 (1.5-5.0)


Biochemistry
Na 142            (133-146)
K 5.9                (3.5-5.3)
Creat 310        (45-85)
Bili 35              (0-21)
ALT 49             (0-40)
ALP 102           (30-130)
CRP 113           (0-5)

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Case 144 – Summary

The case this week focused on the use of Viscoelastic Haemostatic assays (VHA). The patient had a ruptured AAA. Initial TEG testing was normal but she continued to bleed. Repeat TEG showed she had developed shortened R time and increased MA that responded to product replacement with FFP and platelets. She had an increased Ly 30 % but the team were uncertain about the use of TXA. Eventually a repeat TEG showed Ly 30 % > 70% and TXA was given to good effect and haemostasis was achieved.

VHA are uniquely placed to diagnose hyperfibrinolysis and there is no equivalent conventional lab test to detect this. In TEG studies 10-34% of patients having a major haemorrhage have Hyperfibrinolysis and this can lead to unnecessary mortality and morbidity for patients.

VHA Background:

The ideas behind Viscoelastic Haemostatic Assays (VHA) are old and in fact “whole blood assays” as they were known were first described by Prof Hartert in 1948. These were mainly research tools due to long sample processing times and the susceptibility to external vibration. These issues started to be overcome and over the past few years these have gradually made there way into clinical use. It should be acknowledged that the evidence base is limited. A 2014 NICE DG13 only recommends the use of TEG and ROTEM post cardiac surgery and states there is insufficient evidence to recommend the routine adoption of ROTEM and TEG in trauma and post partum haemorrhage. The research has continued and in 2018 a BSH guideline was published on their use as an adjunct to usual care. Many hospitals in the UK have access to VHA and these are being used in settings other than the accepted role post cardiac surgery.

BENEFITS VHA:

  • SPEED – Traditional coagulation tests are slow and can lag behind in rapidly evolving clinical situations like haemorrhage. Viscoelastic assays are quick taking 30 mins but a rapid TEG is available in 15 minutes.
  • HYPERFIBRINOLYSIS DIAGNOSIS- uniquely placed to diagnose this issue and allow correction with TXA like in case 144.
  • LIVER DISEASE ? Recognised for some time that PT/APTT prolongation in liver disease for example don’t correlate with bleeding risk due to fall in protein C or S levels. Viscoelastic assays may help in this setting.
  • PLATELET FUNCTION – Useful for platelet inhibition testing for anti platelet agents – may yield important information regarding drug resistance.
  • PATIENT BLOOD MANAGEMENT – Good evidence to show can reduce blood product use in a variety of settings.

Difficulties VHA:

  • STANDARDISATION – Poorly standardised no generalised reference ranges.
  • TRAINING ISSUES – Older Viscoelastic assays rely on pipetting rather than cartridges so issues with user were common.
  • REPLACING TRIED AND TESTED TESTS – Temptation this is used as replacement for tried and tested lab tests rather than adjunct to care.
  • INCREASES COST OF CARE – Additional costs to testing with unclear benefit in some settings such as trauma.
  • INTERPRETATION/ COMPLEXITY – Specialised test needs someone who understands to interpret and apply to clinical situation and this may be difficult in stressful situations like Major haemorrhage.
  • ONLY INFORMATION ON SECONDARY HAEMOSTASIS- No use in assessing vascular issues or primary haemostasis as evidenced by the normal traces seen in VWD, Lupus, HITT or Protein C or S deficiencies.
  • ACTING ON SINGLE RESULT – Generally trends helpful in these assays rather than a one off result often tempting to over interpret one abnormal trace.

Types of VH Assay:

All are VHA’s are useful tests and there is little difference between ROTEM and TEG. They are based on the same technology both are viscoelastic methods that provides graph of clotting process.

  • Thromboelastography (TEG) – Whole blood into cup with activator. Cup moves around pin that is static and resistance recorded using torsion wire.
  • Thromboelastometry (ROTEM) – Like TEG uses whole blood in cup but this time pin moves and cup is static. Change in optical density detected.
  • SONOCLOT – Plastic probe on electromagnetic transducer vibrates vertically resistance as blood clot forms is measured.

Each system has its own nomenclature and interpretation system. Our hospital in the case had TEG so we will focus on this for the interpretation. There is a good summary in BSH guidance if your hospital uses other systems.

