Case 105 update 2

Our patient was discussed at MDT and as many have suggested, he is treated with intensive chemotherapy.

MATRIX – HD MTX, cytarabine, thiotepa and rituximab is the current regime recommended in the UK.  Intrathecal chemotherapy is not advocated in the BSH guidelines.  MTX should be delivered at doses of at least 3g/m2 with an infusion time of 2-4 hours.

He had a repeat MRI after two cycles showing complete remission.  His stem cells were harvested after the second cycle. He goes onto to have a further 2 cycles of MATRIX followed by autologous stem cell transplant.

Repeat MRI at 6 weeks following treatment shows no evidence of disease.  However 5 months following ASCT he presents with slurred speech and further MRI shows two new cerebral lesions.

 

What is your differential? Management plan?

 

 

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Case 105 update 1

MRI performed at the tertiary centre showed no evidence of a cerebral lesion.  You therefore plan with the neurosurgical team to stop the steroids and repeat the MRI after a short interval (2-4 weeks) whilst monitoring the patient closely.

 

Alongside this plan you have requested the following investigations

  • FBC, – within normal parameters
  • U&ES, – no abnormality
  • LFTS, – no abnormality
  • blood film – morphologically normal
  • LDH, – elevated
  • testicular ultrasound – no evidence of testicular lesion
  • CSF examination – flow cytometry or PCR for IGHV gene rearrangements – no clonal B cell population identified
  • PET-CT – no evidence of systemic involvement
  • HIV/hepatitis screen – negative
  • Paraprotein – no evidence of a paraprotein
  • opthalomology review – slit lamp exam – no abnormality

 

Repeat MRI exam at 2 weeks shows evidence of a cerebral lesion.  A biopsy is carried out which confirms DLBCL.  Steroids are recommenced. The MRI and histology findings are discussed at MDT.

 

How would you manage this patient?  How do you decide upon treatment plan?

What type of regime would you use?

How would you assess response to treatment?

What are the risks to the patient? how would these be managed?

Would you offer any other treatment alongside intensive chemotherapy?

 

 

 

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Case 105

Welcome back!

During your on call as the haematology registrar on the 2nd January you are contacted by the neurosurgical team.  A 54 year gentleman had been referred into the tertiary centre from a local hospital over the Christmas holidays.  He had presented to his local hospital with weakness of the right arm and some “altered behaviour” over the previous week.  CT head on admission had shown an isolated cerebral mass with surrounding oedema.  Steroids had been administered prior to transfer.  Symptoms had shown some signs of improvement on arrival to the tertiary centre.

The neurosurgical team would like some input from haematology as the suspicion is that of CNS lymphoma.

What would you advise?

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CASE 105 – summary

Primary CNS lymphoma

 

1% of all non Hodgkin lymphomas, 3 % of all brain tumours.  It may [resent with a range of symptoms including focal motor deficits and behavioural change as seen in the patient in this case.

 

Investigations should include:

  • Bloods – FBC/U&ES/LFTS/LDH/PARAPROTEIN/BLOOD FILM/HEPATITIS/HIV
  • Contrast enhanced MRI – brain and spine
  • Slit lamp exam and ophthalmology review – if necessary vitreous biopsy
  • Stereotactic brain biopsy is recommended for histological diagnosis
  • PET – CT – to determine systemic involvement.
  • Bone marrow not essential if PET excludes systemic disease, normal FBC and no evidence of monoclonal paraprotein
  • Testicular ultrasound (testicular involvement cannot be excluded on PET)
  • Performance status
  • CSF examination – cytology and flow.  IGH rearrangments by PCR may improve diagnostic yield
  • neuropsychological assessment
  • LVEF assessment
  • Baseline MMSE

 

 

Steroids

Steroids had already been administered to the patient in our case.  Steroids can have a substantial negative impact on yielding diagnosis and therefore should be avoided if possible prior to biopsy.  Non‐diagnostic rates range from 33% after a short course (<1 week) to 57% after a longer course of steroid.  If steroids have already been given, repeating the MRI to determine if the lesion is still visible is essential following discontinuation of steroids.  If no lesion is visible, close monitoring/imaging is essential in these patients until biopsy is possible.

Intraocular involvement

Up to 20% of primary CNS lymphomas have intraocular involvement, which can be difficult to establish.  Slit lamp exam and opthalmoscopy are essential followed by vitreous biopsy if necessary.  Intravitreal chemotherapy is not routinely recommended in patients who are fit for HD-MTX based regime, but could be consider for patients who are not fit for this treatment and who have isolated intraocular disease.

 

Treatment approach

The gentleman’s performance status was 2 at presentation, however his family inform you he was working full time prior to the Christmas holidays, suggesting a performance status of 0 prior to the onset of symptoms of lymphoma.  He was also reasonably fit, undertaking moderate exercise once or twice a week.  Performance status is frequently impaired due to the nature of disease, therefore decision for treatment should be based on physiological fitness.  Our patient was discussed at MDT and as many have suggested, he is treated with intensive chemotherapy.

