YL6: 04.

21 Hematopoietic Agents and Hematinics

10/11/2019 Basic Pathologies 2
07:30-08:30 Rico Paolo Tee, MD
PHARMACOLOGY

TABLE OF CONTENTS Iron Absorption

General absorption and iron cycle in the body
I. HEMATINICS .................................................................................... 1 • Daily intake (~10-20 mg)
A. IRON ....................................................................................... 1 • Absorbed in the duodenum (~1-2 mg)
B. VITAMIN B12 AND FOLATE .................................................... 3 • Most of the iron is found in the hemoglobin (blood)
II. HEMATOPOIETICS ......................................................................... 3 • Transferrin (transportation of iron)
A. ERYTHROPOIETIN (EPO) ...................................................... 3
→ 75% for erythropoiesis
B. G-CSF/GM-CSF ...................................................................... 4
C. THROMBOPOIETIC AGENTS................................................. 4 → 1-2% as ferritin (storage form) in the liver
III. TRANSFUSION THERAPY ............................................................. 4 → 5-15% for other processes
A. COLLECTION OF BLOOD COMPONENTS ............................. 4 • No physiologic excretion
B. TRANSFUSION PRODUCTS AND BLOOD COMPONENTS ... 5
C. ETHICAL ISSUES ................................................................... 6 Heme Iron Absorption
QUICK REVIEW ................................................................................... 6 1. Iron is absorbed in the duodenum
SUMMARY OF TERMS ............................................................... 6 2. At the brush border of the duodenal cell, the heme iron is
REVIEW QUESTIONS ................................................................. 7 absorbed via endocytosis through the HCP1 receptor
REFERENCES..................................................................................... 8
3. Ferrous ions (Fe2+) are liberated from the receptor by heme
REQUIRED.................................................................................. 8
oxidase before it goes out of the vesicle
APPENDIX ........................................................................................... 8
4. Fe2+ is converted back to Fe3+ by hephaestin as it is transported
into bloodstream by ferroportin
5. Fe3+ is then transported by transferrin to the bone marrow
I. HEMATINICS
A. IRON Nonheme Iron Absorption
• Iron is an important part of oxygen-carrying protein molecules 1. Nonheme iron circulating in the body is available as ferric ions
→ Hemoglobin (Fe3+)
→ Myoglobin → This form cannot be transported intracellularly for absorption
• Sources: Diet (mainly), recycled RBCs, iron supplements 2. Ferric ions (Fe3+) must be reduced to ferrous ions (Fe2+)
→ Heme iron → Conversion of iron is catalyzed by the reductase enzyme
▪ From meat, especially red meat (e.g. poultry, chicken, duodenum cytochrome B (dcytB)
fish, seafood) 3. Newly converted ferrous ions (Fe2+) are transported into the
▪ Easily absorbed by the body and is the best source of duodenal cell
iron especially for people with iron deficiency → Via the divalent metal transporter 1 (DMT1) found on the
→ Nonheme iron apical membrane of the duodenum
▪ From vegetables, grains, eggs, fruits → Co-transport with H+ ion is necessary for this process
▪ Less readily absorbed and must undergo metabolic ▪ Hence, an acidic environment is optimal for iron
processes of conversion absorption
→ It also needs an efflux of ions so it uses the Na-K+ pump to
maintain homeostasis
4. The ferrous ions (Fe2+) are transported out into the circulation as
ferric ions (Fe3+) once again
→ Ferroportin allows for exit of the ferrous ions (Fe2+) from the
enterocyte
→ Hephaestin is a ferroxidase that converts ferrous ion (Fe2+) to
ferric ion (Fe3+) once again
5. Hepcidin mediates the regulation of all these processes:
→ Regulates exit of iron from duodenum
→ Controls ferroportin
→ Hepcidin concentration is inversely proportional to the
amount of iron transported out of the duodenal cell
6. After absorption, iron can be:
→ Brought into the circulation as ferric ions (Fe3+)
→ Stored in the body as ferritin (mainly in the liver)

Figure 1. Sources of iron (Tee, 2019).