INTERPRETING TEG:

  • CK TEG OVERVIEW:

R time – Time taken for the pin to start to detect resistance and is when fibrin starts to form. Long R suggests prolongation in PT/APTT. FFP is the agent of choice to address this.

K time- Time for clot to form and fibrin to polymerise.

MA – Maximum clot strength. Depends on PLT and FFP. Referring to CFF trace will help assess if platelet dysfunction or fibrinogen issue mainly to blame for reduced MA.

Ly30 – Defines the amount of fibrinolysis. If prolonged Tranexamic acid will help here. If MA increased alongside increased LY 30 this is functional fibrinolysis and doesn’t need TXA.

Types of trace on TEG:

  • Citrated Kaolin (CK) – Kaolin only the “standard” TEG
  • Heparinise (CKH) – Kaolin and Heparinase. Useful to detect if heparin affecting results.
  • Functional fibrinogen (CFF) – Tissue factor and platelet inhibitor. Shows the function of fibrinogen. Results should show 20-30% contribution by fibrinogen. 
  • Rapid TEG (CRT) – Kaolin and tissue factor. Result in 10-15 mins so useful in MHP. Tells the MA but no R time as uses Kaolin and tissue factor to activate coagulation. 
  • Platelet mapping – ADP and Arachidonic acid.

REFERENCE TABLE FOR ACTIONS WITH VARIOUS RESULTS ON TEG: (Reference ranges vary according to local standards hence not used in table)

Profile/TestTEG Measure ResultActions
CKRProlonged**check CKHeparinase R time?Heparin contamination
Otherwise consider FFP
CK or CRTMADecreased**Check CFF MA if normal give PLT. If abnormal CFF Cryo or consider both Plt/Cryo
CKLY30Increased*Consider TXA 
*If MA on CK is increased then TXA not indicated as likely reactive Hyperfibrinolysis
CFFMADecreasedCryo 
CKHeparinaseRIf R time shorter than CK R timeSuggests Heparin in sample

Evidence for VHA use in trauma:

Interestingly as mentioned earlier although the use of VHA is fairly widespread in the context of trauma the evidence base for VHA driven Major Haemorrhage protocols is actually fairly weak. There has been a recent large RCT of 390 patients (ITACTIC study) with major bleeding comparing conventional coagulation test driven MHP to VHA driven MHP. This failed to show improved patient mortality or reduced massive transfusion in first 24 hours for the VHA group. This study perhaps shows that although tempting to adopt novel therapies on the basis they seem superior the evidence for VHA driven MHPs is still lacking. Enthusiasts for the role VHA has would suggest this is due to poor interpretation of the VHAs. In the centres that used VHA in ITACTIC study were not familiar in applying the technique in a pressurised situation that may have affected outcomes.

In reality VHA may have a role to play but certainly this doesn’t replace the use of conventional haemostatic tests at present. VHA is advocated in American college of surgeons advanced trauma life support recommendations. It has a 1C recommendation in European guidelines of major bleeding and coagulopathy following trauma 4th edition. The same European guidelines give conventional coagulation driven MHP protocols a rating of 1A. Therefore VHA are adjuncts to usual care and do not replace laboratory tests in major haemorrhage at this stage.

There are some other things we do know about VHA in trauma and these are outlined below:

  • There is evidence to suggests a Normal VHA is useful to rule out need for transfusion. (2B recommendation from BSH guideline on VHA).
  • Low clot strength (MA) and Ly30 >3% can be used as increased risk factor for transfusion. (2C recommendation BSH guideline on VHA).
  • Use of VHA seems to reduce transfusions used in terms of Red cells and FFP. (Gonzalez et al).
  • There is no basis to withhold TXA based on VHA results in trauma. (1B BSH guideline on VHA)
  • BSH guidelines state there may be a reduction in mortality when using VHA driven MHP based on Gonzalez et al study. This however as discussed above has not been found in more recent large multi-centre study ITACTIC.

I hope this case has been helpful and thank you for your contributions to the case. Please feel free to post any comments.

References:

NICE DG13 – detecting, managing and monitoring haemostasis: vistoelastometric point of care testing. (ROTEM, TEG and Sonoclot systems. 20/8/14.

Curry et al. The use of viscoelastic haemostatic assays in the management of major bleeding. British Journal of Haematology (2018) 182; 789-806.

The use of viscoelastic haemostatic assays in goal-directing treatment with allogeneic blood products – A systematic review and Meta-analysis. Scandinavian journal of trauma, resuscitation and emergency medicine. (2017) 25:39.