Treatment approach should be considered in two stages

  1. Remission induction
  2. Consolidation (radiotherapy or autologous stem cell transplant)

 

Remission induction

For the patient the approach of choice would be intensive methotrexate based induction immunochemotherapy.  MATRIX was a regime suggested by most of our followers and most commonly used in the UK.  MATRIX has a clear overall survival benefit over HD-MTX/cytarabine regime

MATRIX  – HD MTX, cytarabine, thiotepa and rituximab.  MTX should be delivered at doses of at least 3g/m2 with an infusion time of 2-4 hours.  This is due penetration of the CNS being influenced by the total dose and the rate of infusion – this rapid infusion maximises the therapeutic CSF concentrations. The additional benefit of intrathecal chemotherapy is unknown, given risks of the procedure and low level of evidence, guidelines suggest intrathecal chemotherapy should not be undertaken.

Treatment related mortality associated with MATRIX is 4-7%.  Treatment related deaths more commonly occur in the first cycle.  Supportive treatment for this regime should include GCSF, PCP and herpes simplex prophylaxis.  As our patient suffered with a serious infection following cycle 1, it is important to reassess the chemotherapy plan prior to the second cycle.   Guidelines suggest reducing the dose of cytarabine and thiotepa by 25%

Consolidation

Clinicians should aim for this to be undertaken within 6-8 weeks from the first day of the final induction chemotherapy.

Patients who had recieved tiotepa based chemotherapy regime and have achieved at least stable disease should be considered for autologous stem cell transplant.  BEAM should not be used as conditioning for transplant, due to previous trials showing poor outcomes.  Stem cell collection can be undertaken following cycle 1 or 2

Our patient completed 4 cycles of chemotherapy and ASCT.  Follow should include a response assessment at 1-2 months, then MRI every 3-4 months for up to 2 years.

 

Unfortunately we discovered he had relapsed shortly after treatment.  Perhaps we will cover this in a future case!

 

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Christmas quiz

Thankyou for taking part in our Christmas quiz!

Here are the questions and answers!

1. Which animals have:

• Blue blood

• Green blood

• Yellow blood

2. The Japanese traditionally associate blood groups with personality. Can you match them up correctly?

• Unpredictable, distant, careful, considerate, efficient and sensitive

• Serious, calm, composed, level headed and trustworthy

• Outgoing, expressive, clumsy, flexible, idealistic, natural leader, carefree and generous

• Curious, excitable, cheerful, bright, enthusiastic  and independent

3. Where were the first allogeneic stem cell transplants done?

4. Who was Anthony Nolan?

5. When was the American register started and who campaigned for it?

6. When did the 1 millionth BMT (worldwide) take place?

7.What is Christmas disease?

8.What incident in WW2 resulted in information that helped develop a chemotherapy agent?

9.What was the original source of vincristine?

10. Where does palitaxel come from?

11. How were platinum chemos discovered?

Answers!

Answers:

1.

Blue – spiders, crustacions, squids, octopuses and some types of molluscs. Green – many types of worms, slugs and leeches

Yellow – starfish/beetles/sea cucumber/sea squirts

2.

a)AB

b)A

c)O

d)B

3. Yugoslavia – after a radiation leak at a nuclear research facility. 5 workers, none engrafted.

4. Anthony Nolan was a child with Wiscott Aldrich syndrome. Born 1971. Never received transplant and died age 8. His mum started the register in 1974

5. American register started 1986, family of Laura Graves who was a child with leukaemia. Her donor was found in lab of her hospital.

6. 2012

7. Haemophilia B

8.An air raid in Bari, Italy led to hundreds of soldiers and civilians having mustard gas exposure. Survivors were found to have low lymphocytes. Results were combined with the Yale study group which lead to the search for similar compounds resulting in mustine chemotherapy.

9. Madagascan periwinkle

10. Pacific yew tree bark

11. Bacteria on agar plates stopped dividing when electricity applied to them – turned out platinum on electrodes was the cause, leading to development of chemo.

Let us know if we have missed anything!

Thankyou for all your participation with teamhaem this year, we couldn’t do it without you!

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TeamHaem saves Christmas 🎄- the summary

“A DOAC, dear sir, and some stockings to boot!”

“Thank you dear doctor, now off I must shoot!”
“Take it easy!” I called as he jumped up tall,

“We’ll review you in clinic, here’s a helpline to call.

 

Please take care not to fall from your sleigh!”

He gave me a wink and then bounded away.

 

So TeamHaem saves Christmas and all the elves cheer

Merry Christmas to all and a Happy New Year!

 

For guidelines relating to VTE management see:

https://journal.chestnet.org/article/S0012-3692(15)00335-9/fulltext

http://www.hematology.org/VTE/

Join us on Twitter @TeamHaem and let us know what your thoughts are, what questions you have and what you want to do as we see this case evolve over the next week. Remember to use #teamhaem on all your posts to help us follow the case! Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality. TeamHaem are not a position of authority. It is an educational platform to allow discussion and learning.

 

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TeamHaem saves Christmas 🎄- Part 3

‘Has anything changed since this time last year?

Any illnesses or weight loss? Tell me all, do not fear!’

