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 Uncategorised

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 Anticoagulation, Acquired bleeding, 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 , , , , , , ,

Case 80 – update 2

The blood film showed a population of lymphoid cells with ‘hairy projections’. There was absolute monocytopenia. Both of these are consistent with a diagnosis of hairy cell leukaemia. However, hairy cell leukaemia variant and other low grade lymphoma may have similar appearances and the diagnosis needs to be confirmed.

Please review the flow cytometry here:

Questions

  • What is the immunophenotype of the abnormal population?
  • How else is hairy cell leukaemia diagnosed?
  • How is hairy cell leukaemia treated?

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 1

Our patient has pancytopenia. On examination there is no specific findings. There is no palpable lymphadenopathy or hepatosplenomegly. There is no rash or gum infiltration. There are no features of chronic liver disease. However review of recent imaging has noted splenomegaly at 16cm. He has not received any recent chemotherapy.

 

After discussion with the surgical team it is felt that delaying the surgery is in the the best interests of the patient as it is not life threatening. In emergency situations support with GCSF may be appropriate on a case by case basis depending on differential diagnosis.

 

A blood film is made and here are some pictures:

 

Questions

  • What further investigations would you perform to find the cause of pancytopenia?
  • Can the surgery safely proceed?
  • What do you notice on the blood film?

 

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 – the beginning

Welcome to our new case. You are the surgical house officer reviewing a new elective admission. He is 65 years old gentleman and has been admitted for resection of a gastric cancer. He is an ex-smoker, takes ramipril for hypertension and simvastatin for hypercholesterolaemia and has slight elevated fasting glucose. He drinks moderate amounts of alcohol (20-25 units per week). A preoperative full blood count reveals:

  • Hb 105g/l (130-180)
  • MCV 97fl (82-98)
  • WCC 3.5×10*9/l (4-11)
  • Neutrophils 0.9×10*9/l (1.7-7.5)
  • Lymphocytes 2.0×10*9/l (1.5-4.5)
  • Platelets 110×10*9/l (150-450)

 

He was at preoperative assessment clinic two weeks earlier and the results were similar there but no additional work up was performed. The surgeon is worried about infection and asks whether GCSF should be administered as the surgery is urgent.

 

Questions

  • What are the differential diagnosis of the FBC findings?
  • What may you look for on examination?
  • Would you give GCSF?

 

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, Lymphoma | Tagged , ,

Case 79 – summary

Thankyou for your help this week!

This week we had a look at HHT. Our patient was diagnosed with HHT aged 30 after a history of epistaxis was noted. On further questioning she was also found to have cutaneous telangectasia.

Her mother died aged 35 when our patient was old 1 from a ‘brain haemorrhage’, however she also had a history of significant epistaxis and telangectasia. Her grandfather also had recurrent epistaxis, telangectasia and suffered with recurrent GI bleeding.

HHT is a rare systemic disorder of fibrovascular tissue. It is thought to be autosomal dominant with 5 genetic variants, most of which affect the VEG-F beta receptors. The condition results in an overgrowth of blood vessels and abnormal vessel formation. >90% of patients who carry the mutation will have some bleeding, this tends to worsen with age.

It can affect many systems, and can cause problems with GI tract, nasal, lungs, brain, liver and skin. Some mutations have also been associated with juvenile polyposis and primary PAH.

Diagnostic criteria for HHT- curacao criteria.

3 or more criteria met indicate definite HHT

2 criteria met indicate possible HHT

Less than 2 criteria met indicates HHT unlikely

1. recurrent and spontaneous nosebleeds which may be mild to severe

2. Multiple telangectasia on the skin of the hands, lips, face or inside of the nose or mouth. Telangectasia are small blood vessels that appear as bed spots that disappear when push on.

3. AVM (arteriovenous malformations) or telangectasia that affect internal organs such as brain/liver/lungs/gi tract/spinal cord.

4. A family history of a first degree relative who meets the criteria for definite HHT or who has been genetically diagnosed.

Haematologist may often find that they are caring for patients, either by ensuring that they are getting regular iron or blood transfusion, or other treatments, or by coordinating care and ensuring that the patient is being seen by the appropriate specialties for management or screening for complications.

