Viva answers

Malignant

1. In suspected plasma cell dyscrasias the first thing to do would be to do a standard myeloma screen (protein electrophoresis, immunoglobulins, urine BJP and serum free light chains). If these are abnormal then proceed onto skeletal survey and bone marrow biopsy, beta-2 micro globulin and albumin. Particular aspects of interest in the history would include rash, peripheral neuropathy and endocrinopathy as conditions such as amyloidosis and POEMS should be considered, as well as the usual bony pain/fractures, symptoms of hypercalcaemia and infections. Testing for Congo red staining on biopsy and VEGF levels would be useful for the respective conditions. Please note that 95% of POEMS is associated with a lambda paraprotein - kappa chain POEMS is very rare.

The second aspect of this question will test whether amyloidosis has been considered as a possible diagnosis if this was not previously mentioned in the first part of the question - the peripheral neuropathy symptoms may have alluded to this - especially in view of the renal failure. You may suggest requesting an echocardiogram as well to check for features of amyloid there. Treatment would in the context of renal failure with myeloid would be bortezomib with usual supportive medication (e.g. co-trimoxazole, aciclovir) and written guidance as well as clinical nurse specialist support.

2. This tests your knowledge about Hodgkin's disease and an excellent summary is detailed here by Towsend and Linch on the disease. There are many variations on a theme with this question (such as treatment in pregnancy, advanced disease and not simply related to age or comorbidities which could complicate issues). Alternatively there are some guidelines now on the BCSH website on Hodgkin’s published in 2013/14 on classical Hodgkin’s in first line and refractory cases. Early favourable would now be treated with ABVD x2 and radiotherapy; early unfavourable with ABVD x4 and radiotherapy.

In terms of investigation the notable mentions are that pre-treatment baseline blood tests, LDH and virology screening is essential (especially for HIV, even in his age bracket). It’s unlikely that he will require sperm preservation though fertility is something that could be briefly discussed with the patient. CT PET scanning is now considered the gold standard (if not already done since the question has already given you the staging of the patient as 2E). If there is no evidence of bony disease on imaging, a bone marrow biopsy is not essential.

This man’s treatment is slightly complicated by his age and his risk factors, which could potentially put him into the frail category. This man doesn’t fit into the category of early disease as demonstrated with his staging. With ABVD care is required with doxorubicin in the context of his angina (which is cardiotoxic) and cigarette smoking, which could also have a complementary effect with bleomycin toxicity given his age. If he is relatively fit then in discussion with the patient it would be reasonable to offer ABVD with a normal LVEF and cardiac function, in the knowledge of a treatment related mortality risk of 5-10%; otherwise options such as COPP, VEPEMB or ChIVPP would be more appropriate (the last of which would be most appropriate given the lack of an anthracycline in the regimen).

Transfusion

1. You need to show that you have categorised your response rather than just offering multiple things that you would do. Summarise your response into three categories; what you would do immediately; what you will do today; and what you will do later as follow up.

Immediately

• stop all further units from being issued from that refrigerator and check other refrigerators for temperature control
• implement the SOP relating to refrigeration failure
• obtain replacement refrigerator if needed or call out for an engineer to repair the faulty fridge
• Inform teams that regularly need blood that supplies through the transfusion practitioner that stocks may be low and that operations or transfusions may need to be cancelled or rescheduled; if there is another secondary blood bank in the local area that is utilised in the SOP they should be contacted and arrangements made for them to process all samples that require electronic issue and cross-matching.
• Speak to NHSBT to stop any deliveries that may be coming which could overload capacity to store blood

Today

• Discuss later with transfusion practitioner and medical teams about delaying any non-urgent transfusions and elective procedures if there is not sufficient blood available
• Track units that have been issued and transfused since refrigerator failure and ensure the medical teams have been informed to speak to patients and ensure clinical safety

Later

• Ensure SOP in this case was followed with refrigeration failure and update as required
• Start a root cause analysis to establish why the failure had occurred (and whether changes to the SOP are needed to prevent this from happening again; or other strategies on how to minimise inconvenience caused by interruption in blood supply)
• Report the incident to SABRE/SHOT
• Follow up at the next hospital transfusion committee and hospital transfusion team meetings to track progress of investigations and changes in protocol where necessary.