 

Coyly he blushed as red as his suit

‘I’m afraid the answer is hidden by my boot’

 

Mrs Claus is so loving, a wonderful wife,

she looks after me well there are no quarrels or strife.

 

A few weeks ago, a new recipe she tried,

‘This years Christmas pud will be epic she cried!’

 

Extra fruit, nuts and brandy, in they all went,

By the time it had cooked the steamer had bent!

 

I puffed and I panted as I lifted out

But it dropped on my leg and loudly did I shout!

 

I couldn’t hurt the feelings of my beautiful wife,

So I bandaged my leg and hid it from sight.

 

Unfortunately I’ve limped for over a week

He muttered quietly, embarrassed and meek

 

Under the bandage was a large red graze

Surrounded by infection a light pink haze

 

“Don’t worry’ I said, ‘this we can tend.

With antibiotics it will mend.

 

Blood thinners we’ll give there’s no need to cry”

But now dear readers, can he still fly?

 

Join us on Twitter @TeamHaem and let us know what your thoughts are, what questions you have and what you want to do as we see this case evolve over the next week. Remember to use #teamhaem on all your posts to help us follow the case! Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality. TeamHaem are not a position of authority. It is an educational platform to allow discussion and learning

 

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TeamHaem saves Christmas 🎄- Part 2

His eyes twinkled like stars, his sats 92,

“You must let me home I have work to do!”

 

I have no time to lounge around here,

Who is going to train and feed the reindeer?”

 

“Do you fly often?” I mused to myself,

Under the bed I found a chuckling elf.

 

“For centuries I’ve zoomed across the sky,

No problem the distance, no problem how high.”

 

“Seems strange that it would be this year you clot?”

Dear reader can you think of something I’ve not?

 

What other tests or scans should we perform?

Or shall he be discharged, is this the norm?

 

Join us on Twitter @TeamHaem and let us know what your thoughts are, what questions you have and what you want to do as we see this case evolve over the next week. Remember to use #teamhaem on all your posts to help us follow the case! Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality. TeamHaem are not a position of authority. It is an educational platform to allow discussion and learning

 

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Team Haem saves Christmas 🎄 – Part 1

Twas the week before Christmas and all through the lab

not an analyser was stirring, ten winks I did grab.

 

When then from my call phone there arose such a clatter,

I sprang from my bench to see what was matter!

 

An elderly gentleman with a swollen red leg

complained of some chest pain, my help he did beg.

 

He looked out of puff with a large round belly

that shook when he coughed like a bowl full of jelly.

 

“Help me! Oh help me! For oft I have flew,

Long haul and cramped, my leg it did grew.

 

Out on manoeuvres preparing for flight,

Exercising reindeer for an important night.”

 

“Quickly!” I shouted, “let there be no delay!”

This man needs an urgent CTPA.

 

A clot we did find, in a segmental artery,

Dear readers, what shall our therapy’s start be?

 

TeamHaem apologises unreservedly to Clement Clarke Moore!

Join us on Twitter @TeamHaem and let us know what your thoughts are, what questions you have and what you want to do as we see this case evolve over the next week. Remember to use #teamhaem on all your posts to help us follow the case! Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality. TeamHaem are not a position of authority. It is an educational platform to allow discussion and learning

 

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Case 103 – summary

Thankyou for your help with this week’s case!

Our patient has an intravascular transfusion reaction which was likely due anti C with undetectable antibodies. Red cell phenotyping of the patient and the transfused red cells help identify the likely antibody. Red cell survival studies offered reassurance in this patient, although not widely used for this purpose. This is an unusual case, but aims to demonstrate the presentation of an intravascular haemolytic transfusion reaction and the process of investigating difficult to identify antibodies.

Following the red cell survival studies our patient went on to have transfusions with C negative red cells with no reactions. Creatinine returned to baseline and she was discharged. She went on to complete her adjuvant chemotherapy with some red cell support. Our patient was provided with an antibody card to make people aware if she has future transfusions.

In this summary we will discuss more generally about transfusion reactions, and then about haemolytic reactions, and the possible reasons for the unidentifiable antibody in this case.

Acute transfusion reactions are a relatively common complication of transfusion. The causes of reactions eg haemolytic, bacterial contamination, TACO, TRALI can often present with similar symptoms and the same steps should be put in place for every transfusion in order to minimise the risk of reactions, and to enable early identification and appropriate management of a patient when a reaction does occur.

Processes are put in place before the blood even reaches the patient to ensure safer transfusion, such as donor questionnaire, testing of the donation for various infections and leucodepletion.

Appropriate patient blood management tries to ensure that patients only get necessary transfusions.

Once it has been decided a patient needs a transfusion this needs to be done in an appropriate place with staff trained in transfusion and complications arising from it.

Complications from transfusions do not always happen during the transfusion, so it is important to advise patients to seek medical advice if they become unwell within 24 hours of the transfusion (although complications such as delayed haemolytic transfusion reaction can present several days later).

If the patient becomes unwell during the transfusion, it should be stopped and the patient assessed. It is important to ensure the unit and the patient details are checked to ensure correct blood component and correct patient. The unit should also be inspected to see if there is an unusual appearance/clumps that may suggest bacterial contamination.

