RBC

and BLEEDING
DISORDERS

RBC and Bleeding Disorders

NORMAL
Anatomy, histology
Development
Physiology

ANEMIAS
Blood loss: acute, chronic
Hemolytic
Diminished erythropoesis

POLYCYTHEMIA
BLEEDING DISORDERS

TABLE 13-2 -- Adult Reference Ranges for Red Blood

Cells
Measurement (units)
Hemoglobin (gm/dL)

Men
Women
13.617.2 12.015.0

Hematocrit (%)
Red cell count (10 /L)
6

Reticulocyte count (%)

3949

3343

4.35.9

3.55.0

0.51.5

Mean cell volume (m ) MCV

8296

Mean corpuscular hemoglobin

(pg) MCH
Mean corpuscular hemoglobin
concentration (gm/dL) MCHC

2733

RBC distribution width

3337
11.514.5

WHERE is
MARROW?
Yolk Sac: very early embryo
Liver, Spleen: NEWBORN
BONE
CHILDHOOD: AXIAL SKELETON &
APPENDICULAR SKELETON BOTH
HAVE RED (active) MARROW
ADULT: AXIAL SKELETON RED
MARROW, APPENDICULAR
SKELETON YELLOW MARROW

MARROW
FEATURES
CELLULARITY
50%

MEGAKARYOCYTES at least 1-2/hpf

M:E RATIO 3:1
MYELOID MATURATION 1/3 bands or more
ERYTHROID MATURATION
nucleus/cytoplasm
LYMPHS, PLASMA CELLS small
percentage
STORAGE IRON, i.e., HEMOSIDERIN
present
FOREIGN CELLS

MARROW
DIFFERENTIATIO
N

ANEMIAS*
BLOOD LOSS
ACUTE
CHRONIC

IN-creased destruction
(HEMOLYTIC)
DE-creased production

* A good definition would be a decrease in OXYGEN CARRYING

CAPACITY, rather than just a decrease in red blood cells, because
you need to have enough blood cells THAT FUNCTION, and not just
enough blood cells.

Features of ALL
anemias

Pallor, where?
Tiredness
Weakness
Dyspnea, why?
Palpitations
Heart Failure (high output),
why?

Blood Loss
Acute: trauma
Chronic: lesions of
gastrointestinal tract, gynecologic
disturbances. The features of
chronic blood loss anemia are the
same as iron deficiency anemia,
and is defined as a situation in
which the production cannot keep
up with the loss.

HEMOLYTIC
HEREDITARY
MEMBRANE disorders: e.g., spherocytosis
ENZYME disorders: e.g., G6PD deficciency
HGB disorders (hemoglobinopathies)

ACQUIRED
MEMBRANE disorders (PNH)
ANTIBODY MEDIATED, transfusion or
autoantibodies
MECHANICAL TRAUMA (vascular or mechanic)
INFECTIONS
DRUGS, TOXINS
HYPERSPLENISM

IMPAIRED PRODUCTION
Disturbance of proliferation and
differentiation of stem cells:
aplastic anemias, pure RBC aplasia,
renal failure
Disturbance of proliferation and
maturation of erythroblasts
Defective DNA synthesis:
(Megaloblastic)
Defective heme synthesis: (Fe)
Deficient globin synthesis:
(Thalassemias)

MODIFIERS
MCV, microcytosis,
macrocytosis
MCH
MCHC, hypochromic
RDW, anisocytosis

HEMOLYTIC
ANEMIAS

Life span LESS than 120 days

Marrow hyperplasia (M:E),
EPO+
Increased catabolic products,
e.g., bilirubin, serum HGB,
hemosiderin, haptoglobinHGB

HEMOLYSIS
INTRA-vascular
(vessels)
EXTRA-vascular
(spleen)

M:E Ratio normally

3:1

HEREDITARY
SPHEROCYTOSIS

Genetic defects affecting

ankyrin, spectrin, usually
autosomal dominant
Children, adults
Anemia, hemolysis,
jaundice, splenomegaly,
gallstones (what kind?)