Gonzalez E et al. Goal directed haemostatic resuscitation of trauma -induced coagulopathy: a pragmatic randomised clinical trial comparing a viscoelastic assay to conventional coagulation assays. Ann Surg 2016;263:1051-9.

Casper et al. Clinical validation of precision medicine protocols: the last mile is the longest. intensive care med (2021) 47;80-82.

Baksaas-Arsenal K et al. Viscoelastic haemostatic assay augmented protocols for major trauma haemorrhage (ITACTIC): a randomised controlled trial. Intensive care med (2020)

Rossaint R et al. The European guideline on management of major bleeding and coagulopathy post trauma: fourth edition. 2016. Crit care 20:100.

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Case 144 -update 4

The clinical team looking after the lady are not happy to give tranexamic acid as they feel it will be a thrombotic risk.

They do accept advice to give 4FFP and a pool of platelets given the long R time and low MA. 

Blood results from arrival in theatre are now available:

Hb 74, plt 54, PT 25 seconds (12 sec to 14.8 sec) , APTT 49 (27sec -41 sec), Fib 1.4g /l (1.9g/l -8g/l)

They have repeated the TEG and call you again.

The Blue line is the CK TEG from arrival in theatre.

The Purple line is the new CK TEG post FFP, Cryoprecipitate and RBC.

R time (min) 5 (5-10)

Angle (degrees) 53 (53-72)

MA (mm) 60 (50-70)

Ly30 (%) 70 (0-8)

What advice would you give the team ?

Are there any other results you could check that can worsen a major haemorrhage situation?

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Case 144 – update 4

The clinical team looking after the lady are not happy to give tranexamic acid as they feel will be a thrombotic risk.

They do accept advice to give 4FFP and a pool of platelets given the long R time and low MA.

Blood results from arrival in theatre are now available:

Hb 74, plt 54, PT 25 seconds (12 sec to 14.8 sec) , APTT 49 (27sec -41 sec), Fib 1.4g /l (1.9g/l -8g/l)

They have repeated the TEG and call you again.

The Blue line is the CK TEG from arrival in theatre.

The Purple line is the new CK TEG post FFP, Cryoprecipitate and RBC.

R time (min) 5 (5-10)

Angle (degrees) 53 (53-72)

MA (mm) 60 (50-70)

Ly30 (%) 70 (0-8)

What advice would you give the team ?

Are there any other results you could check that can worsen a major haemorrhage situation?

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Case 144 – update 3

The lady has been taken to theatre but the team have noted she is becoming more unstable despite ongoing replacement with the Major Haemorrhage packs

She had 4 RBC 4 FFP and you advised 2 cryo following initial lab tests. Her TEG was normal at that time point.

She has been given a further 2 RBC and 2 FFP but is still haemodynamically unstable in theatre.

They decide to send further lab tests which are awaited and repeat the TEG.

They call you to ask for advice with the CK TEG trace below:

Green line : Patients Initial CK TEG

Blue line : Patients CK TEG in theatre (heparinise cup also run no evidence of heparin contamination)

R (min) 9.4 (5-10)

Angle (degrees) 48 (53-72)

MA (mm) 40 (50-70)

Ly30 (%) 45 (0-8)

What does the TEG show?

Would you advise anything further based on TEG results?

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Case 144 – update 1

You establish the patients isn’t on any anticoagulants or antiplatelet agents. She has no cardiac history and the team don’t know about her blood group. She had an ABG that shows a Hb of 64.

You advise the team that they should be aiming to keep her APTTR and PTR <1.5, Fibrinogen >1.5, Hb >80 and plt >50.

In the hospital there is a Thromboelastography (TEG ) available as a viscoelastic Haemostatic assay and you suggest this may be helpful to guide the situation. 

What are the benefits of viscoelastic haemostatic assays compared to traditional coagulation screens?

What are the potential difficulties with TEG and other similar viscoelastic haemostatic assays such as ROTEM or Sonoclot?

What are the differences between the different assays TEG, ROTEM and Sonoclot?

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Case 144 – Update 2

You establish the patients isn’t on any anticoagulants or antiplatelet agents. She has no cardiac history and the team don’t know about her blood group. She had an ABG that shows a Hb of 64.

You advise the team that they should be aiming to keep her APTTR and PTR <1.5, Fibrinogen >1.5, Hb >80 and plt >50.

In the hospital there is a Thromboelastography (TEG ) available as a viscoelastic Haemostatic assay and you suggest this may be helpful to guide the situation.

