Case 84 – summary

Thank you for all your help with this weeks case!

This week we looked at a case of a patient with type 1 Gaucher’s disease . She was found to be mildly anaemia with a mild thrombocytopenia.

A CT scan revealed splenomegaly and blood tests showed a raised serum ACE and ferritin which are typically found in Gaucher’s disease.

A bone marrow biopsy was consistent with a diagnosis of Gaucher’s disease, and a glucocerebrosidase enzyme activity assay was reduced confirming the diagnosis of Gaucher’s disease. Genetic testing can also be done for homozygosity in N370S GBA gene which is found in the majority of cases of type 1 Gaucher’s disease.

Gaucher’s disease is a lipid storage disorder where glucosylceramide will accumulate in macrophages, and results from a deficiency in lysosomal hydrolase glucocerebrosidase. 
Gaucher’s disease is an inherited autosomal recessive condition, and phenotype can vary greatly, with some patient’s not being diagnosed until very late in life, whereas other are diagnosed in infancy. 

The prevalence of Gaucher’s disease varies in different populations and for type 1 Gaucher’s disease can be 1:50000-1:100000, and up to 1:850 in the Ashkenazi Jewish population. Type 3 Gaucher’s disease is most common in the Norrbottnian area of Sweden with a prevalence of 1:50000.

There are different types of Gaucher’s disease.

Type 1 Gaucher’s disease, as in our case, can present in childhood or adulthood, and some patient’s may have signs/symptoms for a few years before the diagnosis is made. This type of Gaucher’s does not usually result in brain or spinal cord involvement. Patient’s may present with anaemia, thrombocytopenia and hepatosplenomegally. There may also be lung and bony involvement – resulting in bone pain and fractures.

Type 2 and 3 Gaucher’s disease are known as nuronopathatic types as they will typically have nerve and spinal cord involvement. Patient’s can get the symptoms of type 1 Gaucher’s disease, but in addition will have central nervous symptom effects, such as seizures. Type 2 Gaucher’s disease will usually present in infancy. Type 3 Gaucher’s disease may progress slower than type 2.

In the severest cases Gaucher’s disease can cause in utero problems such as hydrops fetalis, organomegally and neurological problems and babies may die shortly after birth.

Treatment is with enzyme replacement therapy. An oral glucosylceramide inhibitor can also be considered.

Has anyone got any questions, or any knowledge they would like to add?

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 84 – update 2

So we have the results of our patient’s bone marrow and it looks to be consistent with Gaucher’s disease!

Our patient has a raised serum ACE and ferritin which is typical of Gaucher’s disease.

Our bone marrow shows the typical ‘crushed silk’ appearance of Gaucher’s cells.


What tests would you do to confirm this?

What is Gaucher’s disease?

What types of Gaucher’s are there?

What type of Gaucher’s disease do we think our patient has?

What symptoms and lab findings can be associated with Gaucher’s disease?

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 84 – update 1

So we have an update
We have found our patient is thrombocytopenic, and has a mild normocytic anaemia.

Our patient has been slightly tired for a year or so, but still manages to do her demanding job as a PE teacher.

She has no past medical history and is on no regular medication

The patient does notice she is bruising easily but does not have any bleeding problems. A bleeding score is 1 (isth-ssc), and our patient says her job can be quite physical, so put it down to that.

She denies any night sweats/weight loss.
There is no parental history of bleeding problems.
Our patient’s father was born in Israel and moved to England when he was 2, our patient’s mother was born in the England.
On examination

Chest clear

HS I+II+O

Abdo soft, the spleen can just be felt below the costal margin
There are no rashes.

The patient has a few cutaneous bruising on arms and shins, none >2cm, no palpable haematomas.
We have done a number of blood tests

Blood film – thrombocytopenia, but morpholocicaly normal red/white cells/platelets. No plt clumps.

B12/fol normal
U+E – normal

LFT – normal
Auto immune screen including RH factor, ANA, ENA,ANCA negative
Coag 

PT 13.4

APTT 33

CLAUS FIB 3.7
VWD screen, factor XIII, PFA-100 normal
HIV/hep B/hep C negative
EBV IgG positive, IgM negative

CMV IgG and IgM negative

An ultrasound abdo has been done and shows splenomegaly with a 16.5 cm spleen. Liver appears normal. Renal tract normal.

What are your thoughts now?

Is there anything else you would like to know?

What should we do next?

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 84 – the beginning

Welcome to our new case!

We start in the GP surgery with a 21 year old woman.

She has been feeling tired for a while so has come to get checked. Your colleague did some bloods on the previous visit and she has come for the results

He 110g/l

Wcc 9.0

Neuts 5.0

Plt 92

MCV 97

What would you do next?

Is there any history you would like?

Are there any tests you would do?

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

Posted in Uncategorised

Case 83 – summary

Many thanks to everyone who contributed to our case.

This week the case centred on a pregnant female who was an obligate carrier of Haemophillia A (Her Father was affected). She had a factor VIII level of 54%. She was a carrier of intron 22 inversion. The free fetal DNA testing in this case confirmed she is carrying a male fetus. In this situation CVS would be offered or Amniocentesis for pre natal diagnosis but the patient declined.

