Case 93 – summary

This case highlighted a number of issues in the management of VTE.

1) The investigation of a patient with newly diagnosed DVT

One of the most useful parts in the history taking is the identification of a provoking factor. We know that those with provoked DVT have relatively low risk of recurrence after an initial period of intensive anticoagulation. However frequently patients have ‘soft’ provoking factors or no provoking factors or relapsing-remitting provoking factors e.g. inflammatory bowel disease. Guidance from ISTH can help us decide on whether a provoking factor has occurred.

In those with a clearly provoked VTE e.g. following surgery or hospital admission then investigation into underlying causes may not be needed. A full history and examination should be performed in all patients.

In those with unprovoked VTE the addition of CT abdomen and pelvis was studied in addition to standard of care and in the SOME trial a routine CT scan did not offer any clinical benefit. Patients should have a systematic history and examination in addition to urinalysis, CXR and routine age-appropriate cancer screening. In addition to malignancy features of autoimmune disease should be asked about. Basic laboratory tests should be performed such as FBC, U&E, LFT and bone profile. Further investigations can be performed as guided by history, examination and blood tests. Tests such as autoimmune screening, immunoglobulins, thyroid function, inflammatory markers, ferritin and tumour markers are controversial but can be used on a case-by-case basis.

2) Deciding which anticoagulant to use

Various factors need to be considered and the final approach needs to be individualised to the patient after discussion with them. Factors that may need to be taken into account include:

  • Presence of active cancer – LMWH generally better option if undergoing chemotherapy. DOACs are increasingly used in patients with malignancy.
  • Need for reversal agent – currently warfarin and dabigatran have reversal agents but anti-Xa reversal agent Andexanet alfa has been approved by FDA for reversal of rivaroxaban and apixaban)
  • Preferring oral vs parenteral
  • Extremes of body weight – DOACS generally advised against over 120kg
  • Ability to absorb – if absorption issues then parenteral anticoagulant or an anticoagulant that can be monitored reliably may be preferred
  • Ability to monitor – warfarin and LMWH are easily monitored. DOAC levels can be checked but interpretation is not always straightforward and titration of dose is not generally possible
  • Interacting medications
  • Preference to take once daily – warfarin, LMWH and rivaroxaban are all once daily
  • History or at risk of heavy menstrual bleeding – rivaroxaban has been associated with higher risk in non-randomised comparative studies
  • Not wanting to take any injections – rivaroxaban and apixaban do not require any period of LMWH
  • Ease of monitoring and facilities to do so (community vs hospital visits etc.)
  • Presence of antiphospholipid syndrome – currently warfarin and LWMH are the preferred option here
  • Local policies – this may dictate prescribing
  • Cost – this may dictate prescribing
  • Presence of renal failure – in the presence of severe renal failure warfarin is the best option for treatment of VTE although apixaban has been used for AF in dialysis-dependant patients. All other DOACs have limits and dose reductions depending on the degree of renal failure.
  • Presence of liver disease and coagulopathy – LMWH may be the best option here
  • Current or potential pregnancy – DOACs and warfarin are contraindicated in pregnancy but generally most are happy to become pregnant whilst on warfarin but to change to LMWH as soon as possible
  • History of gastritis and GI bleed – dabigatran has more GI side effects and rivaroxaban has possibly more GI bleeding.
  • Presence of coronary artery disease – dabigatran may have more cardiac side effects

 

Whatever anticoagulant is used patients should be counselled on the risks and benefits and expected side effects. They should be told what medicines to avoid and when next to have blood test monitoring if appropriate. They should be given advice on who to contact if any problems.

3) The use of compression hosiery

Again, another controversial issue with some people advocating its use and others avoiding. Generally use grade 2 stockings 30-40mmHg at ankle and change 3-6 monthly or after 100 washes. Patients should start wearing once the acute swelling has reduced – around two weeks post DVT and may need refitting if swelling reduced. The SOX trial in 2014 enrolled patients with a first DVT  and they wore stockings at least three days a week and they were randomised against sham stockings. The incidence of post-thrombotic syndrome was 14.2% in stockings group versus 12.7% in sham stockings group.

However they can be useful to alleviate symptoms.

4) Diagnosis of recurrent DVT

There is no validated risk score and USS and d-dimer are also not validated. If the recurrence is in the contralateral leg then the diagnosis is usually straightforward. USS is operator dependant and some factors can be used to determine new clot vs old such as extent and appearances but this is not easy. In real life the clinical features, d-dimer and ultrasound findings need to be triangulated. A good review on recurrent DVT is here.

Recurrent DVT investigation.jpg

When someone has a recurrent thrombosis it is important to think about:

  • Are levels required to assess compliance and efficacy?
  • Check compliance with patient
  • Check correct dose, weight, taking with food (if needed), timings
  • Check no medications that may reduce effect
  • On other medications e.g. chemotherapy or hormones that may increase hypercoagulability?
  • Consider
    • Looking for malignancy
    • Looking for pro-thrombotic state e.g. heparin-induced thrombocytopenia (if on heparin), paroxysmal nocturnal haemoglobinuria, myeloproliferative neoplasm and anti-phospholipid syndrome
    • Looking for anatomical abnormality e.g. May Thurner

The treatment of recurrent DVT depends on the circumstance and some options are given:

  • On warfarin but subtherapeutic? Give LWMH and once improving reintroduce warfarin with more intense monitoring and lower threshold for LMWH if subtherapeutic. Investigate why warfarin subtherapeutic. Could also increase target range to reduce likelihood of being subtherapeutic. A DOAC may be a better option here.
  • On warfarin but therapeutic (ensure therapeutic leading up to event)? Give LWMH and once improving reintroduce warfarin with more intense monitoring and lower threshold for LMWH if subtherapeutic. Increase target INR range.
  • On full dose DOAC? Give LWMH and once improving start warfarin.
  • On half dose DOAC? Give full dose.
  • On LWMH? Escalate dose by 20-25%
  • If cancer – start LMWH
  • If new MPN – use LWMH then warfarin and consider cytoreduction.
  • If PNH – consider eculizumab
  • If vascular abnormality refer to vascular surgeons

