Bone marrow failure

syndromes
curs 6
CURS 6
Bone marrow failure syndrome (BMFS) is a group of disorders that
may manifest as single cytopenia (eg, erythroid, myeloid, or
megakaryocytic) or as pancytopenia. It can be either inherited or
acquired.
FA = Fanconi’s anemia, AA = Aplastic anemia, MDS = Myelodysplastic syndromes
DKC = Diskeratosis congenitalia, PNH = Paroxysmal Nocturnal Hemoglobinuria
AML = Acute Myeloid Leukemia, LGL = Large Granular Lymphocyte Leukemia
Aplastic anemia
• Definition: Aplastic anemia is a syndrome of
bone-marrow failure characterized by
peripheral pancytopenia and marrow
hypoplasia.

• Epidemiology:
– the incidence is 0.6-6.1 cases per million
population (median 2)
– Aplastic anemia occurs in all age groups.
 Anemia aplastica
pancitopenie + MO hipocelulara
Dobandita Constitutionala
• Idiopatica: >70-80% • Anemia Fanconi
• Post infectioasa: 5-8%
– Virala: hepatita nonA, nonB, • Diskeratoza congenitala
nonC , EBV, CMV, HHV6, VZV,
HIV, etc
• In cadrul altor sindroame de
– Non-virala: tuberculoza insuficienta medulara:
• Indusa de medicamente – trombocitopenia
– Cloramfenicol, sulfonamide, amegakariocitica congenitala
fenitoin, carbamazepina,
fenilbutazona, saruri de aur, – sdr Schwachman-Diamond
propiltiouracil, etc – anemia Diamond-Blackfan
• Indusa de substante chimice
– Benzen, insecticide (DDT), etc
• Altele: boli autoimune, HPN,
malnutritie severa
 ETIOPATHOGENY

Unknown
Drugs
Drugs
Benzene
Hepatitis
Idiopathic
Pregnancy
Aplastic anemia is an immune-mediated
T-cell destruction of the marrow
 ANEMIA

• Clinical picture:
– Slow onset
– Symptoms and signs of:
• Anemia
INFECTIONS
– fatigue, pallor
• Neutropenia
– infections
• Thrombocytopenia
– bleeding

BLEEDING
• Laboratory findings
– Pancytopenia – sometimes severe
– Bone marrow biopsy
• Hypocellularity
– Reduction of myeloid lineages
• Adipocyte hyperplasia
• Relative increase of lymphocytes and plasma
cells
- Sometimes signs of liver damage
 Bone marow biopsy:
normal cellularity

Various degrees of bone marrow hypoplasia and adipocyte hyperplasia

• Staging is based on the following criteria:

– Peripheral blood criteria

• Neutrophils - Less than 500/mmc
• Platelets - Less than 20,000/mmc
• Reticulocytes - Less than 1%
– Bone marrow criteria
• Severe hypocellularity
• Moderate hypocellularity with hematopoietic cells
representing less than 30% of residual cells

• 3 disease stages are defined:

Definition of aplastic anemia (AA)
and severity of the disease
• Treatment
1. Supportive care:
• Transfusions: red cells and platelets
• Antibiotics
• Hematopoietic growth factors
– Sometimes response to erythropoietin (Epo) and
granulocyte colony stimulating factor (G-CSF)
- Immunosuppression, T-cell targeted
• Anti-thymocyte globulin (ATG) + Cyclosporin
• Therapy of choice in patients >40 years and in those <40 years in
whom stem cell transplant cannot be done