Table 1. Iron compartments in the average person

Compartment Iron Content Total Body Iron (%)
(mg)
Hemoglobin Iron 2000 67
Storage Iron (ferritin, 1000 27
hemosiderin)
Myoglobin Iron 130 3.5
Labile pool 80 2.2
Other tissue Iron 8 0.2
Transport Iron 3 0.08 Figure 2. Summary of iron absorption

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  Patients with frequent emesis
Summary of Heme Absorption (Fig. 2)
• Forms (notice the combination with saccharides, as ferric ion
• Heme iron is absorbed directly from the lumen to the cytoplasm
alone is too toxic to give):
of the cell through HCP1.
→ Iron dextran
• Heme is then catabolized by heme oxidase which results to
▪ IV – induces serious hypersensitivity reactions
non-heme iron and biliverdin.
(anaphylaxis) and even death
• In nonheme iron absorption, ferric iron is initially reduced by
▪ IM – distinct tattoo-like discoloration
DcytB into the ferrous form prior to absorption. Non-heme iron
→ Iron sucrose
is taken up by DMT1 located in the microvilli.
→ Iron carboxymaltose
• Transfer of iron into the circulation is carried out by ferroportin.
Prior to this, ferrous iron is converted to ferric through → Sodium ferric gluconate complex
hephaestin. • Side effects:
→ Allergic reactions which leads to anaphylaxis
▪ Especially iron dextran due to the high molecular weight
Iron Elimination → Pain and discoloration at injection site
• There is no physiologic mechanism for the excretion ▪ Tattoo-like, since the iron formula given IM is colored
→ However, iron can be lost through: black
▪ Blood loss → Headaches and lightheadedness
▪ Pregnancy → Arthralgia
▪ Menstruation (physiological), for women of childbearing → Nausea and vomiting
age → Flank pain
▪ Malignancies in the GIT (pathologic), for males (e.g.
tumor masses that can lead to bleeding) Iron Overload
▪ Malnutrition • Could be caused by:
o Note that these factors can lead to iron deficiency → Thalassemia
anemia ▪ Dysregulated hepcidin function, thus iron keeps
• Indirect measure: ferritin entering
→ Since it is in equilibrium with bone marrow iron ▪ Excess iron gets deposited in different organs:
o Liver: liver failure
Iron Therapies o Heart: causes myocardial damage
Oral Iron Therapy o Pancreas: causes Bronze diabetes (darkening
• Oral administration of iron is preferred since it is convenient skin and hyperglycemia)
• Given for at least 3-6 months (or more) given the saturable nature o Gonads: causes ovarian/testicular failure leading to
of the receptors failure to attain secondary sexual
 It takes months to years to deplete your iron stores, so characteristics
replenishment also takes time → Usually in children
 As early as 2-3 months of intake, ferritin increases, followed o Other organs it can get deposited in: Thyroid and
by hemoglobin Parathyroid glands, Adrenal glands, Pituitary gland
• Best time to take iron is before meals → Chronic transfusions, especially in patients with
→ Absorption needs an acidic environment, and food can thalassemia and aplastic anemia
compete with absorption o Both “defective” blood disorders, so there is no
→ While the usual adult dosage for treatment is 2-4 tablets/day, choice but to give transfusions
recent studies have shown that even 1 tablet/day is → 1 PRBC (packed RBC) unit = 1mg/ml of iron
sufficient before a meal in the morning → 150-300 PRBC units are usually given
▪ Hepcidin is found to be less active in the morning, and • Treatment
carrier proteins are more active in the morning since they → Prevention: not all anemias need iron, only iron deficiency
are already saturated in the afternoon anemias
• Side effects: → Phlebotomy – taking the blood out
→ Abdominal symptoms → Iron chelators – agents that bind to iron, allowing it to be
▪ Pain (iron intake produces more HCl as it interacts with excreted in urine
gastric acid)
▪ Feeling of constipation, bloating, nausea, vomiting Acute Overload
→ Black stool • Leads to metabolic acidosis, coma, or death
▪ Resembles melena (i.e. upper GI bleeding) • Treatment option: Iron chelators
• If intolerant to side effects, the brand is usually changed → Desferrioxamine, given IV for fast action
 Success indicator: pink rose color of urine indicative of
Table 2. Some commonly used iron preparations iron excretion
Preparation Tablet Elemental Usual Adult
Size Iron per Dosage for Chronic Overload
Tablet Treatment of
• Leads to secondary hemochromatosis, damaging liver and the
Iron
heart muscles (Kasper et al., 2015)
Deficiency
• Treatment options: other iron chelating agents
Ferrous sulfate, 325 mg 65 mg 2-4 tablets per
hydrated day → Desferrioxamine
▪ Given continuously IV via a subcutaneous pump
Ferrous sulfate, 200 mg 65 mg 2-4 tablets per
▪ Infused for 24 hours
desiccated day
→ Deferiprone
Ferrous 325 mg 36 mg 3-4 tablets per
 Better for cardiac iron overload
gluconate day
▪ Oral intake, tablet
Ferrous 325 mg 106 mg 2-3 days
▪ 50mg/kilo
fumarate
▪ 1 tablet = 105 php
o Taken for a year
Parenteral Iron Therapy (Intravenous, Intramuscular)
→ Deferasirox
• Parenteral iron therapy is beneficial particularly for: ▪ Good for all organs affected
→ Intolerance to oral iron (due to excessive abdominal ▪ Oral intake, tablet
symptoms from oral intake) ▪ 25 mg/kilo per day
→ Chronic Kidney Disease (CKD1) patients ▪ One box (around 13 tablets) = Php 22,000
→ Malabsorption syndromes, which are seen in patients with o Treatment of more than a year
resected portions of the duodenum