5) Duration of therapy

For provoked DVT generally 3-6 months anticoagulation is sufficient assuming the risk factors have gone. Patients should be counselled about risk in the future and symptoms to look out for. In unprovoked DVT treatment duration is less clear. Male sex, obesity and extent of DVT are all risk factors for recurrence. Consider long term anticoagulation in all unprovoked – reduces risk by 80-90%

  • Distal do not need long term
  • If don’t want need to way up risks and benefits
  • Bleeding risk factors include: ETOH, hypertension, CKD, cirrhosis, previous bleed, over 65s, aspirin too)
  • Options include
    • Stop and no monitoring
    • Stop and d-dimer monitoring e.g. DASH score (or similar)
    • Stop and thromboprophylaxis during high risk events
    • Extended anticoagulation with reduced dose
    • Extended anticoagulation same dose

6) IVC filters

General points:

To prevent PE in patients who can’t be anticoagulated. Once inserted should start anticoagulation when no contraindication due to risk of recurrence and filter blocking, however no known benefit for starting anticoagulation for filter alone as patients with filter and anticoagulation still get VTE therefore decision to restart should be made on underlying condition not filter alone. Filter and anticoagulation reduces risk of PE but increases risk of DVT and no difference in overall survival. If anticoagulation fails – intensify first. Free-flowing thrombus is not an indication for filter. Remove filter in two months and definitely less than three months. Consider filter if:

  • Pre op and VTE in last month where anticoagulation must be interrupted and surgery can’t be delayed
  • Pregnant and contraindication to anticoagulation or within two weeks of delivery
  • Chronic thromboembolic pulmonary hypertension pre pulmonary endarterectomy
  • Platelets too low for treatment

Complications:

  • Recurrent DCT 20%
  • IVC thrombus 10%
  • Post thrombotic syndrome 15-40%
  • Pneumothorax
  • Migration
  • Misplaced
  • Entrapment of guidewires

7) Cancer-associated VTE

LMWH has the most established use in this scenario having superiority to warfarin (CLOT trial). Edoxaban and rivaroxaban have been studied, however these may be less easier to manipulate during thrombocytopenia, interactions may not be easy to spot and during chemotherapy absorption may be altered and vomiting may occur. In the pilot data with use of rivaroxaban there was more bleeding in the rivaroxaban arm. The risks and benefits of oral agents should be discussed with patients and in those that find LMWH painful and difficult DOACs may be an option.

Summary

Our patient was diagnosed with an unprovoked DVT and was started on rivaroxaban. Whilst on treatment he had a recurrence which lead to the diagnosis of pancreatic malignancy. He was started on LMWH but needed urgent surgery (within two weeks of recurrence), so an IVC filter was inserted with instructions to stop LMWH 36 hours pre surgery and restart as soon as bleeding risk reduced (usually after 48-72 hours). At 48 hours prophylactic LWMH was introduced and then escalated to treatment dose BD until he was established on once a day. Once there was no bleeding and no further intervention planned the filter was removed three weeks later. He had a total of six months anticoagulation with LMWH and during repeat imaging he was declared cancer free. He had a monitoring scan two years later and remained cancer-free and off anticoagulation with no VTE recurrence. He was educated on the signs and symptoms to look out for and advised to be on prophylactic LMWH during times of risk.

Conclusion

Management of VTE is not straightforward. There are a number of debated issues:

  • Treatment of isolated distal DVT
  • Biomarkers for DVT diagnosis
  • Treatment of recurrent DVT
  • Investigations of the newly diagnosed patient
  • Use of compression hosiery
  • How long should patients be on treatment
  • Risk factors: provoked vs unprovoked
  • Incidental VTE
  • Role of inherited thrombophilia screening
  • Localised thrombolysis

The above issues may need to be discussed with patients and uncertainty acknowledged in order to promote shared decision making.

 

References

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Case 93 – update 4

Our patient has had one left leg DVT which was treated with rivaroxaban. He had no symptoms of malignancy. Two months later he presents again with increased leg swelling and pain and has the thrombosis has increased compared to previous. A recurrent DVT is diagnosed despite compliance with anticoagulation. He has a CT scan which suspects pancreatic malignancy and he undergoes surgery two weeks later. Because of the high risk of bleeding during the procedure and the likelihood he will require a significant amount of time without anticoagulation postoperatively he has an IVC filter inserted.

 

Post operatively he recovers well and after two weeks he is back on full dose anticoagulation and the IVC filter is removed.

Three months after the recurrence he is deemed cancer free and has no more treatment planned.

 

Questions

  • What is the optimal anticoagulation for cancer-associated VTE?
  • How long should patients be anticoagulated for?

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

Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality.

TeamHaem are not a position of authority.  It is an educational platform to allow discussion and learning.

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Case 93 – update 3

Our patient has his d-dimer checked which is positive and has an ultrasound scan of the left leg which has confirmed a clot. On review of the images the clot is more extensive that previously. This combined with the clinical history is strongly suggestive of recurrent thrombosis.

When someone has a recurrent thrombosis it is important to think about:

  • Are levels required to assess compliance and efficacy?
  • Check compliance with patient
  • Check correct dose, weight, taking with food (if needed), timings
  • Check no medications that may reduce effect
  • On other medications e.g. chemotherapy or hormones that may increase hypercoagulability?
  • Consider
    • Looking for malignancy
    • Looking for pro-thrombotic state e.g. heparin-induced thrombocytopenia (if on heparin), paroxysmal nocturnal haemoglobinuria, myeloproliferative neoplasm and anti-phospholipid syndrome
    • Looking for anatomical abnormality e.g. May Thurner

 

Our patient now reports some upper abdominal discomfort and a CT scan reveals a mass at the head of the pancreas. Following a MDT discussion this is very likely to be a  pancreatic malignancy and surgery is indicated. His surgeon recommends surgery as soon as possible and does not want to wait for more than three weeks. The surgery planned would be a Whipple’s procedure.