2. This question tests your knowledge around managing RhD negative women in pregnancy, both in the prophylactic and management setting - so do review the BCSH guidelines on the website. **Please** whatever you do don't say that this is passive anti-D! It is too early for this to be the case at 10 weeks. In the situation where you are beyond 32 weeks it is possible but the level is relatively high even for that (passive levels rarely exceed 1U/ml). In the situation where it's not clear and the timing is beyond when you have given anti-D to the mother, it would be useful to check historic results to establish a trend of the antibody, confirm any administration of anti-D and repeat the test again in a week to further establish the trend. You should assume that in the context of post administration of anti-D this is passive anti-D until proven otherwise.

Assuming that the level of 3.2U/ml is correct at 10 weeks, please recall the levels by which antibody levels are considered important in pregnancy (please note that anti-c levels and thresholds are different!):

0-4 - Haemolytic disease of newborn unlikely

4-15 - Moderate risk of HDN

15+ - High risk of HDN and inter uterine death from hydrops fetalis

At the moment given the cut off criteria as per recommendations, simply it will be a case of monitoring the levels at the interval mentioned in the guidelines. If the levels rise as dictated above (>4U/ml), then referral to a foetal medicine unit will be essential. The anti-D will only come into play when the foetus starts developing a circulation sufficient for the antibody to cross the placenta and cause haemolysis. Regular uterine artery dopplers will be the main way in which anaemia is monitored non-invasively. It is unlikely that this is the first pregnancy for this woman because of the alloimmunisation which has occurred, most likely from a D- foetus in a prior pregnancy peri-delivery. If possible, suggest free foetal DNA testing (currently done at Filton, NHSBT Bristol) which covers anti-D; otherwise it would be useful to ascertain the status of the father of the unborn child (which may or may not be the father of her previous child). If the examiners are being tricky and suggest that this is her first pregnancy - then don't forget that alloimmunisation may also occur through blood transfusion in the past. Such errors of transfusing D+ blood should not occur in the setting in the UK but they do occasionally happen; or that she was transfused in another country without strict safeguards.

At birth assuming this is immune anti-D then a cord blood sample to check the direct antiglobulin test (plus FBC) will be important to look for evidence of HDN (although a positive DAT in itself does not mean that the baby has HDN). If there is a strong suspicion of HDN, eluates may still be essential.

It would also be a cop-out to say that you would refer this patient to the foetal medicine unit without having outlined any of the steps above (that may go down badly). Also given alloimmunisation it would not be appropriate to give any further anti-D in this case.

In the case of an intra-uterine transfusion being necessary, recall all the requirements of blood in this situation (we may not have included all of them here but by the time you get to 10 requirements most examiners will be satisfied!)

• blood from non-first time donors
• PANTS (antibody screen negative)
• HbS, K negative blood, Rh matched as far as possible (not always possible with all the other requirements)
• Blood <5 days old, in CPD (not SAG-M)
• CMV negative, irradiated blood only
• O (low titre) or ABO matched; cross-match compatible with maternal plasma by IAT
• Hct <0.75
• Transfused via a blood warmer and not directly from 4C

Coagulation

1. Criteria for consideration of NOAC will differ from region to region, but there are some criteria which will be useful in this instance; these are the North Central London guidelines from the website regarding the use of new anticoagulants.

Laboratory assessment of rivaroxaban use is limited at present - antiXa assays specifically used to monitor rivaroxaban have not been validated for use but in theory could be used (it would be reasonable to state this in the viva until there are some reliable assays). Prothrombin time can be used to show whether rivaroxaban is active in the circulation (but there is no linear relationship between PT and the intensity of anticoagulation). If the PT is normal then there is no anticoagulant effect present. (For dabigatran a normal APTT and TT exclude anticoagulant effect).

2. The magic words will be to invoke the multidisciplinary team in the setting of this lady's pregnancy (i.e. involving the obstetricians and obstetric anaesthetist who will be looking after the baby and plan her delivery. You may have local guidelines regarding management of von Willebrand's patients or an obstetric haematology clinic, but otherwise the patient needs some tertiary centre review (at least once) if she is managed at a DGH. Ideally she should deliver at a centre with haemophilia expertise, but for logistical reasons this may not be possible.

You have information about her vW levels and retesting again is probably not required as they would be expected to go up until term.

Deviations might be where the Ag/RCo have not been tested - this should be done at roughly 34-36/40 and decision made about whether DDAVP challenges could be used - these are safe in pregnancy with careful monitoring.

For type 1 - no treatment may be required but a careful decision should be made about epidural catheters (this is feasible but there is a risk of postpartum spinal haematoma) - they are best avoided but the decision lies with the obstetric anaesthetist. Cord blood not useful in testing for T1 vWD inheritance.