She was keen for an elective c-section as she lives some way from the specialist centre and after careful discussion this was arranged for 37 weeks. A comprehensive care plan was agreed with MDT:

  • Premise is to assume baby may have Severe Haemophillia A
  • C-section planned for 37 weeks safe to proceed if factor VIII >50% and also safe for spinal if threshold reached. To deliver between 9-5 and inform MDT on initiation of section.
  • VTE prophylaxis safe if VIII level >60%
  • Mechanical VTE prophylaxis and adequate hydration to be encouraged.
  • If admission in spontaneous labour no fetal blood has sampling or fetal scalp electrodes. No forceps or ventousse.

At delivery:

  • Urgent cord blood for factor VIII level.
  • Oral vitamin K not IM.
  • Any bleeding concerns contact Haem consultant on call.
  • Neonatal team to review on delivery.
  • Cranial USS will be required if affected baby.
  • Actively managed third stage of labour.

She had a successful C-section and factor VIII level at delivery on the neonate is 36%. This is slightly lower than may be expected for a neonate but certainly excludes severe Haemophillia A a repeat sample at 6 months confirmed factor VIII level of 85%.

This case hopefully highlighted the importance of MDT working when caring for a pregnant patient.

Ideally this lady should have had pre-natal counselling and reproductive options discussed with her given her obligate carrier status. It is important when caring for patients with severe Haemophillia to contemplate extended family and offer genetic screening as appropriate particularly to females of childbearing potential.

Carriers of severe Haemophillia A should receive genetic counselling  and the options of preimplantation genetic diagnosis discussed. In England the NHS will find 3 cycles of pre implantation genetic diagnosis with a success rate of around 30%.

Other options for diagnosis:

  • Free fetal DNA to determine sex from 9 weeks gestation.
  • Carriers of Haemophillia A and male fetus should be offered Pre natal diagnosis via CVS at 11-14 weeks gestation.
  • Third trimester amniocentesis could also be considered for a male fetus.

If no diagnostic testing must treat male fetus as affected by Haemophillia A.

Antenatal care needs a coordinated MDT approach. In the case of Haemophillia A factor VIII levels generally rise during pregnancy from 6 weeks to around 2-3x baseline by term. Falling by day 2-3 post partum. Most carriers will have a level of 50-60% but lyonisation and ABO blood group can affect an individuals level.

Factor levels should be checked at booking and pre procedure as well as in third trimester to assist in planning for delivery. It should be noted that individuals carrying Haemophillia have an increased bleeding risk even when levels are between 40-60%. They are also at higher risk of PPH.

Factor VIII levels should be >50% for delivery and epidural. They should be >60% for LMWH prophylaxis.

If levels of VIII are low then DDAVP (0.3 micro grams per kg based on pre pregnancy weight)  should be given as a trial. Tachyphalaxis can occur with repeat doses. DDAVP is contraindicated if any evidence of pre-eclampsia. A fluid restriction should be kept to 1 litre post treatment. If trial of DDAVP fails then recombinant factor VIII should be used with levels checked before and after doses and after 4-6 hours. Tranexamic acid should also be used. Treatment should be continued for 3-5 days post delivery depending on circumstances.

Intrapartum care should be agreed with MDT and an anaesthetic opinion as well as obstetric advice is vital. A plan should be written and agreed before 37 weeks.

The options of delivery need careful discussion but a vaginal delivery is not contraindicated though induction may be needed if concerns about distance from specialist care centre. The optimal mode of delivery is uncertain but there is an increased risk of ICH in babies born with assisted vaginal delivery especially ventose. There is a suggestion of lower risks of ICH with planned Caesarean section and this should be offered to mothers for discussion depending on other additional risk factors.

During labour fetal blood sampling, fetal scalp electrode use and mid cavity or ventouse should be avoided. IM vitamin K should not be given oral used instead until confirmation of babies Haemophillia status via urgent cord blood.

Post delivery tranexamic acid is recommended for mothers until bleeding post delivery stops or lightens to normal menstrual period. This is felt to be safe with breast feeding. Women should be advised lochia passage can occur for long period upto 58 days post delivery.

If the baby is affected then cranial USS is recommended due to increased rates of ICH in these babies. MRI may be considered if suspicion of ICH. Prophylaxis may be considered for premature babies or those with traumatic delivery on a case by case basis.

There is a highly comprehensive guideline available on which the above case advice has been taken:

Pavord S et al. RCOG Green top guideline no 71. Management of inherited bleeding disorders in pregnancy. BJOG 2017;124:e193-e263. 

Posted in Inherited bleeding, Paediatric haematology, Related to other specialities | Tagged , , , , , , ,

Case 83 – update 3 

Our pregnant patient had a factor VIII level of 54%. She is a carrier of intron 22 inversion as predicted from family history.  The free fetal DNA testing confirms she is carrying a male fetus. The patient has decided that she does not wish to undergo CVS for diagnosis.

She was keen for an elective c-section as she lives some way from the specialist centre and after careful discussion this was arranged for 37 weeks. A comprehensive care plan was agreed with MDT:

  • Premise is to assume baby may have Severe Haemophillia A 
  • C-section planned for 37 weeks safe to proceed if factor VIII >50% and also safe for spinal if threshold reached. To deliver between 9-5 and inform MDT on initiation of section.
  • VTE prophylaxis safe if VIII level >60%
  • Mechanical VTE prophylaxis and adequate hydration to be encouraged.
  • If admission in spontaneous labour no fetal blood has sampling or fetal scalp electrodes. No forceps or ventousse.