 

Questions

  • How do you manage anticoagulation around elective but urgent surgery?
  • What anticoagulant do you recommend?
  • Any other interventions need considering?
  • What about post-operatively?

 

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 Anticoagulation, Thrombosis | Tagged , , , ,

Case 93 – update 2

We discussed what anticoagulant to start in our patient with a newly diagnosed DVT. There are a number of options and the main ones will include:

  • LMWH then warfarin
  • LWMH then dabigatran
  • Rivaroxaban
  • Apixaban
  • LMWH then edoxaban

 

Various factors need to be considered and the final approach needs to be individualised to the patient after discussion with them. Factors that may need to be taken into account include:

  • Presence of active cancer – LMWH generally better option if undergoing chemotherapy. DOACs are increasingly used in patients with malignancy.
  • Need for reversal agent – currently warfarin and dabigatran have reversal agents but anti-Xa reversal agent Andexanet alfa has been approved by FDA for reversal of rivaroxaban and apixaban)
  • Preferring oral vs parenteral
  • Extremes of body weight – DOACS generally advised against over 120kg
  • Ability to absorb – if absorption issues then parenteral anticoagulant or an anticoagulant that can be monitored reliably may be preferred
  • Ability to monitor – warfarin and LMWH are easily monitored. DOAC levels can be checked but interpretation is not always straightforward and titration of dose is not generally possible
  • Interacting medications
  • Preference to take once daily – warfarin, LMWH and rivaroxaban are all once daily
  • History or at risk of heavy menstrual bleeding – rivaroxaban has been associated with higher risk in non-randomised comparative studies
  • Not wanting to take any injections – rivaroxaban and apixaban do not require any period of LMWH
  • Ease of monitoring and facilities to do so (community vs hospital visits etc.)
  • Presence of antiphospholipid syndrome – currently warfarin and LWMH are the preferred option here
  • Local policies – this may dictate prescribing
  • Cost – this may dictate prescribing
  • Presence of renal failure – in the presence of severe renal failure warfarin is the best option for treatment of VTE although apixaban has been used for AF in dialysis-dependant patients. All other DOACs have limits and dose reductions depending on the degree of renal failure.
  • Presence of liver disease and coagulopathy – LMWH may be the best option here
  • Current or potential pregnancy – DOACs and warfarin are contraindicated in pregnancy but generally most are happy to become pregnant whilst on warfarin but to change to LMWH as soon as possible
  • History of gastritis and GI bleed – dabigatran has more GI side effects and rivaroxaban has possibly more GI bleeding.
  • Presence of coronary artery disease – dabigatran may have more cardiac side effects

 

Our patient prefers an oral option and would like a tablet to take once a day as he would find it easier to remember. He starts on rivaroxaban 15mg BD with a plan to drop to 20mg od after three weeks. He notices an improvement in his symptoms. He is asymptomatic and has no signs or symptoms of malignancy or autoimmune disease. He has a chest X-ray which is normal. Urinalysis is unremarkable and FBC, U&E, LFT and calcium are all within the reference range.

 

Two months later he attends again with extensive left leg swelling after having an initial improvement.

Questions

  • How do you counsel patients about to start anticoagulation? Any dos and don’ts?
  • Do you offer compression hosiery routinely?
  • His leg is worse again – how do you proceed?

 

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 Anticoagulation, Thrombosis | Tagged , , ,

Case 93 – update 1

Our patient has a confirmed proximal DVT and we recognised the important points in the clinical evaluation by looking for provoking factors:

  • Malignancy
  • Family history
  • Periods of immobility
  • Recent surgery or hospital stays
  • Hormonal therapy or pregnancy
  • Nephrotic syndrome
  • Autoimmune or other inflammatory disorder

In our patient nothing obvious came to light. He’d been on a short train journey and his cousin also had a DVT – neither enough to make us wonder about a convincing risk factor.

He needs treatment for the DVT. His renal and liver function are normal.

Questions

  • How do you decide which anticoagulant to use?
  • What risks and side effects would you tell him?
  • What investigations may you wish to perform to look for causes of VTE?

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 Anticoagulation, Thrombosis | Tagged , ,

Case 93 – the beginning

Welcome to our new #TeamHaem case.

You are the acute medicine senior house officer working in ambulatory care. A GP has referred a 58 year old gentleman with left leg swelling and is concerned about deep vein thrombosis (DVT). He has never had a blood clot before. Blood tests reveal a positive d-dimer and an ultrasound scan confirms a clot in the femoral vein extending into the external iliac vein.

Questions:

  • What further information in the history is useful to know here?
  • What would you look for on examination?

 

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 Anticoagulation, Thrombosis | Tagged ,

Case 92 – summary

Thanks for your help with the cases.

This week we have looked at three different scenarios regarding bleeding or bruising presenting in the paediatric population.

The cases although different have some common themes:

Coagulation testing in paediatrics is challenging for several reasons:

  1. lack of local reference ranges for tests due to ethical concerns.
  2. physiological differences in coagulation factor and other coagulation protein levels (Factor II, VII, X, IX, XII don’t reach adult range until 6 months with other differences such as elevated factor VIII and VWF levels, reduced platelet function and low protein C and S levels at birth). Children’s reference ranges should be used until age 16.
  3. Sampling much more challenging particularly in babies. Platelet function and nucleotide testing not recommended before 1 year due to challenges of obtaining samples and interpreting results. Stress of venipuncture in children can also affect VWF results. Difficulties in obtaining samples can lead to pre activated samples.