For type 2 - baby can be diagnosed by ristocetin platelet aggregation assay (RIPA) on cord blood (types 2A/2B/2M) +/- FVIII in 2N.

Type 3 - should be closely monitored as higher risk of miscarriage and should be treated for 7 days or more days with vWF concentrate around the peridelivery period. A planned delivery would be safer.

Consult the UKHCDO guidelines website for management of pregnant women with von Willebrand's disease.

3. Dual pathology is certainly one possibility in this case but the likelihood is that you are dealing with a single disease. With anaemia and thrombocytopenia the first consideration must be to rule out TTP or another kind of thrombotic microangiopathy. She could fit the parameters of someone having either congenital or acquired TTP. An infection (not otherwise specified) may mean she has ongoing diarrhoea that might point towards HUS/aHUS. A blood film, coagulation screen, renal profile would be most useful in the first instance. Abnormal coagulation would point more towards DIC as a picture, while renal impairment and diarrhoea might suggest HUS; normal renal function and normal clotting screen would suggest TTP. The degree of fragmentation seen on the film should be equivalent to the relative fall in haemoglobin (so if Hb was 100g/L, the threshold of suspicion should be lower even if there are only rarely fragments on the blood film). In the context of a MAHA which is not DIC you will likely need to plasma exchange this lady so obtaining a baseline height/weight plus a group and antibody screen sample should be taken as soon as possible in anticipation of needing large volumes of FFP.

In establishing TTP, the ADAMTS13 level should be <5% of normal (normal range 50-150%); whereas in HUS the levels should be higher but >5%. Risk stratification of disease would include establishing any evidence of neurological dysfunction as well as cardiac TTP (so testing of troponin rise will give an indication of any microvascular thrombosis and should be treated more aggressively with larger volumes of plasma). Other tests to establish the cause should include a pregnancy test (typically congenital TTP can present first time in pregnancy), amylase (check for pancreatitis associated TTP); lupus anticoagulant and autoimmune profiles (to check for SLE); virology (HIV and hepatitis serology), and requesting anti-ADAMTS13 IgG antibodies (for acquired TTP). Treatment would be daily plasmapheresis and this would continue until the platelet count has normalised, and the protocol would be as per the local guidelines. Aspirin and thromboprophylaxis should be given when Plt > 50x10⁹/L. Acquired TTP patients should be given high dose steroids (e.g. 500-1000mg of methylprednisolone with PPI cover for three days consecutively), folic acid and considered for rituximab (first line if available but otherwise in resistant cases); pancreatitis, HIV or congenital TTPs should not be offered rituximab. This lady's infection should be aggressively treated as persistent infection will consume platelets and increase the number of days plasmapheresis will be required.

General

1. Further investigations would include a blood film, reticulocyte count, and a haemolytic screen (although this is relatively unlikely) plus a general examination and enquiry into family history. The differentials would include Diamond-Blackfan anaemia; transient erythropenia of childhood, or parvovirus B19 plus another potential cause. Pure red cell aplasia secondary to thymoma/lymphoma would be unlikely given the child's age. Given the significantly low Hb you would have been expected to mention transfusion, even if the history might suggest that this is relatively chronic given the child is fairly well - and arrange follow up in the tertiary paediatric haematology clinic.
2. This question tests your knowledge of the BCSH thrombocytosis guidelines which were written in 2010. Ensure you know the criteria by which ET is diagnosed (there are five).

The key here is to say you would perform a bone marrow biopsy (minimum of aspirate and trephine), especially requesting reticulin staining - consider cytogenetics if you are worried about myelodysplasia at the same time having reviewed the film; request an ultrasound of the abdomen to assess splenic size and fasting blood tests (lipid profile and glucose), and check his blood pressure - as part of aggressively managing his vascular risk factors. Whether to start cytoreductive therapy would include his current platelet count (>1500 being the cut off); any microvascular symptoms or bleeding/thrombosis.

For the second part of the question it would be important not to exclude simple causes of a mild anaemia - enquiring about bleeding/bowel habit, checking his MCV, blood film (to look for evidence of transformation or myelodysplasia) - if on hydroxycarbamide his neutrophils are likely to be hypersegmented anyway; so checking B12/folate/ferritin (MCV may have fallen if iron deficiency but may not be microcytic). The main concern would be to exclude progression of disease to myelofibrosis or a mixed myeloproliferative/myelodysplastic disorder. There was no mention in the question that he had regular surveillance marrows. A suggested answer would be to cut back on his hydroxycarbamide slightly and review him in 2-3 weeks with a repeat FBC - if this has not improved the count then he should have a repeat bone marrow sooner; but if his counts recover then he could have a routine surveillance marrow but would not be as urgent. The key should be that you should insist on a bone marrow biopsy to the examiner (they may push you to try and dissuade you from ordering one). If there is confirmation of progression then you would prognosticate him using the DIPSS/DIPSS+ scoring system - and given his age consider enrolling him onto a clinical trial, or if he falls into the high risk or intermediate-2 category - he should be tissue typed and considered for an allogeneic stem cell transplant. Here is a link to a Blood paper on 'How I treat myelofibrosis'.

