Case 119 – Update 2

Our patient with Stage IIB Mycosis Fungoides was discussed at the relevant MDT and his care remained primarily under the dermatology and clinical oncology service. They instigated topical treatment alongside localized radiotherapy to his tumour site on the right arm. He also required systemic treatment with oral methotrexate. He responded well and achieved a good partial response (PR) with resolution of his severe itch.

2 years later he is referred urgently to haematology clinic. Several new lesions have appeared, at the original site of disease (right arm) but also on his chest wall and left ankle. These lesions initially responded to radiotherapy but recurred within a few weeks. His skin disease is less responsive to topical treatment.

He feels generally fatigued and describes unintentional weight loss over the last few months. On examination, he has nodular, ulcerating lesions in the distribution above, as well as bilateral axillary and inguinal lymphadenopathy.

Re-staging investigations demonstrate Stage IVA disease.

What treatment options would you consider?

 

Please reply to us (@TeamHaem) on Twitter and always include #TeamHaem to allow others to follow your comments. Please join in the debate and learn about haematological problems along the way. The case will continue to evolve over the coming week so keep checking #TeamHaem on Twitter for more information.

 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 119 – Update 1

We are assisting the dermatology team in their investigation of a 68 year old man, with a longstanding history of eczema, presenting with erythematous, well defined patches and plaques over his trunk and limbs, a 2cm firm lesion on his right arm and right axillary lymphadenopathy.

Many thanks for everyone’s input thus far. Summary of requested investigations:

  • Bloods look unremarkable except for non-specific increase in inflammatory markers
  • Viral serology, including HIV and Human T-cell lymphotropic virus type 1, is negative
  • Skin biopsy reported as demonstrating an epidermotropic infiltrate of T cells (CD3+ CD4+ CD30+)
  • Peripheral blood flow cytometry does not indicate an excess of Sezary cells and there is no evidence of a clonal TCR gene rearrangement
  • Lymph node biopsy demonstrates reactive changes
  • PET-CT confirms a right axillary lymph node measuring 2.7 cm with moderate FDG avidity (SUV max, 3.9). Increased uptake at the right arm corresponding with the clinical lesion.

As you have stated, investigation findings are suggestive of cutaneous T cell lymphoma (CTCL), specifically mycosis fungoides (MF).

How would you go about staging and risk stratifying the disease? What treatment options would you consider at this point, and under which medical team?

 

Please reply to us (@TeamHaem) on Twitter and always include #TeamHaem to allow others to follow your comments. Please join in the debate and learn about haematological problems along the way. The case will continue to evolve over the coming week so keep checking #TeamHaem on Twitter for more information.

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 119 – The beginning

Welcome to a new case for TeamHaem!

You get a phone call for advice from a dermatology registrar who has seen a 68 year old man in outpatient clinic.

The patient has a 20-year history of eczema which has been managed by his GP with topical treatment. He has experienced gradual worsening control of his skin over recent months and now complains of unbearable itching. On examination the SpR noted erythematous, well defined patches and plaques over his trunk and limbs. She also noted a 2cm firm lesion on his right arm with associated right axillary lymphadenopathy, and would therefore value your input.

What further information would you like to know? What investigations would you suggest that the team arrange?

Please reply to us (@TeamHaem) on Twitter and always include #TeamHaem to allow others to follow your comments. Please join in the debate and learn about haematological problems along the way. The case will continue to evolve over the coming week so keep checking #TeamHaem on Twitter for more information.

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 118 – the summary

This is a case of a 3 month old infant girl presenting with evidence of haemolysis.

Blood film showed irregularly contracted cells, target cells and polychromasia.  The reticulocyte count was raised and direct antibody test (DAT) was negative.

This is suggestive of a congenital haemolytic anaemia.  The causes of congenital haemolytic anaemia can be divided into two causes: membrane or enzyme deficiency.

Membrane causes include amongst others, hereditary spherocytosis and hereditary elliptocytosis.  There was no evidence of such causes on this blood film.