1
CKD: Chronic kidney disease

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 B. VITAMIN B12 AND FOLATE → May enter as dietary folate: converted to N5-
Cobalamin (Vitamin B12) methyltetrahydrofolate
• Cobalamin facilitates conversion of methyltetrahydrofolate to ▪ Methyltetrahydrofolate is converted to tetrahydrofolate,
tetrahydrofolate made possible by cobalamin
→ Tetrahydrofolate is necessary for purine and dTMP ▪ Methylcobalamin donates methyl group to
production (DNA synthesis) homocysteine to make methionine (start codon)
→ In the process, cobalamin becomes methylcobalamin → May also enter as folic acid: converted to dihydrofolate
→ Methylcobalamin is needed for the conversion of ▪ By folate reductase
homocysteine to methionine
• Sources: Folate deficiency can lead to:
→ Meat sources • Megaloblastic anemia
• Absorption: • Neurologic effects:
→ B12 is absorbed in brush border of terminal ileum along with → Infantile neural tube defects (e.g. spina bifida, anencephaly)
intrinsic factor (secreted by parietal cells) via
transcobalamin II Causes of folate deficiency:
• Storage: • Increased demand with poor intake
→ The liver stores cobalamin in an amount that is enough to • Alcoholism
supply the body for three years • Liver disease
• Forms: • Malabsorption
→ Cyanocobalamin and Hydroxycobalamin • Drugs
▪ Both tablet forms; metabolized to methylcobalamin → Drugs that inhibit folate by either dihydrofolate reductase or
→ Methylcobalamin (bioactive form) dihydropteroate synthase
→ Intramuscular vitamin B12 ▪ Methotrexate
• See figure 3 for a diagram of these processes ▪ Trimethoprim
▪ Sulfamethoxazole
Vitamin B12 deficiency can lead to: • Treatment
• Megaloblastic anemia due to the problem in cell or DNA maturation → Give folic acid supplements (not available on IV, only oral)
• Myelodysplastic syndrome-like cytopenia
• Neurologic deficits: Paresthesia, ataxia, CNS symptoms
→ Usually patients look drunk: gait ataxia, cerebellar signs

Usual causes of B12 deficiency/anemia:

• Juvenile pernicious anemia
→ Autoimmune response on parietal cells: less or no intrinsic
factor
→ Leads to defective B12 absorption
• Malabsorption syndrome
→ Secondary to Diphyllobothrium latum (tapeworm) infections
• Gastrectomy/Defective stomach
→ Gastric cancer patients would not be able to produce
intrinsic factor
→ Manifests as macrocytic anemia on peripheral smear
▪ To augment, give Vit. B12

Folate

Figure 4. The Relationship of Folate and Vitamin B12 (Tee, 2019).

