Haematology

1. Haematology The Good, The NICE , The Bad and the Ugly Dr Simon Watt www.mccollumconsultants.com

2. Introduction • The Good: Useful guidelines • NICE guidance and its limitations • The Bad: Why Haematology cases are sometimes difficult to prove, the difference between haematology and the law • The Ugly: Growth areas in haematology

3. What do haematologists do? • Clinical work- lots of relatively rare diseases • Malignancies e.g. lymphoma, leukaemia, myeloma • Red cells e.g. thalassaemia and sickle cell diseases • Coagulation e.g. thrombosis, bleeding disorders • Anticoagulation clinics i.e. warfarin • Transfusion • We tend to sit on a lot of advisory groups. • Laboratory- in charge of the haematology lab and interpretation of blood and bone marrow tests.

4. Good guidance • BCSH- British Committee for Standards in Haematology • ACCP- American College of Chest Physicians • ASH- American Society of Haematology • Cochrane reviews. E.g. Mechanical thromboprophylaxis • Other international guidance e.g. ELN • Other speciality guidance that overlaps

5. Other useful readingNatural History of Venous Thromboembolism • Most studies focus on intervention and/or don’t compare with omission of treatment • Keiron 2001 • 10% of Pulmonary Emboli (PE) are fatal in the first hour • <25% of patients who present with a PE will have a symptomatic Deep Vein Thrombosis (DVT) • Most fatal PEs occur 3-7 days post surgery • UNANSWERED QUESTION: Does prophylaxis prevent a clot that has already formed e.g. during surgery?

6. BRIDGE study • Area of concern around stopping anticoagulation during surgery • Surgery is a risk factor for thrombosis in someone already at risk of thrombosis • Showed no benefit in continuing anticoagulation in atrial fibrillation in pre-op period- didn’t prevent clots • AND increased risk of bleeding

8. NICE GUIDANCE Thrombosis/prevention • Sometimes not supported by evidence • Doesn’t cover out of hospital settings well e.g. rehab, plaster casts, long term conditions • Consider pharmacological VTE prophylaxis with LMWH[4] or fondaparinux sodium[5] for people with lower limb immobilisation whose risk of VTE outweighs their risk of bleeding. Consider stopping prophylaxis if lower limb immobilisation continues beyond 42 days.

9. SIGN • Often clearer, more practical • Gives levels of evidence and better referenced • Less comprehensive cover than NICE • E.g SIGN 122- VTE and prevention.

10. NICE Haematological Malignancy • Limited mostly by QALY judgements i.e. value for money • Shapes treatment plans outside of clinical trials • Can be very complex • BUT sometimes recommends things that are not value- tests which don’t change management e.g. recommends genetic testing in myeloma… treatment options remain the same • Molecular panels and whole gene sequencing will open a whole other can of worms….

11. Myeloma • Incurable cancer of bone marrow- plasma cells • Effective treatment • Life expectancy can be from 1y to 10y+ • Causes fractures • Kidney failure • Anaemia • Usually can be diagnosed with blood tests • Radiology useful for assessing fracture risk and sometimes monitoring disease

12. Myeloma NICE pathways • 1st line Bortezomib or Thalidomide or both • Stem cell transplant in fitter patients • 2nd line Carfilzomib (if no bortezomib) Bortezomib plus antibody • 3rd line Lenalidomide, Ixazomib • 4th line antibody (if not second line then only 4th line) Pomalidomide or Lenalidomide, Ixazomib • 5th line pomalidomide some other combination • Then add in clinical trials which try treatments at different lines plus maintenance treatments • NICE guidance constantly updated

13. Venous thromboembolism

15. WHAT CAUSES VTE ? Three main components were identified by Rudolph Virchow,19th century German pathologist A change in blood flow due to immobility/paralysis resulting in stasis Hypercoaguability causing the blood to clot more readily, e.g. hormone replacement, clotting disorders or thrombophilias Injury to the vessel wall, e.g. trauma or infection

16. ICEBERG EFFECT Acute DVT/PE is the tip of the iceberg Death Post thrombotic syndromePulmonary hypertensionVenous ulcersRecurrent VTETreatment /complications-7% per year

17. Venous thromboembolism is Multifactorial • Risk factors include but not limited to: • Age • Oestrogen • Surgery • Any hospital admission • Cancer • Thrombophilia/family history • Some risk factors seem to vary depending on what we are studying e.g. obesity

18. Treatment/prophylaxis • Sometimes works • E.g. hips and knees

19. Bergqvist, 1996

20. Immobilised lower limb • 59 y old • Ruptured achilles tendon • Father had fatal PE post surgery in 60s • Overweight • Smoker • Seen in hospital but also seen privately • Given an inflating boot but it is argued not shown how to use it properly • Private consultant claims to have examined the leg • Flight to Greece • Fatal PE 24 hours later

21. Treatment/prophylaxis cont. • Sometimes it doesn’t work or the evidence isn’t there. • E.g. POT-KAST/POT-CAST • Salami slicing • Generalisation for unusual conditions • Usually justification for not giving thromboprophylaxis is inadequately documented

23. Trial exclusion criteria • Contra-indications for LMWH use (recent major bleeding, bleeding disorder, allergy) • Pregnancy • Pre-existent indication for anticoagulation therapy, either LMWH or vitamin K antagonists. • History of venous thromboembolism (indication for anticoagulation therapy for prophylaxis of recurrence)