Glucose-6-Phosphate
Dehydrogenase (G6PD)
Deficiency
A- and Mediterranean are most significant types

FEATURES of G6PD
Defic.
Genetic: X-linked
Can be triggered by foods (fava
beans), oxidant substances drugs
(primaquine, chloroquine), or
infections
HGB can precipitate as HEINZ bodies
Acute intravascular hemolysis can
occur:
Hemoglobinuria
Hemoglobinemia
Anemia

Sickle Cell
Disease

Classic hemoglobinopathy
Normal HGB is 2 2:
-chain defects (Val>Glu)
Reduced hemoglobin sickles in homozygous
8% of American blacks are heterozygous

Clinical features of HGB-S

disease

Severe anemia
Jaundice
PAIN (pain CRISIS)
Vaso-occlusive disease:
EVERYWHERE, but clinically
significant bone, spleen
(autosplenectomy)
Infections: Pneumococcus, Hem.
Influ., Salmonella osteomyelitis

THALASSEMIA
S

A WIDE VARIETY of diseases involving GLOBIN

synthesis, COMPLEX genetics

Alpha or beta chains deficient synthesis

involved
Often termed MAJOR or MINOR, depending on
severity, silent carriers and traits are seen
HEMOLYSIS is uniformly a feature, and
microcytic anemia, i.e, LOW MCV (just like
iron deficiency anemia has a low MCV)
A crew cut skull x-ray appearance may be
seen in severe erythroid hyperplasia.

Hemoglobin H
Disease
Deletion of THREE alpha chain
genes
HGB-H is primarilly Asian

HIGH

HGBhas a
affinity
for oxygen
HGB-H is unstable and therefore
has classical hemolytic behavior

HYDROPS
FETALIS
FOUR alpha chain genes are deleted, so
this is the MOST SEVERE form of
thalassemia
Many/most never make it to term
Children born will have a SEVERE
hemolytic anemia as in the
erythroblastosis fetalis of Rh disease:
Pallor (as in all anemias), jaundice,
kernicterus
Edema (hence the name hydrops)
Massive hepatosplenomegaly (hemolysis)

Nocturnal
Hemoglobinuria
(PNH)

GlycosylphosPhatidylInositol
(lipid rafts)

ACQUIRED, NOT INHERITED like all the

previous hemolytic anemias were
ACQUIRED mutations in
phosphatidylinositol glycan A (PIGA)
Note: It is P and N only 25% of the
time!

Immunohemolytic
Anemia

All of these have the presence of

antibodies and/or compliment
present on RBC surfaces
NOT all are AUTOimmune, some
are caused by drugs
Antibodies can be
WARM AGGLUTININ (IgG)
COLD AGGLUTININ (IgM)
COLD HEMOLYSIN (paroxysmal)
(IgG)

IMMUNOHEMOLYTIC
ANEMIAS
WARM AGGLUTININS
(IgG), will NOT
hemolyze at room temp

Primary Idiopathic (most common)

Secondary (Tumors, especially
leuk/lymph, drugs)

COLD AGGLUTININS: (IgM), WILL

hemolyze at room temp
Mycoplasma pneumoniae, HIV,
mononucleosis

COLD HEMOLYSINS: (IgG) Cold

Paroxysmal Hemoglobinuria, hemoLYSIS in body, ALSO often follows
mycoplasma pneumoniae

COOMBS
TEST
DIRECT: Patients CELLS
are tested for surface
Abs
INDIRECT: Patients
SERUM is tested for
Abs.

HEMOLYSIS/HEMOLYTIC
ANEMIAS DUE TO RBC
TRAUMA
Mechanical heart
valves breaking
RBCs
MICROANGIOPATHIE
S:
TTP
Hemolytic Uremic
Syndrome

NON-Hemolytic Anemias:
i.e., DE-creased
Production
Megaloblastic
Anemias

B12 Deficiency (Pernicious Anemia)

Folate Deficiency
Iron Deficiency
Anemia of Chronic Disease
Aplastic Anemia
Pure Red Cell Aplasia
OTHER forms of Marrow Failure

MEGALOBLASTIC
ANEMIAS
Differentiating

megaloblasts (marrow)
from macrocytes
(peripheral smear,
MCV>94)
Impaired DNA synthesis
For all practical
purposes, also called
the anemias of B12 and
FOLATE deficiency
Often VERY
hyperplastic/hypercellul
ar marrow* (* exception
to the rule)

Decreased intake
Inadequate diet, vegetarianism
Impaired absorption
Intrinsic factor deficiency
Pernicious anemia
Gastrectomy
Malabsorption states
Diffuse intestinal disease, e.g., lymphoma, systemic sclerosis
Ileal resection, ileitis
Competitive parasitic uptake
Fish tapeworm infestation
Bacterial overgrowth in blind loops and diverticula of bowel
Increased requirement
Pregnancy, hyperthyroidism, disseminated cancer

Vit-B12
Physiology
Oral ingestion
Combines with INTRINSIC
FACTOR in the gastric mucosa
Absorbed in the terminal

ileum

DEFECTS at ANY of these sites

can produce a MEGALOBLASTIC
anemia

Please remember that ALL

megaloblastic anemias are also
MACROCYTIC (MCV>94 or
MCV~100), and that not only are
the RBCs BIG and
hyperplastic/hypercellular, but so
are the neutrophils, and
neutrophilic precursors in the
bone marrow too, and even more
so, HYPERSEGMENTED!!!

