649-659

IRON DEFICIENCY ANEMIA -TRANSFERRIN major function is: deliver iron to

cells such as erythroid precursors (requires iron
-Most common nutritional disorder resulting to for hemoglobin synthesis)
symptoms mostly related to inadequate
hemoglobin. -Erythroid precursors has high affinity receptors
for transferrin- mediates iron import by
receptor-mediated endocytosis.
IRON METABOLISM
Iron distribution table
-normal daily consumed iron is 10-20 mg Pool MEN WOMEN
Total 3450 2450
-most from heme contained in meats functional 2100 1750
Hemoglobin 300 250
-some are from veggies
Myoglobin 50 50
-20% of heme iron is absorbable. Storage: 1000 400
ferritin,
TOTA BODY IRON: hemosiderin
-2.5 gm in women

-6 gm in men

-divided into functional and storage

-80% of functional iron is in hemoglobin;

myoglobin and iron-containing enzymes
(catalase, cytochromes)

-Major iron storage sites: LIVER and

MONONUCLEAR PHAGOCYTES

-healthy young females= smaller iron stores,

due to blood loss during menstruation

-some develops iron deficiency during

excess loss of iron, or increased iron demand
during pregnancy.

-Iron in the body is recycled between functional

and storage pool.

-transported in plasma by iron binding

glycoprotein (TRANSFERRIN)[synthesized by the
LIVER] FREE IRON IS HIGHLY TOXIC, it is important that
iron storage is sequestered.
-TRANSFERRIN is 1/3 saturated with iron,
yielding serum iron levels is to averaging 120 -it is secured by binding of iron is
µg/dL (MEN) and 100µg/dL (WOMEN). storage pool: FERRITIN or HEMOSIDERIN
649-659

FERRITIN- ubiquitous protein-iron complex seen -Fe2+ is transported across apical membrane by
in LIVER, SPLEEN, BONE MARROW, SKELETAL divalent metal transporter (DMT1)
MUSCLES.
-absorption of nonheme iron is variable, usually
-in LIVER, it is stored in parenchymal inefficient
cells
-being inhibited by substances
-in other tissues like SPLEEN and consumed that bind and stabilize Fe3+(ferric)
MARROW, they are found in MACROPHAGES
-absorption is enhanced by substances that
-Hepatocyte iron is from plasma transferrin enhance fe2+(ferrous) iron.

-storage iron in macrophages is from RBC -5% dietary nonheme iron is absorbed
breakdown
-25% heme iron are absorbed (from
-INTRACELLULAR FERRITIN- located in cytosol myoglobin, hemoglobin, and other animal
and lysosomes proteins)

-partially degraded protein shells of -heme iron is moved across the apical
ferritin aggregate into hemosiderin granules. membrane cytoplasm (through incompletely
characterized transporters)
-iron in HEMOSIDERIN is chemically
reactive, it turns BLUE-BLACK when exposed to -in here, heme iron is metabolized to
POTASSIUM FERROCYANIDE (basis of Prussian release fe2+ iron enters common pool with
blue stain) nonheme fe2+

-normally, HEMOSIDERIN is only in trace Iron entering duodenal cells can go in 2

amounts in the body, such as Macrophages of pathways:
MARROW, SPLEEN, and LIVER
(1) Transport to the blood
-during Iron-overload in cells, most iron is (2) Storage as mucosal iron
stored in hemosiderin
(This distribution/pathways is influenced by
-Iron balance is maintained by regulation of iron body iron stores)
absorption in proximal duodenum
-Fe2+ iron destined for circulation is
-there is no regulated pathway for iron transported from cytoplasm across basolateral
excretion enterocyte membrane (transferred by
FERROPORTIN)
-only limited to 1 to 2 mg iron loss each
day through mucosal and skin cell shedding. -this process is coupled with oxidation
of fe2+ iron to fe3+ iron
“In contrast, iron stores increase, absorption
falls, and vice versa” -it is then carried by iron oxidases
hephaestin and ceruloplasmin.
ABSORPTION PATHWAY
-Newly absorbed Fe3+ iron binds to plasma
-luminal nonheme iron is mostly Fe3+(ferric), it protein TRANSFERRIN, delivering iron to RBC
must be reduced to Fe2+ (ferrous) by progenitors in bone marrow
ferrireductases (ex. Cytochromes and STEAP3.
649-659

