Case 120 – Summary!

Thank you for everyone’s contributions this week. We discussed the management of a 57 year old lady who was suffering a major haemorrhage secondary to a road traffic accident.

The key points of managing a major haemorrhage (from haem perspective) are highlighted below:

  1. Identify Major Haemorrhage
    1. Early recognition essential to enable prompt provision of blood products
    2. Definitions:
      1. Bleeding which leads to heart rate >110bpm +/- systolic BP <90mmHg (NB be aware of patients baseline HR / SBP as individuals may be significantly compromised at the above parameters if their baseline levels vary from the general population)
      2. Loss of 1 blood volume in 24 hours / 50% blood volume in 3 hours / 125ml blood loss in 1 minute (NB these definitions are generally considered less useful as often detected retrospectively)
  1. Activate major haemorrhage protocol
    1. All hospitals within the UK should have a protocol
    2. Typically involves senior clinician, senior nurse, anaesthetist, transfusion lab, porter
    3. Ideally the team leader should designate one member of staff to liaise with the haematology lab

 

  1. Initial Management
    1. ABC approach and local control of bleeding
    2. Bloods:
      1. FBC, coag and clauss fibrinogen, biochem
      2. Group and save (x2 different times)
        1. Minimum identifiers: name, DoB, unique patient identifier number
        2. If unknown patient: Unique patient identifier number and gender
      3. Transfusion support (see below)
      4. Ascertain if on anti-platelets / anticoagulation (if possible)

 

  1. Transfusion Support
    1. Urgent blood / blood component transfusion. Major haemorrhage packs should be available as part of the major haemorrhage protocol. The documented ‘packs’ below are a guide and will vary slightly between hospitals such as 1 pool platelets may be available in pack. Need to switch to group specific / cross-matched packed red cells (PRCs) asap. Use cell salvage if available. Ongoing PRCs and components should be guided by blood results and near patient tests as soon as available alongside the ongoing clinical situation.
    2. Pack 1 of major haemorrhage pack
      1. PRCs and FFP in 1:1 ratio or 2:1 ratio (based on PROPPR trial – which improved deaths from bleeding but note no benefit in overall survival)
      2. 4 units PRCs
        1. If female of child bearing potential (<50 yrs) give Group O Rh D-ve Kell-ve
        2. If adult male or female >50yrs can consider Group O Rh D+ve
        3. Switch to group specific as soon as possible
      3. 4 units FFP
        1. Ideally Group AB but often in short supply in which case Group A (negative for high-titre anti-B)
    3. Pack 2 of major haemorrhage pack
      1. PRCs and FFP in 1:1 or 2:1 ratio (4 units PRCs : 4 units FFP)
      2. 1 pool platelets (consider giving platelets earlier if known to be on anti-platelets)
      3. Consider cryoprecipitate
    4. Transfusion based on blood results / near patient tests
      1. Aim to do traditional coagulation tests (PT, APTT, clauss fib) approximately every 30 mins. Be aware that these tests are not real-time so don’t represent the current clinical picture
      2. TEG / ROTEM provide real time results but should be used alongside traditional coag tests.Aim parameters
        1. Falling Hb: PRCS
        2. PTr / APTTr >1.5 : FFP 15-20ml/kg
        3. Clauss fibrinogen <1.5 (2 if obstetric haemorrhage) : 2 ppols of cryoprecipitate
        4. Platelets <50 : 1 pool platelets
  1. Pharmacological agents
    1. Tranexamic acid
      1. If trauma <3hrs / or risk of major haemorrhage / or not contraindicated as per CRASH 2 trial which demonstrated increased overall survival with TXA use. Give 1g TXA bolus then further 1g over 8 hours.
    2. Reversal agents for anti-coagulation (i.e protamine for heparin, praxbind for dabigatran)
  1. Other supportive measures
    1. Optimisation of hypothermia (aim >36.5C), acidosis, hypocalcaemia to reduce coagulopathy.
  1. Measures post major haemorrhage
    1. When bleeding has ceased – DEACTIVATE PROTOCOL (inform blood bank)
    2. Return unused stock to blood bank
    3. Monitor for complications from transfusions such as TACO
    4. Consider VTE prophylaxis when considered safe from bleeding perspective

 

References:

  1. Hunt BJ et al. A practical guideline for the haematological management of major haemorrhage. British Journal of Haematology. 170 (6). 788-803. 2015.
  2. Norfolk D. Handbook of Transfusion medicine 5th Edition. TSO. 2013.
Posted in Uncategorised

Case 120 – Update 4!

Well done team – with your input I’m pleased to say she has now stabilised and has stopped bleeding!!! To achieve this she has been transfused:

  1. 8 units red blood cells
  2. 8 units FFP
  3. 1 pool of platelets
  4. 2 pools cryoprecipitate

She undergoes surgery to stabilise her pelvis and is likely to be an inpatient for some time whilst she undergoes rehabilitation.

Questions:

  1. Now she is stable what would be the threshold to transfuse red blood cells? What her Hb target?
  2. What methods would you use to reduce her risk of thromboembolism?
  3. How would you ensure your hospital is managing major haemorrhages appropriately?

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.

Posted in Uncategorised

Case 120 – Update 3!

Thank you for everyone’s ongoing input. Our patient is more haemodynamically stable but continues to have ongoing bleeding. She is now receiving group specific/compatible blood products. She has currently received:

  1. 6 units packed red cells.
  2. 6 units FFP
  3. 1g tranexamic acid with a further 1g TXA being infused

A repeat FBC / coagulation screen is in progress. Her latest TEG is below (dotted line is normal TEG for comparison).