Patients should receive medical attention and be treated symptomatically with assessment of A,B,C. Further details of management of reactions can be found in the BSH guidelines on acute transfusion reactions listed at the end of this summary.

Laboratory investigations

If transfusion reaction is suspected the basic tests that should be performed are

FBC

DAT

LDH

Haptoglobins

LFT

U&E

Urine for haemoglobinuria if concern regarding HTR

Repeat samples for compatibility testing, antibody screen

Coagulation

Blood cultures if pyrexia or concern of bacterial contamination

Implicated units should be returned to the lab

If mucosal swelling/angioedema/anaphylaxis – IgA testing.

If severe allergy or anaphylaxis consider serial mast cell tryptase measurements

If any respiratory symptoms – CXR

If there are infective/febrile symptoms of moderate severity then the units should be returned to the lab and the blood service informed straight away so any associated units are withdrawn.

All transfusion reactions in the UK, bar mild febrile reactions and allergy, should be reported to SHOT.

Haemolytic transfusion reactions

Acute haemolytic transfusion reactions happen within 24 hours of a transfusion. They are usually related to incompatible red cells, however can occur with plasma.

A secondary immune response to an antigen on the donor red cells causes delayed HTRs. There can also be some bystander haemolysis in these reactions. These will usually occur if a patient had been immunised some time ago and the antibody may now be at such a low level that it is undetectable by antibody screening prior to transfusion. These will produce IgG antibodies within a week of exposure. Delayed HTRs are usually caused by antibodies to Rh, Kidd, Kell, Duffy, MNS antigens. The reason a repeat sample is required after 72 hours if there has been a transfusion within the last month to ensure the production of a new antibody (or the increase in a previously undetectable one) is not missed.

Reactions can occur due to antibodies in patient plasma against antigens on donor cells (major incompatibility), antibodies in donor plasma to patient cells (minor incompatibility), or very rarely, anti bodies in donor plasma to antigens of red cells from another transfused donor product.

Haemolysis occurs by different mechanisms – complete complement activation resulting in intravascular haemolysis, incomplete complement activation and resulting phagocytosis by macrophages of c3b covered cells, cell to cell contact with k cells by IgG covered cells.

The clinical picture of HTR can vary greatly, some patients may have no apparent symptoms, some may have a failure of expected Hb rise following a transfusion while others may have a severe life threatening reaction. Symptoms can include feeling generally unwell, rigors, pain, discomfort around infusion site, nausea/vomitting, diarrhoea, headache, breathlessness, visible haemoglobinuria. Signs can include tachycardia, hypo or hypertension, pyrexia, jaundice, microscopic haemoglobinuria, anuria due to renal failure, bleeding as a consequence of DIC, fall or lower than expected rise in Hb level following transfusion. Given the wide spectrum of signs and symptoms that can occur and the potential for these to be at some time after the transfusion it is also important to consider other potential diagnosis when assessing a patient during/following a transfusion.

The systemic symptoms of HTR can be caused by cytokine release, coagulation cascade activation and fibrinolysis and kinin activation. These can result in a SIRs pictures, DIC, hypotension and renal failure.

Factors that can influence the severity of a reaction can include antibody class. IgG will usually bind at 37 degrees Celsius, as opposed to IgM which normally bind optimally at lower temperatures. A higher number of antigens on the red cell surface will allow greater antibody bonding resulting in greater complement activation. The antibody level is also significant, with greater titres allowing for increased binding with antigens.

When intravascular haemolysis occurs, free haemoglobin can be found in the urine. This occurs when haptoglobin, albumin and haemopexin have been saturated and the excess haemoglobin makes it’s way to the kidneys, where some may not be able to be reabsorbed by the renal tubuli. Although free haemoglobin does pass through the kidney it is thought that the disruptions in micro circulation resulting from the systemic responses to coagulation, fibrinolysis, cytokine and kinin pathway activation are the main cause of the renal impairment that can be seen in HTRs.

As seen in our case a centrifuged fbc sample can show a reddish discolouration of plasma due to the haemoglobin. Urine can also be tested for the presence of free haemoglobin. As in other types of haemolysis, haptoglobins will be reduced and LDH raised. These results should always be interpreted in the clinical context as other conditions can cause these abnormalities. There may or may not be a reticulocytosis depending upon the patient’s underlying bone marrow function. The patient may be jaundiced with a rise in indirect bilirubin.

Pre transfusion, post transfusion and the donor unit should also be taken for evaluation. The DAT on the pre and post transfusion sample as well as blood group and antibody screen should be checked. Crossmatch on the patient’s plasma before and after the transfusion and the donor red cells. If the polyspecific DAT is positive, monospecific DAT should be performed. Antibodies may not be detected initially following a reaction, and samples should be taken and retested over the subsequent weeks to check for appearance of an antibody or positive DAT.