With the above in mind when faced with a child with bleeding or bruising given limitations of the tests the focus should be on good history and examination.

Testing should focus on excluding major bleeding disorders rather than investigating for milder conditions that are unlikely to be cause of presentation. Repeat testing can be helpful if results unclear particularly with VWF tests that are affected by acute trauma and stress. Platelet nucleotide and function should not be performed in young babies as not possible to interpret results with certainty.

History points to consider:

  • Is the bruising or bleeding consistent with history given? – NAI clearly may have inconsistent story but equally bleeding disorders may also cause bruising with apparently minimal trauma.

Pattern of Bruising or bleeding:

  • Bruises consistent with a pattern like a hand would be consistent with NAI.
  • Bruising over shins much less concerning than sites that are not exposed such as the abdomen .

Bleeding history and challenges to haemostasis:

  • Birth: stump bleeds ( suggestive XIII deficiency), cephalohaematomas.
  • Vaccines: significant bleed or bruise post IM injections
  • Mucosal bleeding: VWD
  • Surgery: circumcision, tooth extraction

General Health:

  • Liver disease?
  • Sepsis- DIC picture
  • Recent Infection – Henoch scholein purpura, ITP

Family History:

  • Bleeding issues
  • Hypermobility

Ethnicity:

  • Consanguineous relationships – recessive bleeding traits.
  • Ashkenazy Jewish population – factor XI deficiency

Drug History:

  • Anticoagulants
  • Steroids
  • Maternal drug Hx – Vit K def more common if taking some antiepileptic medications

Diet:

  • Breast fed – risk for Vit k deficiency
  • Poor diet – Vit C deficiency

Hypermobility – Ehlers Danlos

Examination points to consider:

  • Sites of bruising and age – abuse and bleeding disorders varied ages of bruises
  • Petechia? – ITP or HSP?
  • Joint bleeds? – Haemophillia
  • Hypermobility? Scars?- Ehlers Danlos

Investigations:

These are dependent on history and examination and are not needed in all cases. For example if a child has a clear belt buckle shaped bruise that is consistent with NAI further tests won’t be needed. A baby who had clearly prolonged PT and history of breastfeeding may only require Vit K and repeat Coag not the full range of factors.

Basic screen:

  • PT/APTT
  • Thrombin time
  • Fibrinogen
  • 50:50 mix of prolonged Coag times
  • Factor VIII,IX,XI
  • VWD screen
  • Other tests such as factor XIII and platelet function depends on history and presentation.

 

Notes on Specific cases this week:

  1. Vitamin K deficiency resulting in intracranial haemorrhage:

Levels of Vitamin K dependent coagulation factors (II,VII,IX, and X ) are low at birth and these factors are functionally inactive without vitamin K. Vitamin K deficiency classically prolongs PT in isolation but in severe cases may prolong APTT.

It should always be considered as a cause of neonatal bleeding and vitamin K should be given even prior to coagulation results being available in cases of severe bleeding.

Vitamin K deficiency bleeding (VKDB) risk factors are exclusive Breastfeeding (Breast milk does not contain VitK), missing treatment at birth, mother on drugs such as phenytoin that interfere with Vit K metabolism or babies with Liver disease who don’t use vit K the body stores or bowel problems who don’t absorb the vitamin K.

There are 3 types of vitamin K deficiency:

  • Early: first 24 hours after birth commonly due to maternal medications
  • Classical: 1-7 days post delivery
  • Late: 2-12 weeks of age but can be seen up to 6 months. These babies are otherwise well and sadly up to 60% present with significant intracranial bleeds as first event.

Management of vitamin K prophylaxis is varied and there are several approaches.

If a mother is on antiepileptic such as phenytoin she should be counselled about risks and given choice to change medication. She should receive 20mg vit K per day in last 4 weeks of pregnancy and IM 1mg Vit K given at birth.

IM vit K 1mg was traditionally given at birth but there was a single study that linked this to possible childhood cancer ( though no further studies have shown no link). Oral regimens give 2mg at birth and then daily for the next 3 months instead.

Any infant presenting with possible bleeding related to vitamin K deficiency should receive IV or S/C vit K (avoid IM route). This should occur before confirmation.

Octoplas 15ml/kg should be used to correct coagulation anomalies. Care should be taken to avoid volume overload and changes in BP due to rapid volume expansion.

2. Ehlers Danlos

This is a group of 13 different inherited conditions that affect the connective tissues, usually collagen.

The commonest type is classical Ehlers Danlos. This condition causes a defect in type V collagen leading to fragility of collagen fibrils. In classical ED under an electron microscope collagen flowers can be seen due to defects in collagen fibres.

Given the classical clinical presentation of Hypermobile joints, skin elasticity and easy bruising with atrophic scaring the diagnosis is often given on clinical grounds. Skin biopsy and microscopy was the previous diagnostic test however Genetic tests can be performed looking for mutations in COL5a or COL5A2 genes if needed (The condition is autosomal dominant).

A patient will often have fragile skin and inspection will show scars with wide defects or over shins, elbows and knees. They will demonstrate Hypermobile joints and a useful clinical tool is the Beighton score which if >5 suggests hyper mobility. They may also have easy bruising and stretchy skin. There is often a family history of hyper mobility and hernias or prolapses due to weak collagen.

Management of Ehlers Danlos is supportive. Advice includes avoiding skin trauma and contact sport should be avoided due to dislocation risk. Cardiac echo should be considered to ensure cardiac valves not affected. If pregnant then additional care should be taken as high risk for perineal tear and prolapse.

In our case the patient had easy bruising and advice should be to avoid trauma as much as possible. She should have an echo and be advised to inform obstetric team if ever pregnant due to increased perineal tearing rate. Family can be referred to local genetic service if they are concerned.