Enzyme causes include G6PD deficiency but this is unlikely in a female patient (it is inherited in an X-linked fashion).  Other possibilities include pyruvate kinase deficiency or triosephosphate isomerase deficiency.

In this case the diagnosis was triosephosphate isomerase deficiency.

  • inheritied in an autosomal recessive manner
  • due to mutations in the TPI1 gene
  • presents in infancy with pallor and jaundice
  • associated with movement disorders in older patients (usually apparent by 2 years of age)

 

Further information can be found here:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5503903/pdf/br-52-84.pdf

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Case 118 – update 2

You ask the paediatrician about the baby’s history and discover:

  • she has never had a blood tranfusion
  • mum does not have an allogenic antibody
  • there is no known family history of haemolysis
  • there are signs of jaundice

Further tests show

Reticulocyte count 436 (reference range for age 50-100)

Direct antibody test is negative

What is the most likely differential diagnosis and what further tests could be done to make the diagnosis?

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Case 118 – update 1

You review a peripheral blood film on the sample (shown below).  What is your differential diagnosis?  What questions to you want to ask the paediatrician?

50HD0998.JPG

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Case 118 – the beginning

You’re the oncall haematology registrar and a worried paediatrician rings you about a new patient.

Baby A is female infant of 3 months of age.  She has just been brought to accident and emergency by her mother who is concerned that she is sleepy and is feeding less and less.

The paediatrician noted that Baby A looked pale and some bloods were taken.  The full blood count has just been phoned through to the paediatric team by the haematology laboratory and she would like some advice.

Hb 66 g/dL

MCV 93.4

PLT 479

WBC 11

Neut 2.89
What would you do next?

Please reply to us (@TeamHaem) on Twitter and always include #TeamHaem to allow others to follow your comments. Please join in the debate and learn about haematological problems along the way. The case will continue to  evolve over the coming week so keep checking #TeamHaem on Twitter for more information.

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 117 summary

This week we discussed a case of a young gentleman with pancytopenia.

Initial investigations for the cause of pancytopenia were undertaken and these included

  • Repeat FBC
  • Blood film
  • Reticulocyte count
  • Haematinics
  • Liver function
  • Viral studies- cmv, hepatitis, HIV, parvo, hepatitis, EBV
  • Autoantibody screen –  as during our case this has its own limitations and needs to be interpreted appropriately within clinical context.
  • Reviewing medications – gold/chloramphenicol/carbamazepine/phenytoin
  • Review family history
  • Bone marrow aspirate and trephine- incl FISH for cytogenetics
  • HbF% in children for prognostication
  • Peripheral blood chromosomal breakage analysis for Fanconi anaemia
  • flow cytometry for PNH
  • CXR- useful at presentation to exclude infection
  • X-rays of hands and feet if inhertited BMfs suspected
  • HRCT if Dyskeratosis congenita suspected or RUNX1 BMFs

Aplastic anaemia is defined as pancytopenia with a hypocellular marrow in the absence of abnormal infiltrate or marrow fibrosis

Diagnosis

Two of the following criteria must be met:

  1. Hb <100g/l
  2. Platelet count <50
  3. Neutrophil count <1.5

There is a biphasic distribution of 10-25 and 60+

Assessing severity:

Severe – marrow cellularity <25%, plus at least 2 is the following

    Neuts <0.5
    Plts<20
    Retics <20

 

Very severe – neuts <0.2

 

Supportive treatment

    Transfusional support- phenotype matched red cells (Rh and Kell). Platelet transfusion to keep plts >10, or if fever/sepsis >20
  • Prophylactic antibiotics and antifungals for patients who are severely neutropenia
  • Antivirals for patients receiving immunosuppressive therapy
  • Regular mouth care including antiseptic mouthwash
  • Food of low bacterial contant
  • Irradiated blood products should be used for patients receiving ATG/HSCT/alemtuzumab/granulocyte infusions/HLA matched platelets
  • Iron chelation should be considered on an individual patient basis
  • Granulocyte transfusions – irradiated – can be used in life threatening infection related to severe neutropenia (although data regarding effetiveness of granulocyte infusions is limited.