What are the benefits of viscoelastic haemostatic assays compared to traditional coagulation screens?

What are the potential difficulties with TEG and other similar viscoelastic haemostatic assays such as ROTEM or Sonoclot?

What are the differences between the different assays TEG, ROTEM and Sonoclot?

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Case 144 – The Beginning

A 76 year old lady with a history of Hypertension and Diverticular disease collapses while out having her Sunday lunch with her family. An ambulance is called and she is hypotensive complaining of abdominal pains. The Paramedics bring her to A&E resus.

On arrival her Observations: BP 78/30 P 110 R 20 Sats 96% on air.

The resus team have gained IV access and performed an ABG and FAST USS scan of her abdomen. She has intraperitoneal free fluid visible on plain USS and in this context it is assumed she has a ruptured aortic aneurysm. The resus team activate the Major Haemorrhage Protocol and fast bleep the vascular team.

You are the on call Haematology Registrar and they ring you asking for advice regarding parameters for transfusion. They tell you they have no blood results available and that these may be slower than usual due to the hospital IT system having an upgrade. 

What history may be useful?

What advice would you give them? 

Is there any other test that may be available quicker than usual FBC/coagulation screen could be helpful when bleeding?

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Case 144: The Beginning

A 76 year old lady with a history of Hypertension and Diverticular disease collapses while out having her Sunday lunch with her family. An ambulance is called and she is hypotensive complaining of abdominal pains. The Paramedics bring her to A&E resus.

On arrival her Observations: BP 78/30 P 110 R 20 Sats 96% on air.

The resus team have gained IV access and performed an ABG and FAST USS scan of her abdomen. She has intraperitoneal free fluid visible on plain USS and in this context it is assumed she has a ruptured aortic aneurysm. Her Hb on the ABG is reading as 64. The resus team activate the Major Haemorrhage Protocol and fast bleep the vascular team.

You are the on call Haematology Registrar and they ring you asking for advice regarding parameters for transfusion. They tell you they have no blood results available and that these may be slower than usual due to the hospital IT system having an upgrade.

What history may be useful?

What advice would you give them?

Is there any other test that may be available quicker than usual FBC/coagulation screen could be helpful when bleeding?

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Case 143: summary

Thanks for your help with this week’s case!

We discussed a 55 year old man who presented with persistent erythrocytosis, thrombocytosis, and leukocytosis. This was associated with a thrombotic event (myocardial infarction).

Further investigations revealed JAK2 V617 positivity and a bone marrow showing hypercellularity, left shifted granulopoiesis, megakaryocyte clustering. Reticulin was not increased.

He was diagnosed with polycythaemia vera (myeloproliferative neoplasm) and commenced urgent venesection to reduce his thrombotic risk. This resulted in symptomatic iron deficiency and he was commenced on cytoreductive treatment with hydroxycarbamide.

He required high doses of hydroxycarbamide to achieve disease control and this was accompanied by significant side effects. He was switched to ruxolitinib therapy with good effect.

However, after a year he became pancytopenic and further bone marrow assessment showed his condition had progressed to myelofibrosis. Due to his age and performance status, he was referred for an allogeneic stem cell transplant.

Myeloproliferative neoplasm is a term used to describe a heterogeneous group of bone marrow disorders. Polycythaemia vera is an example of this and its morbidity and mortality are mainly associated with its increased risk of thrombosis and progression to myelofibrosis and acute myeloid leukaemia.

The British Society of Haematology have recently published helpful guidance on how to diagnose and manage this condition: https://onlinelibrary.wiley.com/doi/full/10.1111/bjh.15647

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Case 143: update 5

Our patient has a repeat bone marrow biopsy which unfortunately demonstrates progression to myelofibrosis. His spleen has also increased in size.

He is referred to the regional centre for an allogeneic stem cell transplant and ongoing care.

Well done, team!

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Case 143: update 4

Our patient wants to stop hydroxycarbamide side effects. He agrees to switch to ruxolitinib therapy.

His condition is well controlled on this for over a year until one day in clinic he complains of
abdominal discomfort and his blood counts are as follows:

Hb 121 g/L
Hct 43%
MCV 76 fL
Plt 102 x109/L
WCC 3.19 x109/L
Neut 1.03 x109/L
Lymph 1.26 x109/L
Mono 0.70 x109/L
Baso 0.10 x109/L
Eosino 0.00 x109/L

What would you do at this point?