3. Factor XII deficiency and probable NAI:

Factor XII deficiency s autosomal recessive and affects 1 in a million of the population. Occasionally patients with this condition have poor wound healing but this does not cause bleeding problems.

In this case the factor XII deficiency does not explain bruising and given the bruises suspicious location on the abdomen it is likely NAI is the cause for the presentation.

If NAI is considered you may need to perform testing for rarer bleeding conditions even if initial screen is negative for legal reasons. It is important if NAI is thought to be an issue that advice is sought from experts at an early stage and any testing done in major centre so results can be as accurate as possible.

References:

AE Thomas The bleeding child; is it NAI?. Arch Dis Child 2004, 89, 1163-1167.

CDC website vitamin K deficiency bleeding

The investigation and management or neonatal haemostasis and thrombosis. BJHaem 2002, 119, 295-309.

Ehlers Danlos association website

Factor XII deficiency – Haemophillia.org website

Posted in Acquired bleeding, Inherited bleeding, Paediatric haematology | Tagged , , , , , , , , , , , , , , , ,

Case 92- update part C

We have a 7 year old boy who has presented with bruises over abdomen and one on his ear.

Social services have been contacted as there is concern this may be an NAI.

The boy is otherwise well has no family history of bleeding disorders and has no bleeding history of note.

 

The boy was asked to attend the tertiary centre for coagulation tests to be performed. This is because of concerns regarding delay in transportation of samples. If further special tests like platelet function required would also need to be taken at site that can perform the tests.

 

Tests taken and results:

 

  • Full blood count, blood film – Normal
  • PT 13 sec (Normal) APTT 50 sec (Prolonged), thrombin time – Normal, Clauss fibrinogen 3.2 (Normal)
  • Von Willebrand screen – Normal
  • Lupus screen – Normal
  • 50:50 mix APTT – 37 Sec (Normal)
  • FVIII level – 100% (Normal)
  • FIX level – 96% (Normal)
  • FXI level – 110% (Normal)
  • FXII level – 30% (Low)

What is the likely cause for the prolonged APTT?

 

Does this explain the bruises in this case?

 

Would you perform any other tests in this case?

Posted in Acquired bleeding, Inherited bleeding, Paediatric haematology | Tagged , , , ,

Case 92 – part C

Thanks for your help with case 2 the patient has been diagnosed with Ehlers Danlos and will have an echo arranged to check for any cardiac problems.

You now receive a call from the local district general hospital regarding a 7 year old boy who has presented with bruises over abdomen and one on his ear. They have called the tertiary centre in line with regional policy as initial FBC and coagulation screen was normal apart from a prolonged APTT of 50 seconds. They wonder if this finding is significant?

Social services have been contacted as there is concern this may be an NAI.

The boy is otherwise well has no family history of bleeding disorders and has no bleeding history of note.

What tests would you ask for to clarify long APTT?

Would you ask them to perform further tests locally or send the child to your centre?

What is the differential at this stage for the prolonged APTT?

Posted in Acquired bleeding, Inherited bleeding | Tagged , , , ,

Case 92 – part B

Thanks for your help with case 1 the baby is improving. The following morning you as the Haematology registrar have been referred a 5 year old girl who presented due to parental concern with easy bruising. The bruising was noted since she was about one but become more evident since she started school. She has small bruises of varied age over forearm and shins. She has no past medical history of note. She has a maternal grandma who “bruises easily”

What history would you take?

What would you look for in the examination?

What investigations would you consider?

Posted in Acquired bleeding, Inherited bleeding, Paediatric haematology | Tagged , , , , , ,

Case 92 – update part A

Thanks for your help so far

An 8 week old baby boy born at 40+2 by Normal vaginal delivery has a CT that confirms a subdural haemorrhage.

Results: (With age adjusted reference ranges)

  • FBC – Hb 120 (Low) MCV 120 (upper normal) plt 200 (Normal) Wcc 15 (Normal) Retics 220 (upper normal range)
  • Coag – PT 74 secs (High) APTT 55 sec (upper normal) Fib 2 (Normal). PT corrects on mixing.
  • Film– unremarkable with normal platelet morphology.

The team give Vitamin K 1mg IV as severe bleeding.

The mother is well apart from epilepsy. She has no previous pregnancies. She is not in consanguineous relationship. She reports the boy was well no bleeding of umbilical stump or mucocutaneous bleeding noted. He was on 50th centile for weight. He is exclusively breastfed.

What is the most likely cause of this presentation?

How should this be managed?

What is the relevance of maternal epilepsy in this case?

Posted in Acquired bleeding, Inherited bleeding, Paediatric haematology | Tagged , , , , , ,

Case 92 – the beginning

This week we will be looking at investigation of bleeding and bruising in the paediatric setting with three short cases.

Case 1

An 8 week old baby boy born at 40+2 by Normal vaginal delivery presents with a reduced consciousness level, bulging fontanelle and respiratory distress. He is transferred to NICU and a CT confirms a subdural haemorrhage.

You are contacted as the Haematology registrar on call and asked for advice on investigation of this presentation.

What history would you take?

What investigations would you recommend the paediatric team undertake?

What is the differential diagnosis for the bleed in this case?

Posted in Acquired bleeding, Inherited bleeding, Paediatric haematology | Tagged , , , , ,

Case 91 – summary

Thank you for all your contributions this week!

This week we had a look at MGUS (monoclonal gammopathy of undetermined significance).

Our patient was diagnosed with IgA lambda MGUS, which was monitored 6 monthly for 4 years. This then progresses to myeloma.

MGUS is a clonal disorder of plasma cells that can be associated with a variety of conditions. There is an excellent table of conditions which should prompt testing for monoclonal paraprotein in the ‘How I manage monoclonal gammopathy of undetermined significance’ article, a link is at the end of the summary.