 

PNH

All patients should be screened for PNH

  1. using flow cytometry on perioheral blood to detect a deficiency in GPI anchored proteins – i.e. CD 14, CD16, CD24 and using FLAER for white blood cells and CD55/CD59 for red cell analysis
  2. if negative  test 6 monthly for 2 years.  If test becomes positive, check 3 mohtly for the first 2 years and reduce frequency if the proportion of PNH cells remains stable
  3. presence of small of moderate clones does not influence choice of treatment
  4. new PNH patients should be referred to the PNH national service

 

ATG

  • Provide prophylactic antiviral, antibiotic and antifungal treatment alongside ATG
  • Exclude platlet refractoriness prior to commencing treatment
  • Risk of anaphylaxis therefore test dose should be given
  • admisnter via central venous catheter
  • each dose should be preceded by methyl pred/chlorphenamine and plt transfusion to keep plts>20
  • commnece steroids on day after ATG is completed at 1mg/kg/day for 2 weeks followed by a rapid tapering
  • ciclosporing comenced as prednisolone dose is tapered at a dose of 5mg/kg/day aiming for trough levels of 100-200 micrograms/l.  slowly taper ciclosporin after at least a further 12 months of therapy
  • side effects – fever, rash, rigors, hypo/hypertension/fluid retention/pulmonary oedema/ARDS/anaphylaxis/serum sickness (treated with IV hydrocortisone 100mg QDS)
  • Response is delayed, starting at approx 3-4 months.  70% response rate at 6 months follwoing horse ATG.  Response to a second course will be further reduced
  • other immunosupressives may be considered if transplant is not an option

 

Transplantation

Current BCSH guidelines

image

However, data is suggesting that upfront transplant in young patients with severe aplastic anaemia has better outcomes, therefore if the timeline allows MUD/haplo transplant this may have better outcomes.

References

Severe aplastic anemia: allogeneic bone marrow transplantation as first-line treatment.  George E. Georges, Kris Doney and Rainer Storb. 

Guidelines for the diagnosis and management of aplastic anaemia.  BSH guidelines.  Killick, S, B.

 

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Case 117 update 2

Bone marrow trephine shows a hypocellular trephine throughout the specimen, supporting your suspicion of aplastic anaemia. There are no dysplastic features present

There is no evidence of a PNH clone.

How would you classify this patient?

What are your immediate management plans?

What are your longer term treatment options for this patient?

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Case 117 update 1

So far our investigations have shown:

  • Normal haematinics
  • Negative viral screen
  • Negative autoimmune screen
  • Blood film – no blasts/no dysplasia. Anisopoikilocytosis
  • Normal LDH
  • Negative abdominal ultrasound
  • Reticulocytopenia

Patient has no significant past medical history and is not taking any regular medications

A bone marrow is performed and bone marrow aspirate results are available:

Hypocellular particles and trails. Erythropoiesis, granulopoesis and megakarycytes appears reduced.

What is your differentials diagnosis? Are there any further investigations you would perform?

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Case 117

31 year old man attends GP feeling tired. Bloods show

HB 65

Platelets 45

WCC 1.2

What further test would you advise? Immediate management??

Please reply to us (@TeamHaem) on Twitter and always include #TeamHaem to allow others to follow your comments. Please join in the debate and learn about haematological problems along the way. The case will continue to  evolve over the coming week so keep checking #TeamHaem on Twitter for more information.

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 116 – Summary!

Thank you for everyone’s involvement in the case this week. We discussed a 56 year old man who presented with an acute stroke. This was managed with oral aspirin as his NIHSS score was low at 3 and he presented at 4.5 hours after his symptoms developed.

His initial investigations revealed polycythaemia with iron deficient picture (Hb 122, HCT 0.52, MCV low) and mild thrombocytosis (480).