When investigating possible reactions performing an eluate to release the bound antibody from the red cell membrane may be useful in identifying the possible antibody. A variety of serological techniques may need to be employed if the antibody is proving difficult to identify eg enzyme, LISS tube

Preventing reactions

As antibodies can ‘diasappear’ from serological testing, all patient’s should be given an antibody card and units with the corresponding antigen should be avoided in subsequent transfusions. It needs to be noted, and the patient informed, as different hospital blood banks may not have the antibody information from previous antibody investigations so the patient should be empowered to inform people of the antibody every time they may need a transfusion.

Prevention of antibody production through transfusion is important, Rh D is the most immunogenic antigen and wherever possible patient’s should be transfused with RhD compatible blood. There may be situations e.g. emergency situations in males or post menopausal women that RhD positive blood may have to be used if no RhD negative blood is available and a delay would impact on patient care. Sensitisation to other antibodies eg kell is also avoided in pre menopausal women. The appropriate administration of anti-D to women in pregnancy/postpartum has also made huge differences in the incidence of maternal antibody production and subsequently to the rates of HDFN.

To try and prevent antibody production through transfusion in patients who are expected to be multiply transfused over a period of time can have extended red cell phenotyping performed prior to transfusion to try and avoid potentially sensitising antigens.

Our case

In our case the patient was assumed to have an anti C as the cause for the HTR following phenotyping of patient and donor red cells. 5/6 transfused units were C antigen positive, while our patient C antigen negative.

Given that our patient needed further transfusion and had very precarious renal function further reassurance was sought prior to transfusion through nuclear medicine with red cell survival studies. In these studies small volumes (a few mls) of Tc99m labelled donor red cells which are suspect antigen positive and negative are transfused into the patient (on separate days). Serial blood tests at 1,2,3,4 and 24 hours are performed to assess the amount of radioactive material remaining. Gamma camera images can also be taken to see the location of the radioactive material eg in the spleen/urinary tract if being destroyed/excreted, or in the heart if within the circulating blood pool. In our case these showed accelerated destruction of the C positive red cells.

Our patient had a repeatedly negative DAT, this may be been due to all of the transfused red cells being destroyed. Other reasons for negative DAT in haemolysis can be low affinity antibody, red cell body antibody below the level of detection, an antibody (eg IgA or IgM) which the standard DAT will not detect.

The reason for the undetectable C antibody is not known but could be down to a potent antibody at too low a level to be detected by invitro testing. Antibody mediated lymphocytotoxic activation is also been postulated as a cause for HTRs with undetectable antibodies.

There have been several case reports of patients with haemolytic transfusion reactions with undetectable(or difficult to detect) antibodies, therefore if there is a high clinical suspicion of a haemolytic transfusion reaction, if initial investigations are negative further investigation should be undertaken.

Do you have any questions about this week’s case? Any knowledge you would like to share?

Join us on Twitter @TeamHaem and let us know what your thoughts are, what questions you have and what you want to do as we see this case evolve over the next week. Remember to use #teamhaem on all your posts to help us follow the case! Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality. TeamHaem are not a position of authority. It is an educational platform to allow discussion and learning

further reading

BSH guidelines – Investigation and management of acute transfusion reactions- H Tinegate et al British journal of haematology 2012 vol 159

https://onlinelibrary.wiley.com/doi/full/10.1111/bjh.12017

Haemolytic transfusion reactions – Erwin Strobel transfusion medicine and haemotherapy.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3076326/#!po=2.11268

Intravascular haemolytic transfusion reaction without detectable antibodies: a case report and review of literature. C.R. Harrison et al 1986 Vox Sang 51:96-101

https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1423-0410.1986.tb00222.x

Haemolytic transfusion reaction due to Rh antibodies detectable only by polybrene and polyethylene glycol technique Lin CK Am J Clin Pathol. 1995 Dec;104(6):660-2.

https://www.ncbi.nlm.nih.gov/m/pubmed/8526209/

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Case 103 – update 2

We think our patient may have had an intravascular haemolytic transfusion reaction, although our negative investigations so far are unusual.

The patient’s Hb is now around 55g/l. The creatinine is now around 500umol/l. Bilirubin is now 20 and haemoglobinuria resolves a day following the last transfusion. The patient is breathless when she walks around the hospital ward with occasional dizzy episodes. As a result of the chemotherapy her retic response has been poor therefore there has not been the expected rise in Hb. She is is overdue her next cycle of chemotherapy, however this has been suspended currently.

The patient is group O RhD+, the transfused units have been checked and are also ORhD+

So far our results have shown:

Haptoglobins – undetectable

LDH raised

Retics reduced

Haemoglobinura – confirmed

Samples have been sent to NHSBT for further investigations.

On pre and post transfusion samples:-

DAT negative (IgG, IgM,IgA,C3c,C3d)

Eluate against panel negative

Serum and plasma antibody panals on all samples

IAT – Negative

Enzyme IAT – Negative

IAT anti IgA – Negative

LISS tube – Negative

Polyethylene glycol – Negative

We have arranged to phenotype the patient’s pre transfusion sample and the transfused red cells.

What do these show?

What is the most likely antibody?

Are there any other investigations we could consider?

Are there any other clinical measures we can consider for our patient?