The incidence of MGUS increases with age, and around 3% of the >50year old population may have it.

Risk factors for developing MGUS include being male, increasing age, family history of myeloma or MGUS and there is also a increase risk in people of African American or black African heritage.

MGUS can progress to a malignant plasma cell disorder eg myeloma, amyloid. IgM MGUS is typically associated with lymphocytes/lymphoplasmacytoid cells and can progress to lymphoplasmocytic lymphoma. Very rarely it can progress to IgM myeloma.

There are several characteristics which may influence likelihood of progression.

The overall risk of progression to myeloma is around 1% year.

Of the none IgM MGUS 69% have IgG pp, 11% IgA, 3% have both IgG and IgA pp and there are occasional patients with IgE and IgD MGUS.

17% of all patient’s with MGUS from the Mayo clinic data had IgM MGUS

 

Diagnostic criteria IMWG 2010 guidelines:

Non-IgM MGUS

  • Serum monoclonal protein <30g/L
  • Clonal bone marrow plasma cells <10%
  • Absence of end-organ damage such as hypercalcemia, renal insufficiency, anemia, and bone lesions (CRAB) or amyloidosis that can be attributed to the plasma cell proliferative disorder

IgM MGUS

  • Serum IgM monoclonal protein <30g/L
  • No evidence of anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, hepatosplenomegaly, or other end-organ damage that can be attributed to the plasma cell proliferative disorder

Light chain MGUS

  • Abnormal FLC ratio (<0.26 or >1.65)
  • Increased level of the appropriate free light chain (increased FLC in patients with ratio >1.65 and increased FLC in patients with ratio <0.26)
  • No immunoglobulin heavy chain expression on immunofixation

All

  • Absence of end-organ damage such as hypercalcemia, renal insufficiency, anemia, and bone lesions (CRAB) or amyloidosis that can be attributed to the plasma cell proliferative disorder
  • Clonal bone marrow plasma cells <10%
  • Urinary monoclonal protein <500mg/24h

 

Smouldering multiple myeloma

Both criteria must be met –

  • Serum monoclonal protein (IgG or IgA)>30g/L or urinary monoclonal protein >500mg per 24h and/or clonal bone marrow plasma cells 10-60%
  • Absence of myeloma-defining events or amyloidosis

 

Myeloma

  • Clonal bone marrow plasma cells 10% or biopsy-proven bony or extramedullary plasmacytoma and any one or more of the following CRAB features and myeloma-defining events:
    • Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically:
    • Hypercalcemia: serum calcium >0.25 mmol/L (>1mg/dL) higher than the upper limit of normal or >2.75 mmol/L (>11mg/dL)
    • Renal insufficiency: creatinine clearance <40 mL per minute or serum creatinine >177mol/L (>2mg/dL)
    • Anemia: hemoglobin valure of >20g/L below the lowest limit of normal, or a hemoglobin value <100g/L
    • Bone lesions: one or more osteolytic lesion on skeletal radiography, CT, or PET/CT. If bone marrow has <10% clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement
  • Any one or more of the following biomarkers of malignancy (MDEs):
    • 60% or greater clonal plasma cells on bone marrow examination
    • Serum involved / uninvolved free light chain ratio of 100 or greater, provided the absolute level of the involved light chain is at least 100mg/L (a patients involved free light chain either kappa or lambda is the one that is above the normal reference range; the uninvolved free light chain is the one that is typically in, or below, the normal range)
    • More than one focal lesion on MRI that is at least 5mm or greater in size.

 

Investigations – IMWG 2010 guidelines

If there is a suspicion that a patient with a paraprotein may have myeloma/smouldering myeloma they should have

  • FBC with diff and blood film
  • Biochemistry panal including calcium
  • Serum protein electrophoresis and immunofixation
  • Nephelometric quantitation of immunoglobulins
  • Urinalysis, 24 hour urine collection for proteinuria,electrophoresis and immunofixation
  • Quantification of both urine M-component level and albuminuria
  • Bone marrow
    • Aspirate, trephine, immunophenotyping and tests for cytogenetics and FISH
  • Imaging
    • Skeletal survey including skull, pelvis, humeri, femurs, spine
    • Low dose whole body CT or MRI is recommended in the work up of smouldering myeloma
    • If smouldering myeloma is suspected, PET CT, Low dose whole body CT or MRI can be done dependant on local availability

 

Risk factors for progression

Factors that can increase likelihood of progression from the MAYO clinic and Spanish study group for MGUS:

  • none IgG paraprotein
  • Monoclonal paraprotein >15g/L
  • abnormal SFLC ratio
  • DNA aneuploidy
  • >95% aberrant plasma cell population (of total plasma cells)demonstrated by flow. (Aberrant plasma cell populations express dim CD38, CD56+, lack of CD19−, and/or absence of CD45.)

 

Management

The IMWG 2010 guidelines suggested that monitoring of patients with MGUS could be guided based on risk stratification.

Patients who were low risk by the Mayo clinic criteria (IgG paraprotein < 15 g/L with normal SFLC ratio) could be monitored 6 monthly initially and then 2-3 yearly if stable. Patients who were higher risk should have a baseline bone marrow and cytogenetic analysis. If this is consistent with MGUS then 6 monthly monitoring for the first year, with annual monitoring of serum protein electrophoresis biochemistry/FBC.

Many advances have been made in the last 10-20 years giving us more effective treatments for myeloma. As cytogenetic/molecular genetic advances are made, patients with MGUS who may be at greater risk of progression could be identified and this may enable more effective monitoring and timely treatment strategies.