We took a thorough history to assess for potential secondary causes and cardiovascular risk factors. The only identifiable factors were a renal transplant 6 months ago (no prior dialysis and acute renal disease necessitating need for transplant) and smoking history. However he only smoked 5 cigarettes per day and had normal saturations so it wasn’t felt this was a significant contributory cause although he has obviously been recommended to stop. We also assessed cardiovascular risk status.

An important learning point from our case is the need to repeat the FBC/look back at previous results to ensure it is not just an erroneous result. Doing so highlighted that his polycythaemia was longstanding and pre-dated his renal disease and transplant. This prompted us to perform JAK2 V617F mutation analysis which was present confirming the diagnosis of polycythaemia vera.

Our patient was stratified as high risk due to his acute stroke and underwent venesection to try promptly reduced his HCT as well commencing hydroxycarbamide therapy. We discussed the importance of optimizing other cardiovascular risk factors and continuing anti-platelet therapy.

Below is a summary of polycythaemia and post-renal transplant erythrocytosis.

Polycythaemia

Polycythaemia is a frequent finding in general medicine and general practice. The vast majority of causes are due to relative/apparent polycythaemia (reduced plasma volume making the blood more concentrate) or secondary or reactive to other causes.

Causes

PV causes

Investigations

Those with a persistently raised venous haematocrit (male >0.52; females >0.48) should be reviewed and investigated. However, if there is a clear secondary cause no further investigations may be necessary.

 BSH guidelines recommend using the following investigative algorithm: https://onlinelibrary.wiley.com/doi/full/10.1111/bjh.15648

Polycythaemia algorithm

 Stage 1 Investigations:

  • History and examination
  • FBC/film (NB film not generally helpful in diagnosing polythaemia but needed to look for signs of myelofibrosis)
  • Ferritin, U&E, LFT (frequently patients are iron deficient)
  • Serum erythropoietin
  • ABG (or Sp02 but beware if at risk of carbon monoxide poisoning, sleep apnoea or high affinity haemoglobins as may be normal). An SaO2 <92% is associated with absolute erythrocytosis
  • JAK2V617F mutation (allele burden equivalent in bone marrow and peripheral blood)

Stage 2 investigations (if JAK2 negative):

  • Red cell mass
  • Abdominal USS (splenomegaly, renal pathology etc)
  • JAK2 exon 12 analysis (can have discrepancy between allele burden in bone marrow and peripheral blood)
  • Marrow aspirate/trephine/cytogenetics
    • – Marked increased erythropoiesis, moderate increase in granulopoiesis and megakaryopoiesis. Highly variable megakrycocyte including hyperlobulated nuclei, absent iron stores.
    • – Abnormal karyotype, SH2B3 mutation, TET2, DNMT3A

 

Polycythaemia Vera

 Polycythaemia vera is a clonal haematopoietic neoplasm which presents usually in the 60s with a slight male predominance. The substitution of phenylalanine for valine at position 617 of the JAK2 gene is responsible for approximately 95% of cases of polycythaemia vera and costs approximately £50. Progenitor cells have increased sensitivity to growth factors as the V617F mutation allows the JAK protein to become active even when no growth factor is bound leading to increased cell survival and proliferation. The incidence is approximately 2-3 per 100 000 per year.  When the V617F mutation is not found, mutations in exon 12 should be looked for as these account for a further 2-4% of cases of polycythaemia vera.

Clinical features:

  • Night sweats
  • Weight loss, lethargy
  • Splenomegaly
  • Aquagenic pruritis
  • Thrombosis (venous/arterial/microvascular) and bleeding
  • Arterial thrombosis more common (75%)
  • Abdominal vein thrombosis should be investigated for the JAK2v617F and exon 12 mutations even with a normal FBC.
  • Headache/visual disturbance
  • Dizziness
  • Erythromelalgia

 

Diagnostic criteria

JAK2-positive polycythaemia vera (requires both criteria)

  • High HCT (>0.52 in men, >0.48 in women) OR raised red cell mass (>25% above predicted)
  • Mutation in JAK2

JAK2-negative polycythaemia vera (requires A1-A4) plus another A or two B criteria)