ENT are very often involved for management of epistaxis. This may involve topical treatments. Teaching the patient low pressure packing techniques, cauterisation, or other procedures such as septodermoplasty (skin graft in the nose) or Young’s procedure (surgical closure of the nostrils)

The respiratory team will also be involved. 1/3 of patients with have pulmonary AVMs. This causes a right to left shunt, although they rarely bleed they can an can require coiling. Paradoxical emboli can occur causing stroke or brain abscess. As a result if any patient with known AVM or any unscreened patient requires dental work they should have prophylactic antibiotics. Patients can also develop pulmonary arterial hypertension, this may be primary or can be secondary to liver AVMs causing high output heart failure or recurrent VTE. 

The liver team may also be involved. 80% of patients will have liver AVMs, although only 5% will be symptomatic. These can cause portal HTN, biliary disease or high output heart failure.

The gastroenterology team may also be involved. 80% of patients will have lesions on endoscopy, although only 1/3 will have bleeding. Repeated endoscopy with coagulation of these lesions is often necessary. In patients who have juvenile polyposis they will need regular screening endoscopy.

The brain can affected 25% of patients. These can be telangectasia, AVM or venous malformations. Symptoms can include headaches, seizure and ICH.

Patients will need to be closely monitored through any pregnancy, they may require transfusion and problems with bleeding pulmonary AVM can occur. There is a 1% maternal mortality associated with pregnancy in the context of HHT.

Patients with HHT and chronic iron deficiency also appear to be prothrombotic, presumably due to the increase in factor VIII associated with chronic blood loss. 

If the patient develops AF with an indication for anticoagulation, although anticoagulation should not be withheld definitive treatment e.g. Definitive treatment for AF +/- left atrial appendage if ongoing anticoagulation is indicated.

When screening a new patient genetic testing should be considered, with screening of first degree relatives if a mutation is found.

A bubble echo to look for pulmonary AVMs should be considered, with a repeat every 5 years if negative. If positive further imaging is required.

MRA brain to look for cerebrovascular defects

Consider liver U/S

General managment will include ensuring adequate b12/folate/iron replacement and if regular transfusion is needed, appropriate vaccination and blood provision.

Drugs that have been used in the treatment of HHT include tranexamic acid, hormone therapy, tamoxifen, raloxifene, thalidomide and bevacizumab(avastin). Bevacizumab is a VEG-F inhibitor which is usually used in malignancies, but small studies and case reports have shown there may be benefit in certain patients with HHT. (Dupuis-girod 2014, JAMA)

Further information can be found in international guidelines for the diagnosis and management of hereditary haemorrhaging telangectasia, journal of medical genetics 2011 faughnan ME, Palma VA, Garcia-Tsao G et al

http://www.cureHHT.org
VASCERN.org – vascular European research network
Geisthoff et al 2015 BJHaem review 
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 Inherited bleeding | Tagged , , , ,

Case 79 – update 2

We have found out our patient has HHT.

We know she has epistaxis, and cutaneous telangectasia. She has also required courses of iron for iron deficiency, and is currently anaemic.

Patients with HHT may develop AVM and some teamhaem follower have suggested that we screen our patient for cerebral AVM and pulmonary AVM.

Where else might you develop problems? What other conditions can be associated with HHT?

What screening should patients with HHT receive?

How would you manage our patient currently?

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 Inherited bleeding | Tagged , , , ,

Case 79 – update 1

So we have an update

Our patient has presented with a long history of epistaxis.

There is no history of easy bruising. 

No bleeding after tooth extraction

Her mother died of a brain haemorrhage and also had significant history of epistaxis. The patient also thinks her maternal grandfather had significant history of epistaxis and gi bleeds, and needed several blood transfusions.

On examination, no hepatosplenomegally, no visible oral telangegtasia although there do appear to be several cutaneous telangectasia on the hands.

Fbc shows a microcytic hypochromic anaemia. Ferritin 5.

Pt 13

Aptt 27

Claus fib 4.0

Vwd screen 

Factor VIII 160%

Vw antigen 130%

VW activity 120%

RICOF 130%

Platelet function test normal

What are the thoughts now?

Are there any other investigations you would like? 