 

Further reading

  • International myeloma working group 2010 guidelines
  • Multiple Myeloma: Diagnosis and Treatment, S. Vincent Rajkumar, Shaji Kumar – Mayo clinic proceedings
  • How I manage monoclonal gammopathy of undetermined significance – Ronald S. Go and S. Vincent Rajkumar – Blood 2018 131:163-173; doi: https://doi.org/10.1182/blood-2017-09-807560
  • http://www.bloodjournal.org/content/131/2/163?sso-checked=true
  • Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM): novel biological insights and development of early treatment strategies – N.korde et al Blood. 2011 May 26; 117(21): 5573–5581.

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 Myeloma/paraproteins | Tagged , , ,

Case 91 – update 2

We have been monitoring our patient 6 monthly for 4 years. His para protein has been slowly rising and was 10g/l on his last visit 3 months ago. He has been bought to clinic slightly earlier to monitor his paraprotein.

Our patient attends his routine review and mentions a lump he has noticed on one of his ribs. It isn’t tender, and is none mobile.

Questions:

  • What could this be? What other information do you need?
  • How would you proceed?
  • What blood tests would you normally do at a routine 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 Myeloma/paraproteins | Tagged , , ,

Case 91 – update 1

So our patient has been seen by haematology.

He initially presented with shoulder pain. Following X-ray and MRI this has been shown to be due to osteoarthritis with no evidence of lytic lesions.

Bone marrow had shown a normocellular marrow with 4% plasma cells

We have diagnosed our patient with IgA MGUS.

Questions:

  • How would you proceed?
  • What information would you tell the patient?

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

Posted in Myeloma/paraproteins | Tagged , , ,

Case 91 – the beginning

Welcome to this week’s TeamHaem case!

This week we start in general practice.

A 70 year old man saw your colleague complaining of shoulder pain.

Some bloods were done as he was due his ‘well man’ bloods around the same time.

FBC

  • Hb 145g/l
  • Plt 270
  • Wcc 8.0
  • Neuts 3.5

U&E

  • Na 136
  • K+ 4.1
  • Urea 4.0
  • Creat 77

Immunology

  • IgA 2.97g/L normal range 0.64-2.97
  • IgG 10g/l normal range 5.8-15.4g/l
  • IgM 1.5g/l normal range 0.24-1.9g/l
  • There is a monoclonal igA lambda paraprotein 2g/l

 

Questions:

  • What would you say to the patient?
  • What other information would you like to know?

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 Myeloma/paraproteins | Tagged , , ,

Case 90 – summary

We started with a 74 year old gentleman who was admitted with weight loss, fatigue and change in bowel habit. A mass in the right iliac fossa was palpated and a colonic malignancy was suspected. He had thrombocytosis with microcytic indices and Hb 74g/l consistent with iron deficiency. This was confirmed with a ferritin of 7μg/l. The management of iron deficiency consists of:

  1. Finding and correcting the cause
  2. Replacing iron

A colonoscopy was organised and therefore it was suggested that iron was replaced. This can be done in a number of ways:

  • Modification of diet – this is unlikely to replace depleted stores but can be useful to maintain adequate stores
  • Oral iron supplementation
    • Can be bought from health food shops alone or as a multivitamin – doses are generally low
    • Can be prescribed at higher doses (there is an increasing evidence base that alternate days 60mg elemental iron (e.g. ferrous sulphate 200mg) is more efficacious and better tolerate than the traditional TDS regime – see references)
  • Intravenous iron supplementation
  • Red cell transfusion – generally avoided unless the patient is very symptomatic or intervention is required and cannot wait for the effects of iron supplementation

Features can vary from being pale and fatigued to cardiac complications. The history can often help determine the speed of onset – here this was a gradual decline in function so it is likely iron deficiency has been longstanding. Often these patients can tolerate a lower haemoglobin as their body has time to compensate. Unfortunately in this case the patient was prescribed two units of red cells without taking this into account – especially as the patient did not describe chest pains, palpitations or severe breathlessness. The other key point was the patient’s body weight. He was only 48kg and patients with lower body weight should have their prescription altered. As a general guide, transfusing a volume of 4ml/kg will typically give a Hb increment of 1g/dl. The concept that one unit of red cells gives a Hb increment of 1g/dl should only be applied as an approximation for a 70-80 kg patient.

 

Transfusion-associated circulatory overload (TACO)

Our patient became more short of breath and hypoxic towards the end of the second unit. A CXR revealed some upper lobe diversion and small pleural effusions.CXR oedema

TACO is the most common cause of death associated with transfusion. There were 86 reported to SHOT in the UK in 2016. There were 14 deaths where the transfusion was considered to be contributory, 1 definitely related, 5 probably related and 8 possibly related. This likely represents an under-reporting.

Presents with:

  • Acute or worsening respiratory distress within 6 hours of transfusion (some cases may occur up to 12 hours).
  • Hypertension
  • Pulmonary oedema, raised JVP
  • Hypoxia
  • Positive fluid balance
  • PA pressures above 18mmHg
  • No neutropenia
  • Raised Hb

 

Those at risk are:

  • Elderly
  • Pregnant
  • Heart disease
  • B12/folate deficiency
  • Already overloaded/positive fluid balance
  • Renal failure
  • Co-administration of IV fluids

This may help in the assessment of those at risk (Taken from 2016 SHOT report):

TACO.jpg

Investigations/management

  • Stop the transfusion
  • Assess the patient: ABCDE
  • Give oxygen
  • Bloods: FBC, U&E, pro-NT-BNP, repeat group and screen (sometimes the cause of deterioration is not clear initially)
  • CXR
  • Intravenous diuretic

 

Transfusion-associated lung injury (TRALI)

TRALI and TACO can appear similar, but TRALI is very rare. There were no confirmed cases in the UK in 2016. This is usually due to anti-HLA class I and II or anti-HNA antibodies (especially HNA-1a and HNA-3) in donated product against patient WCC and pulmonary epithelium. Results in ARDS picture with tissue damage to lungs and alveolar spaces filled with fluid. It occurs within six hours of transfusion and plasma-containing products are more commonly implicated. May get mild neutropenia and the JVP is not elevated. Blood pressure may go down and there may be fever. It is comfirmed with clinical features and an antibody in the patient’s plasma with concordant antigen on the donated product. Management is supportive and often ventilation is required. Incidence has reduced due to better testing and definitions in addition to using male only plasma in FFP and platelets (men are less likely to have HLA/HNA antibodies than women who are sensitised during pregnancy) or the use of pooled FFP (e.g. Octaplas) where any antibody in donors is dilute due to the number of people that contribute to one unit.