PERNICIOUS
ANEMIA
MEGALOBLASTIC anemia
LEUKOPENIA and HYPERSEGS
JAUNDICE???
NEUROLOGIC posterolateral spinal
tracts
ACHLORHYDRIA
Cant absorb B12
LOW serum B12
Flunk Schilling test, i.e., cant
absorb B12, using a radioactive
tracer

FOLATE DEFICIENCY
MEGALOBLASTIC
AMEMIAS

Decreased Intake: diet, etoh-ism,

infancy
Impaired Absorption: intestinal
disease
DRUGS: anticonvulsants, BCPs,
CHEMO
Increased Loss: hemodialysis
Increased Requirement: pregnancy,
infancy
Impaired Usage

Fe Deficiency
Anemia

Due to increased loss or

decreased ingestion, almost
always, in USA, nowadays,
increased loss is the reason
Microcytic (low MCV),
Hypochromic (low MCHC)
THE ONLY WAY WE CAN LOSE
IRON IS BY LOSING BLOOD,
because FE is recycled!

Fe
Transferrin
Ferritin/apo- (GREAT
test)
Hemosiderin

Clinical Fe-DeficAnemia

Adult men: GI Blood Loss

PRE menopausal women:
menorrhagia
POST menopausal women:
GI Blood Loss

2 BEST lab
tests:

Serum Ferritin
Prussian blue
hemosiderin stain of
marrow (also called
an iron stain)

Anemia of Chronic
Disease*

CHRONIC INFECTIONS
CHRONIC IMMUNE
DISORDERS
NEOPLASMS
LIVER, KIDNEY failure
* Please remember these patients may very very much
look like iron deficiency anemia, BUT, they have
ABUNDANT STAINABLE HEMOSIDERIN in the marrow!

APLASTIC
ANEMIAS
ALMOST ALWAYS involve platelet
and WBC suppression as well
Some are idiopathic, but MOST
are related to drugs, radiation
FANCONIs ANEMIA is the only one
that is inherited, and NOT
acquired
Act at STEM CELL level, except for
pure red cell aplasia

APLASTIC
ANEMIAS

APLASTIC
ANEMIAS
CHLORAMPHENICOL
OTHER ANTIBIOTICS
CHEMO
INSECTICIDES, benzene, toluene,
TNT
VIRUSES
EBV
HEPATITIS
VZ

MYELOPHTHISIC
ANEMIAS
Are anemias caused by
metastatic tumor cells replacing
the bone marrow extensively

POLYCYTHEMIA
Relative (e.g., hemoconcentration)
Absolute
POLYCYTHEMIA VERA (Primary) (LOW EPO),
mutation in tyrosine kinase, making RBCs hyper
responsive to EPO
POLYCYTHEMIA (Secondary) (HIGH EPO)
HIGH ALTITUDE
EPO TUMORS
EPO Doping
CVAC, the trendy California bubble pods

P. VERA

A
myeloproliferative
disease
ALL cell lines are
increased, not just
RBCs

BLEEDING DISORDERS
(aka, Hemorrhagic
DIATHESES)
Blood vessel wall abnormalities
Reduced platelets

Decreased platelet function

Abnormal clotting factors

DIC (Disseminated INTRAvascular

plats.

Coagulation), also has

VESSEL WALL
ABNORMALITIES
(angiopathic
thrombocytopenias)
(NON-thrombotic
purpuras)
Infections, especially, meningococcemia,

and rickettsia
Drug reactions causing a leukocytoclastic
vasculitis
Scurvy, Ehlers-Danlos, Cushing syndrome
Henoch-Schnlein purpura (mesangial
deposits too)
Hereditary hemorrhagic telangiectasia
Amyloid

THROMBOCYTOPENI
AS

Like RBCs:

DE-creased production
IN-creased destruction
Sequestration (Hypersplenism)
Dilutional