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 Inherited bleeding | Tagged , ,

Case 79 – the beginning

Welcome to our new case!
This week we start with a 30 year old lady who has come to her GP for a routine discussion for the contraceptive pill. In her medical history you note that she has had significant epistaxis which she has needed to attend A&E 3 times in the last year for, and has needed cauterising.
What questions would you like to ask in her history?
Are there any investigations you would like to 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 Inherited bleeding | Tagged , ,

Case 78 – Summary

Thanks for your help this week. We had a case of T-LGL associated with rheumatoid arthritis. In our case her planned surgery was postponed. She was given GCSF and responded to this and this was used pre operatively for optimisation. She commenced MTX weekly and continues on this with a reasonable Blood count response: HB 95, plt 200, wcc 2.5, neu 1.7. She has not had any infective complications from her T- LGL

Background:

T cell Large granular lymphocyte leukaemia is a rare disorder accounting for around 2- 5% of cases of chronic lymphoproliferative disorders in the USA. It is usually diagnosed in older patients >60 years with an equal proportion of men and women affected.  85% of cases are of a more indolent T cell type but an agressive NK cell LGL is recognised particularly in the far east where it is linked to EBV infection and has a poor prognosis. In this summary we will discuss T LGL only.

Aetiology:

T-LGL provides an interesting insight into the working of T cell mediated immunity. The response of the disease to immune suppression has lead researchers to feel that this was a condition caused by dysregulation of the immune system. This is also supported by the proponderance of this disorder in patients with pre-existing immune conditions.

T-LGL is derived from  CD 8 positive cytotoxic T cells. In healthy patients these function as part of the immune system and are activated via the TCR interacting with peptides expressed on MHC. Activated cytotoxic T cells then proliferate and cause cell death through perforin and granzyme release killing virally infected cells.

In the case of T LGL it is postulated that chronic antigen expression causes initial oligoclonal cytotoxic T cell expansion. Then a subclone is selected for over time in cases where antigen is chronically expressed. This hypothesis is backed up by detailed PCR of T-LGL cells TCR (T cell receptor) that show limited diversity of the TCR LGL suggesting they are clonal.

A recent blood article by Lamy et al 2017 describes 28-75% of T-LGL patients have a STAT3 mutation. This finding is an important step in understanding the pathogenesis of T-LGL. This STAT 3 signalling may also predict the patients who will respond to MTX therapy though this is still under investigation.

Here the expansion of a sub-clone of cytotoxic T cells that has a STAT 3 signalling mutation leads to increased cytokine production and cytotoxic granule release causing anaemia, neutropenia and fatigue. The faulty STAT 3 signalling allows the clone to escape the normal apoptotic mechanism via a variety of mechanisms including increased production of platelet derived growth factor and IL15 and also the cells secrete excessive amounts of soluble FAS ligand to act as decoy allowing these cells to evade apoptosis.

Diagnosis of T LGL requires the following

Appropriate clinical context:

Splenomegaly (50% cases)

Cytopenias (85% Neutropenia, 50% Anaemia and  20% Thrombocytopenia)

Lymphocytosis (though often this is mild)

History of an autoimmune disease (up to 40% cases linked RA but also associations with Red cell aplasia, post BMT, Post solid organ transplant, CML, Cyclical Neutropenia, Pulmonary hypertension, HIV infection).

Blood film:

Large granular lymphocytes with prominent auzorophillic granules >0.5 x10^9. It should be stressed that on morphology alone these cant be distinuguished from usual LGL cells.

Flow:

An excess of Large granular lymphocytes that express CD 3 and CD8, CD 57 and or CD16

Clonality:

PCR of TCR gama gene.

Rarely there will not be a lymphocytosis and there is not a good clinical background, in these cases a bone marrow is recommended as trephines can highlight areas of infiltration of LGL. It may also help exclude MDS or Aplastic anaemia as a cause for cytopenias.

When to treat LGL?

Watch and wait is a valid option if cytopenias are asymptomatic. Prognosis is often good >70% at 10 years. Many patients may never require any treatment and lamy et al point out that mortality from infection in LGL is low.

How I treat authors describe four situations where they feel treatment is valid:

  1. Recurrent infections and neutrophils <1
  2. Systemic treatment needed for other autoimmune condition
  3. Transfusion dependent anaemia
  4. Severe neutropenia neu <0.5

 

Treatment options:

It should be noted that large scale trials are lacking in T LGL treatment and many of the treatment evidence bases are built on small case series. These recommendations are from the Blood How I treat paper 2011 and recent Lamy et al paper 2017.

Prednisolone:

  • Not a longterm option but may be useful as adjunct while other therapy taking time to have effect. How I treat authors advocate its use if neu <0.5 at initiation of therapy suggesting 1mg/k for a month and then tapering.