At delivery:

  • Urgent cord blood for factor VIII level.
  • Oral vitamin K not IM.
  • Any bleeding concerns contact Haem consultant on call.
  • Neonatal team to review on delivery.
  • Cranial USS will be required if affected baby.
  • Actively managed third stage of labour. 

She has a successful C-section and factor VIII level at delivery on the neonate is 36%

Does this exclude baby being affected by severe Haemophillia A? 

What should you tell the parents?

What are the generally expected levels of factors in neonates? 



Posted in Inherited bleeding, Paediatric haematology, Related to other specialities | Tagged , , , , , , ,

Case 83 – update 2

Our pregnant patient returns to clinic she is now 13 weeks pregnant. 

Her factor VIII level was 54%. She is a carrier of intron 22 inversion as predicted from family history. 

The free fetal DNA testing confirms she is carrying a male fetus. The patient has decided that she does not wish to undergo CVS for diagnosis.

Is the patients factor VIII level safe for intervention / delivery?

When should her factor VIII level be re-checked?

What should be considered when formulating a birth plan with the patient? 

Any interventions that should be avoided during delivery?

Posted in Inherited bleeding, Related to other specialities | Tagged , , , , , ,

Case 83 – update 1

After consideration of her family tree you realise  if there are no non-paternity issues she is an “obligate carrier” of Haemophillia A. 

After counselling and discussion she agrees to having genetic testing for herself. She is willing to have free fetal DNA testing for fetal sex that can be carried out after 11 weeks. She also consents to checking her factor VIII level. 

A discussion regarding the next steps for diagnosis if the fetus is a male occurs. The lady is not keen to undergo CVS due to miscarriage risk and is clear she would continue with the pregnancy regardless of the outcome. 

She is otherwise well and all her booking bloods are satisfactory. Her bleeding history is unremarkable she has had a dental extraction a few years ago without complication and has not had any other bleeding. 

You agree to review her in clinic with the results of the above tests. 

What is the commonest mutation seen in Haemophillia A patients? 

If the patient was keen for CVS for pre natal diagnostic testing what level of factor VIII would you aim for to minimise bleeding risks? 

What treatment would you use if required to increase maternal factor VIII in preparation for CVS? 

Posted in Inherited bleeding, Related to other specialities | Tagged , , , , ,

Case 83 – the beginning

You are in a joint obstetric haematology clinic and have been referred a 24 year old lady who is 13 weeks pregnant P0 G1

You take a family history and find her father and paternal uncle have severe Haemophillia A. See pedigree below:


She is worried about the prospect of having a child with Haemophillia A. She is keen to know if there is anything that can be done to find out of the pregnancy is affected. 

1) How likely is she to be a carrier of Haemophillia A? 

2) What options are there for pre delivery diagnosis of Haemophillia A ?

Posted in Inherited bleeding, Related to other specialities | Tagged , , , , , ,

Case 82 – summary

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

This week we discussed a 45 year old man who presented with a recurrent pulmonary embolism (PE) whilst on rivaroxaban. He had had a PE 2 years prior to his current admission.

  • From our history/examination we established:
  • He had no overt risk factors for venous thromboembolism (VTE) with no recent immobility, surgery and no symptoms/signs suggestive of malignancy/autoimmune disease.
  • He was compliant with his rivaroxaban and taking it with meals (reduced absorption of rivaroxaban with fasting state) and was not on any interacting medications.
  • • He had no family history of VTE.
  • He was haemodynamically stable with no evidence of right heart strain / pulmonary hypertension on echo.

 

As he had had failed to be adequately anticoagulated whilst on rivaroxiban he was initially switched to therapeutic low molecular weight heparin whilst being loaded with warfarin.

 

On discharge follow up was arranged in the anticoagulation clinic (warfarin monitoring) and thrombosis clinic for review and follow up of the extensive investigations that we had requested (see below). Unfortunately only 3 days later he represented with confirmed extension of his PE and renal/liver dysfunction.

 

The following are the results of the multiple investigations we requested throughout our complicated case:

  • Progressive thrombocytopenia (nadir 75) and new anaemia (Hb 103)
  • MAHA
  • Deranged LFTs with mixed conjugated and unconjugated bilirubin
  • Stage 1 AKI
  • USS liver: Suggestive of sinusoidal obstructive syndrome
  • CT CAP: No evidence of malignancy
  • JAK2 negative
  • No PNH clone
  • No Factor V leiden / FII genetic mutation (NB other aspects of thrombophilia screen not requested as recent event and on anticoagulation)
  • Antiphospholipid antibodies: Positive
    • Lupus anticoagulant final ratio: 2.1 (<1.2 normal)
      • Note this was performed on anticoagulation so could be a false positive
    • IgG and IgM cardiolipin antibodies: <10 U/ml.
    • Anti IgG B2 glycoprotein antibodies 347 U/ml (0-7).
  • Autoantibody screem negative.
  • Therapeutically anticoagulated
    • Peak anti-Xa levels on re-admission: 0.84. INR 2.2 on readmission
  • HIT pre-test probability score: low risk therefore no further HIT investigations performed.