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Case 143: update 3

The patient is diagnosed with a myeloproliferative neoplasm. He is not keen on chemotherapy and is commenced on a venesection programme, aiming for Hct <0.45.

Although his counts start to show some improvement, he eventually becomes troubled by symptomatic iron deficiency and agrees to commence hydroxycarbamide therapy.

After several months, his counts eventually improve to normal ranges with a dose of 2g daily.
However, he starts developing leg ulcers and his treatment is stopped.

What are the treatment options now?

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Case 143: update 2

This man is referred to the haematology clinic. Apart from his recent hospital admission, there is
nothing else of note in his history apart from the fact that he smokes. Examination is also
unremarkable.

You organise JAK2 testing, an ultrasound of his abdomen and a bone marrow biopsy. Results are as
follows:

JAK2 V617F detected (40%). Other pathogenic variants not detected.

Ultrasound abdomen: splenomegaly (14cm), otherwise unremarkable.

Bone marrow biopsy:

Bone marrow aspirate
Bone marrow trephine (H&E)
Bone marrow trephine (reticulin)

What is the likely diagnosis and what are the management options?

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Case 143: update 1

This man has no known past medical history and takes no regular medications. He is usually fit and
well and works as a chef. He smokes 10 cigarettes per day and drinks alcohol within recommended
limits. He lives in Newcastle, UK.

Examination is unremarkable (no hepatosplenomegaly). His treating team are concerned he is having a myocardial infarction. He undergoes successful coronary stenting and is discharged from hospital the following day on dual antiplatelets, a statin, an ACE-inhibitor and a beta-blocker.

His GP is asked to repeat his FBC the following week, which shows the following:

Hb 189 g/L
Hct 58%
MCV 85 fL
Plt 611 x109/L
WCC 16.3 x109/L

Neut 8.43 x109/L

Lymph 4.26 x109/L
Mono 3.51 x109/L
Baso 0.10 x109/L
Eosino 0.00 x109/L

Given his background and recent events, what would you advise at this point? Do you think this is a primary or secondary problem?

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Case 143: the beginning

A 55 year old man is admitted to the emergency department complaining of shortness of breath.

This came on suddenly a few hours ago. He had a full blood count taken in triage:

Hb 192 g/L
Hct 59%
MCV 84 fL
Plt 512 x109 /L
WCC 15.6 x109/L
Neut 9.73 x109/L
Lymph 2.26 x109/L
Mono 3.51 x109/L
Baso 0.10 x109/L
Eosino 0.00 x109/L

There are no previous results for comparison. The emergency department contact haematology for
advice on his abnormal full blood count.

What more would you like to know and what advice would you give?

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Case 142: summary

Pregnancy-associated TTP

Definition:

  • Rare but life-threatening thrombotic microangiopathy characterised by thrombocytopenia, MAHA and end organ damage due to microvascular thrombosis

Pathogenesis:

  • Severe ADAMTS13 deficiency (acquired or congenital)
    • ULVWF multimers lead to platelet adhesion resulting in platelet-rich microthrombi, red cell fragmentation (MAHA) and end organ damage
  • Acquired – autoantibody-mediated, more common
  • Congenital – genetic, less common
  • Pregnancy provoking factor for both acquired and congenital acute TTP episodes
    • Haemostatic changes: rising VWF levels, falling ADAMTS13 levels
    • Immunologic: changes in immune tolerance both during pregnancy and postpartum leading to autoimmunity
    • Often first provoking event in adult-onset congenital TTP

Presentation:

  • More common third trimester and postpartum
  • Microangiopathic haemolytic anaemia
    • Red cell fragments on blood smear
    • Features of non-immune haemolysis: raised LDH, raised reticulocytes, raised bilirubin, low haptoglobin, DAT negative
  • Severe thrombocytopenia can lead to bleeding complications although not usually severe/life-threatening
  • Usually normal coagulation
  • End organ damage
    • Gastrointestinal: abdominal pain and vomiting
    • Cardiac: chest pain, dyspnoea, raised troponin
    • Neurological: confusion, lethargy, seizures, focal deficits, coma
    • Renal: acute kidney injury (usually only mild-moderate)

Differential diagnosis (with differentiating features):