Methotrexate:

  • Proven treatment benefit as DMARD in RA hence useful treatment in this context.
  • Starting dose 10mg/m2 weekly
  • Around 50% ORR
  • 2-12 weeks for response
  • May not be durable beyond a few years?
  • lamy et al describe recent data that suggests STAT3 mutated patients respond better to MTX
  • Monitoring for Liver toxicity and pulmonary complications important

Cyclophosphamide:

  • 50-100mg daily
  • ORR 50-60%
  • Up to 4 months response
  • Adinistration beyond a six months to a year not recommended due to carcinogenesis and bladder toxicity. Need to re-start if progressing cytopenias after treatment break.

Ciclosporin:

  • Possibly useful if severe anaemia/ red cell aplasia or in context of a solid organ transplant where ciclosporin may already be required
  • Needs level monitoring
  • Problematic if Hypertension or pre-existing renal impairment

If above options fail:

  • Campath – Need to be fit and usually older demographic affected. Lower CD 52 expression on T LGL cells compared to usual cytotoxic T cells  hence only about 60% response rates seen.
  • Purine analogues – Need to be fit and usually older demographic affected. Up to 70% ORR and these can be durable lasting several years.
  • Splenectomy – very limited evidence for benefit.
  • ?JAK/Stat inhibitors – Lamy et al describe early data showing use of JAK 3 inhibitor Tofacitinib citrate used in 9 patients T LGL and 6 patients responded.

Assessment of Treatment response

  • Assess after 4 months
  • CR – Normalisation of FBC
  • PR – Improvent in FBC
  • PD – No response to cytopenias at 4 months

Many thanks for your help with the case this week. Please feel free to tweet any questions or comments. 

References:

Lamy et al. LGL Leukaemia:from pathogenesis to treatment. Blood 2017;129 (9) 1082-1094.

Lamy T, Loughran T. How I treat LGL leukaemia. Blood 2011;117 (10) 2764-2774.

Rose M, Berlinder N. T cell large granular lymphocyte leukaemia and related disorders. The Oncologist 2004;9:247-258

 

 

Posted in Chronic leukaemia | Tagged , , , , , , ,

Case 78 – update 2

Flow results are back:

CD 3 pos, CD 8 pos, CD 4 neg, CD 56 neg, CD 16 neg, CD 5 neg, CD7 wk/variable, TCR alpha/beta pos

PCR TCR studies confirm clonality

A Diagnosis of T Large Granular Lymphocytic leukameia is confirmed

What are the options for treatment?

What are the indications for treatment of T LGL?

If surgery is required what options are available to improve neutropenia?

Posted in Chronic leukaemia | Tagged , , , , , ,

Case 78 – Update 1

Thank for all the suggestions so far. We followed your advice and the lady has had her surgery postponed and we have established the following:

History:

  • Chronic anaemia since 2011 stable at around 90.
  • No history of bleeding/Malena
  • No weight loss
  • No night sweats
  • Neutropenia since Jan 2016, progressive but no history of infections.
  • RA diagnosed thirty years ago following birth of third child previously on Methotrexate, stopped at patient request as stable for several years.
  • PMHx: Hypertension, Previous gastric ulcer secondary to NSAIDs 20 years ago, Rheumatoid arthritis with previous knuckle replacements 20 years ago and a previous left hip replacement 10 years ago.
  • Medications: Amlodipine for hypertension and Co-codamol for hip.
  • No alcohol intake
  • Non-smoker

Examination:

  • No features of acute joint inflammation noted however she has rheumatoid nodules at elbows and deformity of hands due to previous failed knuckle replacements for rheumatoid arthritis of hands (see pictures).
  • Noted to have spleen tip palpable on examination
  • No lymphadenopathy

Investigations:

  • Normal B12/folate
  • Serum Ferritin 500
  • Imunoglobulin screen Normsl and Normal SFLC Ratio
  • HIV/Hepatiitis screen – negative
  • Rheumatoid factor positive and Anti CCP antibodies positive
  • CRP 30
  • ESR 50
  • Negative DAT, Normal LDH, Normal Haptoglobins and Retic count
  • Normal LFTs and Renal function
  • Film: Re-reviewed noted to have many large lymphocytes some with granulation – sample sent for flow cytometry.
  • USS confirms mild splenomegaly

 

What is the possible diagnosis in this case?

Is the history of Rheumatoid arthritis relevant to the case? – if so how?

What flow results may you expect given the possible diagnosis? 

 

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 | Tagged , ,

Case 78 – the Beginning

A 72 year old lady has attended pre- assessment clinic for an elective hip replacement and had routine bloods taken.

Blood results:

Hb 93, MCV 97, Plt 220, Wcc 7.5,  Neu 0.9, lymph 6.0.