 

To summarise our patient had rapidly recurrent thrombosis despite adequate anticoagulation, AKI, evidence of sinusoidal obstructive syndrome, MAHA. The investigations demonstrated strongly positive anti IgG B2 glycoprotein antibodies. The clinical and laboratory features are all consistent with Catastrophic Antiphospholipid Syndrome.

 

Antiphospholipid syndrome (APS)

APS is an acquired autoimmune condition. It is a clinicopathological diagnosis characterised by thrombosis / pregnancy morbidity and the persistence of antiphospholipid antibodies. It affects approximately 1% of the population and the median age of onset is 31 years. It can be primary (idiopathic) or secondary (commonly associated with other autoimmune conditions, malignancy).

 

APS Diagnostic criteria

APS syndrome is present if at least one of the following clinical criteria AND at least one of the laboratory criteria are met.

Clinical Criteria

  • Vascular thrombosis
    • ≥1 arterial, venous or small vessel thrombosis
  • Pregnancy morbidity
    • ≥1 unexplained deaths of a morphologically normal fetus ≥10th week of gestation
    • ≥1 pre-term births of a morphologically normal neonate <34th week of gestation secondary to eclampsia/pre-eclampsia or recognised placental insufficiency
    • ≥3 unexplained consecutive spontaneous miscarriages <10th week of gestation

Laboratory Criteria

  • Lupus anticoagulant (LA) on ≥2 occasions at least 12 weeks apart
  • IgG / IgM aCL antibodies present in medium/high titre on ≥2 occasions at least 12 weeks apart
  • IgG / IgM Anti-β2-glycoprotein antibody on ≥2 occasions at least 12 weeks apart

 

Antiphospholipid antibodies (aPL)

Incidental findings of aPL is reasonably common and found in approximately 1% of the general population. aPL are frequently temporary, for example following infection. It is believed that additional factors contribute to the thrombotic / pregnancy morbidity – a ‘second hit phenomenon’ and indeed the majority of people with aPL do not develop the clinical features of APS.

Lupus anticoagulant

• Two tests based on different principles should be performed. DRVVT should be one of these tests and the other is typically be an APTT using a reagent with lupus anticoagulant sensitivity. Patients should be regarded as lupus anticoagulant positive if one test is positive.

• Testing for lupus anticoagulant is not accurate when on the patient is anticoagulation (VKA antagonists, DOACs and heparin) and should be avoided.

• Testing for coagulation factors in the presence of lupus anticoagulant can be misleading especially those for intrinsic pathway factors based on 1-stage methods.

• Monitoring of oral anticoagulants in patients with lupus anticoagulant can be misleading and a baseline PT /APTT should be performed. If this is prolonged an alternative PT reagent for which the baseline is normal should be used. Point-of-care devices should be used with caution for INR determination. Anti-Xa levels should be used to monitor heparin if the APTT is prolonged.

• Lupus anticoagulant is more strongly associated with thrombosis in comparison to the other antiphospholipid antibodies.

Anticardiolipin antibodies

  • Detected using an ELISA technique
  • Can be reliably tested for when on anticoagulation
  • IgG isotype and higher titres are more associated with thrombosis.

Anti-β 2 glycoprotein 1 antibodies

  • Detected using an ELISA technique
  • Can be reliably tested for when on anticoagulation
  • The IgG isotype is more commonly associated with thrombotic sequelae but overall β 2 glycoprotein 1 antibodies are less commonly associated with pathological sequelae than the other aPL.

 

Who should be tested for aPL?

It should be tested for in individuals in which it’ll alter there management.

  • Unprovoked proximal DVT / PE
  • Young adults (<50 years) with ischaemic stroke
  • Obstetric morbidity / mortality

 

Management of APS?

There is limited evidence to guide upon the management of APS. It is important to modify other risk factors for thrombosis / pregnancy morbidity.

Venous thrombosis

Standard dosing of anticoagulation. Patients with APS have a higher risk of recurrence and if VTE is unprovoked anticoagulation should be longterm. If there is a contributory risk factor for thrombosis in addition to APS then the individual risks/beenfits need to reviewed. To decide upon duration of the anticoagulation.

Arterial thrombosis

Patients with ischaemic stroke / MI with APS may be at higher risk of recurrence and cohort studies suggest that anticoagulation with warfarin should be considered but there is no strong evidence that it is better than antiplatelet therapy

Pregnancy morbidity

Recurrent (≥3) pregnancy loss: Antenatal administration of heparin combined with low dose aspirin is recommended throughout pregnancy and should be initiated as soon as pregnancy is confirmed.

History of pre-eclampsia or fetal growth restriction: Low dose aspirin.

Women with aPL should be considered for post-partum thromboprophylaxis

 

Catastrophic Antiphospholipid Syndrome (CAPS)

Life threatening condition with acute onset characterised by multiple organ thrombosis commonly involving the microvasculature. This is a rare condition affecting <1% of APS cases. It can be a diagnostic challenge as it is the first presentation of APS in ~50% of adults and can affect any organ or tissues although does tend to have a predilection for the kidneys, lungs and brain. It also shares similarities with other conditions such as thrombotic microangiopathies, HITT, etc. Mortality rates of CAPS is high at approximately ~37% in the acute setting.

