Investigation and Management of Pancytopenia

Dr Sarah Wharin

Consultant

Haematologist

Aims

Case-based

Investigation of a patient with pancytopenia

Specific situations

When to involve haematology

De-mystify some haematology lingo

Curriculum areas covered

Recognise when specialist Haematology opinion is indicated

Bone marrow failure: causes and complications

Myelodysplastic syndromes

Leukaemia

Thrombocytopaenia

Case 1

62 year old gentleman, previously very fit and well

Attended GP with extreme fatigue and SOBOE

FBC: HB 100g/L, MCV 125, WCC 1.4, Neuts 0.10, Plts110

History and examination?

History and examination

No serious infections/ fever. No bruising bleeding

No regular medications, no other health problems.

Normal diet, no change in bowel habit, no significant weight loss

Fit- runs, swims, cycles

Office worker, no occupational exposure

No previous chemotherapy or radiotherapy

Examination: Pale. Small groin node

No hepatosplenomegaly

Investigations?

B12 172, folate 8.3, ferritin 326

LDH 196. Virology negative

CT: No lymhpadenopathy/ hepatosplenomegaly

Serum Igs: Normal levels but IgG kappa paraprotein of 6g/L. Normal kappa/lamda ratio

Investigations continued- blood film

Film: Macrocytic anaemia with oval

macrocytes, tear drops. Note Vit B12 low, results

could be consistent with B12 deficiency

although the neutropenia is very severe.

Atypical lymphocytes also seen- ?recent viral

infection? Suggest replace B12 (6 injections of

hydroxycobalamin in next 2 weeks). Recheck

bloods in 7 days to ensure counts are

recovering. If any fever or signs of infection, will

need treating as neutropenic sepsis (SW, SpR)

What Next?

Phone discussion- if

not improving, will need a

bone marrow biopsy

Severe neutropenia BUT-had film features

convincing of B12 with an

associated low level

What about the

paraprotein??

Discharged with follow up

arranged

7 days post

admission

HB 101, MCV 122

Plts 125

Neuts 0.1

Retics 52

What now?

Bone Marrow Biopsy

This marrow aspirate contains a ~40-

45% population of small/medium

sized cells with intermediate

granularity and the phenotype

CD45w+ CD117+ CD34+ CD13-.

CD33w+ CD14- CD64- CD15- DR+

CD79a- cCD3- TdT+ MPOw+,

consistent with AML

FISH and cytogenetics normal

Diagnosis: AML

Can present with leucopenia or leucocytosis

Leukaemia ‘blasts’ usually but not always visible on the blood film

AML and ALL are often indistinguishable clinically and morphologically

Cause cytopenias by ‘replacement’ and resulting bone marrow failure

Risk stratified by cytogenetics, mutation profile and response to chemo

High risk fit patients are offered bone marrow transplants after remission

is achieved.

What

happened

next?

Treated on AML-18 trial.

Had standard treatment with Daunorubicin and Cytarabine (DA3+10)

Refractory disease after 1st cycle of chemo.

Had second line chemo with Fludarabine, Idarubicin and cytarabine

Achieved a remission. Received a second cycle of FLAG-Ida

Has just been discharged after his allogeneic bone marrow transplant!

Causes of

cytopenias

Reduced production : infiltration

(haematological, non- haematological),

fibrosis, myelosuppression (drugs, infections)

Bone marrow failure: Immune destruction

(Aplastic anaemia), Nutritional, ineffective

haematopoiesis (e.g. MDS)

Destruction/ Consumption:

Hypersplenism of any cause, sepsis

Haematological Cause of pancytopenia

Diagnosis Clues in history and examination Blood film/ lab results

MDS Usually older patient.

Suspect if previous chemotherapy

Insiduous onset

‘dysplastic changes’, ‘red cell

poiklocytosis’. ‘Pseudo-Pelger-Huët’

Usually macrocytic. Ferritin may be high

Myelofibrosis Constitutional symptoms, itching.

Spleen symptoms (eg early satiety)

Splenomegaly

‘Leucoerythroblastic film’ (‘nucleated

red blood cells, neutrophil left shift,

blasts’). ‘Tear drop poiklocytes’. High

LDH.

Hairy Cell

leukaemia

Insiduous onset- anaemia symptoms, infections.

May have B symptoms

Splenomegaly

‘large to medium size lymphocytes with

eccentric ‘lentiform’ nuclei and

cytoplasmic villi’. Monocytopenia

Aplastic

Anaemia

Symptoms of bone marrow failure. May be

prior viral infections and inflammatory

conditions

Nothing specific. Low retics.

Bone marrow

infiltration

Other systemic symptoms or history of cancer

(esp prostate)

Leucoerythroblastic film

Leucoerythroblastic

film

(Myelofibrosis, marrow

infiltration, B12 deficiency)

Blast cell Nucleated RBCs

Tear drop poiklocytes immature granulocytes

Hairy cell leukaemia MDS

Normal Bone marrow trephine vs Aplastic

anaemia

Learning

points

Baseline investigations: Haematinics,

LDH, retics, viral serology, film

Consider CT if any B symptoms or

lymphadenopathy

If haematinic deficiency: Should see

improvement in retic count in 4 days

and in blood parameters in 7-10 days

If no improvement, needs urgent BM

biopsy

Case 2

86 year old man

Admitted with SOB and dizziness.