Normal Liver and Renal function 

Blood film report:

“Mild normocytic anaemia with normal red cell morphology. Mild neutropenia, neutrophils are normal in morphology with no dysplastic features. There are some Large atypical lymphocytes, some with prominent granulation. No previous full blood counts available on system. Given anaemia suggest check haematinics. Lymphocytosis may be reactive, particularly in combination with neutropenia please correlate with clinical details, consider repeat sample if results unexpected. Please discuss if persisting as I note this is a pre-op sample.”

You receive a call from the pre-assessment clinic, they tell you that they repeated her blood count and the results were similar. She has recently moved to the area but has had chronic anaemia, with a Hb of around 90 since 2011. She has been noted to have progressive neutropenia since Jan 2016, however the most recent results are the first result when her neutrophils have been less than one. She is not on any regular medications apart from Amlodipine and Co-codamol.

She is due an elective hip replacement as she has a history of Rheumatoid arthritis. Over the last few years she has not required any treatment for her arthritis but she was previously on methotrexate up to 2014.

What further history would you like from the patient?

What would you ask the team to examine for?

What further tests should be undertaken to investigate the chronic anaemia and neutropenia?

Should surgery be delayed while these investigations are performed?

 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 | Tagged , , , ,

Case 77 – summary

Case 77 Summary

 

Thanks to everyone who contributed to the case this week.

 

Our case started with a blood film to test our morphology skills.  We picked up that the blood film showed:

  • Dysplastic neutrophils
  • Blasts
  • NRBCs
  • Tear drop poikilocytes
  • Thrombocytopenia

IMG_2154

The FBC indices identified that the patient was anaemic, thrombocytopenic and neutropenic.  The initial response to these bloods should be to ensure the safety of the patient – i.e. evidence of bleeding/sepsis/ symptomatic anaemia.  As a haematologist reviewing the blood film I would also look for any previous results on the system for this patient or clinic letter i.e. was he known to haematology already.    Urgent discussion with GP is required if these are new findings to ensure they are aware of the results, and allow the GP to make a judgement on the clinical symptoms and whether urgent haematology review is required.  If the patient is symptomatic he should be admitted to hospital urgently.  However if he remains relatively stable, he could be assess as an outpatient on an urgent basis.

 

The next step was a bone marrow marrow biopsy.  In real life we would also suggest checking haematinics/medication history/review comorbidities.  We requested a coagulation screen also for this patient which I think is useful, specifically if he was bleeding, given the thrombocytopenia.  A clotting may also be useful if we felt this picture may have developed due to an underlying sepsis so ensure there was no evidence of DIC.

 

The bone marrow showed evidence of dysplasia and 13% blast count.  Previous diagnostic criteria would have classified this as RAEB-2, however WHO classification has recently been revised and the diagnosis would be MDS-EB-2

 

WHO classification for MDS 2016.

PB and BM findings and cytogenetics of MDS

Name Dysplastic lineages Cytopenias* Ring sideroblasts as % of marrow erythroid elements BM and PB blasts Cytogenetics by conventional karyotype analysis
MDS with single lineage dysplasia (MDS-SLD) 1 1 or 2 <15%/<5% BM <5%, PB <1%, no Auer rods Any, unless fulfills all criteria for MDS with isolated del(5q)
MDS with multilineage dysplasia (MDS-MLD) 2 or 3 1-3 <15%/<5% BM <5%, PB <1%, no Auer rods Any, unless fulfills all criteria for MDS with isolated del(5q)
MDS with ring sideroblasts (MDS-RS)
 MDS-RS with single lineage dysplasia (MDS-RS-SLD) 1 1 or 2 ≥15%/≥5% BM <5%, PB <1%, no Auer rods Any, unless fulfills all criteria for MDS with isolated del(5q)
 MDS-RS with multilineage dysplasia (MDS-RS-MLD) 2 or 3 1-3 ≥15%/≥5% BM <5%, PB <1%, no Auer rods Any, unless fulfills all criteria for MDS with isolated del(5q)
MDS with isolated del(5q) 1-3 1-2 None or any BM <5%, PB <1%, no Auer rods del(5q) alone or with 1 additional abnormality except −7 or del(7q)
MDS with excess blasts (MDS-EB)
 MDS-EB-1 0-3 1-3 None or any BM 5%-9% or PB 2%-4%, no Auer rods Any
 MDS-EB-2 0-3 1-3 None or any BM 10%-19% or PB 5%-19% or Auer rods Any
MDS, unclassifiable (MDS-U)
 with 1% blood blasts 1-3 1-3 None or any BM <5%, PB = 1%,no Auer rods Any
 with single lineage dysplasia and pancytopenia 1 3 None or any BM <5%, PB <1%, no Auer rods Any
 based on defining cytogenetic abnormality 0 1-3 <15%§ BM <5%, PB <1%, no Auer rods MDS-defining abnormality
Refractory cytopenia of childhood 1-3 1-3 None BM <5%, PB <2% Any