 

In particular relevance to our case CAPS has multiple abdominal manifestations including sinusoidal obstructive syndrome. It also one the many causes of MAHA. According to the CAPS Classification criteria our patient had ‘probable CAPS’ as we did not have a biopsy confirming small vessel occlusion.

CAPS Classification Criteria

  • Evidence of involvement of ≥3 organs, systems, tissues
  • Development of manifestations simultaneously or <1 week
  • Confirmation by histopathology of small vessel occlusion
  • Laboratory confirmation of the presence of aPL

Definite CAPS: All four criteria

Probable CAPS:

  • All 4 criteria, except only 2 organs, systems, tissues
  • All 4 criteria, except for the absence of laboratory confirmation of aPL
  • Criteria 1,2 and 4
  • Criteria 1, 3 and 4 with the development of a 3rd event ≥1 week <1 month of presentation, despite anticoagulation

 

Management of CAPS

There is only limited data to guide on the management of CAPS. It requires an multidisciplinary approach and prompt treatment is essential to reduce morbidity and mortality.

Initial management:

  • Therapeutic anticoagulation
    • Due to critical illness unfractioned heparin is often instituted
    • If recurrent VTE then target INR / anti-Xa level should be increased
  • Corticosteroids – initially high dose methylprednisolone for 3 days following by slow wean of prednisolone.
  • Plasma exchange – there is an approximate >20% increase in survival with the addition of plasma exchange to anticoagulation and steroids.
  • If patients aren’t responding adequately IVIg can be considered. If the patient is undergoing plasma exchange IVIg should be instituted when this has finished.

Secondary management:

Immunosuppressive therapies– there are no large, prospective trials to guide upon which immunosuppressive therapy to use. The following are used:

  • Azathioprine
  • Cyclophosphamide
    • Associated with improved survival if CAPS is in association with SLE.
  • Hydroxychloroquine
  • Rituximab
    • Tending to be increasing used.
  • Eculizumab
    • Not licensed but experts have used as a last resort.

 

References

● Keeling et al. Guideline on the investigation and management of APS. British Journal of Haematology. 157 (1): 47-58. 2012.

● Galli et al. Lupus anticoagulants are stronger risk factors for thrombosis than aCL antibodies in the antiphospholipid syndrome: a systemic review of the literature. Blood. 101 (5). 1827-1832. 2003

● Giannakapoulos et al. How I treat APS. Blood. 114 (10). 2020-2031. 2009

● Ortel et al. How I treat CAPS. Blood 126: 1285-1293. 2015.

● Kazzaz et al. Treatment of antiphospholipid syndrome. https://www.ncbi.nlm.nih.gov/pubmed/26927441

 

Posted in Uncategorised

Case 82 – Update 3

Thanks for your continued contributions for this tricky case! We’ve got some new investigations results from what you have requested:

Peak anti-Xa levels on re-admission: 0.84. INR 2.2.

No evidence of malignancy on recent CTPA / CT abdo pelvis.

HIT pre-test probability score: low risk therefore no further HIT investigations performed.

PNH: negative. JAK 2 negative.

Lupus anticoagulant final ratio: 2.1 (<1.2 normal)

IgG and IgM cardiolipin antibodies: <10 U/ml.

Anti IgG B2 glycoprotein antibodies 347 U/ml (0-7).

Our patient remains very unwell due to his progressive PEs (but haemodynamically stable), acute kidney injury, liver dysfunction (likely due to microvascular thrombi), and rash.

What is the likely diagnosis and how would you manage this patient?

Posted in Anticoagulation | Tagged , , , , , ,

Case 82 – update 2

Our patient continues to deteriorate and the following investigations are now back:

Hb 103, Plts 75, WCC 3.4, Neuts 1.6.

Blood film: red cell fragments with infrequent spherocytes and polychromasia.

Bili 152 (predominantly conjugated), ALT 54, Alk phos 340.

Urea 9.8, Creatinine 198

USS liver: suggestive of sinusoidal obstructive syndrome

 

Lots of tests results for this complicated patient! Any thoughts on the differential diagnosis? Any additional investigations at this stage?

Posted in Anticoagulation, Thrombosis | Tagged , , , , , ,

Case 82 – update 1

Thanks for all the contributions! We now know from the history and investigations requested that:

This patient has had no obvious provoking factors for both his previous and current PE – including no symptoms/signs suggestive of autoimmune disorder / maligancy. He is compliant with his rivaroxiban, taking it appropriately with his main meal and is not on any other medications. He has no family history of thrombosis.

Investigations to date:

Hb 135, Plts 120, WCC 3.8, Neuts 1.9. U+Es, LFTs normal.

CT abdo / pelvis: no evidence of maligancy. Echo: NAD.

Paroxysmal nocturnal haemoglobinuria and antiphospholipid screen in progress (with understanding that lupus anticogulant may be false positive result as on anticoagulation).

Thrombophilia screen not performed as not going to change management and no family history with known disorder.