  • A1 Raised red cell mass (>25% above predicted) OR HCT >0.6 in men; >0.56 in women
  • A2 Absence of mutation in JAK2
  • A3 No cause of secondary erythrocytosis
  • A4 Bone marrow histology consistent with PV
  • A5 Palpable splenomegaly
  • A6 Presence of an acquired genetic abnormality (excluding BCR-ABL1) in the haemopoietic cells
  • B1 Thrombocytosis (Plts >450 x 109/l)
  • B2 Neutrophil leukocytosis (neutrophil count >10 x 109/l in non-smokers, >12.5 x 109/l in smokers)
  • B3 Radiological evidence of splenomegaly
  • B4 Low serum erythropoietin

 

Risk stratification (of thrombotic risk based on ECLAP data):

  • Low risk: <65 years and no PV-associated thrombotic history
  • High risk: >65 years and/OR prior PV-associated arterial or venous thrombosis
  • NB: other factors contributing to thrombotic risk include: WCC >15 x 109/l, smoking, diabetes mellitus, hypertension, hypercholesterolaemia. Patients with these features even if stratified as low risk should be considered as high risk.
  • Mortality is predominantly based on thromboembolic events

 

Factors associated with an increased risk of transformation to myelofibrosis

~Incidence of transformation 5-10% in 10 years

  • Longer disease duration
  • Splenomegaly
  • Raised LDH
  • Presence of reticulin fibrosis at diagnosis
  • JAK2 V617F allele burden >50%

Factors associated with an increased risk of transformation to AML

  • Age
  • WCC >15 x 109/l
  • Splenomegaly
  • Abnormal karyotype

Management

 All Patients

  • HCT target <0.45
    • based on CYTO-PV data on reduction of major thrombosis/cardiovascular death
  • Aspirin 75mg – 100mg per day (+ PPI if high bleeding risk including age >75)
  • Optimisation of other cardiovascular risk factors e.g hypertension
  • Avoid excess of dietary iron

Low risk patients

  • Venesection alone to achieve target HCT
  • In the acute setting this may be needed frequently e.g. alternate days and concomitant fluid replacement may be necessary
  • ≥3 venesections per year is associated with higher thrombotic risk. If maintenance venesection frequency high cytoreductive treatment should be considered.
  • Patients otherwise catergorised as low risk should be managed with cytoreductive therapy if extreme thrombocytosis (>1500 – haemorrhage risk), progressive splenomegaly/progressive leukocytosis. Or marked constitutional symptoms.

High risk patients

  • Require use of cytoreductive therapy
  • Hydroxycarbamide or interferon are first line

 

  • Hydroxycarbamide
    • No definitive evidence that it increases risk of transformation to leukaemia.
    • Advise to stop 3 months prior to conception

European LeukaemiaNet criteria for hydroxycarbamide intolerance and resistance:

  1. Need for phlebotomy to keep haematocrit <0·45 after 3 months of at least 2 g/day of hydroxycarbamide OR
  2. Uncontrolled myeloproliferation, i.e. platelet count >400 × 109/l AND white blood cell count >10 × 109/l after 3 months of at least 2 g/day of hydroxycarbamide OR
  3. Failure to reduce massiveasplenomegaly by more than 50% as measured by palpation OR failure to completely relieve symptoms related to splenomegaly, after 3 months of at least 2 g/day of hydroxycarbamide OR
  4. Absolute neutrophil count <1·0 × 109/l OR platelet count <100 × 109/l OR haemoglobin <100 g/l at the lowest dose of hydroxycarbamide required to achieve a complete or partial clinico‐haematological response OR
  5. Presence of leg ulcers or other unacceptable hydroxycarbamide ‐related non‐haematological toxicities, such as mucocutaneous manifestations, gastrointestinal symptoms, pneumonitis or fever at any dose of hydroxycarbamide.