 

 

Assessing risk

Once the patient has been diagnosed, we need to be able to assess the patients isk in order to develop an optimal management plan for that individual.  Important factors to take into account are the patients age, co-morbidities and ECOG status, as these will potential affect the type of treatment appropriate for each individual patient.

IPSS-R is a decision support tool designed to assess risk of disease and therefore prognosis based on blood indices, cytogenetics, and blast count.

 

IPSS-R Cytogenetic risk groups*,**

Cytogenetic prognostic subgroups Cytogenetic abnormalities
Very good -Y, del(11q)
Good Normal, del(5q), del(12p), del(20q), double including del(5q)
Intermediate del(7q), +8, +19, i(17q), any other single or double independent clones
Poor -7, inv(3)/t(3q)/del(3q), double including -7/del(7q), Complex: 3 abnormalities
Very poor Complex: >3 abnormalities

IPSS-R Prognostic Score Values*

Prognostic variable 0 0.5 1 1.5 2 3 4
Cytogenetics Very Good Good Intermediate Poor Very Poor
BM Blast % <=2 >2-<5% 5-10% >10%
Hemoglobin =>10 8-<10 <8
Platelets =>100 50-<100 <50
ANC =>0.8 <0.8  

 

IPSS-R Prognostic Risk Categories/Scores*

RISK CATEGORY RISK SCORE
Very Low <=1.5
Low >1.5 – 3
Intermediate >3 – 4.5
High >4.5 – 6
Very High >6

IPSS-R: Prognostic Risk Category Clinical Outcomes*

No. pts Very Low Low Intermediate High Very High
Patients (%) 7012 19% 38% 20% 13% 10%
Survival*** 8.8 5.3 3.0 1.6 0.8
AML/25%***,^ NR 10.8 3.2 1.4 0.7

 

Somatic mutation profile was also suggested by one of our followers.  This can also help provide prognostic information and risk stratification, but has not been incorporated into the IPPS-R scoring system currently.  Somatic mutations in MDS driver genes especially TP53, ASXL1, DNMT3A, EZH2, and RUNX1, are associated with poorer outcomes and have been shown to add independent prognostic information.  The number and types of specific mutations are strongly associated with disease outcome in MDS, and the addition of mutation data improves the prognostic value of existing risk-stratification schemes in MDS.

 

Approach to treatment

The patient in this case would be classified as very high risk disease given his IPSS-R score.  Given his age and relative fitness, the approach of transplant should be considered.  Options pre-transplant which were suggested included azacitidine, and AML – type chemo (AML 18 and AML 19 are trials currently available in the UK and would be options for this patient).  Discussion with the transplant team is important early, as some patient may be consider for transplants upfront if donors were available.

 

 

References:

  1. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia.  Arber, Attilio Orazi, Robert Hasserjian, Jürgen Thiele, Michael J. Borowitz, Michelle M. Le Beau, Clara D. Bloomfield, Mario Cazzola and James W. Vardiman

Blood 2016 127:2391-2405; doi: https://doi.org/10.1182/blood-2016-03-643544

  1. Recent developments in myelodysplastic syndromes

Rafael Bejar and David P. Steensma

Blood 2014 124:2793-2803; doi: https://doi.org/10.1182/blood-2014-04-522136

  1. Revised International Prognostic Scoring System (IPSS-R) for Myelodysplastic Syndromes Risk Assessment Calculator. International working group for the prognosis of MDS.  http://ipss-r.com/
  2. How I treat patients with myelodysplastic syndromes

    Richard M. Stone

 

Posted in Acute leukaemia, Bone marrow failure | Tagged , , , , ,

Case 77 – update 2

Bone marrow results:

13% blasts

evidence of dysplasia in the erythroid and myeloid cell lines

Cytogenetics:trisomy 8

 

How would you classify this patient? What would be your approach to management?

Posted in Acute leukaemia, Bone marrow failure | Tagged , , , , ,