– Allogeneic hematopoietic stem cell transplantation

(HSCT)
• Therapy of choice in young (<40 years) patients
• Second line therapy for those who fail immunosupressive
therapy or in those who do not have a donor
Two first-line treatment options for
SAA: Both improved with time
SAA: best donor?
• Prognosis
– Good in moderate aplastic anemia
– In severe AA (SAA) - variable
• 50-60% long term survival with
immunosuppressive therapy
– In few cases progression to myelodysplasia, or acute
leukemia
• 60-70% long term survival with allogeneic BMT
– Not all patients eligible for transplants
Myelodysplastic syndromes
• Definition:
– Clonal hematopoietic disorders
– Hypercellular marrow + peripheral blood
cytopenias
– Impaired morphology and maturation
(dysmyelopoiesis)
– 20-30% of MDS cases progress towards
acute myeloid leukemia (AML).
 MDS epidemiology
• MDS Epidemiology
– Common bone marrow 20
disorder

Number of patients
15
– Worldwide incidence
is ~5 per 100,000 in the
10
general population

• Median age at onset 5

is in the range 65–70 years

0
21 37 47 56 62 68 74 80 86 92
31 44 53 59 65 71 77 83 89
Age at diagnosis (years)
• Etiology
• 60-70% of patients do not have an obvious
cause - primary MDS
• Patients who survive malignancy
treatment with alkylating agents, and/or
radiotherapy, have a high risk of MDS
• Exposure to benzene, insecticides
• Pathogenesis
– Clonal expansion of a mutated
hematopoietic stem cell clone
– Increased apoptosis in hematopoietic
progenitors – peripheral cytopenias
– In late stages, new mutations appear,
leading to acute myeloid leukemia (AML)
• Clinical picture:
– Sign and symptoms:
• Anemia
– fatigue
• Neutropenia
– infections
• Thrombocytopenia
– bleeding
• Laboratory findings:
– Cytopenias
• Almost always – anemia
• Later stages: bicytopenia, pancytopenia

– Peripheral smear:
• Macrocytosis/microcytosis
• Dysplastic granulocytes
– Hypolobulated neutrophils
– Hypogranulated neutrophils
– In late stages – the presence of blastic cells
• Giant platelets
Normal
neutrophils

Hypolobulated neutrophils – the Pelger Huet

anomaly
– Bone marrow
• Hypercellular – rarely
hypocellular
• Dysplastic changes: Erythroid dysplasia

– Diserythropoiesis:
» Megaloblastosis
» Multinucleated
erythroblasts
» Ring sideroblasts

Ring sideroblasts
• Disgranulopoiesis
– Giant precursors
– Increased blasts

Disgranulopoieis

• Dismegakaryopoiesis
– Micromegakaryocytes

Dismegakaryopoieis
• Cytogenetics
– Various cytogenetical Complex karyotype (multiple abnormalities)
abnormalities – have
prognostic impact:
• Good: normal
karyptype, 5q-, -Y, 20q-
• Poor: multiple
abnormalities (complex
karyotype),
chromosome 7 7q- (del of long arm of cz 7)
abnormalities
• Intermediate: other
abnormalities

5q- (del of long arm of cz 5)

 Classification
FAB
✓ Refractory anemia (RA)
(<5% bone marrow blasts)
✓ Refractory anemia with ringed
syderoblasts (RARS) (<5%
marrow blasts plus >15% ringed
syderoblasts)
✓ Refractory anemia with excess
blasts (RAEB) (5-20% marrow
blasts)
✓ RAEB in transformation (RAEB-
T) (21-30% marrow blasts)
WHO
✓ Refractory anemia
✓ Refractory cytopenia with
multilineage dysplasia
✓ MDS-unclassified
✓ MDS with isolated del (5q)
✓ RARS
✓ Refractory cytopenias with
multilineage dysplasia and
ringed sideroblasts
✓ RAEB-1 (5-9% blasts)
✓ RAEB-2 (10-19% blasts)
International Prognostic Scoring System
 International Prognostic Scoring System
(IPSS)

Median survival (years)