II. HEMATOPOIETICS
A. ERYTHROPOIETIN (EPO)
Epoetin (Drug)
• Interacts with erythroid receptors on red cell progenitors
• Induces release of reticulocytes from the bone marrow
• Eliminates the need for transfusions and improves patient’s
quality of life (anemia can be resolved)
• Recommended for:
→ Patients with chronic kidney disease
▪ Kidneys are not producing EPO
▪ Epoetin injection is usually given after a kidney dialysis
treatment
▪ Usually given recombinant EPO
→ Anemia of chronic disease
▪ In this condition, EPO levels are inappropriately low for
the degree of anemia (Kumar et al., 2015)
▪ Hepcidin is upregulated because of inflammation
Figure 3. Folate Cycle (Tee, 2019). o In effect, less iron is transported out
▪ EPO allows iron transportation to take place via hepcidin
• Important in the process of DNA synthesis inhibition, thus removing the need for transfusion
• Absorption: • Cannot be used for:
→ Iron is absorbed in the duodenum → Aplastic anemia: EPO needs to interact with red cell
→ Folate is absorbed in the duodenum progenitors which are not present in aplastic anemia
→ Cobalamin is absorbed in the terminal ileum → Iron-deficiency anemia: EPO stimulates RBC production,
• Sources: using up even more iron, making the patient even more iron-
→ Vegetables like beets, broccoli, okra, leafy greens, and deficient
avocado → Leukemia: can’t be stimulated since the bone marrow only
• Folate cycle: has leukemia

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 Forms with longer half-life:
• Drugs
→ Darbepoetin
→ Mircera (Methoxy-polyethylene glycol epoetin beta)
• EPO is usually given every 2-3 days or more depending on the
symptoms of anemia
• Longer half-life of Darbepoetin and Mircera allow patients to take
EPO once a month or once every 2 months
• Toxicity:
→ Can cause thrombosis
▪ Blood produced may be hypercoagulable
▪ Risky for patients with hypertension since it could lead to
strokes
→ PRCA (Pure Red Cell Aplasia)
▪ Development of antibodies to red cell progenitors leads
to greater anemia

B. G-CSF/GM-CSF Figure 5. Summary Diagram of G-CSF Actions (Tee, 2019).

• Two possible hematopoietic growth factors may be given:
→ G-CSF
C. THROMBOPOIETIC AGENTS
▪ Granulocyte-colony stimulating factor (Filgrastim) Thrombopoietin (TPO)
→ GM-CSF • Stimulates thrombopoietin receptors to produce more platelets
▪ Granulocyte-Macrophage colony stimulating factor → Binds to c-Mpl receptor on megakaryocytes
(Sargramostim) • Side effect:
• Both have the following actions: → Saturation of receptors: results to even lower platelets due to
→ Act as primary mimics for G-CSF and GM-CSF immediate sensitization
▪ Mobilize stem cells to the peripheral blood
→ Stimulate proliferation and differentiation via receptors on TPOR mimetics/Mpl receptor agonists
myeloid cells • Alternatives to TPO: do not oversaturate receptors
▪ Increase the number of granulocytes • Romiplostim
→ Activates phagocytic activity of mature neutrophils → Injected
• Indications for the two drugs are summarized on Table 3 • Eltrombopag
→ For refractory immune thrombocytopenia and cancer
Table 3. Clinical Uses of G-CSF and GM-CSF (parts with the book icon • IL-11 (Oprelvekin)
were lifted from Katzung, along with Doc Tee’s lecture points). → Stimulates production of megakaryocytes
Clinical Recipients • See appendix for a complete summary of the drugs discussed so
Condition far and their actions
Addressed
Neutropenia • Cancer patients undergoing III. TRANSFUSION THERAPY
myelosuppressive therapy • Provides immediate correction of deficient cellular and soluble
→ Febrile neutropenia in post- blood components
chemotherapy patients is
shortened
• Patients with severe chronic neutropenia
• Patients recovering from bone marrow
transplantation
Stem cell or Bone  Treat or prevent bleeding due to low
marrow platelet levels
transplantation  Correct functional platelet problems
→ E.g. Von Willebrand disease
Mobilization of  Stem cell donors for allogeneic or
peripheral blood autologous transplantation
progenitor cells

• Aplastic anemia is not an indication for G-CSF and GM-CSF

→ This is because the stem cells are abnormal in themselves
(intrinsic type); or
→ The stem cells are immunologically suppressed (extrinsic
type)
→ Thus, preferred treatment of aplastic anemia is then bone
marrow transplantation rather than G-CSF or GM-CSF
• Toxic effects:
→ Fever
→ Bone pains
▪ A result of bone marrow compensation Figure 6. Breakdown of Whole Blood Components (Tee, 2019).
▪ Only a rare risk
→ Splenic rupture (low and rare risk) A. COLLECTION OF BLOOD COMPONENTS
Fractionation
• The process of separating a unit of blood into its components (e.g.
red cells, plasma, platelets, granulocytes) (2021 Trans)