“DMT1 and ferroportin are widely spread in the ETIOLOGY

body and also mediates other fucntions”
(1) Dietary lack
-example: DMT1 also mediates uptake (2) Loss of absorption
of functional iron (iron derived from (3) Increased requirement
endocytosed transferrin) across lysosomal (4) Chronic blood loss
membrane into cytosol of RBC precursor in
marrow -To maintain normal iron, at least 1 mg must be
absorbed from diet daily
-example 2: Ferroportin has role in
release of storage iron form macrophages -10 to 15% of ingested iron is absorbed, daily
iron requirement is 7 to 10mg for male and 7 to
“iron absorption is regulated by hepcidin, a 20mg for women.
circulating peptide synthesized by the liver,
responses during increase of intrahepatic iron” -heme iron is more absorbable than inorganic
iron, absorption is influenced by other dietary
-hepcidic inhibits iron transfer from contents.
enterocyte to plasma (binds to ferroportin
causing it to be endocytosed and degraded) -iron absorption is enhanced by ascorbic acid,
citric acid, amino acids, and sugar.
“alteration in hepcidin has central role in
diseases like alteration of iron metabolism” -it is inhibited by tannates (found in
tea), carbonates, oxalates, phosphate
-illustrated by following samples:
-dietary lack is rare, usually happens in
● Anemia of chronic disease is due to developing countries, it also happens even in
inflammatory mediator that increases privileged societies in the ff groups:
hepcidin production
● A rare microcytic anemia caused by (1) infants- high risk due to small amount of iron
mutation disabling TMPRSS6 (serine in milk (0.3 mg/L), cows milk contains twice but
protease that suppress hepcidin has poor bioavailability
production during low iron), resulting to (2) impoverished
continuous reduction of iron
absorption. (3) older adults- little meat due to limited
● Hepcidin is less active in primary and income or poor dentition
secondary hemochromatosis, syndrome (4) teenagers- usually eats junkies
caused by systemic iron overload.
● 2ndary hemochromatosis comes with Impaired absorption found in: Sprue, fat
diseases connected with ineffective malabsorption, chronic diarrhea
erythropoiesis: B-thalassemia and
-gastrectomy impairs iron absorption
myelodysplastic syndrome
due to decreased acidity of proximal duodenum
o Ineffective erythropoiesis
(enhances uptake)
suppress hepcidin production
even with high iron store. -increased speed with which gut
contents pass through the duodenum
649-659

Increased requirement seen in: growing -GIT or gynecologic disease

infants/children, premenopausal in women, and
-malnutrition
pregnancy.
-pregnancy
“Chronic blood loss is the most common cause
of iron deficiency” -malabsorption
-external hemorrhage or GIT bleeding, -in severe and prolonged iron deficiency,
urinary, or genital tracts depletes iron reserves. depletion of iron-containing enzymes in cells
creates other changes:
PATHOGENESIS
-koilonychia
-IRON DEFICIENCY produces HYPOCHROMIC,
MICROCYTIC ANEMIA -alopecia

-due to chronic blood loss or other states of -atrophic change in tongue and git
negative iron balance.
-intestinal malabsorption
-reserves in other forms like ferritin and
-Depletion of iron in nervous system leads to:
hemosiderin may be able to maintain normal
hemoglobin and hematocrit levels (as well as -pica
normal serum iron and transferrin saturation)
-movement of limbs during sleep
-progressive iron depletion of these reserves
will first decrease serum iron and transferrin -esophageal webs
saturation without anemia -atrophic glossitis
-in this early stage, there is increased
erythoid activity in bone marrow
ANEMIA OF CHRONIC DISEASE
-anemia appears when iron stores are
completely depleted, accompanied by low -caused by chronic disease due to systemic
serum iron, ferritin, and transferrin saturation inflammation
level
-due to reduction in proliferation of erythroid
progenitors and impaired iron utilization