  • Pregnancy-specific
    • Pre-eclampsia with severe features (hypertension, proteinuria, peripheral oedema)
    • HELLP syndrome (LFTs more deranged than in TTP, often overlaps with pre-eclampsia)
  • Not pregnancy-specific
    • Acute DIC (deranged coagulation)
    • ST-HUS (acute diarrhoea from Shiga toxin, renal failure)
    • cHUS (renal failure)
    • Systemic vasculitis (acute nephritis, hypertension, positive ANCA)
    • CAPS (multiorgan failure with positive antiphospholipid antibodies)

Diagnosis:

  • Clinical diagnosis – MAHA and thrombocytopenia in the absence of other alternative cause (see differential diagnosis above)
  • Investigations
    • Haematology panel, including haemolysis screen and peripheral blood smear
      • Confirms MAHA and thrombocytopenia
    • LFTs, U/Es, coagulation, urinalysis, ANA, ANCA, anti-phospholipid antibodies, stool culture (if diarrhoea present), blood pressure measurement
      • Excludes differentials
    • Fetal ultrasound
      • Assess for intrauterine growth restriction
    • ADAMTS13 activity and anti-ADAMTS13 IgG
      • Confirms diagnosis and differentiates between acquired and congenital TTP
    • Troponins, CT brain (if neuro symptoms)
      • To assess for cardiac and neuro involvement

 Management (acute episode)

  • MDT approach: haematologists, obstetricians, nephrologists and intensivists
  • PEX and steroids as soon as clinical diagnosis is made (send ADAMTS13 assay off first)
  • Regular fetal monitoring for growth restriction
  • Confirmed aTTP = ADAMTS13 activity <10%, positive anti-ADAMTS13 IgG
    • Daily PEX and corticosteroids
    • Monitor response with platelet count, LDH, serial blood smears, clinical status
    • Stop PEX when platelets > 150 x 10^9/L for at least two days and monitor for recurrence
    • Gradual wean of steroids when in remission
    • Consider thromboprophylaxis and aspirin when platelets > 50 x 10^9/L
    • Normal obstetric indications for delivery of foetus
  • Confirmed cTTP = ADAMTS13 activity <10%, negative anti-ADAMTS13 IgG
    • Switch to plasma infusions – daily until remission
    • Ongoing management outside scope of this case but requires specialist tertiary care service with experience in managing this rare condition

Management (subsequent pregnancies)

  • Counselling re: risk of recurrence
  • Previous aTTP with persistently low ADAMTS13 activity
    • Pre-emptive treatment with rituximab to normalise ADAMTS13 activity
    • Avoid conception for at least 6 months after rituximab
  • Clinical and laboratory monitoring during pregnancy for relapse
    • ADAMTS13 activity normal – watchful waiting
    • ADAMTS13 activity borderline (10-20%) – low dose steroids
    • ADAMTS13 activity <10% – prophylactic PEX and low dose steroids
    • Overt acute TTP – see above management for acute episode

References

BSH guidelines: https://b-s-h.org.uk/guidelines/guidelines/diagnosis-and-management-of-thrombocytopenic-purpura-and-other-thrombotic-microangiopathies/

ISTH guidelines: https://www.isth.org/page/TTPGuidelines

Blood – “How I treat thrombotic thrombocytopenic purpura in pregnancy”: https://doi.org/10.1182/blood.2019000962

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Case 142: update 3

ADAMTS13 activity level subsequently comes back at <5% with positive anti-ADAMTS13 IgG antibodies, consistent with a diagnosis of acquired, immune TTP. The patient continues on daily PEX and 1 mg/kg prednisolone for immunosuppression. The patient responds well with resolution of neurologic symptoms and resolution of thrombocytopenia after 13 PEX sessions. PEX is continued for a further 3 days then discontinued. Steroids are continued and she is commenced on LMWH thromboprophylaxis and aspirin.

The patient remains in hospital for the remainder of her pregnancy for strict monitoring. ADAMTS13 activity recovers to 43% and she is successfully weaned off steroids. She goes into labour at 38 weeks gestation with an uncomplicated vaginal delivery of a healthy baby boy. She enters of period of surveillance for clinical, biochemical and serological relapse but after 6 months is lost to follow up.

Two years later, she is re-referred to haematology by her GP as she has expressed a desire to become pregnant again. On review in clinic, her blood counts are completely normal and she is asymptomatic. ADAMTS13 activity level is checked, which demonstrates an activity level of 11%.

How would you counsel the patient on the potential risks of further pregnancy?

How would you manage the patient to reduce the risk of TTP relapse?

How would you monitor the patient during the pregnancy? Is there a role for prophylactic PEX during pregnancy?

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