He was sent home on enoxaparin whilst being loaded on warfarin. However, he represents 3 days later feeling awful with increasing SOB and CTPA imaging confirms extension of his recent PE. He also has new renal and liver dysfunction.

What is your potential differential diagnosis and what additional investigations would you want at this stage?

Remember to use #teamhaem on all your posts to help us follow the case!

 

Posted in Anticoagulation, Thrombosis | Tagged , , , , , ,

Case 82 – the beginning

Welcome to our new case!

A 45 year old gentleman is admitted to the medical assessment unit as he has been diagnosed with a large pulmonary embolus (PE) within the right pulmonary artery. He is requiring 2 litres of oxygen but is haemodynamically stable. He has a previous history of PE 2 years ago and was still prescribed rivaroxiban at the time of current presentation.

What further history would you want to obtain?

What initial investigations would you want to perform?

What would your initial management be?

 

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.

 

Posted in Anticoagulation, Thrombosis | Tagged , , ,

Case 81 – summary

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

The case

We looked at a case of a 58 year gentleman who had an incidental finding of thrombocytopenia, whilst on apixaban therapy.

Immediate intervention was required to stop the apixaban in order to limit the risk of bleeding.  We looked into the management of bleeding in the case of thrombocytopenia, as well as how to determine whether the apixaban could be contributing to the bleeding.

Our followers came up with a very extensive list of investigations/initial management plans.  These included:

  • stopping apixaban.
  • Checking Fbc ? Any other abnormalities/previous FBC/ clot in sample
  •  coagulation.  Prolonged PT, normal aptt and fibrinogen
  • renal and liver function
  • HIV, hepatitis serology, helicobacter pylori
  • autoimune screen
  • blood film to check for platelet clumps, primitive cells, size of platelets, red cell fragments
  • haematinics
  • Review medications ? Any that cause thrombocytopenia.  Thrombocytopenia is listed as an uncommon potential side effect of apixaban therapy.
  • history  ? Any red flags for malignancy
  • examination for lymphadenopathy, hepatosplenomegaly
  • Bleeding history/alcohol history/transfusion history

 

Patients presenting with thrombocytopenia can have numerous precipitating factors which may be reversible, such as infections and medications, or it may be a presenting feature of an underlying malignancy.  Primary ITP was defined by the international working group as a platelet count less than 100 × 109/L in the absence of other causes or disorders that may be associated with thrombocytopenia. Treatment should be administered for newly diagnosed patients with a platelet count < 30 × 109/L.

 

Apixaban

Apixaban in this case complicated the matter once the patient was bleeding.  With no bleeding symptoms the patient could have simply discontinued the apixaban and its effects would have resolved within 48hours, in a patient with normal renal function.   A key role of the haematologists in this case is trying to determine what is contributing to bleeding, in order to provide an appropriate management plan.  In this case, with normal renal function we can be relatively confident that the apixaban is playing very little role in bleeding.  However the PT was marginally prolonged.  If further confirmation was required then anti-xa assay could be used.  This then allows the clinician to focus improving the platelet count, as well as encouraging surgical intervention to help stem the bleeding.

Antedotes to apixaban were mentioned by our followers.  Currently, andexanet alfa is still in trial and therefore not available for use.  Consideration would still be needed in this case to determine the contributing factors for the bleeding as using the antidote inappropriately would be costly, as well as exposing the patient to potential side effects of the drug unnecessarily.  Options to support a patient with active bleeding secondary to apixaban include supportive measures and consideration for tranexamic acid, PCC, FEIBA and novoseven.  All treatments should be discussed with the haematologist oncall.

 

Steroid treatment and response

The platelet count responds following treatment with IVIG, and dexamethasone 40mg given for four days. Options for steroid treatment include dexamethasone, or prednisolone.  Kindly, one of our follower tweeted a link to a study that had previously compared these two options. This study concluded that high-dose dexamthasone for 4 days produced a higher incidence of overall initial response and complete response compared to prednisolone, as well as time to response being shorter in the dexamethasone group.  Although the overall sustained response was not significantly different between the two groups, dexamethasone was better tolerated and therefore could be the preferred method of treatment.

 
Complete response (CR) A platelet count ≥ 100 × 109/L measured on 2 occasions > 7 days apart and the absence of bleeding.
Response (R) A platelet count ≥ 30 × 109/L and a greater than 2-fold increase in platelet count from baseline measured on 2 occasions > 7 days apart and the absence of bleeding.
No response (NR) A platelet count < 30 × 109/L or a less than 2-fold increase in platelet count from baseline or the presence of bleeding. Platelet count must be measured on 2 occasions more than a day apart.
Loss of complete response A platelet count < 100 × 109/L measured on 2 occasions more than a day apart and/or the presence of bleeding.
Loss of response A platelet count < 30 × 109/L or a less than 2-fold increase in platelet count from baseline or the presence of bleeding. Platelet count must be measured on 2 occasions more than a day apart.

2 weeks following commencement of steroids the platelet count has fallen to 17.  There is value in repeat the course of dexamethsone, however if there are bleeding concerns, an alternative therapy would need to be considered.  Guidelines suggest that >60 year old presenting with ITP, require bone marrow biopsy at diagnosis.  Failure to response to steroids at any age would also be an indicator for biopsy.