-has three categories:

(1) chronic infections: osteomyelitis, bacterial

endocarditis, lung abscess

(2) chronic immune disorders: rheumatoid

arthritis and regional enteritis

(3) neoplasms: cancers of lung, breast, Hodgkin

lymphoma
CLINICAL FEATURES:
-anemia of chronic disease occurs in persistent
-non specific systemic inflammation
649-659

-associated with low serum iron -suspected mainly to autoimmune patietns,

inherited or acquired abnormalities could also
-reduced total iron binding capacity
be contributors on the onset.
-abundant stored iron in tissue macrophage
ETIOLOGY
-several effects of inflammation
-THE “KNOWN” REASONS:
contribute to the abnormalities observed
-drugs and agents like chemotherapy,
-certain inflammatory mediators like IL-6
usually causes marrow suppression
increase hepatic production of hepcidin.
-some are exposure to drugs that are
-decreases ferroportin function in
known to cause LITTLE or NO effect on marrow
macrophages and reduce transfer of iron from
like marrow suppression, hence making it
storage pool
idiopathic. Examples are: gold salts,
-these effect starves precursors for iron chloramphenicol
even if there are enough iron.
-viral infections could also cause
-these progenitors do not proliferate marrow aplasia, like in common viral hepatitis
adequately due to low erythropoietin levels. of non A, non B, non C, non G type, associated
with 5 to 10% of the cases.
-this is caused by high level of
hepcidin expressed, “might” be related to low -radiation therapy or exposure could
erythropoietin levels. also be a factor.

“best hypothesis for iron sequestration during SOME ABNORMALITIES UNDERLYING IN CASES
inflammation? Body fights certain types of OF APLASTIC ANEMIA:
bacteria that needs iron for pathogenicity like
FANCONI ANEMIA
H. influenza.”
- rare autosomal recessive disorder
-we could consider that hepcidin
overproduction is related to defensins (peptides -defects in multiprotein complex required for
for intrinsic antibacterial activity) DNA repair

-this anemia is usually mild, dominant -marrow hypofunction

symptoms are from the underlying disease
-inherited telomerase defects in 5 to 10% of
-rbc could be normocytic or cases adult-onset aplastic anemia
normochromic, or hypochromic and microcytic.
-65 cases are usually

PATHOGENESIS
APLASTIC ANEMIA
2 major etiologies
-primary failure of hematopoiesis, together with 1, extrinsic (immune mediated suppression of
pancytopenia marrow)

2. intrinsic (abnormality in stem cells)

649-659

-Stem cells may be antigenically altered with -when patients with thymoma: hematologic
drugs, infections, or other unidentified improvement in half of patients appear
environmental insult
-when not thymoma: immunosuppression
-this provokes cellular immune therapy is the best
response, where activated Th1 cells creates
-plasmapheresis may also be helpful in unusual
cytokines like IFN-gamma or TNF
patients with pathogenic autoantibodies.
-these cytokines suppress and kill
-special form of rbc aplasia occurs with infection
hematopoietic progenitors
of parvovirus B19, infects and destroys rbc
progenitors.

OTHER FORMS OF MARROW FAILURE:

MYELOPHTHISIC ANEMIA

-marrow failure where space occupying lesions

fill marrow elements
CLINICAL FEATURES
-common cause is metastasis
-PANCYTOPENIA
-others such as infiltrative process
-anemia: progressive weakness, pallor, dyspnea (granulomatous disease) involving marrow
could also produce the finding
-thrombocytopenia heralded by petechiae and
ecchymoses -myelophthisic anemia is feature of spent phase
of myeloproliferative disorders.
-neutropenia: persistent minor infection, chills,
fever, and prostration -these conditions causes the release of
abnormal nucleated erythroid precursors of rbc
-RBC: slightly macrocytic and normochromic.
and granulocyte from marrow.