TEG

R time: 8min (4-8min), K time: 5min (1-4min), a-angle: 30 (47-74), MA: 35 (55-73mm)

Questions:

  1. What blood products would you give based on the TEG?
  2. Based on the traditional FBC / coagulation screen what values would you be aiming for? e.g PT/APTT/fibrinogen/platelets greater than ?

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.

Posted in Uncategorised

Case 120 – Update 2!

Thanks for everyone’s contributions so far!

Our 57 year old female patient is haemorrhaging following a road traffic accident. The multidisciplinary team are trying to establish source control of the bleeding. The major haemorrhage protocol has been activated. She has received packed red cells and FFP in a 1:1 ratio. She has received the following products:

  1. 4 units packed red cells: 1 unit Group O D negative, 3 units Group O D positive
  2. 4 units FFP: 2 units Group AB and 2 units Group A (negative for high-titre anti-B)

The baseline blood results are now available:

Hb 81, Plts 60, WCC 5. PT 19, APTT 42, Clauss Fib 1.4

The ABO group and D status result is available for interpretation (antibody screen in progress):

Forward Group Reverse Group
Anti-A Anti-B Anti-D1 Control A1 cells B cells
5 0 5 0 0 5

Questions:

  1. What ABO group is this patient? What is the Rh D status?
  2. What is the potential impact of the potential blood products that have already been given? How would you manage this?

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.

Posted in Uncategorised

Case 120 – Update 1!

Thanks for everyone’s contributions. Following recommendations from yourselves our patient  is being managed by a multidisciplinary team and the major haemorrhage protocol has been activated. The only information the clinical team know about our patients that she is called ‘Betty and she is 57 years old (DoB unknown).

Questions:

  1. What patient identifiers are required prior to issuing blood for our patient?
  2. What blood / blood products would you want in the major haemorrhage packs?
  3. What group / special requirements are required for the blood / blood products prior to establishing the patients blood group / antibody status?

 

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.

Posted in Uncategorised

Case 120 – The Beginning!

A 57 year old female is in Accident and Emergency following a road traffic accident. She has multiple injuries including a suspected pelvic fracture. She is haemodynamically unstable (heart rate 130, BP 86/54, oxygen saturations 97%). The clinical team are concerned she is still actively bleeding.

What is your initial investigation and management of this patient?

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.

Posted in Uncategorised

Case 119 – Summary

 Many thanks for all your great suggestions and contributions this week. We highlighted the multidisciplinary treatment of our patient with mycosis fungoides, who eventually required systemic treatment with brentuximab vedotin for his CD30+ disease.

Primary cutaneous T cell lymphoma (CTCL) is a type of non-Hodgkin lymphoma (NHL) which presents in the skin. It is the second most common group of extranodal NHL but remains a rare disorder, with an estimated annual incidence of 1 per 100,000 of the population in the UK, with a higher male incidence (1.6:1.0) and peak age between 50 and 74. Mycosis Fungoides (MF) is the most common subtype of CTCL, comprising around 40% of these conditions. Other less common subtypes include primary cutaneous anaplastic large cell lymphoma (pcALCL) and Sezary syndrome.

Patients with MF at different clinical stages present with skin patches/plaques, tumours or erythroderma; accurate staging relies on clinical, histological, immunophenotypical and genetic data.

All patients with suspected or proven primary cutaneous lymphomas should be reviewed at a regional Specialist Skin Cancer Multidisciplinary Team (MDT) meeting, with close involvement of haematology MDT in the presence of systemic disease. The current staging system in use in the UK is the International Society for Cutaneous Lymphomas (ISCL) EORTC revised staging system. This system distinguishes patches and plaques, incorporates a molecular assessment of lymph node and peripheral blood, and provides a quantitative method for assessing peripheral blood disease in SS (see links at bottom).

Treatment options will often be dictated by the clinical stage of disease. Options include skin-directed therapies (SDT) such as topical agents, phototherapy and radiotherapy, and systemic therapies including biologics, chemotherapy and stem-cell transplantation.

Early stage MF (Stage IA – IIA) is often treated with skin-directed therapy including topical steroids and phototherapy. Patients with infiltrative plaques or tumours (stage IIB) may also be offered local radiotherapy.  Those with more systemic disease may be offered skin-directed therapies in conjunction with systemic biologic therapies e.g. interferon alfa or retinoids. Total skin electron beam therapy has also been used in this group. Those with advanced and refractory disease often require antibody therapy or chemotherapy. Allogeneic stem cell transplant can also be considered.

Extra reading:

ESMO clinical practice guideline: https://www.esmo.org/Guidelines/Haematological-Malignancies/Primary-Cutaneous-Lymphoma

British Association of Dermatologists guideline: http://www.bad.org.uk/shared/get-file.ashx?id=6265&itemtype=document

Posted in Uncategorised

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.

Posted in Uncategorised

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.

Posted in Uncategorised

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.

Posted in Uncategorised

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

Posted in Uncategorised

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?

Posted in Uncategorised

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

Posted in Uncategorised

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.

Posted in Uncategorised

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.

 

Posted in Uncategorised

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?

Posted in Uncategorised

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?

Posted in Uncategorised

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.

Posted in Uncategorised

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.
Posted in Uncategorised

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.

Posted in Uncategorised