Wt loss over 1 year

Hb 50 WCC 1.6 neuts 1.10 plts 5 retics 12

Film: Pancytopaenia with severe

anaemia and thrombocytopaenia.

Normal red cell morphology but lack of

appropriate reticulocyte response.

Thrombocytopaenia appears genuine.

Morphologically normal neutrophils.

Haematinics noted to be normal.

Haematology aware. AJS P.Clin.Sci.

Investigations

B12 242

Folate 5.7

Ferritin raised

Serum Igs normal

LDH 209

Viral serology normal

CT CAP showed bladder lesion: Patient didn’t want any further investigation

Severe mitral regurgitation

AF- PPM inserted in March 2019

Recent aspiration pneumonia

Rapid deterioration in GFR

Severe erosive gastritis and

duodenal ulcers on OGD in

March 2019

Discussion with Cardiologists

May 2019: Not fit for surgery.

Diuresis difficult due to renal

function

Differential diagnosis? What

next?

On Reviewing notes

What actually happened…

He had a bone marrow biopsy!

Some dysplastic changes. Hypocellular

CONCLUSION: Hypoplastic anaemia ?MDS. ?AA. Suggest repeat from other side. Check PNH screen.

(He also had 6 units of blood and 2 pools of platelets)

What did we do after this?

Nothing! Patient and family did not want any further tests/ invasive investigations, did not want to come to and from hospital. Came to clinic once and was discharged with an EHCP

Learning Points

MDS is a common cause of cytopenias in the elderly- management is largely supportive

It is a pre-leukaemic condition and a minority of patients with excess blasts will benefit from low dose chemotherapy

Diagnosis is academic if the patient is frail and does not wish to undergo investigations

May help to discuss prognosis and forward planning

Check with patient how much input they want and liaise with haematology accordingly

Case 3

40 year old lady with severe

psoriasis and psoriatic arthropathy

Presented with PR bleeding

Found to be pancytopenic

HB: 68 plts 20 neuts 0.1. CRP 200

History?

Management?

Case 3

Medications: Methotrexate, Adalimumab: Reviewed by rheumatology- both stopped

Given folinic acid

Given platelets, transfused blood.

Treated for infective exacerbation of psoriasis/ neutropenic sepsis with broad spectrum antibiotics

Case 3

Day 5 of admission. Counts not improving.

Seen by Haem SpR- Needs bone marrow biopsy.

Transferred to haematology on a Friday morning, plan for BM biopsy Monday morning

What is going on??

Case 3

Monday morning… pt very reluctant to

have marrow. Nurses very reluctant to

do it (Pt BMI around 50)

Realised she was not incrementing to

platelet transfusions

Neutrophils had completely recovered

Decided not to do a biopsy and give

steroids instead

Platelets went up to 42 by next day!

Discharged home. Followed up in clinic

Patient not fussed about her blood

counts, wants to get back onto

treatment for arthropathy!

Learning Points

Not all pancytopenias are haematology

badness

Mixed pathology/ multifactorial:

myelosuppression due to MTX and anti-TNFα

+ Consumption due to infection

+ Anaemia due to GI bleed

+ ITP

Check the drug history

Pancytopenias due to medications can take

many weeks to recover. If BM biopsy performed

too early- non diagnostic and confusing

Medications

that can

cause

cytopenias

Immunosuppressants

Cytotoxics

‘Biologics’ (case series in J Am Acad Dermatol 2009 regarding anti-TNFa and low platelets)

Antibiotics (chloramphenicol, co-trimoxazole, linezolid)

Carbimazole, propylthiouracil

Anti-epileptics (Valproate, carbamezapine, phenytoin)

Anti-psychotics

The list goes on and on!

Methotrexate Induced pancytopenia

Risk factors: Elderly, polypharmacy, renal impairment

Monitoring protocols and folic acid prophylaxis

In acute severe pancytopenia: stop drug

Folic acid or folinic acid?? Case series in clinical rheumatology 2018 suggests that folinic acid may speed up haematological recovery compared to folic acid

?GCSF: If we are sure it is MTX/ medication related and film is clear- GCSF can be given

If any doubt- need bone marrow first to exclude acute leukaemia

Next treatment options?

A little word

on platelets

Is patient bleeding or not?

Mild (plts >100), moderate (50-100) or severe (<50)

Stop anticoagulants and antiplatelets if platelets <50

Check clotting- think DIC. If DIC, look for cause (sepsis, malignancy etc).

Any recent viral illness/ immune disorder to make you think ITP?

Always check for HIV/ BBI

Check any recent new medications

HIT is less likely than the above causes.

If in doubt (history of heparin exposure), look up HIT score and take a good history from patient/ review of their drug chart

Platelets

continued

Investigations as for pancytopenia although isolated thrombocytopenia as a presentation of a wider bone marrow problem is rare

ITP can be triggered by a lymphoproliferative disorder (CLL or lymphoma) so CT CAP is useful

Always ask for a blood film:

‘macrothrombocytes’: non-specific, but makes ITP/ consumption more likely

If schistocytes mentioned- think TTP! Look for other features and call haematology immediately! Urgently check haemolysis markers

When to ring the

Haematologist…

If platelets low and patient bleeding

Any suspicions of TTP (neurological symptoms, renal impairment, raised haemolysis markers etc)

If patient is on AC or antiplatelets and you have concerns about stopping

If none of the above but you have done all the investigations and still have no idea what is going on!

Any

Questions?