 

  • Interferon
    • Safe in pregnancy

 

  • Other cytoreductive agents
    • Ruxolitinib (JAK2 inhibitor)
      • Second/third line if HC intolerant/resistant
    • Radioactive phosphorus / busulfan
      • Increased risk of leukaemia transformation so should only be administered to thse with a limited life expectancy.
    • Anagrelide
      • Can be used in combination if plt count not controlled with hydroxycarbamide

 

Post renal transplant erythrocytosis

  • Incidence ~5-20%
  • Various definitions ranging from HCT >0.50 -0.52 persisting for between 1 and 6 months.
  • It typically occurs within the first year post transplant
  • The erythrocytosis is related to EPO levels. Risk factors for developing post transplant erythrocytosis include:
    • Male > female
    • Native kidney in situ
    • Renal artery stenosis
    • Reduced need for EPO pre-transplant or transfusions
    • Poor allograft function
  • It is usually considered to be a benign condition as it is not associated with thrombosis or increased mortality. It can also spontaneously resolve over 1-4 years.
  • Management:
    • ACEi or ARB as these suppress the renin-angiotensin system
    • Treat hypertension
    • No benefit of aspirin
    • Consider venesection if persistent symptoms to target HCT 0.5 (no evidence of benefit)

References

  1. McMullin MF. A guideline for the diagnosis and management of polycythaemia vera. A Britich Society for Haematology Guideline. 184(2):176-191. 2019.
  2. Landolfi R et al. European Collaboration on Low-dose aspirin in polycythaemia vera (ECLAP): A randomised trial. Seminars in Thrombosis and haemostasis. 23(5):473-8. 1997.
  3. Marchioli R et al. Cardiovascular events and intensity of treatment in polycythaemia vera. New England Journal of Medicien. 368:22-33. 2013
  4. McMullin MF. A guideline for the management of specific situations in polycythaemia vera and secondary erythrocytosis. A Britich Society for Haematology Guideline. 184(2):161-175. 2019.
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Case 116 – Update 3!

Thank you for everyone’s contributions.

Due to his history of renal disease and renal transplant it is important that we consider these as potential secondary causes of polycythaemia. However, taking a thorough history and review of previous blood results has identified that he has been polycythaemic for the past 3 years which preceded his renal issues. It is important to note that we can’t exclude post transplant polycythaemia as a contributing cause. There was nil else on his history which was indicative of another secondary cause.

We now have the outstanding blood results that you have all requested:

Erythropoietin: Low

JAK2 V617F: Present

Questions:

  1. What is the main cause of his polycythaemia and how what would your management be for this patient?
  2. What is the management of post-transplant polycythaemia and would you institute it in this case?

Please reply to us (@TeamHaem) on Twitter and always include #TeamHaem to allow others to follow your comments. Please join in the debate and learn about haematological problems along the way. The case will continue to  evolve over the coming week so keep checking #TeamHaem on Twitter for more information.

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 116 – Update 2!

Thank you for everyone’s contributions so far!

It has been noted that our patient who presented with an ischaemic stroke has a raised HCT and you have mentioned that we need to ensure this is an absolute polycythaemia and if so whether there is a primary or secondary cause.

To recap the FBC result taken at the time of his stroke was Hb 122, HCT 0.56, MCV 72, Plts 480, WCC 9.8, Neuts 7.5. NB we have repeated the FBC and th results are similar (lets not forget this!!)

Various information/investigations to determine the aetiology of his polycythaemia have been requested by yourselves as follows:

  • Current smoker: 5/day
  • Lives in the UK at sea level
  • PMH: renal transplant 6 months ago secondary to rapidly progressive glomerulonephritis. Native kidneys in situ. No prior CVA, diabetes, hypertension, or hypercholesterolaemia.
  • On examination: Saturations 99%. BP 139/68.
  • ECG: normal sinus rhythm.
  • Electrolytes normal. Ferritin 13. Albumin 37. Lipid profile unremarkable. Glucose NAD
  • JAK2 V617F, EPO levels pending.