 

Delayed haemolytic transfusion reaction

Delayed haemolytic transfusion reactions (DHTR) are defined as fever and other symptoms/signs of haemolysis more than 24 hours after transfusion; confirmed by one or more of the following: a fall in Hb or failure of increment, rise in bilirubin, incompatible crossmatch not detectable pre transfusion. It is important to remember that in many transfusion labs a serological (or ‘wet’) crossmatch  (i.e. the patients plasma is mixed with the donated red cell) is not performed in all cases. We rely on looking for the ABO group, RhD status, Kell (in some cases) and looking for an antibody. There are over 30 blood group systems and over 300 antigens – it’d be impossible to match for all antigens. Therefore when anyone has a transfusion there is a risk that they will develop an antibody where there has been a mismatch. This is around 2-4%. We look for an antibody by buying three patient’s red cells. These three patients will have a variety of antigens on the red cell surface and assuming our patient’s plasma does not react with any of these red cells we can assume that there is no clinically significant antibody. This is a very robust system but occasionally things can fall through the net. Such as:

  • Wrong blood in tube.
  • Antibody is at a very low level and not detected by the screening panel but can re-appear when transfused) – the Kidd blood group is well recognised for causing this.
  • There is an antibody to an antigen that is not featured on the red cell screening panel (antibody to low frequency antigen) – usually these antibodies are non-significant but can be on occasions

 

Delayed haemolytic transfusion reactions should be suspected if there is new onset jaundice or the haemoglobin has fallen back to baseline after a transfusion. Investigations should include a full haemolysis screen (FBC, reticulocytes, LDH, haptoglobin, direct/indirect bilirubin, blood film, urine haemosiderin and a direct antiglobulin test). The DAT (or Coomb’s test) looks for any antibody on the patient’s red cells. A repeat antibody screen should be performed and a ten red cell panel to specify any antibody. An eluate (washing any antibody off the patient’s red cells) should also be performed to identify any antibody.

 

Management of delayed haemolytic transfusion reaction are generally supportive. Folic acid can be administered. Red cells can be given if required but this may need input from a specialist immuno-haematology transfusion laboratory. Once a patient has developed one antibody they are at risk of another. From now on these patients will require a serological cross match and as well as being ABO and RhD compatible any donated blood should also be negative for the implicated antigen. Some labs may try and match for all of the Rh antigens (C, c, E, e) as these are commonly implicated.

 

In our patient you can see that the blood film showed spherocytes:Case 63 film with answers

You can also see that the repeat screening panel was positive in lines two and three (see that these red cells had Jka antigens on their surface and that the reaction was stronger in two where there was more Jka on the red cell surface (i.e. the red cells in two did not also express Jkb).

 

A more comprehensive red cell panel is below: Anti-JKA

Antibody panel 2.jpg

From these anti-Jka is the most likely culprit and our patient did not express Jka on his red cells. These are pretty advanced transfusion knowledge and would not be expected for most people (just for fun for the transfusion bods!). Our patient probably was sensitised from his transfusion years ago and the antibody was too weak to show on the panel but reared its head once transfused (both units were Jka+).

Important points from this case:

  • Use blood transfusion appropriately – could our patient have managed with iron replacement? IV iron would be appropriate as oral iron not good pre colonoscopy
  • If blood is required then transfuse one then review
  • Assess patients for risk of TACO pretransfusion – especially important if low body weight – our patient’s post transfusion Hb was >105g/l
  • Patients should be made aware of risks of transfusion
  • Be aware of delayed haemolysis – especially if the haemoglobin is back to baseline quickly
  • Both of these complications should be reported to SHOT

 

References

 

Posted in Anaemia, Laboratory morphology, Transfusion | Tagged , , , , , , , , , ,

Case 90 – update 4

Here is the antibody panel.

Can you identify the antibody?

 

Anti-JKA

Posted in Anaemia, Laboratory morphology, Transfusion | Tagged , , , , , , ,

Case 90 – update 3

Our patient is one week post two units of blood and his haemoglobin is back to baseline and has hyperbilirubinaemia. LDH is elevated and haptoglobins are absent. Blood film shows spherocytes.

Case 63 film

Here is the antibody screen

Positive screen.jpg

Antibody screen.jpg

Questions

  • (For fun!) can anyone guess what the antibody may be based on the screen alone?

 

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 Anaemia, Laboratory morphology, Transfusion | Tagged , , , , , , , ,

Case 90 – update 2

Our patient is treated for potential pulmonary oedema associated with blood transfusion (transfusion-associated circulatory overload). The differential was TRALI but given its rarity and the patient’s observations (hypertension and a positive fluid balance) TACO was felt to be more likely. His post transfusion Hb was 105g/l having had two units (he weighs 48kg). After 40mg of IV furosemide he has a good diuresis and within 24 hours his oxygen saturations have normalised.

A week later he is reviewed prior to colonoscopy. He is feeling more fatigued and his daughter thinks he looks yellow. Blood tests reveal:

  • Hb 75g/l
  • WCC 10.8×109/l
  • Neutrophils 6.9×109/l
  • Platelets 450×109/l
  • Bilirubin 52μ/l

 

Questions:

  • What complication of transfusion has happened?
  • What investigations would you do now to confirm?

 

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 Anaemia, Transfusion | Tagged , , , , , , ,