-appears as teardrop-shaped rbc

PURE RED CELL APLASIA

-primary marrow disorder suppressing ONLY CHRONIC RENAL FAILURE

ERYTHROID PROGENITORS
-damaged kidneys cause low erythropoietin=
-when severe, rbc progenitors are low rbc production
COMPLETELY ABSENT FROM THE MARROW
-other causes are the toxic effects of uremia in
-may occur with neoplasms: thumoma and large rbcs and platelets.
granular lymphocytic leukemia.

-drug exposure, autoimmune disorders,

and parvovirus could also aggregate.

-“most likely an autoimmune”

649-659

HEPATOCELLULAR LIVER DISEASE POLYCYTHEMIA

-whether toxic, infectious, or cirrhotic liver -abnormally increased rbc count, increased
disease is associated with anemia due to hemoglobin level
decreased marrow function
-relative when there is
-folate and iron deficiencies due to poor hemoconcentration due to decreased plasma
nutrition and excess bleeding worsen in this volume, or absoulate increase in total red cell
setting mass.
-anemia is macroctic due to lipid abnormalities RELATIVE POLYCYTHEMIA is due to dehydration
with liver failure, causes rbc to acquire or vomiting, or excessive diuretics
phospholipid and cholesterol during rotation in
the whole body. -also associated with obscure unknown
etiology condition of stress polycythemia, called
ENDOCRINE DISORDERS GAISBOCK SYNDROME
-hypothyroidism may be associated with mild -px are usually obese, hypertensive, and
normochromic, normocythic anemia anxious (hence called stress polycythemia.

ABSOLUTE POLYCYTHEMIA is due to intrinsic

abnormality in hematopoietic precursors

-SECONDARY when it is due to

increased erythropoietein

POLYCYTHEMIA VERA most common primary

polycythemia, caused by myeloproliferative
disorder due to mutations, causing
erythropoeietin-independent RBC progenitors

PRIMARY POLYCYTHEMIA- familial mutation in

erythropoietin receptor, inducing
erythropoietin-independent receptor activation

SECONDARY POLYCYTHEMIA- main cause is

compensatory or pathologic increase in
erythropoietin, such as tumors, or inherited
defects leading to HIF-1a stabilization

-HIF-1a is hypoxia induced factor, hence

creating more erythropoietin gene.

BLEEDING DISORDERS: hemorrhagic diatheses

Excess bleeding usually caused from

649-659

(1) inc fragility of vessels -significant hemorrhages occur in the joints,

muscles, and subperiosteal location
(2) platelet deficiency or malfunction
-may take form of menorrhagia,
(3) derangement of coagulation
nosebleeds, GIT bleeding, or hematuria
HEMOSTASIS EVALUATION:
-PLATELETS COUNT and COAGULATION TESTS
PROTHROMBIN TIME (PT)- assess extrinsic and (PT, PTT) are normal in this condition
common coagulation pathway Variety of causes of this abnormality that
-prolonged PT can be due to deficiency causes abnormal bleeding:
or malfunction of factors V, VII, X, prothrombin,
(1) Infections- appears as petechial or
or fibrinogen.
purpuric hemorrhage like in
PARTIAL THROMBOPLASTIN TIME (PTT)- assess meningococcemia or other forms like
intrinsic and common clotting pathway infective endocarditis, this is due to
damage to microvasculature (vasculitis)
-prolonged PTT can be due to deficient and DIC
or altered factors V, VIII, IX, X, XI, or XII, (2) Drug reactions- induces cutaneous
prothrombin, fibrinogen, or interfering petechiae and purpura without
antibodies to phospholipids thrombocytopenia, mediated by drug-
PLATELET COUNT- normal is 150 x 10^3 to 300 x induced immune complex in the
10^3 vessels, leading to hypersensitivity then
to damage.
-abnormality best compared by (3) Scurvy and Ehler-Danlos Syndrome-
inspection of PBS microvascular bleeding due to collagen
-clumping of platelets can cause defects weakened vessel walls
thrombocytopenia, can be sign of (4) Henoch-schonlein purpura- systemic
myeloproliferative disorder immune disorder due to unknown
cause, appears as purpuric rash, colicky
PLATELET FUNCTION TEST- some tests that abdominal pain, polyarthralgia, and
assess the ability of plateltes to aggregate to acute glomerulonephritis.
agonists like thrombin, quantitative and (5) Hereditary hemorrhagic telangiectasia
qualitative tests of von Willebrand factor (aka weber-osler-rendu syndrome) –
autosomal dominant mutation at least
5 genes that modulates TGF-B signaling,
BLEEDING CAUSED BY VESSEL WALL appears as dilated, tortuous blood
ABNORMALITIES vessles with thin walls that bleed.