 

The main differentials suggested are:

  • Primary polycythaemia
  • Polycythaemia post renal transplant

 

Questions:

  1. What further information from the patients history/examination would be useful to  help determine potential secondary causes of polycythaemia?
  2. What are the risk factors for polycythaemia post renal transplant? How would you treat it?

Please reply to us (@TeamHaem) on Twitter and always include #TeamHaem to allow others to follow your comments. Please join in the debate and learn about haematological problems along the way. The case will continue to  evolve over the coming week so keep checking #TeamHaem on Twitter for more information.

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 116 – Update 1!

Thanks for everyone’s contributions so far.

Our 56 year old man was commenced on aspirin by the acute stroke team. He was not suitable for thrombolysis (presented later than 4.5hours of onset of symptoms) and it was felt thrombectomy was not required due to a low NIHSS score of 3. He remains on the acute stroke unit under their care.

Following his renal transplant 6 months ago he has a good baseline function. He has never had a TIA/stroke previously.

Work-up investigations requested by yourselves revealed:

  • BP and glucose: Normal
  • ECG: Normal sinus rhythm
  • FBC: Hb 122, HCT 0.56, MCV 72, Plts 480, WCC 9.8, Neuts 7.5

Question:

  1. What abnormality is apparent and what further investigations would you want to perform?

Please reply to us (@TeamHaem) on Twitter and always include #TeamHaem to allow others to follow your comments. Please join in the debate and learn about haematological problems along the way. The case will continue to  evolve over the coming week so keep checking #TeamHaem on Twitter for more information.

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 116 – The Beginning!

A 56 year old man presents with left sided arm weakness and slurred speech. His symptoms started 6 hours prior to presentation. He has a significant past medical history of a renal transplant 6 months ago. A CT confirms a partial anterior circulation stroke.

Questions:

  1. What further information would you want?
  2. What would be your acute management at this stage?

Please reply to us (@TeamHaem) on Twitter and always include #TeamHaem to allow others to follow your comments. Please join in the debate and learn about haematological problems along the way. The case will continue to  evolve over the coming week so keep checking #TeamHaem on Twitter for more information.

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 115 summary

Our patient presented with MAHA, thrombocytopenia and neurological symptoms which prompted further investigations and confirmation of TTP.

Teamhaem have covered TTP previously in case 7, with a different clinical scenario. Therefore the majority of this summary is taken from the previous case. However key areas to this case are pregnancy, refractory diseaseand new advances in treatment.

Acquired TTP is a potentially life threatening thrombotic microangiopathy, caused by a severe deficiency in ADAMTS13 due to the presence of inhibitory autoantibodies. In our case we demonstrated low levels or ADAMTS13 in the presence of antibodies. This results in aggregation of platelets to ultra large vonwillebrand factor multimers causing micro vascular thrombosis which results in organ ischaemia.

Differential

  • Haemolytic uraemic syndrome
  • Malignant hypertension
  • HELLP (haemolysis elevated liver enzymes low platelets)
  • Pre-eclampsia
  • Disseminated intravascular coagulation
  • Autoimmune diseases e.g. anti-phospholipid syndrome, SLE

TTP – clinical syndrome

The classic clinical presentation is often insidious in inset and consists of the pentad:

  • Pyrexia
  • MAHA
  • Fluctuating neurological impairment – may include personality change and drowsiness to seizures and coma
  • Renal failure
  • Thrombocytopenia

TTP – Investigations

The below are to help in the diagnosis of other MAHA and also to point towards a potential cause.

  • Biochemistry: U&E/LFT/Ca/indirect bili/LDH/troponin/amylase
  • Haematology: FBC, film, reticulocyte count/coag/DAT
  • Viral: HIV/Hep B/C
  • Immunology: Autoimmune screen/haptoglobin
  • ADAMTS13 assay
  • Urinalysis
  • ECG
  • CXR
  • TFTs
  • CT head
  • CT chest abdo pelvis, pregnancy test and stool sample if indicated

Management

Taken from BsH guidelines 2014

New therapies

Caplacuzimab may be used in acquired TTP. An anti-vonwillebrand factor nanobody, inhibits the interaction be ultra large Von willebrand factor multimers and platelets. This results in reduce aggregation, producing faster recovery of the platelet count and reduced incidence of thrombosis, and shortening of the acute episode of TTP.

