OS 2 16

Bone Marrow Failure States HEMATOLOGY

Block B
Trans 15 | Exam
Dr. Beatrice J. Tiangco 1

OUTLINE
I. Clinical Case III Aplastic Anemia (AA)
II. Bone Marrow Failure
III. Aplastic Anemia
IV. Severe Aplastic Anemia
* Clinical disorder defined by pancytopenia and
V. Transfusion Principles for Managing Aplastic bone marrow hypocellularity
Anemia * Must be differentiated from other disease
VI. Pure Red Cell Aplasia (PRCA) conditions presenting with pancytopenia and
VII. Acquired Pure Amegakaryocytic
Thrombocytopenic Purpura (APATP) hypocellular marrow
VIII. Pure White Cell Aplasia
IX. Myelodysplastic Syndrome (MDS) A. DIFFERENTIAL DIAGNOSIS OF PANCYTOPENIA AND BONE
X. Anemia of Chronic Disease (ACD) MARROW HYPOCELLULARITY
* Idiopathic Aplastic Anemia
I Clinical Case * Inherited Aplastic Anemia
* Hypocellular Myelodysplasia
A 14 year old boy presents with sore throat, rash, * Aleukemic Leukemia
gum bleeding. He was well until three weeks ago. * Paroxysmal Nocturnal Hemoglobinuria
The throat was red. His legs have petechiae. No * Myelofibrosis
lymphadenopathy, no organomegaly, with * Hairy Cell Leukemia
temperature of 38 C. * Tuberculosis
* Anorexia Nervosa
Labs: Hb: 8.9g/dl
Hct: .30 B. KEY POINTS IN THE DIAGNOSTIC APPROACH FOR PATIENTS
MCV: 103 fL WITH PANCYTOPENIA
WBC: 2,200/L
Neutrophil: 10-20
Lymphocytes: 80 * History including medications, previous
Platelet: 18,000 chemotherapy and radiotherapy, occupational
Reticulocyte count: 1% toxic exposure and family history
* Physical Examination paying attention to
presence of organomegaly, lymphadenopathy,
II Bone Marrow Failure musculoskeletal abnormalities
* CBC including absolute reticulocyte count and
[picture was shown] peripheral smear
Normal Bone Marrow: 50% is occupied by marrow, * LFT, hepatitis serologies, Vit B12, Folate
non-uniform population of cells due to varying * Bone Marrow Aspirate and Biopsy
degrees of maturation and presence of three cell * Cytogenetic studies for congenital forms
lineages * Chromosomal fragility if <40yo
Abnormal Bone Marrow: marrow is limited to
<10%, mostly occupied by fat; hypocellular C. GRADING AND SEVERITY OF AA

A. CAUSES OF BONE MARROW FAILURE A. SEVERE

* Primary reduction in hematopoietic cells, e.g. Peripheral blood: 2 of three values
ANC/Granulocytes <0.5 x 10 /L
aplastic anemia
Platelets < 20 x 10 /L
* Replacement of marrow by malignant cells, e.g. Corrected Reticulocytes < 1%
leukemia, lymphoma, carcinoma
* Ineffective hematopoiesis, e.g. MDS, MA Bone marrow trephine
* Infiltration by abnormal tissue, e.g. Markedly hypocellular marrow <25% cellular
myelofibrosis, amyloidosis Moderately hypocellular, 25-50%

B. CLINICAL FEATURES Normal cellularity with <30% of remaining cells hematopo

* S/Sx: anemia, infection, bleeding as result of the B. VERY SEVERE

underlying cause As above but granulocytes < 0.2 x 10 /L
* Laboratory features Infection present
~ Leucopenia, thrombocytopenia of varying
severity
~ Blood film may show circulating red cell and
white cell precursors (leukoerythroblastic),
caused by bone marrow infiltration or may
show evidence of primary hematological
malignancy (e.g. blasts)
~ Bone marrow aspirate and biopsy are
required to define the cause

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Bone Marrow Failure States HEMATOLOGY
Block B
Trans 15 | Exam
Dr. Beatrice J. Tiangco 1