Join us on Twitter @TeamHaem and let us know what your thoughts are, what questions you have and what you want to do as we see this case evolve over the next week. Remember to use #teamhaem on all your posts to help us follow the case! Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality. TeamHaem are not a position of authority. It is an educational platform to allow discussion and learning

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Case 103 – update 1

We have found out that our patient has just started adjuvant chemotherapy for breast cancer following surgery.

Five days prior to admission she had a 2 unit blood transfusion, which had no immediate complications.

She had no transfusions prior to this.

4 previous pregnancies with uncomplicated delivery. All babies were born at term with no jaundice or anaemia.

She self discharged from the urology ward and was given a course of antibiotics for a presumed UTI.

She attends her oncology day unit later that day for review following her chemotherapy. This is a different hospital to her local hospital where she attended for the haematuria. She mentioned that she had been feeling increasingly tired and had been admitted under urology for a blood transfusion and antibiotics following blood in her urine which had resolved on admission.

Her Hb is found to be 67g/l and her creatinine 288, with a bili of 106. She is admitted to the oncology ward for iv fluids and antibiotics and she is crossmatched and transfused 2 further units of blood, antibody screen negative. The lab has not been informed regarding the previous possible transfusion reaction. During the 2nd unit of blood she begins to feel very, but none specifically, unwell, and has some chills. She remains haemodynamically stable. The transfusion is stopped and the patient has piriton, hydrocortisone and paracetamol. The iv fluids are continued. The patient is catheterised and her urine again appears to be red.

Our patient has now had a total of 6 units of red cells transfused in the last 8 days. Following the most recent transfusion her bloods show –

Hb 80g/l

Plt 180

Wcc 11

Neuts 5.5

Urea 12

Creatinine 400

Bilirubin 90

Pt 14

Aptt 35

Fib 3.5

LDH 400

Retic 35 (50-100×109/l)

Haptoglobin undetectable

DAT negative

Blood cultures pending

What would you do next? Would you like any more information?

What do we think is happening?

Join us on Twitter @TeamHaem and let us know what your thoughts are, what questions you have and what you want to do as we see this case evolve over the next week. Remember to use #teamhaem on all your posts to help us follow the case! Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality. TeamHaem are not a position of authority. It is an educational platform to allow discussion and learning

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Case 103 – the beginning

Welcome to this week’s teamhaem case!

This week we start with a 50 year old lady who has presented to A&E complaining of feeling tired and she has, over the previous couple of days, noticed blood in her urine, however this has now stopped.

Bloods

Hb 77g/l

Plt 200

Wcc 11

Neuts 5

She is transferred to the urology ward where she is transfused 2 units of blood. After the 2nd unit of blood our patient began to feel unwell and had a rigor. She remained haemodynamically stable. She was assessed by the urology team and started on antibiotics. They have also taken some bloods to check for transfusion reaction.

What types of transfusion reactions are there? What investigations would you do if a transfusion reaction were suspected?

What questions would you like to ask about our patient’s history?

Join us on Twitter @TeamHaem and let us know what your thoughts are, what questions you have and what you want to do as we see this case evolve over the next week. Remember to use #teamhaem on all your posts to help us follow the case! Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality. TeamHaem are not a position of authority. It is an educational platform to allow discussion and learning

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Case 102 – The Summary

 

Thank you for all the contributions to the case this week!

This week we discussed a 29 year old lady who presented with an extensive left arm DVT. She had been on the COCP for 2 years. Further investigations detected a large mediastinal mass that was confirmed to be Stage 2 Primary Mediastinal B cell Lymphoma. From our discussions we covered the following topics that will be discussed further below:

  • Upper extremity DVT
  • Cancer-associated thrombosis
  • Primary mediastinal B cell lymphoma

Upper Extremity DVT1,2

  • Account for upto 10% of all DVTs. The incidence is increasing predominantly due to the increasing use of central venous catheters and pacemakers.
  • Include radial, ulnar, brachial, axillary, subclavian, brachiocephalic and jugular veins.
  • Aetiology
    • Primary
      • Idiopathic
      • Thoracic outlet syndrome (compression of neurovascular bundle secondary to first rib, clavicle or muscle bulk)
      • Paget-Schroetter syndrome (vigorous effort causes microtrauma to the vessel resulting in thrombosis)
    • Secondary
      • Foreign body within vascular system i.e central venous catheter, pacemaker (most common risk factor)
      • Malignancy
      • Surgery, immobilisation
      • Acquired thrombophilia i.e anti-phospholipid syndrome
      • Inherited thrombophilia i.e anti-thrombin deficiency
      • Others (extensive list as for lower limb DVT / PE although Combined oral contraceptive pill / hormonal replacement therapy have not been convincingly found to be risk factors but no RCTs).