3. This should be a fairly straightforward question and is a bit of a gift in the viva as a lot of the answers are fairly standard. The BCSH guidelines are from 2008 so are slightly dated but the points raised will still be the same. Things that will be necessary to bring up:

• producing an SOP (standard operating procedure) document
• who will pay for the machine and its subsequent maintenance - will it be A+E or the pathology/haematology department?
• will there be a rota/single person in charge of the machine and checking it's function on a daily basis
• who will be in charge of QC/EQA of the instrument
• what will be the procedure when the machine fails and the emergency department need alternatives to process the blood samples; and what will be the turnaround times?
• how the IT systems for pathology reporting will link to the new machine and their own reliability
• which staff will be able to use the machine and how will they be trained?

4. What you will require from the GP is the following information to rule out some simple causes of neutrophilia:

• features of infection or inflammation
• smoking history
• medication history (eg steroids which decrease margination of neutrophils)
• history of any pre-malignant conditions which might give rise to an inflammatory response

Other information which would be useful might include recent and current Hb/Plt, and haematocrit if appropriate that might suggest features of a myeloproliferative disorder. It may be in part reassuring that a registrar has previously looked at a film but a) this was when the neutrophils were borderline elevated a year ago; and b) there is no guarantee that what they reported is accurate! It's unlikely your department will be able to store the films for a year and so it will be necessary to examine another blood film without the comparison specifically looking for features that might be compatible with CML.

Given the persistence of the neutrophilia and if there are no other features suggestive of any abnormal pathology, it would be prudent to review the patient in a general haematology clinic; examination for enlarged liver/spleen and specifically requesting FBC, bcr-abl, JAK2. If the neutrophilia continues to be persistent a bone marrow examination would be a useful test.

5. It was probably obvious from the beginning that this is likely to be a case of NAIT, although maternal ITP and cross-placental transfer of IgG antibodies needs to be excluded. A brief history from the doctor who is calling you to enquire about mother's health and a recent blood count would give useful information as to whether this is the case.

Other possible differential diagnoses include:

- active infection

- severe Rh HDN

- causes of placental insufficiency

- TAR/CAMT/Wiskott-Aldrich Syndrome (exceptionally rare but worth mentioning for extra points)

Platelet transfusion is essential in this situation, and none of the above diagnoses will change the need for transfusion at this stage, especially with the purpura and Ventouse delivery. Since this was unexpected and the potential for an intracranial event is moderate/high given the Ventouse delivery, the platelet count target should be 100 x 10^9/L. Repeat group and antibody screen samples should be sent from neonate and mother investigating for this prior to any platelet transfusion, as well as up to date full blood counts at least initially 2-3 times a day from the neonate until the haematoma settles, plus administration of IVIg for the suspected NAIT. The particular aspect of this case assuming this is NAIT is not to jump in with stating that you would give HPA 1a/5b negative platelets. First - the couple are Japanese and are likely to have a different HPA phenotype compared with Caucasian populations; second - is that the platelets will not routinely be available in an emergency and NHSBT will take at least 24 hours to prepare some which are suitable. A better answer would be to suggest that 'HPA-compatible' platelets should be issued. In the emergency situation routine platelet transfusions should be offered (subject to routine neonatal special requirements). While these will not be effective in the long term if they have the antigens that bind to the serum antibodies these platelets will 'mop up' the antibodies which will have been transferred from the mother and are not being produced endogenously in the neonate.

Subsequently samples should be sent to NHSBT for further platelet study investigations (PIFT/MAIPA). It may be important to obtain the father's serum as well as a crossmatch of platelets against the father's serum to see if there are any abnormal findings. Note that post administration of IVIg, there may be a mixed field in a subseuqent group/save sample so pre-transfusion sampling is ideal.

Again - it will be useful to revise what special requirements for platelets that neonates require - review the BCSH guidelines here. A later discussion with the parents is to express the risk of future pregnancies and the interventions required if they wish to have more children in future (regular IVIg infusions may be needed).