24. On the balance of probabilities • Even if we agree he should have had prophylaxis ie breach of duty • Left to expert opinion to assess the risk factors… you can often find someone who says what you want • Even then difficult to prove treatment would change outcome with thromboprophylaxis

25. Treatment/prophylaxis cont. • Many trials have surrogate end points e.g. ultrasound proven clots • In turn this makes it difficult to predict clinically important outcomes e.g. prevention of fatal thrombosis. • And don’t compare with placebo- Unethical! • Lassen 2010

27. Difficult pe case • 53 y old man with a complex surgical history • Developed evidence of renal failure on bloods taken on Friday, not acted on until Monday • Fatal PE on tuesday

28. Difficult pe case • Mr S appears to have had multiple risk factors for venous thrombo-embolism. • These include: • Recent surgery; thrombosis can be linked with surgery up to 3 months post-surgery. • Prolonged hospital stay; all admissions to hospital are recognised risk factors. • Recurring infections and inflammation caused by fistula. • Repeated dehydration from fistula fluid loss and poor oral intake which also appears to have been present between x and x . This alone would be considered. • Obesity; BMI 44.2. This is recognised as a risk factor particularly in surgical patients. • Acute and chronic renal failure. • In my opinion his poorly controlled diabetes over a long period further contributed to iii, iv and vi. • Hickman line in situ. • Possible poor mobility due to medical condition. • Advancing age would be a weak risk factor given he was 53 years old at the time of the thrombosis.

29. thrombophilia • Two parts • Inherited conditions/ genetic • Give a lifelong predisposition to first thrombosis, but not recurrence • Rarely clinically important except perhaps during other periods of risk e.g. pregnancy • Acquired- antiphospholipid syndrome • Important for predicting recurrence • Poor at predicting first event 2% of healthy blood donors will test positive

30. Thrombophilia?

31. Recurrence

32. Schulman et al AJM 1998

33. Guide for Haematological Cancer • Some are curable (potentially) • Acute leukaemias • High grade Lymphomas • Hodgkins lymphoma • Begin treatment as soon as a diagnosis is made • Delayed diagnosis may kill but probably not change quality of life • If the client is alive they probably don’t have that much of a case!

34. Case • 30 Female born in Asia • Chest x-ray for cough- lymph nodes • Respiratory attempt biopsy- non diagnostic • Treated for TB and discharged after finished tx • No definite change in x-ray • “clinically better” • Represented a further 4 months later • Rebiopsy- Hodgkins disease

35. Case cont. • Now stage 4B disease • May have been 2B 12 months earlier • Difference in survival only marginal i.e. 5% • Treatment may be different • Patient in remission 3y later therefore probably cured • Clearly breach of duty by respiratory • Actual harm depends on proving the suffering during the 12 months

36. Guide for Haematological Cancer • Some cancers are not curable • Chronic lymphoid leukaemia • Low grade lymphoma • Myeloma • Delays in treatment will not affect life expectancy • May affect quality of life

37. Case • Male 60 • Myeloma underwent 1st line treatment • Opportunity to detect earlier relapse in myeloma • Underwent blood test at local hospital- not clear who was responsible for test • Radiology report not acted upon resulting in a delay in diagnosis of relapse of myeloma with probable vertebral fracture. • But probably hasn’t affected life expectancy as will have received same treatment (3 months later)

38. Diagnosis of Haematological cancer • Generally easy • Blood tests are abnormal which lead to diagnostic tests/haematological referral • Ignored results! • Exception Lymphoma • Presents to all specialities • Can mimic almost anything e.g. fluid on the lung, TB, Other tumours • Generally requires a large biopsy to diagnose • Poor guidance on what size lymph nodes to biopsy

39. Treatment of haematological cancer • Sometimes more than one available treatment as per NICE e.g. Myeloma • Or different accepted standards of care e.g. Hodgkins lymphoma • ABVD v BEACOPP • No treatment- “watch and wait” may be appropriate • Treatment decisions should be made in MDT meeting, hence should generally be defensible. • MDT may not always work as generally most of the attendees will never have met the patient.

40. Noacs, doacs,oacs • 5 new oral anticoagulant drugs • Dabigatran • Rivaroxaban • Apixaban • Edoxaban • Betrixaban

41. Licenses • I believe all doctors in MFT should stick to the evidence with these potentially dangerous drugs • Treatment of Atrial Fibrillation (irregular heart beat) • Treatment of DVT- clots in the VEINS of the leg • PE. Clots in the lungs • Prophylaxis- Clot prevention in hip and knee replacements

42. Not licensed forAnd there is no evidence! • Arterial thrombosis (not AF) • Heart valve replacements • Prophylaxis of all other things!

43. Grey Areaswhere things can go wrong • Dosing, different dosing for all the drugs and different indications to change the dose. • - Kidney function • - Age • - Body weight • Leaves possibility to both underdose and overdose a patient • Anti-phospholipid syndrome • Thrombophilia • Upper limb thrombosis • Bridging • Cancer

44. Conclusions • Medicolegal is a small part of all the work lawyers do • Haematology is a small part of medicolegal • There are many and varied conditions • You may need some specialist advice • Often a decent local haematologist (if they have one) should be able to advise their trust

45. Conclusions • Thrombosis is multifactorial • Often interventions will only make a small difference to outcome • Thrombosis will usually occur in patients with multiple risk factors • Sometimes guidelines are clear/not clear • Two general sorts of malignancy • Aggressive/curable • Indolent/ incurable • Delayed diagnosis and delayed treatment (often clear cut) • Harm is often less clear cut

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