When considering possible management options it is important to appreciate the expected time to response.  This is important for example when trying to assess a patients response to steroids in the initial phase, or when using second line therapy such as rituximab when response can be seen up to 4 months later

Time to response From start of treatment until either complete response or response
Duration of response Time from complete response or response until loss of complete response or response Measured as the proportion of the cumulative time spent in complete response or response during the period under examination as well as the total time observed from which the proportion is derived
Expected time to response Treatment type Initial response, days Peak response, days
Anti-D 1-3 3-7
Azathioprine 30-90 30-180
Danazol 14-90 28-180
Dexamethasone 2-14 4-28
Eltrombopag 7-28 14-90
IVIg 1-3 2-7
Prednisone 4-14 7-28
Rituximab 7-56 14-180
Romiplostim 5-14 14-60
Splenectomy 1-56 7-56
Vinblastine 7-14 7-42
Vincristine 7-14

TPO agonists

Romiplostim and elthrombopag may be used.  The TPO receptor agonists are novel treatments for patients with chronic ITP aimed at increasing platelet production through interactions with the TPO receptor on megakaryocytes.  Choice of TPO is based on the individual patient and clinican preferences.  Elthrombopag is an oral agent taken once daily, compared to romiplostin which is a once weekly subcutaneous injection.  Although the oral agent may be preferred there are numerous dietary restrictions pre and post ingestion of the drug which may be difficult for some patients to comply with.  Both can be incremented in dosage depending on platelet response.  Both have potential to increase bone marrow reticulin formation, however the relevance of this is still to be determined.  The fibrosis is reversible after short term treatment.  Currently it is recommended to perform bone marrow biopsy on an annual basis and discontinue treatment if grade2/3 marrow fibrosis is identified.

Splenectomy

Guidelines still recommend splenectomy if patients have failed steroid treatment. However current practice in the UK does not represent this.  Advise currently would be to exhaust medical treatment for thrombocytopenia, and only if the patient persistently has plt cout <25, and is having haemorrhagic complications, would splenectomy be considered.  This is due to risks associated with major surgery, risk of infections post operatively, and the inability to accurately predict patients response to splenectomy.

 

 

References

  1. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia.  Cindy NeunertWendy LimMark CrowtherAlan CohenLawrence Solberg Jr and Mark A. Crowther.   
  2. High-dose dexamethasone versus prednisone for treatment of adult immune thrombocytopenia: a prospective multicenter randomized trial.   Yu WeiXue-bin JiYa-wen WangJing-xia WangEn-qin YangZheng-cheng WangYuqi SangZuo-mu BiCui-ai RenFang ZhouGuo-qiang LiuJun Peng and Ming Hou.  
  3. TPO-mimetics and myelofibrosis? A reticulin question!  Michele P. Lambert. 
Posted in Acquired bleeding, Anticoagulation, Platelet disorders | Tagged , , ,

Case 81 – update 2

Thankfully the bleeding resolves and no surgical intervention is required

The platelet count responds to IVIG, and dexamethasone 40mg given for four days.

Any further investigations required?

 

2 week s following commencement of steroids the platelet count has fallen to 17.  How would you manage this patient?

Posted in Acquired bleeding, Anticoagulation, Platelet disorders | Tagged , , ,

Case 81 – update 1

Our followers have come up with a very comprehensive list of investigations! Our advice/investigation included

  • stopping apixaban
  • Checking Fbc ? Any other abnormalities/previous FBC/ clot in sample
  •  coagulation.  Prolonged PT, normal aptt and fibrinogen
  • renal and liver function
  • HIV, hepatitis serology
  • autoimune screen
  • helicobacter
  • blood film to check for platelet clumps, primitive cells, size of platelets, red cell fragments
  • haemtinics
  • Review medications ? Any that cause thrombocytopenia
  • viral serology
  • history  ? Any red flags for malignancy
  • examination for lymphadenopathy, hepatosplenomegaly
  • Bleeding history/alcohol history/transfusion history

 

Blood film showed genuine thrombocytopenia, no platelet clumps, no red cell fragments and leuckocytes were normal in morphology. No primitive cells seen.  the rest of the full blood count was normal, including the MCV.

The patients doctor had contacted him following your discussion, and advise him to seek medical attention if bleeding.  Overnight the patient had noted a fresh PR bleed and presented himself to accident and emergency.

 

How would you manage this patient?

His last dose of apixaban was 18hours ago.

Posted in Acquired bleeding, Anticoagulation, Platelet disorders | Tagged , ,

Case 81 – the beginning

A 58 year old gentlemen has routine bloods taken at the GP surgery.  He is noted to have a platelet count of 38. His doctor rings you as the haematology registrar for advise as he is on apixaban for treatment of AF.

 

What advise would you give the GP/patient?

What further investigations would you suggest?

Posted in Acquired bleeding, Anticoagulation, Platelet disorders | Tagged ,

Case 80 – summary

This week we discussed a 65 year old gentleman who was about to undergo curative surgery for gastric carcinoma. His admission blood tests showed pancytopenia and monocytopenia.