All
Risk groups Score ≤60 >60
patients
Low 0 11.8 4.8 5.7

Intermediate I 0.5–1.0 5.2 2.7 3.5

Intermediate
1.5–2.0 1.8 1.1 1.2
II
High ≥2.5 0.3 0.5 0.4
• Treatment – generally not very effective:
– Supportive care
• Transfusion of RBCs or platelets
• Antibiotic treatment in case of infections
– Pathogenetic treatment aims to stimulate bone marrow cell
production, and decrease bone marrow cell apoptosis.
• Hematopoietic growth factors
– Erythropoietin
– Granulocyte colony-stimulating factor.
• Immunosuppression: ATG + Cyclosporine – in hypoplastic
MDS
• Demethylating agents (azacitidine and decitabine) may prevent
progression to AML
• Lenalidomide, a derivate of thalidomide may lead to complete
remission in MDS associated with the 5q- abnormality (5q-
syndrome)

– Combination chemotherapy – AML regimens – in RAEB –

low remission rate

- Allogeneic bone marrow transplantation in pts <60 years with

poor prognosis (RAEB) and available donor. The results are
poor, with high procedure-related death and high relapse rate.
Transfusiology
• Tranfusions: substitution of whole blood or
blood products from a donor to a recipient

– Whole blood – limited indications

• Acute post-traumatic blood loss
– Fractionated products - preferred
• Red cells – for anemia
• Platelets – for thrombocytopenia
• White blood cells – neutropenia
• Cryoprecipitate - specific clotting factors
• Fresh frozen plasma – coagulation defects, shock
– Coagulation factor concentrates – hemophilias
– Albumin
– Immunoglobulins
 The Principle Aims of
Blood Transfusion are to:-
(1) Improve oxygen carrying
capacity of blood.
(2) Symptomatic
improvement.
(3) Reduce hypovolaemia.
• 1 UNIT of Blood should
increase the Hb by
approx.1g/dL.
• If no improvement or
reduction in Hb – think
about ongoing blood loss
or destruction.
• You need treat the
underlying cause.
 Purposes

• To replace blood lost during surgery or a serious

injury.
• To restore oxygen-carrying capacity of the blood.
• To provide plasma factors to prevent or treat
bleeding.
• Done if patient’s body is not capable of making
blood properly because of an illness.
 Recommendations for Transfusion
• ≤ 9 g/dL – surgery
• ≤ 8 g/ dL – Symptomatic anaemia and blood
loss
• ≤ 7g/dL – Critically ill

But: on-going and further blood loss must be

taken into consideration as must the clinical
situation and co-morbidity!
 Chronic Anaemia

• Transfuse according to
- Symptoms
- Co-morbidities
- Level of Activity
• Correct underlying cause and deficiencies
• ‘Beware the ‘well patient’ with anaemia, Hb of
2g/dL – ‘Slowly down – Slowly up’. A large, rapid
transfusion will cause fluid overload and pulmonary
oedema.
BLOOD TYPES ABO
 Red cell transfusions
• Indications:
– Severe anemia (<7-8g/dl), in the absence of
other therapeutic means

• Compatibility – incompatible transfusions cause

immunologic reactions
– ABO system – blood groups 0, A, B, AB
• Antigens: A, B
• Antibodies: anti-B (type A), anti-A (type B)
Type O (anti A and anti B) Type AB (no anti A
no anti B)
• Incompatible transfusions cause severe
hemolytic reactions
– Rh system
• the presence or absence of Rh antibodies
in the blood.
• Incompatible transfusions cause
hemolytic reactions only after previous
immunization (no reactions at first
contact)
– Minor antigens – Kell, Ii, Lewis, MN, P, etc
• rarely cause reactions
 BLOOD TYPES

Blood Types and their Compatibility

 Whole Blood
PRODUCTS DESCRIPTION
➢ Not commonly used
except for extreme cases
Whole Blood of acute hemorrhage
➢ Replaces blood volume
and all blood products
➢ Used for blood
replacement following
Autologous Red Blood Cells planned elective surgery
➢ Must be donated 4-5
weeks prior to surgery
Packed Red Blood Cells (PRBCs)