-diseases under this are relatively common, -commonly appear on mucous

some usually doesn’t cause severe bleeding membranes such as nose, tongue,
problems. mouth, eyes, and GIT

-usually presents with small hemorrhages like (6) Perivascular amyloidosis- weakened
petechiae and purpura blood vessel walls, complication is
commin with amyloid light-chain
amyloidosis
649-659

BLEEDING RELATED TO REDUCED PLATELETS:: -NON-IMMUNOLOGIC are caused by DIC and

THROMBOCYTOPENIA thrombotic microangiopathies., platelet
activation reduces it’s lifespan and supply.
-an important cause of generalized bleeding
-SEQUESTRATION- spleen sequesters 3- to 35 %
-less than 100,000 platelets per deciliter is of body’s platelets
thrombocytopenia
-DILUTION- massive transfusion can cause
-platelets at 20,000 to 50,000= aggravate dilutional thrombocytopenia.
posttraumatic bleeding

-platelets less than 20,000 is associated with

spontaneous (nontraumatic) bleeding CHRONIC IMMUNE THROMBOCYTOPENIC
PURPURA (ITP)
“IF BLEEDING IS CAUSED BY PLATELET
ABNORMALITY, PT AND PTT TESTS AS NORMAL” caused by autoantibody mediated destruction
of thrombocytes
-spontaneous bleeding due to
thrombocytopenia affects small vessels -occur in px with predisposing condition or
exposure to some risk factors
-common sites are hemorrhage in the
skin, mucous membrane of GIT and -ITP occurs secondarily w/ px with lupus
genitourinary tracts. erythematosus, HIV, B-cell neoplasm

-INTRACRANIAL BLEEDING is the “MOST PATHOGENSIS

FEARED”
-autoantibodies directed to attack platelet
CAUSES OF THROMBOCYTOPENIA membrane glycoproteins (IIb-IIIa or lb-Lx)

(1) DECREASED PLATELET PRODUCTION- due to -autoantibodies might also attack

marrow depression megakaryocutes, leading to low platelet
production.
-certain drugs and alcohol may suppress
platelet creation

-HIV also affects megakaryocytes

(platelet precursor)

-myelodysplastic syndromes

(2) DECREASD PLATELET SURVIVAL- usually due

to immunological or nonimmunological.

-immune thrombocytopenia is caused

by autoantibodies, Alloantibodies can form
when transfused or crossed the placenta from
fetus to mother

-IgG antibodies made in the mother can

cause thrombocytopenia in the baby (new born
hemolytic disease)
649-659

CLINICAL FEATURES: HEPARIN INDUCED THROMBOCYTOPENIA (HIT)

has distinctive pathogenesis, it is important to
-OCCURS IN ADULT WOMEN YOUNGER THAN
understand because of potential severe clinical
40 of AGE
consequences
-female ratio is 3:1
-Thrombocytopenia occurs in 5% of persons
-bleeding into skin and mucosal surfaces taking heparin, is 2 types:

-cutaneous bleedin in form of pinpoint -TYPE 1 THROMBOCYTOPENIA- occur

hemorrhage(petechiae) rapidly after onset of therapy

-petechiae can also rise to ecchymoses -little clinical importance

-there are usually history of bruising, -usually results from direct

nosebleeds, gum bleed, hemorrhage of soft platelet-aggregating effect of heparin
tissue due to minor trauma

-the disease manifest as melena with hematuria

-TYPE 2 THROMBOCYTPENIA- less
or excessive menstrual flow
common, BUT GREATER CLINICAL SIGNIFICANCE

