PANCYTOPENIA approach and management.pptx

APPROACH TO PANCYTOPENIA
PRESENTOR : DR. SOUNDARYA
MODERATOR : DR. KATHIRAVAN

CONTENTS
• DEFINITION
• MECHANISMS OF PANCYTOPENIA
• CAUSES OF PANCYTOPENIA
• INITIAL EVALUATION
• SUBSEQUENT EVALUATION
• EMERGENCIES IN PANCYTOPENIA
• SPECIAL CLINICAL SCENARIOS

DEFINTION
Pancytopenia refers to decrease in all peripheral blood lineages.
• Red blood cells - Hemoglobin < 12 g/dl for non pregnant women and <13 g/dl for
men
• White blood cells - Because neutrophils constitute majority of leukocytes in the
peripheral blood and bone marrow, nearly all cases of low white blood cells
( leukopenia ) manifests as neutropenia.
• Absolute neutrophil count (ANC) < 1800/microL
• < ANC= Total white blood cells/microL x (percent{polymorphs + bands} ÷ 100 >
• Platelets - Platelet count < 1,50,000/microL

MECHANISMS OF PANCYTOPENIA
• Hematopoiesis in the healthy adult takes place in the bone marrow, from which
mature blood cells migrate into circulation, spleen and other sites.
• Bone marrow is a dynamic organ and a hematopoietic reservoir that responds
to ongoing needs for blood cell production.
• Hence a balance between blood cell production, distribution in other organs,
and ongoing cellular destruction determines the level of circulating blood cells.
Broadly speaking pancytopenia may be caused by one or more of the following
mechanisms :

MECHANISMS OF PANCYTOPENIA
• BONE MARROW INFILTRATION/ REPLACEMENT - Hematologic malignancies (eg:
leukaemia, lymphoma, multiple myeloma, myelodysplastic syndromes ), metastatic
cancer, myelofibrosis and infectious diseases (military tuberculosis, fungal
infections)
• BONE MARROW APLASIA - Nutritional disorders (eg: deficiencies of Vitamin B12 or
folate), aplastic anaemia, infectious diseases ( eg: HIV, viral hepatitis, parvovirus
B19), immune destruction and medications
• BLOOD CELL DESTRUCTION OR SEQUESTRATION - Excessive blood cell destruction
in disseminated intravascular coagulation, thrombotic thrombocytopenic purpura
and ineffective hematopoiesis (eg: myelodysplastic syndromes, megaloblastic
disorders), while excessive sequestration may be due to hypersplenism ( eg: liver
cirrhosis, storage diseases, lymphoma, or autoimmune disorders)

CAUSES OF
PANCYTOPENIA
• Acquired
• Congenital

INITIAL EVALUATION
HISTORY:
Important considerations in the history include :
• Time course and clinical severity - Prior lab results (when available) and severity and
duration of symptoms should be evaluated.
SYMPTOMS ASSOCIATED WITH CYTOPENIAS:
• Recurrent, severe or unusual infections that may be due to leukopenia/neutropenia
• Fatigue, dyspnea, chest pain, hemodynamic instability due to anaemia
• Bleeding or easy bruising due to thrombocytopenia or disseminated intravascular
coagulation
• Constitutional symptoms, including fevers, night sweats and/or weight loss
• Nausea, vomiting and jaundice that may be associated with liver disease

HISTORY
PREVIOUS TREATMENTS :
• Determine if the patient has previously been treated for hematologic disorders,
including prior transfusions, hematinics (eg. Vitamin B12, folate, iron) or other
treatments (eg. apheresis, plasma exchange)
OTHER MEDICAL CONDITIONS :
• Almost any comorbid medical conditions or surgical procedure can contribute to
or exacerbate cytopenias
PROBLEMATIC MEDICATIONS :
• Many medications ( including prescription and over-the-couter medications,
health supplements and home/folk remedies) may cause or contribute to
cytopenias.

HISTORY
• Some medications (cytotoxic or immunosuppressive agents) cause predictable
decrease in blood counts that are generally reversible if the agent is reduced or
stopped.
PERSONAL AND OCCUPATIONAL EXPOSURES:
• Certain personal habits (eg. alcohol consumption, diet), infection history (eg. HIV,
viral hepatitis), exposure to toxic agents at work or home (eg.organic solvents),
and travel history (eg. exposure to malaria, leishmania) may also be relevant.