Clinical presentation:

  • Venous congestion e.g swelling, pain, dilation of the superficial veins

Investigations:

  • Compression ultrasound / venography
  • Investigations of underlying cause (directed by history / examination)

NB: DDimer has NOT been validated for the use of upper limb DVT

Complications:

  • PE
  • Post thrombotic syndrome
  • Superior vena cava syndrome
  • Recurrence

Management:

  • Anticoagulation
    • Various options regarding the type of anticoagulation exist including
      • LMWH
      • LMWH for 5 days followed by warfarin
      • DOACs are being increasing used (note studies regarding the efficacy of DOACs were not specific for upper limb DVT)
    • The optimal duration of anticoagulation is unknown. Periods of anticoagulation of 3-6 months tend to be associated with low risk of recurrence (<5%) but the risk needs to be individually assessed.
  • Catheter directed thrombolysis / thrombectomy can be considered in specific circumstances
  • Treatment of risk factor e.g resection of cervical rib, scalenotomy

 

Cancer-associated Thrombosis3,4:

  • Initial anticoagulation should be for 6 months if tolerated. In on-going active malignancy anticoagulation should be continued (with consideration of patient preference, bleeding risk etc)
  • Anticoagulation options
    • LMWH (lower VTE recurrence rate vs warfarin -7.9% vs 15%)
    • DOACs4
      • 2 RCTs for edoxaban and rivaroxaban (HOKUSAI Cancer and SELECT-D respectively) demonstrated non-inferiority vs LMWH in recurrence of VTE in cancer patients. However there was increased risk of bleeding especially in gastrointestinal and urological malignancies. Therefore in setting of thrombocytopenia one may opt for LMWH.
      • The effects of cancer treatment needs to also be considered when deciding re use of edoxaban or rivaroxaban in this setting. For example, whether will be absorbed and drug-drug interactions.
  • Anticoagulation in setting of thrombocytopenia3:
    • Platelets <50 x 109/l: Give plt transfusions to elevate plt >50 to allow full dose anticoagulation (especially in acute period 4-6 weeks)
    • Platelets 25-50 x 109/l: Frequent assessment of anticoagulation should occur
    • Platelets <25 x 109/l: Avoid full dose anticoagulation.

 

Primary Mediastinal B Cell Lymphoma (PMBCL)5

  • Subtype of DLBCL (~10%), derived from a thymic B cell
  • Females > males
  • Typically presents in 3rd and 4th decades

Clinical presentation

  • Bulky anterior mediastinal mass
  • 75% stage 1 or 2
  • Symptoms relating to local compression e.g airway compromise, superior vena cava obstruction
  • Symptoms relating to local invasion
  • B symptoms
  • 50% have pleural or pericardial effusions. CNS / bone marrow involvement not uncommon.

Investigations:

  • FBC, U+Es, LFTs, bone profile, LDH, urate
  • HIV, hepatitis B+C
  • CT neck/chest/abdo/pelvis
  • PET CT
  • Biopsy
    • Significant histopathological overlap between PMBCL and nodular sclerosing Hodgkin lymphoma
    • Morphology: Medium-large lymphoid cells, often sclerosis and some cells can resemble Reed-Sternberg cells. Often extensive fibrosis.
    • Immunophenotype: CD20+, CD22+, CD79a+, sIg-, CD30weak, CD15-, CD5-.

Management:

There is no single approach to treatment currently and the need for consolidative radiotherapy and role of PETCT after R-chemo remains controversial. It is important to optimise upfront therapy as salvage treatment once disease has relapsed is rarely curative. However, the longer-term toxicities need to be considered in this young patient cohort.

Chemo-immunotherapy options:

  • DA-EPOCH-R (6 cycles)

3 year PFS 83-93% (Dunleavy 2013, Kryachok 2016 ESMO). May be able to omit radiotherapy if end of treatment PET shows complete metabolic remission but ongoing IELSG 37 trial to assess this. Would currently recommend discussion with oncologist to discuss potential options. Note this regime contains high anthracycline doses.

  • R-CHOP (6 cycles)

3 year PFS ~70% (Rieger 2011 MInT, Kryachok 2016 ESMO). Typically require radiotherapy.

  • (R-)V/MACOP/B – less commonly used.

Thromboprophylaxis

  • To be considered as high risk of thrombotic complications (28.2% – Roth 2017, Lugano) including upper extremity DVT, superior vena cava, intracardiac etc.

Supportive therapies:

  • Blood product support
  • Antimicrobial support
  • Pyschological

References

  1. Tait C et al. Guidelines on the investigation and management of venous thrombosis at unusual sites. British Journal of Haematology. 2012. 159(1): 28-38.
  2. Heil J et al. Deep Vein Thrombosis of Upper Extremity. Deutsches Arzteblatt International. 2017. 114(14): 244-249.
  3. Watson H et al. Guideline on aspects of cancer-related venous thrombosis. British Journal of Haematology. 2015. 170(5): 640-648.
  4. Khorana A et al. Role of Direct Oral Anticoagulants in the treatment of cancer-associated venous thromboembolism: guidance from the SSC of the ISTH. Journal of Thrombosis and Haemostasis. 2018. 16:1891-1894.
  5. Giulino-Roth L. How I treat Mediastinal B-cell Lymphoma. Blood. 2018. http://www.bloodjournal.org/content/bloodjournal/early/2018/07/05/blood-2018-04-791566.full.pdf?sso-checked=true

 

Join us on Twitter @TeamHaem and let us know what your thoughts are, what questions you have and what you want to do as we see this case evolve over the next week. 