D. EPIDEMIOLOGY chondropla
sia
* May present at any age, predominantly a Median 7.5 yrs 16 yrs 4 months
disease of young people (median 20-25 years) age at
* Annual European/North American incidence: 2 diagnosis
per million First pancytope pancytope Pancytope
* Asian countries: 11 per million hematolog nia nia nia
* Poor prognosis, 1 year survival of <20% with ic
manifestat
supportive treatment only
ion
Bone aplastic aplastic Hypocellul
E. PATHOGENESIS marrow ar,
maturation
* Stem cell defects
arrest
* Stromal cell defect and overproduction of Features Fanconi Dyskerat Shwachm
negative hematopoietic regulatory growth Anemia osis an-
factors, e.g. interferon, TNF Congenit Diamond
* Lymphocyte-mediated suppression of a Syndrom
hematopoiesis e
Leukemia 12% 0.4% 5%
Solid 5% 10% 0%
F. ETIOLOGY OF ACQUIRED APLASTIC ANEMIA Tumors
Chromoso Increased Bleomycin Normal
* Idiopathic: 70% in NA, 50% in the Philippines mes breaks sensitive
* Toxins: benzene, petroleum products, with
insecticides clastogens
* Drugs: NSAIDs, anticonvulsants, antithyroid, (DEB,
mitomyoci
gold, quinacrine, sulfonamides, phenothiazines,
n C)
etc.
* Viruses: hepatitis, infectious mononucleosis
* Radiation
IV Severe Aplastic Anemia (SAA)
* Chemotherapy
* Pregnancy
* Marrow biopsy <25% cellularity
* Any two of the following
G. ETIOLOGY OF GENETIC APLASTIC ANEMIA
~ ANC < 500
* Fanconi’s anemia with or without physical ~ Platelets < 20,000
abnormalities ~ Absolute reticulocyte count < 60,000
~ Microcephaly
~ hypogonadism A. TREATMENT CONSIDERATIONS
* Dyskeratosis congenita
* Severity of aplasia
~ Hyperpigmentation
* Age
~ Dystrophic nails
* Availability of HLA-id donor
~ Mucosal leukoplakia
~ Pancytopenia
B. TREATMENT MODALITIES IN SAA
* Shwachman Diamond Syndrome
~ Pancreatic exocrine insufficiency * Bone Marrow Transplantation (BMT)
~ Neutropenia, pancytopenia ~ Hematopoietic recovery is faster, complete,
stable
Table: Salient and clinical features of inherited bone marrow ~ High TRM
failure states
Features Fanconi Dyskerat Shwachm ~ Long-term complications
Anemia osis an-
Congenit Diamond
a Syndrom
e
Cases 1000 225 200
reported
Genetics Autosomal X-linked Autosomal
recessive recessive
Physical Microceph Reticulate Failure to
abnormalit aly, d thrive,
ies hypogonad pigmentati diarrhea
ism, on, (pancreatic
malformati dystrophic insufficien
on of nails, cy),
thumb and leukoplaki metaphyse
kidney a al

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Dr. Beatrice J. Tiangco 1

Cyclophosphamide: Used in the preparation of Bone Marrow

ATG
Methylprednisone: immunosuppressant and is afterwards
useful in countering the effects of ATG (eg. fever, chills) – Only
done in PGH, not in other hospitals

* Immunosuppressive Therapy
~ Hematopoietic response is slow, often Bone marrow transplantation has a higher survival
incomplete rate (60-70%) compared to Immunosuppressive
~ Transfusion independent rather than Therapy (<50%)
normalization of blood counts
~ Relapse is common
~ Evolution to clonal disease

Patients >40yo are better candidates for

Immunosuppressive Therapy than BMT (because
of side effects)
Cyclosporine may have effect on the BM of the patient C. KEY POINTS: TREATMENT OF APLASTIC ANEMIA
* SCT from a mismatched sibling donor is the
treatment of choice for patients < 30 -years with
ANC < 500 and adults 20-40 years with ANC
<200
* For older patients, those without sibling donors,
and those who refuse SCT, immunosuppression
with ATG and cyclosporine should be initiated
within 14 days of diagnosis