PHYSICAL FINDINGS
• Rashes that may be related to drug reactions, rheumatological disorders,
infections and malignancies
• Oral lesions such as thrush suggests immune compromise; oral ulcers may be
seen in diseases such as SLE
• Lymphadenopathy and/or splenomegaly
• Jaundice and stigmata of liver disease; Pallor
• Petechiae, ecchymosis, bruises

LABORATORY STUDIES
• Complete blood count
• Peripheral blood smear
• Reticulocyte count
• Prothrombin Time and partial thromboplastin time
• Renal and liver function tests, electrolytes, LDH, uric acid
• Blood type and Screening

SUBSEQUENT EVALUATION
BONE MARROW ASPIRATE AND BIOPSY :
• It is important in patients for whom primary hematologic disorder is suspected as cause of
pancytopenia. (Eg: acute leukaemia, aplastic anaemia, multiple myeloma) or when cause of
pancytopenia remains elusive after initial evaluation.
• Differential diagnosis of pancytopenia will inform further specialised testing of bone
marrow and/ or peripheral blood (eg: flow cytometry, cytogenetics, molecular studies,
microbiologic cultures)
• Example: Direct antiglobulin testing and flow cytometry may be needed to confirm the
diagnosis of PNH.
• Cytogenetic testing (FISH or karyotype) of bone marrow or peripheral blood may be
required for confirmation of diagnosis of many hematologic malignancies (eg: leukemias,
myelodysplastic syndrome, myeloproliferative neoplasms, lymphomas)

EMERGENCIES
• Clinical stabilisation is the highest priority for patients with pancytopenia.
• Immediate hospitalisation may be required to control life-threatening infections,
provide blood product support, and/or manage other medical emergencies.
Pancytopenia associated with the following clinical situations will require immediate
haematology consultation or hospitalisation:
• Neutropenia
• Symptomatic anaemia
• Thrombocytopenia
• Suspected DIC, TTP, HUS, acute leukaemia, severe aplastic anaemia,
hemophagocytic lymphohistiocytosis

EMERGENCIES
NEUTROPENIA :
• Absolute neutrophil count < 1000/microL with fever and/or other evidence of
infection or other acute illness.
• New diagnosis of moderate or severe neutropenia (ANC <1000/microL and
<500/microL, respectively)
THROMBOCYTOPENIA :
• New finding of platelets < 10,000/microL
• Clinically significant bleeding with platelets <50,000/microL

EMERGENCIES
• Suspected DIC, TTP, HUS or other thrombotic microangiopathy because of schistocytes
on peripheral blood smear accompanied by elevated lactate dehydrogenase.
Suspected acute leukaemia:
• New diagnosis (eg. circulating blasts)
• Medical emergencies associated with leukaemia (DIC from acute promyelocytic
leukaemia, tumour lysis syndrome)
• Suspected severe aplastic anaemia (ANC < 500/microL, platelets < 20,000/microL,
anaemia with reticulocyte count <20,000/microL) or other bone marrow failure
syndrome.
• Suspected hemophagocytic lymphohistiocytosis (HLH) because of unexplained fever,
hepatomegaly, lymphadenopathy, and/or neurologic symptoms in association with
very high serum ferritin, liver function abnormalities and/or coagulopathy.

METABOLIC EMERGENCIES IN PANCYTOPENIA
• Hypercalcemia with symptoms (eg: delirium, abdominal pain, dehydration)
associated with cause of pancytopenia (eg: multiple myeloma, metastatic cancer,
adult T cell leukemia/ lymphoma)
• Acute renal failure (eg: hyperkalemia, dehydration, fluid overload) associated
with the cause of pancytopenia (eg. multiple myeloma, tumour lysis syndrome)
• Hyperuricemia with renal failure associated with the cause of pancytopenia.

COAGULOPATHY
• Finding of elevated PT and/or APTT in the setting of pancytopenia should focus
immediate attention on determining if MAHA is present.
• This requires urgent examination of peripheral blood smear for presence of
schistocytes with thrombocytopenia.
• Presence of MAHA may raise possibility of DIC that may be due to sepsis, acute
promyelocytic leukaemia or other causes.
• If MAHA is not found, other explanations should be sought for abnormal
coagulation profile. (Eg: liver disease, vitamin K deficiency, medications)

ABNORMAL CELLS ON BLOOD SMEAR
• Abnormal cells on peripheral smear should be
examined to distinguish hematologic
malignancies (Eg: leukaemia, lymphoma,
myelodysplastic syndrome) from other
disorders, such as infections (eg: atypical
lymphocytes associated with viral or other
infections), marrow replacement disorders (eg:
myelofibrosis, metastatic cancer, multiple
myeloma), and megaloblastic conditions.