Apheresis
• The process of isolating and separating a particular component
from a patient’s blood through a specialized apparatus

Procedure
1. Blood is drawn and flows into the apheresis machine
2. Blood is separated into components by a centrifuge

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3. Needed components are collected into sterile bags → Cryoprecipitate
4. Unused components are returned to the donor
• Take note that unlike blood fractionation, the unused components
may be returned to the donor
• Advantage: obtains a greater volume of a desired component
from a single donation

Table 4. Storage and Shelf Life of Blood Components

Component Storage Temp. Shelf Life
(°C)
Whole Blood 1-6 35 days
RBCs 1-6 35-42 days
10 years if in
freezer
Platelets 20-24 5 days
Fresh Frozen Plasma < -18 1 year
(FFP2)
Cryoprecipitate < -18 1 year

Platelet collection
• Apheresis is most often used in the collection of platelets
→ Apheresed platelets are called single donor platelets
→ 6 to 8 units of platelets can be collected from a single round
▪ Apheresis allows a much larger number of platelets to be
collected from a single donor than is possible through
whole blood donation
▪ Whole blood donation can only be done once every 3 Figure 8. Blood component preparation and transfusion products
months, while apheresis which can be done every 4 (2021 trans)
days
▪ Apheresis is advantageous if the blood type is rare since Fresh Whole Blood
more platelets can be collected in a shorter period of time • Contains all the components
→ Platelets are often concurrently collected with plasma • Rarely used
→ Platelets must be continuously agitated to avoid → Difficult to store along with all blood components – must be
aggregation transfused immediately
→ Fresh frozen plasma (FFP) and cryoprecipitate requires deep → Used only in emergent situations (i.e. military use in the
freezing to keep factors functional field)
• Alternatives:
Stem cell collection  For hypovolemia – give fluids like normal saline solution
 Stem cell collection is used for autologous or allogeneic (NSS4)
transplantation  For decreased oxygen-carrying capacity – give RBCs
 G-CSF is used to mobilize the stem cells from the bone marrow to
the peripheral blood Whole Blood
• Provides both oxygen-carrying capacity and volume expansion
Therapeutic uses of apheresis • Disadvantages:
• Antibody removal for autoimmune disease (E.g. myasthenia gravis) → Contains only RBCs and WBCs but no viable platelets or
coagulation factors
• Von Willebrand factor (vWF3) filtration to treat thrombotic
▪ Whole blood needs to be stored at 4°C to retain
thrombocytopenic purpura (TTP)
erythrocyte viability
 Thrombotic microangiopathy without another apparent cause
▪ Coagulation factors have a short half-life and need -18°C
and without acute renal failure caused by unregulated VWF-
to be preserved
dependent platelet thrombosis (2021 Trans)
▪ Platelets are also degraded readily at 4°C
• Leukemia treatment
→ Immunogenic due to presence of plasma
• Elimination of harmful or excessive blood components (e.g. as
• Only used for exchange transfusion in neonates
seen in leukocytosis)
→ For all other cases, use blood components
B. TRANSFUSION PRODUCTS AND BLOOD There is no clear indication for giving whole blood, opt instead to give its
COMPONENTS different components (Tee, 2018)

Platelets
• Only used to treat or prevent hemorrhage in cases of
thrombocytopenia or general functional platelet disorders

Plasma
• Uses
→ Corrects coagulation factor deficiencies (e.g. hemophilia, von
Willebrand disease)
→ Shock treatment due to plasma loss from burns or massive
bleeds
 Be careful when giving to patients with heart failure
Figure 7. Blood Components and their Storage and Shelf Life (Tee,  Large volumes may not be pumped as efficiently as normal
2019) individuals: this results in pulmonary congestion

• Whole blood is fractionated into four main components Irradiated Packed RBC/Platelets
→ RBCs • Gamma radiation of cellular blood components to prevent
→ Platelets transfusion-associated Graft versus Host Disease
→ FFP • For patients undergoing immunosuppressive therapy

2 4
FPP: Fresh Frozen Plasma NSS: Normal Saline Solution
3
vWF: von Willebrand Factor