D. MAJOR FACTORS WHICH INCREASE RISK OF

GRAFT REJECTION IN BMT IN SAA

Not Discussed
* Any degree of HLA mismatching
* Sensitization of recipient through multiple blood/platelet
transfusions prior to BMT
* Infusion of low numbers of donor cells
* Reduction in strength of IS conditioning regimen employed
* Reduction in post-transplant immunosuppression

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Bone Marrow Failure States HEMATOLOGY
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Dr. Beatrice J. Tiangco 1
* Use of T-cell depletion to prevent GVHD B. PATHOGENESIS OF PRCA
* Antibody-mediated
* Lymphocyte-mediated erythroid aplasia
* Human Parvovirus-induced (attach to
erythroblast)
* Stem cell disorder – PRCA as a preleukemic
manifestation

C. PROGNOSIS OF PRCA
* Acute and self-limited disease in children
* Chronic and relapsing course in adults
* Spontaneous remissions in 10-12%
* Evolution to AA
* Transformation to ANLL

D. THERAPY OF PRCA
* Discontinuation of suspected offending drugs
V Transfusion Principles for * Immunologic surgery (thymectomy,
Managing AA splenectomy)
* Immunosuppressive therapy, cytotoxic
* Transfuse RBCs for symptomatics only, for Hb < * Immunosuppressive therapy, biological
8 g/dL * Plasmapheresis, lymphocytopheresis
* Transfuse platelets for bleeding only or if * Immunomodulating-IV Ig
platelets < 10,000
* Employ prophylactic EACA (E-Amino Caproic VI Acquired Pure Amegakaryocytic
Acid) to reduce mucosal bleeding I
Thrombocytopenic Purpura (APATP)
* Use leukocyte-poor filtered and irradiated blood
products to minimize allosensitization * Severe thrombocytopenia associated with total
absence or marked reduction in BM
* Avoid use of family members as blood donors
megakaryocytes
(because of transfusion-associated GVHD)
* Minimal changes in other hematopoietic cellular
elements
***OUTCOME OF CLINICAL CASE***
* Pathogenesis of APATP
* Accordingly, the recommended treatment for the ~ Viral: hepatitis, parvo, HIV, measles
14 year old boy would be bone marrow ~ Immune-mediated: systemic lupus
transplant. erythematosus (SLE)
* The patient has an HLA-compatible sister and ~ Stem-cell disorder: evolution to AA
he received a bone marrow transplant within 6
months of his diagnosis. His transplant was
uncomplicated and he is now finishing his high VIII Pure White Cell Aplasia
school.
* Complete disappearance of granulocytopoietic
tissue from the BM
* Normal erythroid/megakaryocytopoiesis
VI Pure Red Cell Aplasia (PRCA) * Associated with thymoma, infections, drugs
* Recurrent infections with fever, chills, sepsis
* Selective aplasia of the erythroid cell line IX MyeloDysplastic Syndrome (MDS)
* Anemia and reticulocytopenia
* Normal WBC and platelet counts * Heterogenous group of clonal hematologic
disorders characterized by ineffective
A. CLASSIFICATION OF PRCA hematopoiesis (unable to mature and
differentiate  pancytopenia) and usually,
* Congenital – Diamond Blackfan Syndrome
hypercellular bone marrow
* Acquired
* Dysplastic features of the erythroid, myeloid,
~ Primary – autoimmune, idiopathic, megakaryocytic cell lines (at least two cell
preleukemia
lines)
~ Secondary – associated with thymoma,
* Preleukemic disease
infections, nonthymic solid tumors,
hematologic malignancies, collagen vascular A. CLASSIFICATION OF MDS
diseases, drugs, pregnancy, severe renal
failure, ABO incompatible BMT FAB Classification of WHO classification of
MDS: MDS:

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Dr. Beatrice J. Tiangco 1

E. PROGNOSIS OF MDS
Refractory Anemia (RA) Refractory Anemia
With ringed Low risk 0 3.9 – 11.8 y
Refractory anemia with sideroblasts INT – 1 0.5-1.0 2.4 – 5.2 y
ringed sideroblasts (FAB RARS) INT – 2 1.0-2.0 1.2 – 1.8 y
(RARS) Without ringed HIGH >2.5 0.3 – 0.4 y
Refractory anemia with sideroblasts (FAB
excess blasts (RAEB) RA)
Refractory anemia with Refractory Cytopenia
excess blasts in with multilineage X Anemia of Chronic Disease (ACD)
transformation (RAEB-T) dysplasia (new)
Chronic myelomonocytic 5q- Syndrome (New)
* Anemia associated with reduced erythropoietin
leukemia (CMML) Unclassified (New) response
* Inflammatory states: acute and chronic bacterial
infections, collagen vascular disease, AIDS,
B. CLINICAL FEATURES OF MDS malignancies
* Renal disease: nephritis, ESRD
* Most prevalent in older adults (median age – 64 * Hypometabolic states: protein deprivation,
years) endocrine deficiency states (hypothyroidism,
* Natural history ranges from rapid progression to hypopituitarism, hyperparathyroidism)
AML or chronic course that can last for years * Therapy of ACD
* Death due to complications of cytopenias, ~ Treat underlying cause
progression to AML, or other co-morbidities not ~ Transfusion support
related to MDS ~ Erythropoietin

C. PATHOGENESIS OF MDS
* Ineffective hematopoiesis rather than lack of
hematopoietic activity – increased levels of
apoptotic mediators like TNF-a
* Chromosomal abnormalities – deletions or gains
in all or parts of chromosomes 5, 7, 8, 20
* Therapy-related MDS

Table: FAB Classification of MDS

Disease Periphera Bone Median
l Blood Marrow Survival
RA Blasts < Blasts < 50 months
1% 5%
RARS Blasts < RS > 15% 50 months
1%
RAEB Blasts < Blasts 5- 11 months
5% 20%
RAEB-1 Blasts > Blasts 20- 5 months * in patients with chronic disease anemia has
5% 30% multiple etiologies: poor nutrition, blood loss,
CMML > 1x10/L Any of the 11 months
anemia of chronic disease (ACD)
monocytes above
* ACD is 2nd to iron deficiency anemia in
Table: International Prognostic Scoring System (IPSS) for MDS incidence
Parameter Criteria Score * There is decreased serum iron and transferrin
BM Blast Count < 5% 0 saturation
5-10% 0.5 * There is normal to increased ferritin and
11-20% 1.5 increased iron in bone marrow macrophages
21-30% 2.0
Karyotype Normal/5q- 0 Jan: Hello 2010! Last trans for this module. Sana magamit
Other 0.5 niyo ito, dahil pinaghirapan namin ito. Last People, the
3 abnormalities 1.0 fun never stops with you guys around! The End, ang
galing talaga natin, same ang date ng lecture at ng trans
Cytopenias None or 1 0
deadline, pero ano, nagawa natin! Thanks for the effort!
2 or 3 0.5 Hehe. Block B, good luck sa exam tomorrow! Punta kayo
bukas sa diliman, bahay ng alumni, What’s up doc?
D. TREATMENT OF MDS Heroes on Call:The Step UP concert feat parokya ni edgar,
kjwan, mojofly, sago, pedicab, hemp republic, typecast
* Conventional chemotherapy and many more.…P50 lang tickets for UP students, 100
for nonUP. Sulit talagang pangdetox after ng hema. Punta
* Growth factor support and supportive care na! God bless!
* Transplantation Table: Comparison of IDA and Anemia due to Chronic Disease
* Novel therapies: azacytidine, decitabine, Normal Iron Chronic
thalidomide, arsenic trioxide range defiency disease
anemia

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 OS 2 16
Bone Marrow Failure States HEMATOLOGY
Block B
Trans 15 | Exam
Dr. Beatrice J. Tiangco 1