PRODUCT DESCRIPTION

➢ Most common type of blood

product for transfusion
➢ Used to increase the oxygen-
carrying capacity of blood
➢ Help the body get rid of
carbon dioxide and other
waste products
➢ 1 unit of PRBCs = raises
hematocrit by 2-3%
 Does the patient need the transfusion?
Yes:
• Symptomatic anaemia
• Significant blood loss
• Anaemia / severe illness
• Improving Oxygen capacity of the blood

No:
• Asymptomatic Hb ≥ 8 g/dL
• ‘Well’ patient receiving alternative therapies –
EPO or Iron
• ‘Euvolaemic’ Anaemia secondary to B12 and
folate deficiencies
 Platelets
PRODUCT DESCRIPTION
✓ Severe central
thrombocytopenia
(<10,000/mmc)
✓ Usually not efficient in
immune
thrombocytopenia
✓ Replaces platelets in
clients with bleeding
disorders, or platelet
deficiency
✓ 1 unit = increases the
average adult client’s
platelet count by about
5,000 platelets/microliter
 Fresh Frozen Plasma (FFP)
PRODUCT DESCRIPTION
➢ Plasma is the liquid
component of blood; it has
proteins called clotting
factors
➢ Expands blood volume
and provides clotting
factors
➢ Contains no RBCs
➢ 1 unit of FFP = increases
level of any clotting factor
by 2-3%
 Cryoprecipitate
PRODUCT DESCRIPTION

➢ A portion of plasma
containing certain specific
clotting factors
➢ Used for clients with
clotting factor deficiencies
➢ Contains Fibrinogen
White blood cell transfusions (buffy coat)

• Few indications
– Neutropenic fever,
persistent after 48 hours
of targeted
antibiotherapy

• Compatibility
– HLA compatibility
preferred – hard to obtain
 Post-transfusion complications
• Febrile reactions
– Frequent – chills, fever
– Caused by contaminating leucocytes
– Easily treated with antipyretics
• Alergic reactions
– Frequent – rash, edema, rarely shock
– Caused by foreign plasma protein
– Treated with antihystamine drugs, corticosteroids, adrenalin
• Hemolytic reactions
– Rare – constitute medical and legal emergencies
– Caused by ABO or Rh incompatibility
– May lead to shock, acute renal failure
– Complex, intensive care treatment, may require dialysis
• Transfusion of infected blood
– Caused by incorrect handling of blood products
– May lead to toxic-septic shock
– Intensive care complex treatment
• Infectious disease transmission
– Became rare at least in certain countries
– Mostly hepatitis C, B, also HIV, other viruses
– Requires careful selection of donors, blood testing
• Hemosiderosis
– Occurs after repeated transfusions in chronic anemias
– Leads to multiple organ damage
– Requires iron chelating therapy
• Transfusion Related Acute Lung Injury (TRALI)
• Nonimune reaction
– Fluid overload

Beta-thalassemia major:
hyperpigmentation due to post-
transfusional hemosiderosis
 Generic Management of Acute Transfusion Reaction
• Most ‘reactions’ occur within the first fifteen minutes of blood being started – this is the
most important time for observations to be done. Do not hide the patient away during this
time – let the nurses know transfusions are running and that they should do formal
observations for the first fifteen minutes and then routinely.

If a reaction occurs:-
• Stop the unit of blood being transfused!

• Ensure patient is clinically well and no other pathology is present (why are they having
transfusion etc) - Treat the underlying cause of ‘reaction’; Once patient is deemed OK:-

• Disconnect and take down entire transfusion giving set and blood unit.
• Maintain venous access with normal saline
• Check administrative details from transfusion forms and patient’s wrist band
• Contact the haematology / transfusion lab and inform them you are returning the unit of
blood for testing.
• Take bloods – Blood film, FBC, Cultures, Clotting, Cross match sample (U&Es)
• If blood transfusion is essential or serious reaction occurs need further advice from
haematologist
• Nursing staff need to observe patient for signs of ‘shock’, DIC, acute renal failure
Thus ‘Regular’ observations of BP, Pulse, ToC, Urine output