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 Graft versus Host Disease (GvHD) C. ETHICAL ISSUES
 GVHD is the result of allogeneic T cells that are transferred with Refusal of Transfusion due to Religious Beliefs
the donor’s stem cell inoculum reacting with antigenic targets on • Certain religions (e.g. Jehovah’s Witness) are not allowed to
host cells (Kasper et al., 2015) handle blood of other people
→ Also seen in hematopoietic stem cell transplants • Many religions have released guidelines on what is and is not
 Clinical manifestations: allowed
 Occlusions in the liver • For Jehovah's Witness:
 Skin changes → Not acceptable: RBC, WBC, plasma, platelets
 99% mortality → Acceptable alternatives:
• Treatment: ▪ For RBC: hemoglobin-based blood substitutes
→ Minimize transfusions from family members ▪ For WBC: interferons, interleukins
→ Irradiation of blood components ▪ For plasma: albumin, globulins, clotting factors
▪ Kills lymphocytes to allow transfusion ▪ For platelets: wound healing factor
• Bottomline: Decision to transfuse will always still depend on the
Cryopreserved Red Cell Concentrates / Platelets / Stem Cells informed consent of the patient
• Used for:
→ Rare blood types
▪ Bombay phenotype
→ Preparation for autologous stem cell transplantation
• Stem cells will come from the patient himself/herself and then
preserved
• Used for times when the patient needs to replenish his/her stem
cell stores
→ For procedures like chemotherapy that kill off a lot of the cells
during the process

Leuko-depleted Packed RBC

• Can be done “lab-side” or “bedside”
• Used for:
→ Prevention of febrile transfusion reactions by delaying
sensitization to leukocyte antigens
 Febrile nonhemolytic transfusion reactions (FNTR):
Chills, rigors, and fever caused by antigen response
directed against donor leukocyte and HLA antibodies
(Jameson et al., 2018)
→ Prevention transmission of cytomegalovirus (CMV)
→ Avoiding possible alloimmunization Figure 9. Jehovah’s Witnesses’ Basic Position on Blood

Washed Packed RBC QUICK REVIEW

• “Plasma protein reduced” SUMMARY OF TERMS
 NSS is added to the packed RBCs to “wash” off the other cells Iron
• Used for • Important part in oxygen-carrying protein molecules
→ For patients with antibodies to plasma proteins • Heme iron
→ For patients with previous severe allergic reaction to blood → From meat, especially red meat
transfusion → Easily absorbed by the body
• Non-heme iron
Fresh Frozen Plasma (FFP) → From vegetables, eggs, grain, fruits
 FFP contains stable coagulation factors and plasma proteins: → Less readily absorbed; must undergo process of conversion
fibrinogen, antithrombin, albumin, and proteins C and S (Jameson
et al., 2018). Iron Absorption
 Indications for FFP:
• Daily intake: ~10-20 mg
 Correction of coagulopathies, including the rapid reversal of
• Absorption: duodenum
warfarin
 Supplying deficient plasma proteins; • Heme Iron Absorption
 And treatment of thrombotic thrombocytopenic purpura → At the brush border, Fe2+ is absorbed via endocytosis through
 FFP should not be routinely used to expand blood volume the HCP1 receptor
(Jameson et al., 2018) → Fe2+ liberated from the receptor by heme oxidase before it
• Used to correct a deficiency in coagulation factors or to treat shock goes out of the vesicle
due to plasma loss from burns or massive bleeding → Fe2+ is transported into bloodstream by ferroportin and
• The following are derived from fresh frozen plasma: converted back to Fe3+ by hephaestin
→ Cryoprecipitate → Fe3+ is then transported by transferrin to the bone marrow
→ Cryosupernatant • Nonheme Iron Absorption
→ Fe3+ is reduced to Fe2+ by dcytb
Cryoprecipitate → Fe2+ enters the intestine through DMT1, which also needs H+
as a co-transporter
• Source of fibrinogen, factor VIII, and vWF
▪ The need for H+ means that iron is best absorbed in
 The only adequate source of fibrinogen for intravenous use
 Used for supplying fibrinogen to the volume-sensitive patient or acidic environments
Factor VIII when concentrates are not available (Jameson et al., • Hepcidin
2018) → Mediates the regulation of all these processes:
▪ Regulates exit of iron from duodenum
Cryosupernatant ▪ Controls ferroportin
▪ Hepcidin concentration is inversely proportional to the
• Decreased fibrinogen content
amount of iron transported out of the duodenal cell
• Contains factors II, VII, IX, X, XIII and fibronectin
• No large multimers of vWF Iron Elimination
• Indication: plasma exchange in Thrombotic
• There is no physiologic mechanism for excretion
Thrombocytopenic Purpura (TPP)
• Iron can be lost through pregnancy, menstruation, malignancies in
GIT (usually the reason for iron loss in males), and malnutrition
• Indirect measure of iron stores: ferritin