Remember to use #teamhaem on all your posts to help us follow the case! Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality. TeamHaem are not a position of authority. It is an educational platform to allow discussion and learning.

 

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Case 102 – Update 3.

We now have further results for our 29 year old female who presented with an extensive left arm DVT and SOB. She was commenced on therapeutic LMWH. This thrombosis was provoked as she has been found to have a 11cm anterior mediastinal mass.

FBC, U+Es, calcium and phosphate: within normal range. LDH: 700.

CT CAP and PET CT confirms stage 2 disease.

Histology (core biopsy): Medium to large lymphoid cells with abundant cytoplasm.

Immunophenotype: CD20+, CD22+, CD79a+, sIg-, CD30 weak, CD15-.

Questions:

  1. What is the diagnosis?
  2. How would you manage this patient?

Join us on Twitter @TeamHaem and let us know what your thoughts are, what questions you have and what you want to do as we see this case evolve over the next week. 

Remember to use #teamhaem on all your posts to help us follow the case! Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality. TeamHaem are not a position of authority. It is an educational platform to allow discussion and learning.

 

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Case 102 – Update 2.

Thanks for everyone’s contributions!

We have been discussing the management of a predominantly idiopathic upper limb DVT in our young lady on the combined OCP. She is on therapeutic LMWH and currently continues on the combined OCP. However, your requested investigations have now been completed and are as follows:

  1. CTPA: No evidence of PE or accessory rib but large mediastinal mass (11cm).
  2. Antiphospholipid screen: Normal.

Questions:

  1. What are your main differential diagnoses?
  2. What further investigations do you want?

Join us on Twitter @TeamHaem and let us know what your thoughts are, what questions you have and what you want to do as we see this case evolve over the next week. 

Remember to use #teamhaem on all your posts to help us follow the case! Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality. TeamHaem are not a position of authority. It is an educational platform to allow discussion and learning.

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Case 102 – Update 1.

Thanks for everyones contributions!

Following everyone’s suggestions we now know that this 29 year old with an extensive upper limb DVT, has been short of breath over the past few weeks and non-specifically unwell. She has been on the combined oral contraceptive pill for 2 years and rarely misses any doses. She has had no other recent relevant personal history including no venous catheters, surgeries and does not undergo excessive exercise regimes. She has no relevant family history.

She has been commenced on therapeutic anticoagulation. An antiphospholipid screen and CTPA (to assess for both PE and an accessory rib) are pending.

Questions:

  1. What risk would you attribute to the COCP and thrombosis?
  2. What would you advise about the use of OCP to this lady now?
  3. If this appears to be idiopathic upper limb DVT with no other known risk factors how would you manage?

Join us on Twitter @TeamHaem and let us know what your thoughts are, what questions you have and what you want to do as we see this case evolve over the next week.

Remember to use #teamhaem on all your posts to help us follow the case! Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality. TeamHaem are not a position of authority. It is an educational platform to allow discussion and learning.

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Case 102 – The Beginning

Welcome to the new #TeamHaem Case!

You are working in the acute medical day unit. A 29 year old female has been referred in with a week long history of progressive left arm swelling. An ultrasound has confirmed an extensive DVT in the axillary and subclavian vein.

Questions:

1. What further history and investigations would you like?

2. What immediate management would you suggest?

Join us on Twitter @TeamHaem and let us know what your thoughts are, what questions you have and what you want to do as we see this case evolve over the next week.

Remember to use #teamhaem on all your posts to help us follow the case! Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality. TeamHaem are not a position of authority. It is an educational platform to allow discussion and learning.

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Case 101 – summary

This is a case of super warfarin overdose. It was complicated by the lack of accurate history from the patient due to presentation with an intra cranial haemorrhage.

Super warfarin are easily available as rodenticides. The most common in the UK are difenacoum, bromodialone and brodifacoum. All have long half lives. In the case of difenacoum, it’s half life in the plasma is approximately 20 days and 60 days in tissue.

Frequently many months of daily treatment with higher doses of vitamin K are required. Initially in this case daily intravenous doses of 50 – 100 mg are likely to be needed, followed by many months of 100mg a day orally.

Suggestions for further reading:

Card, D.J., Francis, S., Deuchande, K. and Harrington, D.J., 2014. Case Report: Superwarfarin poisoning and its management. BMJ case reports, 2014.

King, N. and Tran, M.H., 2015. Long-acting anticoagulant rodenticide (superwarfarin) poisoning: a review of its historical development, epidemiology, and clinical management. Transfusion medicine reviews, 29(4), pp.250-258.

Spahr, J.E., Maul, J.S. and Rodgers, G.M., 2007. Superwarfarin poisoning: a report of two cases and review of the literature. American journal of hematology, 82(7), pp.656-660.

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Case 101 – update 3

Further history is sort and her partner confirms the presence of rat poison in the house.

Repeat factor levels show:

Factor II – 24%                         Factor VII – 9%

Factor X – 30%                        Factor V – 101%

Factor VIII – 156%                   Factor IX – 27%

Difenacoum is detected in the plasma

A diagnosis of super warfarin overdose is made.

Question: how should this case be managed?

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