Malignant Qu 1

You SHO phones you for advice. They have been asked to review a 35 year old man who started his steroid pre-phase for ALL yesterday. The patient complained of palpitations and an ECG shows some T wave abnormalities.

What do you suspect and how will you proceed?

  • TLS

  • R/v fluid balance

  • ABG + Bloods

  • Cardiac monitoring + reverse K+

  • Contact Renal / ITU

What are the diagnostic criteria for TLS?

Lab: 2 or more of:

  • Uric acid          >476 or 25% above baseline

  • K+                    >6.0 or 25% above baseline

  • Phos                >1.45 or 25% above baseline

  • Calcium           <1.75 or 25% below baseline

Clinical: Lab plus one of:

  • Creatinine >1.5x ULN

  • Arrythmia

  • Seizures

  • Sudden Death

Can you give me any examples of risk factors for TLS?

  • High tumour burden

  • High grade tumours (ALL, BL)

  • Increasing Age

  • Pre-existing renal impairment

  • Cell cycle specific chemotherapy

  • Other drugs – alcohol, Vit C, aspirin, Caffeine, Cisplatin, Thiazides, Levodopa, Phenothiazines, theophylline

Can you tell me how rasburicase works?

  • Exogenous recombinant urate oxidase

  • Converts uric acid —> allantoin, 10x more soluble

What is the dose in prophylaxis?

  • 3mg

 

Malignant Qu 2

A GP refers a 57 year old man to you with a Hb 170, Hct 0.53, plt 320, WBC 6.0.

How would you approach the investigation of this patient?

Repeat test with adequate hydration

Hx & Ex

O2 sats, BP, urine dip

FBC, Film, U&E, LFT

JAK2 Mutation (V617F, Exon 12)

If JAK2 neg – RCM, Epo, ABG, USS, BM Bx, Cytogenetics, PFTs, Sleep Study, VHL gene

The patient is positive for the JAK2 V617F mutation. Can you tell me about any diagnostic criteria for PV?

WHO vs BCSH

WHO: 3 major (Hct >0.49 / 0.48 M:F, BM Biopsy, JAK2+) or 2 major plus low Epo

How will you manage this patient?

4 goals:

  • Reduce thrombosis and haemorrhage

  • Reduce risk of MF / AML

  • Manage complications

  • (Manage pregnancy)

Starts aspirin 75mg OD, Venesect to Hct <0.45, control CVS risk factors

Would you not start cytoreduction?

No

BCSH – poor tolerance of venesection, progressive splenomegaly, thrombocytosis, constitutional symptoms

ELN – Age >60, Plt >1500, Prev thrombosis

Three years later patient is still venesection dependent as he did not tolerate hydroxycarbamide and he is now experiencing early satiety and LUQ discomfort. Would you give him ruxolitinib?

RESPONSE 2015 —> licensed for HU resistant/intolerant PV. 222 patients, complex study.

RELIEF 2014 – no better than HU

MAJIC 2016 – results awaited

 

MALIGNANT QU 3

What further medical history would you ask of this patient?

Personal cancer history (2+, one of which is haematological, is significant finding)

Family history - Significant findings include relatives within two generations with a haematological malignancy, solid tumour under age of 50 or other haematopoietic abnormalities.

Systemic enquiry for evidence of congenital syndrome which have gone un-diagnosed, e.g. skeletal abnormalities, lifelong thrombocytopenia etc

You receive the results of his myeloid gene panel, can you give me any examples of genes associated with a germline predisposition to leukaemia?

DDX41,CEBPA, RUNX1, ETV6, TP53, ANKRD26, CHEK2, GATA2

This patient is found to have two somatic DDX41 mutations, one with a variant allele frequency of 50% and one of 18%. What relevance does the variant allele frequency have to the assessment of this case?

A VAF of 50% is highly suspicious for a germline mutation (i.e. heterozygous inheritance of the mutation. In relatiy, due to the PCR technology used for testing, a VAF of 30% or above may indicate a germline mutation).

DDX41 has probably the strongest association with germline predispositions to myeloid cancers. The pattern given in this case is the classic example - a 50% germline mutation, followed later in life by a somatic mutation acting as a trigger.

What further testing would offer this patient?