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 Iron Therapies Forms with longer half-life
• Oral Iron Therapy • Drugs with long half-life that allow patients to take EPO once a
→ Preferred route month or every 2 months
→ Given for at least 3-6 months (or more) → Darbepoetin
→ As early as 2-3 months of intake, ferritin increases, and then → Mircera (Methoxy-polyethylene glycol epoetin beta)
hemoglobin • EPO is usually given every 2-3 days or more
→ Best time to take iron: before meals • Toxicity:
→ Side effects: abdominal pain, feeling of constipation, bloating, → Can cause thrombosis; hypercoagulable blood
nausea, black stool → PRCA (Pure Red Cell Aplasia)
• Parenteral Iron Therapy (IV, IM) ▪ Development of antibodies to red cell progenitors leads
→ This route is beneficial for: intolerance to oral iron, patients to greater anemia
with frequent emesis, CKD patients, malabsorption
syndromes GM-CSF/G-CSF
→ Forms: iron dextran, iron sucrose, iron carboxymaltose and • Filgramstim (G-CSF) or Sargramostim (GM-CSF)
sodium ferric gluconate complex • Actions:
→ Side effects: allergic reactions/anaphylaxis (especially → Proliferation and differentiation of precursors via receptors of
towards iron dextran), pain and discoloration (tatoo-like) at myeloid lineage
injection site, headaches, lightheadedness, arthralgia, → Activates phagocytic activity in mature neutrophils
nausea and vomiting, flank pain → Mobilizes stem cells to the periphery
• Indications:
Iron Overload → Neutropenia: shortens the duration of febrile neutropenia
• Causes: Defective hepcidin function → Patients undergoing chemotherapy
• Excess iron accumulates in several organs in the body: liver, heart, • Toxicity:
pancreas, gonads. → Fever
• Treatment: → Bone pains (rare)
→ Prevention: not all anemias need iron, only iron deficiency → Splenic rupture (rare)
anemia
→ Phlebotomy Thrombopoietin
→ Iron chelators • Forms:
• Acute Overload – metabolic acidosis, coma, death → IL-11
→ Treatment: Desferrioxamine via IV → Thrombopoietin
• Chronic Overload – secondary hemochromatosis, damage to → TPOR mimetics/Mpl receptor agonists
organs ▪ Romiplostim
→ Treatment: Desferrioxamine, Deferiprone (for cardiac iron ▪ Eltrombopag
overload), Deferasirox
Blood Apheresis
Cobalamin (Vitamin B12) • Process of separating blood into its separate components
• Facilitates conversion of methyltetrahydrofolate to • Fresh whole blood: used rarely, only for emergent situations
tetrahydrofolate • Whole blood: for restoring oxygen carrying capacity and plasma
• Essential in DNA synthesis expansion
• Absorption: Terminal Ileum (with intrinsic factor) → Does not have platelets, and only has degraded coagulation
• Deficiency can lead to: Megaloblastic anemia, Myelodysplastic factors
syndrome-like cytopenia, Neurologic deficits (Paresthesia, → Immunogenic
ataxia, CNS symptoms) → Only indication: exchange transfusion in neonates
• Cause of B12 deficiency/anemia: Juvenile pernicious anemia, → Blood components are used if it does not follow this indication
Malabsorption syndrome, Gastrectomy/Defective stomach
Whole blood components and uses
Folate • RBCs: To replenish after trauma or surgery and treat severe
• Dietary folate is needed in the conversion of N5 – anemia
Methyltetrahydrofolate to tetrahydrofolate • Platelets: To treat or prevent bleeding due thrombocytopenia by
→ Methyl group is donated to cobalamin (Vit. B12) increasing platelet levels and correct functional platelet problems
→ Methylcobalamin donates methyl group to homocysteine to (e.g. Von Willebrand disease)
make methionine • FFP: To correct a deficiency in coagulation factors, treat
→ Tetrahydrofolate is needed for DNA, thymine, and hypovolemic shock, and supply albumin or immunoglobulins
thymidine synthesis → Cryoprecipitate: To treat fibrinogen and factor VIII
• Absorption: Duodenum deficiencies
• Deficiency can lead to: Megaloblastic anemia, infantile neural → Cryosupernatant: for plasma exchange in Thrombotic
tube defects Thrombocytopenic Purpura (TPP)
• Causes: Increased demand with poor intake, alcoholism, liver
disease, malabsorption, drugs (methotrexate, trimethoprim, Ethical issue in transfusion: Jehovah's Witnesses
sulfamethoxazole) • Not acceptable: RBC, WBC, plasma, platelets
• Drugs that inhibit folate: Methotrexate, Trimethoprim, • Acceptable:
Sulfamethoxazole → For RBC: hemoglobin-based blood substitutes
• Treatment: Folic acid supplements (only oral is available) → For WBC: interferons, interleukins
→ For plasma: albumin, globulins, clotting factor
Epoetin (Drug) → For platelets: wound healing factor
• Interacts with erythroid receptors
• Induces release of reticulocytes REVIEW QUESTIONS
• Recommended for: 1. Alex accidentally stabbed his hand using a butter knife. He lost 10
→ Patients with CKD (given after a kidney dialysis treatment) mL of blood. He was scared that he might have lost too much blood,
→ Anemia of chronic disease thus fearing he might end up having iron deficiency. He started
• Cannot be used for: taking 5 tablets of iron supplement (65mg of elemental iron)
everyday. He started having some heart problems after. Which of
→ Aplastic anemia
the following drugs should you prescribe?
→ Iron deficiency anemia
a) Deferiprone
→ Leukemia b) Deferasirox
c) Deferoprone
d) Desferrioxamine