ABNORMAL MALIGNANT CELLS ON SMEAR
• Circulating blasts : Leukemia
• Dysplastic leukocytes, including pseudo-Pelger-Huet cells or reduced neutrophil
cytoplasmic granules : Myelodysplastic syndromes
• Immature myeloid cells - Promyelocytes, myelocytes, and metamyelocytes :
Myeloproliferative neoplasm like primary myelofibrosis
• Leukoerythroblastic findings - nucleated red blood cells : Myelofibrosis or other
MPNs

ABNORMAL MALIGNANT CELLS ON SMEAR
Confirmation of the nature of such abnormal cells will require further specialised
testing including:
• Bone marrow aspirate and biopsy
• Flow cytometry of peripheral blood and/or bone marrow
• Cytogenetic testing (fluorescence in situ hybridisation {FISH} or karyotype) of
bone marrow or peripheral blood
• Molecular studies (eg: mutation analysis, gene expression profiling)

NON-MALIGNANT CELLS ON SMEAR
• Hypersegmented neutrophils (five or more nuclear lobes) in association with
ovalomacrocytes : megaloblastic disorder (folate and/or vitamin B12 deficiency)
• Atypical lymphocytes (lymphoid cells with generous and malleable cytoplasm
indented by surrounding red cells : during or following viral infections such as IM
or hypersplenism
• Leukoerythroblastic appearance of blood smear with RBS teardrops, nucleated
RBCs and MAHA : myelofibrosis or metastatic cancer
• Presence of schistocytes or MAHA : DIC, due to sepsis, acute promyelocytic
leukaemia or other causes

HYPOPROLIFERTAIVE CONDITIONS
• Reticulocytopenia ( < 20,000/microL ) - hypo proliferative pancytopenia
• Suspected severe aplastic anaemia along with reticulocytopenia requires
emergency evaluation.
Defining the nature of a hypoproliferative bone marrow condition usually requires
testing the following:
• Serum vitamin B12, folate and/or copper
• Serologic studies to evaluate viral etiologies or autoimmune illness
• Bone marrow aspirate and biopsy, flow cytometry of peripheral blood

SPLENOMEGALY AND/OR LIVER DISEASE
• Presence of splenomegaly and
pancytopenia suggests
hypersplenism (sequestration or
excessive destruction of blood cells in
an enlarged spleen).
• All cell lineages may be affected.
• The extent of cytopenias are
generally less severe than that
caused by primary bone marrow
disorders.
Conditions associated with
pancytopenia in the setting of
splenomegaly and/or liver disease
include:
Liver disease/ cirrhosis and
Portal hypertension
Congestion (right sided
congestive heart failure)
Infections (virals infections,
malaria, leishmaniasis,
endocarditis)
Inflammation (associated
with rheumatoid arthritis
[Felty syndrome])
Hematologic malignancies
(lymphomas, hairy cell
leukaemia,
myeloproliferative
neoplasms
Primary splenic disease
(haemorrhage, thrombosis)
Extramedullary
hematopoiesis (associated
with myelofibrosis or
thalassemia)
Storage diseases (Gaucher
disease); Hemophagocytic
lymphohistiocytosis

LYMPHADENOPATHY
Detection of lymphadenopathy (localised or generalised) provides information
regarding the cause of pancytopenia which includes:
• Hematologic malignancies (lymphoma, leukaemia)
• Autoimmune illness
• Infectious diseases
Evaluation includes:
• Imaging (CT scan, USG or PET scan)
• Lymph node biopsy (including morphology, molecular studies)
• Bone marrow aspirate and biopsy; Flow cytometry of peripheral blood; serological
studies

AUTOIMMUNE CONDITIONS
Autoimmune diseases associated with pancytopenia includes:
• Rheumatoid arthritis/ Felty syndrome
• Systemic lupus erythematosus
• Sarcoidosis
An important component of management of cytopenia in autoimmune illness is
identifying conditions that contributes cytopenias:
• Folate/ Vitamin B12 deficiency associated with pernicious anaemia, autoimmune
thyroid disease should be sought and managed.
• Alternative therapeutic agents may be considered to lessen bone marrow
suppression
• Splenectomy may be considered in some patients with symptomatic Felty
syndrome.