HERCULES trial – Caplacuzimab treatment for acquired thrombotic thrombocytopenic purpura. NEJM January 2019 Scully, M et al

https://t.co/KNjhbSumYo Link to podcast discussing the role of caplacizumab

TTP and pregnancy

Pregnancy can be the initiating event for TTP. This may be acquired or late onset congenital TTP. Patients may present at any point during pregnancy, but the majority of presentation occur at 30+ weeks gestation a or in the immediate post-part in period.

Diagnosis of TTP can be challenging especially in pregnancy. PEX should be started immediately if there is uncertainty in the diagnosis.

Treatment

  • Delivery is the definitive treatment in pregnancy, however it may not guarantee remission.
  • Congenital TTP may be managed with plasma infusions alone.
  • Steroids and PEX comprises main treatment plan
  • PEX can be continued throughout pregnancy and may allow continuation of pregnancy and delivery of a live foetus
  • Rituximab has been used in pregnancy in other conditions (autoimmune/lymphoma) but there is no data available for its use in pregnancy in acute TTP, although it would be considered in a case such as ours.

The following can be considered when managing a pregnancy in a patient with previous TTP

  • Low dose aspirin
  • LMWH
  • Azathioprine
  • Rituximab can be given pre-conceptually to reduce the risk of relapse during pregnancy
  • PEX

Baseline ADAMTS13 level and IgG should be taken and monitored regularly during pregnancy. Treatment plan will depend upon baseline ADAMTS13 levels and often patients will required additional treatments by the third trimester. The obstetric team would require early and regular reviews to perform foetal ultrasound +\- uterine artery doppler. Delivery should be planned for 37weeks gestation.

Pregnancy outcomes are closely related to gestation with pregnancy loss typically occurring in the second trimester.

ADAMTS13 levels may be reduced in other TMAs related to pregnancy I.e HELLP and pre-eclampsia, but ranging from 12% to 40%, and antibodies to ADAMTS13 are not found.

References

HERCULES trial – Caplacuzimab treatment for acquired thrombotic thrombocytopenic purpura. NEJM January 2019 Scully, M et al

Diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies. BSH guideline 2014

Thrombotic thrombocytopenic purpura and pregnancy: presentation, management and subsequent pregnancy outcomes. Blood 2014 Scully et al.

TTP diagnosis and management in pregnancy. Thrombosis UK. Prof Marie Scully. https://m.youtube.com/watch?v=-c8BFywDGbs

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Case 115 update 3

Our patient improves clinically with PEX/steroids/rituximab.

Unfortunately she also suffers a miscarriage.

What is your ongoing treatment plan?

How would you council her for future pregnancies? Would you offer any treatment pre.conceptually?

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Case 115 update 2

TTP is confirmed by ADAMTS13 level of 2%. What further information would be useful and why?

Plasma exchange was initiated promptly along with methylprednisone. The patient has had 1.5 plasma volume exchange over the first 3 days of admission. Platelet count is 30. How would you continue to manage this patient?

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Case 115 update 1

You have reviewed the film and concur with the finishing of marked red cell fragmentation. Thrombocytopenia is also confirmed.

You contact the A&E doctor who has reviewed the patient and they confirm as history of a possible seizure prompted hospital review. A history of alcohol excess has also been reported by the patient partner.

Patient usually fit and well, no recent travel, no new medications

Further blood tests undertaken include:

Na- 134

K- 5.4

Crest – 231

Urea – 9

DAT- negative

LDH – elevated

Coagulation screen – PT 12 APTT 33 fibrinogen 3.4

Trop T- elevated

Amylase – within normal range

Hep B/Hep C/ HIV – negative

BetaHCG- elevated

ADAMTS13- awaited as not available out of hours in your area

What is your differential diagnosis?

How would you manage this patient?

Please remember to include #teamhaem in your reply!

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