Plasma 70-190 30 (↓) 30 (↓) underKeeping me from seeing the real thing?Love hurts…But sometimes
it’s a good hurtAnd it feels like I’m aliveLove singsWhen it transcends the
iron, μg/dl bad thingsHave a heart And try me, ‘cause without love I won’t surviveI’m
TIBC, μg/dl 250-400 450 (↑) 200 (↓) fettered and abusedI stand naked and accusedShould I surface this one
% 30 7 (↓↓) 15 (↓) man submarine?I only want the truthSo tonight we drink to youthI’ll never
lose what I had as a boySometimes when I’m alone, I wonderIs it a spell
saturation hat I am underKeeping me from seeing the real thing?Love hurts…
Macrophag 2+ 0 (↓)/none 3+ (↑) But sometimes it’s a good hurtAnd it feels like I’m aliveLove singsWhen it
e iron in transcends the bad thingsHave a heart and try me,‘Cause without love I
won’t survive!
bone
marrow Iaia: (umalis na siya eh) Hi friends! Hi charmed ones!
Serum 20-200 10 (↓) 50 (↔) Blessed be!
ferritin,
μg/L
Serum 8-28 Increased Normal
ferritin
receptor,
nmol

* three separate pathophysiological defects exist

and interact in ACD:
~ failure of erythropoiesis
~ lack of iron for Hb synthesis
~ decreased RBC survival
* the above defects result from increased TNF-α
(due to inflammation), which causes sustained
secretion of IL-1
* increased levels of TNF- α and IL-1 tend to:
~ decreased plasma iron
~ decreased transferring
~ shunting of iron to macrophages via
lactoferrin; once iron is bound to lactoferrin, it
is delivered exclusively to macrophages and
is no longer available for erythropoiesis

GREeTINGs!
TINA: Thank you Shiney for helping me type the
additional notes! Tatang, are you ready for love?
Lalalalala =D Mamai, brace yourself for my stories!
bwahaha! Japs, it’s a privilege to be your ex. =b Fidesky,
bata ka pa. Tarsky, Mel R., Leah, Jo T, Jobs, Vivi, Trina,
Sheng, Odelle, Iaia, Glai, Mabelle, thank you! Last People
Standing, sayang hindi ako nakasama.  Psychmates,
and saya ng elective natin! Ang saya niyong kasama!
Agape, I’m so excited for Overjoyed! Domdom, I’ll miss
you a lot when you go to the community  hay, three
months of med school left…God bless you all! 

PeeWeeWee: Sabog na ako and stressed so baka di ko

magreet ang lahat ng greetables. Gid (borrow ng
Melancholy Whores ni Marquez ), Siena (sorry nahawa
ka sa akin! Here’s to never assuming), Aldi and Kimmy
ng 2011, was fun going to the island with you. Sama uli
ako next time. The End: Jan (kilabot ka talaga ng mga
pasyente) Iaia (salamat sa pagformat), Tina (salamat sa
pagpicture and patypeng ppt!), to more transes til the
year ends. Kris, samahan mo na ako sa Agent X44, ikaw
lang gusto ko makasama dun. Sige na para di naman
puro Taming of the Shrew ang maexpose tayo sa mga
Dunkin Donato type films. Lastpeoplestanding (LPS),
here’s to more outing extremes. Bakit puro We love you
lahat? Nakakain lang kayo ng crispy pata, nasenti na
kayo? Pero sige na nga (pee)We(e) love(s) you LPS na din.
I cant’t speak for my group kasi. Anne Lim! Hi, gusto lang
kita igreet. Ang ganda ng combination ng
RAW/Smackdown at Disney Songs? Hehe Download ka ng
Hercules, yung song ni meg. Speaking of downloads,
sinong may Light Grenades ng Incubus? Parip/burn/copy
naman! Please, please please? Ganda eh (para sakin lang
kahit na pangit ang ibang review nun). Eto lyrics ng isang
song dun Love Hurts by Incubus from Light Grenades
Tonight we drink to youthAnd holding fast to truthI don’t want to lose what I
had as a boyMy heart still has a beatBut love is now a featAs common as a
cold day in LASometimes when I’m alone, I wonderIs it a spell that I am

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