-occurs 5 to 14 days after

ACUTE IMMUNE THROMBOCYTOPENIC therapy begins (or been sensitized to heparin)
PURPURA
-leads to life threatening
-caused by autiantibodies venous and arterial thrombosis

-ITP is a childhood of disease, equal in both -caused by antibodies

sexes recognizing heparin complex and platelet factor
4
-acute ITP is self limited, resolving by itself
within 6 months -binding of the antibodies to
these complex (heparin-platelet factor 4)
-glucocorticoids as a treatment of severe activates thrombosis, even If the condition of
thrombocytopenia patient is thrombocytopenia (nag t-thrombosis
DRUG INDUCED THROMBOCYTOPENIA parin kahit kaunti yung platelets)

-may cause vascular

-can induce thrombocytopenia through direct
insufficiency and limb loss
effects on platelets
-may cause deep venous
-can also be secondary to
thrombosis and cause deadly pulmonary
immunologically mediated platelet destruction
thromboembolism
-drugs commonly suspected are quinine,
quinidine, and vancomycin
HIV-ASSOCIATED THROMBOCYTOPENIA
-binds to platelet glycoprotein, creating
antigenic determinants and recognized by -ONE OF THE MOST COMMON HEMATOLOGIC
antibodies MANIFESTATION OF HIV INFECTION
649-659

-CD4 and CXCR4 receptors in megakaryocytes TTP IS ASSOCAITED WITH DEFICIENCY OF

allows HIV to infect it, it is then prone to ADAMTS13 (a plasma enzyme)
apoptosis of the megakaryocutes
-the enzyme normally degrades very high-
-HIV infection can also cause B-CELL molecular-weight multimers of Vwf or von
HYPERPLASIA and DYSREGULATION, increases willebrand factor
development of autoantibodies
-it’s absence promotes platelet
-in some, antibodies are against platelet activation and aggregation
membrane GLYCOPROTEIN IIb-III complexes
-other endothelial injuries might contribute to
THROMBOTIC MICROANGIOPATHIS: the increase of risk of platelet aggregate
formation.
(A) THROMBOCYTOPENIC PURPURA (TTP)
(B) HEMOLYTHIC-UREMIC SYNDROME “ADAMTS13 DEFICIENCY CAN BE INHERITED OR
(HUS) ACQUIRED”

-The term thrombotic microangiopathy -in acquired, theres an autoantibody that

encompasses a spectrum of clinical syndromes inhibits the metalloprotease action of
that includes TTP and HUS ADAMTS13

-they are caused by insults, activating the -ADAMST13 inherited mutation is uncommon
platelets excessively, depositing thrombi in
-onset is delayed until adolescence,
small blood vessels
symtpoms are episodic
-TTP was originally defined as pentad: (1)Fever,
-TTP is important diagnosis considering any px
(2)Thrombocytopenia, (3)Microangiopathic
that presents with thrombocytopenia and
(4)hemolytic anemia, (5)transient neurologic
microangiopathic hemolytic anemia
deficit and renal failure
-DELAY DIAGNOSIS CAN BE DEADLY
-with time and experience of health
service, these distinctions became blurred, -HUS has normal level of ADAMTS13, initiated
by several other distinct defects
-some will lack one or more symptoms,
removing then from the criteria -Typical HUS is associated with infective
gastroenteritis by E. Coli 0157:H7 (produces
-some HUS patients will have fever and
SHIGA-LIKE TOXIN)
neurologic dysfunction
-Atypical HUS is related to defects in
comnplement factor H, CD46, or factor I
BOTH CONDITIONS CAUSE MICROANGIOPATHIC
-3 proteins normally act to prevent
HEMOLYTIC ANEMIA and ORGAN FAILURE
excess activation of alternative complement
(widespread) due to INTRAVASCULAR THROMBI
pathway
-these symptoms causes the
-deficiencies of these can be acquired
consumption of the platelets leads to
or inherited, associated with remitting,
thrombocytopenia
relapsing course.
-In TTP and HUS, PT and PTT are usually normal.
649-659