Normal value

300K

150K-

DE-CREASED
PRODUCTION

APLASTIC ANEMIA
ACUTE LEUKEMIAS
ALCOHOL, THIAZIDES, CHEMO
MEASLES, HIV
MEGALOBLASTIC ANEMIAS
MYELODYSPLASTIC
SYNDROMES

IN-CREASED
DESTRUCTION

AUTOIMMUNE (ITP)
POST-TRANSFUSION (NEONATAL)
QUINIDINE, HEPARIN, SULFA
MONO, HIV
DIC
TTP
MICROANGIOPATHIC

THROMBOCYTOPENIA
S

ITP (Idiopathic
Thrombocytopenic Purpura)
Acute Immune
DRUG-induced
HIV associated
TTP, Hemolytic Uremic
Syndrome

I.T.P.

ADULTS AND ELDERLY

ACUTE OR CHRONIC
AUTO-IMMUNE
ANTI-PLATELET ANTIBODIES
PRESENT

INCREASED

MARROW
MEGAKARYOCYTES
Rx: STEROIDS

ACUTE ITP
CHILDREN
Follows a VIRAL illness (~ 2
weeks)
ALSO have anti-platelet
antibodies
Platelets usually return to
normal in a few months

DRUGS
Quinine
Quinidine
Sulfonamide
antibiotics

HEPARIN

HIV

BOTH DE-creased
production AND INcreased destruction
factors are present

Thrombotic
Microangiopathies
BOTH are very SERIOUS
CONDITIONS with a HIGH mortality:
TTP (THROMBOTIC
THROMBOCYTOPENIC PURPURA)
H.U.S. (HEMOLYTIC UREMIC SYNDROME)

These can also be called

consumptive coagulopathies, just
like a DIC

QUALITATIVE platelet
disorders

Mostly congenital (genetic):

Bernard-Soulier syndrome
(Glycoprotein-1-b deficiency)
Glanzmanns thrombasthenia
(Glyc.-IIB/IIIA deficiency)
Storage pool disorders, i.e.,
platelets mis-function because of
defective granulation
ACQUIRED: ASPIRIN, ASPIRIN,
ASPIRIN

PTT

PT/INR

BLEEDING DISORDERS due to

CLOTTING FACTOR DEFICIENCIES
NOT spontaneous, but following
surgery or trauma
ALL factor deficiencies are possible
Factor VIII and IX both are the classic
X-linked recessive hemophilias, A and
B, respectively
ACQUIRED disorders often due to
Vitamin-K deficiencies (II, VII, IX, X)
von Willebrand disease the most common,

1%

von Willebrand
1% prevalence,Disease
most common bleeding disorder
Spontaneous and wound bleeding
Usually autosomal dominant
Gazillions of variants, genetics even more
complex
Prolonged BLEEDING TIME, NL platelet count
vWF is von Willebrand Factor, which complexes
with Factor VIII, to join platelets with the
exposed ECM in endothelial disruption. it is the
von Willebrand Factor which is defective in von
Willebrand disease
Usually BOTH platelet and FactorVIII-vWF
disorders are present

PTT

PT/INR

HEMOPHILIA A

The classic HEMOPHILIA

Factor VIII decreased
Co-factor of Factor IX to activate Factor X
Sex-linked recessive
Hemorrhage usually NOT spontaneous
Wide variety of severities

Prolonged PTT (intrinsic) only

Rx: Recombinant Factor VIII

HEMOPHILIA B

The Christmas HEMOPHILIA

Factor IX decreased
Sex-linked recessive
Hemorrhage usually NOT spontaneous
Wide variety of severities

Prolonged PTT (intrinsic) only

Rx: Recombinant Factor IX

DIC, Disseminated INTRAvascular, Coagulation

ENDOTHELIAL INJURY
WIDESPREAD FIBRIN
DEPOSITION
HIGH MORTALITY
ALL MAJOR ORGANS COMMONLY
INVOLVED

DIC, Disseminated INTRAvascular, Coagulation

Extremely SERIOUS condition

NOT a disease in itself but secondary to
many conditions

Obstetric: MAJOR OB complications, toxemia,

sepsis, abruption
Infections: Gm-, meningococcemia, RMSF,
fungi, Malaria
Many neoplasms, acute promyelocytic
leukemia
Massive tissue injury: trauma, burns, surgery

Consumptive

coagulopathy

Common Coagulation
TESTS

PTT (intrinsic)
PT INR (extrinsic)
Platelet count, aggregation
Bleeding Time, so EASY to
do
Fibrinogen
Factor Assays

RBC
LAB

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