After appropriate genetic counselling and consent, further testing can be offered to assess whether this is a germiline mutation, methods include:

Testing non-cancer tissue, e.g. skin biopsy for fibroblast culture and genome sequencing

Testing of bone marrow in remission, e.g. would expect the 18% VAF muation to no longer be detectable but if the 50% VAF mutation is germline then it will still be present at 50% in the remission sample.

What are the potential implications of identifying a germline mutation in this patient?

For patient - consideration of transplant donors - siblings may carry same germline mutation

For his family - referral to genetics service for counselling on potential testing

Ref: See ELN Guidelines 2022 for greater detail on germline predispositions

Coag Qu 1

Tell me the principle of preforming an activated partial thromboplastin time

Blood collected into citrated tube.

Centrifuged to produce PPP

PPP + Activator + Phospholipid, incubated at 37oC

Add calcium and time to clot

Tell me about the method or analyser your lab uses for this?

ACL Top, Silica activator, change in optical density

What is Quality Assurance and how does your lab ensure that is provides its service users with quality APTT results?

QA = Planned and systemic activities to provide adequate confidence that requirements for quality are met. Aims to provide a product that is Accurate, Reliable and Reproducible.

Internal: Staff proficiency, Quality management System (Q-Pulse), Audit, Education

External: EQA, voluntary accreditation (UKAS to ISO standard 15189:2007)

Your lab manager phones you and tells you that your most recent NEQAS submission has been returned as outwith consensus. You reported an APTT of 36 seconds, compared to the method median of other labs which reported 43 seconds. What would your initial actions be?

Think pre-analytical, analytic and post-analytic errors when giving your answer

Look for typographical error in submitting the result to NEQAS - this is a common cause of an apparently serious discrepancy which hasn’t otherwise become apparent from the clinical use of the results you have been reporting in the time since submitting your NEQAS result.

Repeat test if sample still available

In the (unlikely) event of a genuine problem with analyser this will need an urgent response. Think CAPA (Corrective Action, Preventative Action) when discussing your response.

 

Transfusion Qu 1

What is the differential diagnosis for the patient’s thrombocytopenia?

Consumptive (i.e. infection, coagulopathy, splenomegaly), underproduction (ie cytoxic effects of chemo) or excess destruction (ie auto- or allo-immune process). 80% of cases of platelet refractoriness are due to consumptive causes. Bonus: Alloimmune thrombocytopenia much less common following introduction of universal leukodepletion.

How would you assess the response to platelet transfusion?

A one hour post transfusion increment (or similar). An increment <5 on two separate occasions in absence of non-immune factors suggests possible alloimmune thrombocytopenia.

You suspect an alloimmune cause for the thrombocytopenia, how can this be investigated?

HLA antigen typing of patient platelets, HLA antibody screening of patient plasma. If no HLA antibodies detected, consider proceeding to HPA antibody screening.

How will you manage the patient in the meantime?

Use of ABO-identical platelets may be beneficial. E.g. Group A platelets can be given to group O patients, however some people have higher expression of AB antigens on their platelets —> reduced survival if transfused to group O recipient.

transfusion qu 2

What advice would you give with regard to this patient’s blood resuscitation?

This is massive blood loss and I would advise them to activate the major haemorrhage protocol. The primary pack at my hospital contains 5 units RBC and 4 units FFP and I would recommend that these be transfused alternately to prevent coagulopathy. I would ensure that they have contacted gastroenterology to stop the bleeding and I would ask that they urgently send FBC, PT, APPT and FGN to direct further blood products. Also need to be alert to the risks of hypothermia and hypocalcaemia associated with massive transfusion.

What definitions are there for massive blood loss?

BSH 2015 definitions:

>150ml/min

50% of total blood volume in 3 hours (TBV = 70ml/kg)

100% of total blood volume in 24 hours

Would you give this patient tranexamic acid? Are you aware of any relevant trial data to support your decision?

Either way, justify your answer. Suggest: No I would not. The HALT-IT trial was a large multi-centre UK trial assessing tranexamic acid for acute gastrointestinal bleeding. TXA did not reduce death from bleeding and there was a small increase in thrombotic events. 

If you were asked to review your hospital’s major haemorrhage protocol who would you involve in that process?

Hospital Transfusion Committee – oversee protocol development & implementation

Hospital Transfusion Team – support the essential activities for effective use of protocol

Stakeholders include switchboard, porters, blood bank, haematologists, transfusions nurse practitioners, ED/Medicine/Surgery/Obstetrics/Paeds seniors nurses/doctors