CONSTITUTIONAL SYMPTOMS
• Pancytopenia may present in the setting of otherwise unexplained fevers,
soaking sweats, and weight loss.
• It may be especially important to consider an infectious etiology or
hemophagocytic lymphohistiocytosis in this setting.
Possible causes of pancytopenia associated with constitutional symptoms include:
• Infections (Viral illness, miliary tuberculosis, fungal infection, endocarditis)
• Hemophagocytic lymphohistiocytosis (HLH)
• Hematologic malignancies (Eg: lymphoma, leukemia)
• Autoimmune illness

HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS
Diagnosis of HLH is supported by the following:
• Serum ferritin is usually very high (often >5000 ng/ml)
• Elevated liver enzymes (AST, ALT, GGT), LDH and bilirubin
• Hypofibrinogenemia
• Marked elevation of triglycerides
• Soluble CD25 - Elevated soluble IL-2 receptor alpha
• Low/absent NK cell function/ degranulation by flow cytometry
• Bone marrow biopsy - findings of hemophagocytosis and/or infiltration by activated
macrophages
• Splenomegaly and/or hepatomegaly may be present

METABOLIC ABNORMALITIES
• Certain metabolic disorders (eg: hypercalcemia, tumor lysis syndrome, renal
failure, hyperuricemia) may be associated with diseases that also cause
pancytopenia, including multiple myeloma, leukaemia and lymphoma.
• Review of disease status to assess progressive disease or treatment resistance,
including restaging of lymphomas or myeloma should be done (Eg. repeat CT or
PET-CT)
• Assessment of a fundamental change in the disease (eg: Richter transformation
of a previously diagnosed lymphoma, progression of myelodysplastic syndrome
to acute leukaemia) may require repeat bone marrow or lymph node biopsy.
• Complications of treatment (eg: drug associated bone marrow aplasia, treatment
- associated leukaemia) should be assessed

SUSPECTED MEDICATIONS
• When a particular medication is suspected, consideration should be given to
discontinuing that medication or reducing the dose.
• This is influenced by severity of cytopenias, trajectory of blood counts, clinical
symptoms and the reason why the medication is administered.
• For cytotoxic or myelosuppressive agents, blood count recovery can generally be
expected within days to weeks.
• When an idiosyncratic reaction is a likely cause of pancytopenia, a response to
discontinuing the medication is less predictable and recovery of blood counts may
be protracted.
• Clinical presentation and appearance of bone marrow in such situations may be
indistinguishable from idiopathic aplastic anaemia.

SUSPECTED MEDICATIONS
• An immediate bone marrow biopsy may not be helpful when a medication is
suspected to be the cause of pancytopenia.
• Also if a biopsy is performed early in the recovery process, the bone marrow may
erroneously suggest an acute leukaemia, because recovering cells may exhibit a
maturation arrest as hematopoiesis has only progressed to an immature stage of
maturation.
• Mechanism : Allergic reactions that affect bone marrow production and/or
increase peripheral destruction and pseudo-allergic reactions.
• Allergic reactions may be influenced by the patient’s immunologic background (i.e
HLA type), comorbid conditions, pharmacogenomic constitution, prior exposure
to that medication or related drugs, and other clinical features.

YOUNG PATIENTS WITH MILD CYTOPENIAS
• A younger adult with mild, aymptomatic pancytopenia may have no definitive
clinical findings to suggest the cause of cytopenias.
• History may reveal family members with autoimmune conditions, thyroid disease
or pernicious anaemia and the patient may have vague musculoskeletal
symptoms, but does not meet diagnostic criteria for an autoimmune disorder.
• Such an asymptomatic patient with mild pancytopenia may have serial outpatient
evaluation of CBC and peripheral smear and be counselled about monitoring
symptoms.
• A bone marrow biopsy may not be helpful in this setting as no diagnostic
abnormalities may be identified, unless there is suspicion of an associated
immune disorder or lymphoma.

ADULT PRESENTATION OF INBORN ABNORMALITIES
• Rarely patients may present with late onset congenital disorders.
• Patients may have had mild, long standing cytopenias that were not evaluated or
for which initial diagnostic testing was unrevealing.
• In some cases, findings that were previously dismissed (eg: premature graying of
hair, abnormalities of finger nail or skeleton ) may be related to an underlying
congenital abnormality.
• Monocytopenia, recurrent viral infections, disseminated non tuberculous
mycobacterial infections, opportunistic fungal infections, pulmonary alveolar
proteinosis and primary lymphedema may suggest GATA2 deficiency.
• Family history of liver cirrhosis or pulmonary fibrosis raises the possibility of a
telomere biology disorder.

PANCYTOPENIA approach and management.pptx

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