 

The differential diagnosis of pancytopenia includes:

  • Haematological malignancy e.g. myelodysplasia or infiltration from leukaemia/lymphoma/myeloma
  • Systemic autoimmune disease e.g. lupus
  • Aplastic anaemia
  • Inherited genetic changes e.g. dyskeratosis congenita, Shwachman–Diamond syndrome
  • Infiltration from metastatic non-haematopoietic malignancy
  • Severe sepsis/infection including tropical infections
  • Metabolic syndromes e.g. Gaucher’s disease, osteopetrosis
  • B12/folate/trace metal deficiency
  • Viral including HIV
  • Medications e.g. anti-epileptics, chemotherapy
  • Hypersplenism

History and examination will hopefully help you exclude many of these conditions (see references below). As always it is worth repeating the test if the result was unexpected.

Close examination of the blood film revealed a notable absence of monocytes and an infiltration from mature lymphocytes with voluminous pale cytoplasm and hairy projections along with a mature oval nucleus and loose chromatin pattern.

 

After review of the patient’s previous CT scans splenomegaly is noted, which together with the blood count and blood film would be very suspicious for hairy cell leukaemia. Other low grade lymphomas can cause similar patterns (e.g. hairy cell leukaemia variant and splenic marginal zone lymphoma) however immunophenotyping of the peripheral blood showed a kappa-restricted B cell population expressing CD11c, CD103, CD123, CD25 and negative for CD5, CD10 and CD23. This would be consistent with HCL.

 

Hairy cell leukaemia

This is an uncommon B cell malignancy that affects mainly adults in the later half of life (average age 50). Men are more affected than women (ratio 4.5:1). Many patients are asymptomatic but some may complain of abdominal pain due to splenomegaly, night sweats, weight loss, bleeding/bruising, fatigue and atypical infections. Lymphocyte count may be normal. This is an indolent lymphoma/leukaemia which progresses very slowly.

 

Diagnosis

HCL is diagnosed by clinical assessment and morphological appearances. Hairy cell leukaemia has a typical immunophenotype by flow cytometry or by immunohistochemistry on a trephine biopsy. The aspirate may be difficult due to marrow fibrosis (dry tap). Trephine histology is rather unique with cells having a ‘fried egg’ appearance. HCL cells express B cell antigens (e.g. CD19, CD20, CD22, CD79a) along with CD11c, CD103, CD123, CD25, Annexin A1, DBA44, cyclin D1, TRAP. Genetic analysis shows the BRAF V600E mutation in almost all cases.

 

Prognosis

The prognosis of hairy cell leukaemia is excellent with a 95% five year survival. If complete remission is achieved then disease free survival can be over 20 years. However HCL is generally incurable with late relapses occurring.

 

Treatment

In asymptomatic patients watch and wait may be a reasonable way to start especially if blood counts are not too bad.

 

The standard treatment is cladribine or pentostain. Both produce a complete remission of over 80%. Cladribine is often preferred as it can be given as a subcutaneous injection daily for five days as a one off treatment. Pentostatin must be given IV every two weeks. There are a variety of ways to deliver cladribine therapy and this depends on local policy. Pentostatin and cladribine have not been tested against each other. Patients are at risk of viral and PCP infections so aciclovir and co-trimoxazole prophylaxis is usually used. Both these purine analogues require lifelong irradiated blood to prevent against transfusion-associated graft versus host disease.

 

Interferon alpha can also be used but the response is not satisfactory so it is not generally required. It could be used in a pregnant patient or to gain control of counts in the face of severe neutropenia prior to definitive therapy. Splenectomy may also be used as first line therapy and can lead to durable remissions especially if the majority of the disease is in the spleen. Rituximab is often left for residual or refractory disease. BRAF inhibitors can also be used but generally not first line.

 

Our patient

He underwent an urgent bone marrow biopsy which confirmed hairy cell leukaemia. As the patient had a potentially curable gastric malignancy it was felt surgery for this should take priority and this was performed a week later. GCSF was given preoperatively to prevent infection. The patient recovered well following the operation.

References

 

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 Chronic leukaemia, Laboratory morphology, Lymphoma | Tagged , , , , , , ,

Case 80 – update 3

The immunophenotype was:

CD20+, CD79b+, CD22+, CD5 negative, FMC7+, CD103+, CD11c+, CD25+, CD10 negative, CD38 negative, lambda sIg+

This is consistent with hairy cell leukaemia. If further immunophenotypic evidence is required additional stains on the trephine can be undertaken (e.g. DBA44, CD123, cyclin D1, Annexin A1, TRAP) but usually the histology is typical and depending on local policy this may not be necessary. Classically hairy cell leukaemia presents with pancytopenia and monocytopenia with splenomegaly. Atypical infections may occur. Often it may be incidental as in our case. The bone marrow is usually fibrotic and therefore a ‘dry tap’ may occur when aspirating liquid material.

 

The BRAF V600E mutation is present in almost all cases of hairy cell leukaemia and this should also be looked for. As the peripheral blood and marrow aspirate population may be small CD19+ selected cells may be used.

 

Questions

  • How would you treat this gentleman, bearing in mind he needs potentially curative cancer surgery
  • What are the different treatment options?
  • What is the prognosis?

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 Chronic leukaemia, Laboratory morphology, Lymphoma | Tagged , , , , , , ,