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2. Anna was found to have Hemoglobin - 8.1 g/DL, MCV - 70 fL, MCH what he/she should do since they cannot take it anymore. What do
- 20.9 g/dL, serum ferritin level – 300 nanogram/mL. What should you recommend?
you avoid doing in trying to treat Anna? a) Brush them off
a) Give iron supplements b) Tell them that it is normal and to rest
b) Give blood transfusions c) Discontinue
c) Give Deferiprone d) Change brand of drug
3. Cuis Lo, the attending physician, noticed that his patient was 11. What is used during heme iron absorption at the brush border of
having a severe allergic reaction to an iron infused IV. Which of the the duodenal cell?
IV forms is most probably the cause of the reaction? a) HCP1 receptor
a) Iron sucrose b) Heme oxidase
b) Iron carboxymaltose and sodium ferric gluconate complex c) Ferroportin
c) Iron dextran d) Hephaestin
d) Iron dextose
4. You see that your 60-year-old male patient has abnormally low iron Answers (if self-explanatory)
levels; when you asked for his eating habits, he said that he eats 1. A
lots of red meat and vegetables. What could be a possible cause 2. A. Thalassemia is a microcytic hypochromic anemia with dysregulated
for this iron loss/iron deficiency? hepcidin function. Only give iron supplements for iron deficiency
a) It’s impossible for him to have low iron because males can’t anemias. Check iron storage levels first.
excrete iron 3. C
b) Malignancies in the GIT 4. B (For older males, the usual cause of iron loss is malignancies or
c) Malnutrition possible tumors in the GIT)
d) He has insufficient HCP2 receptors 5. D
5. Which of the following blood components is used to treat fibrinogen 6. B.
deficiencies? 7. B. Whole blood is only used for exchange transfusion in neonates.
a) RBCs For all other cases, blood components are used.
b) FFP 8. C.
c) Platelets 9. F
d) Cryoprecipitate 10. D
6. Which is a drug with a long half-life? 11. A
a) EPO
b) Darbepoetin REFERENCES
c) Mercera REQUIRED
d) Deferoxamine (1) Tee, Paolo. 2019. Hematopoietics and Hematinics: Rational Use of
7. Which of the following is false regarding whole blood? Blood [Lecture slides].
a) It is able to elicit an immune response due to the presence of (2) Jameson, J.L., Fauci, A.S., Kasper, D.L., Hauser, S.L., Longo,
plasma. D.L., & Loscalzo, J. Harrison’s Principles of Internal Medicine (20th
b) It is used for exchange transfusion in children and adults. Ed.) New York, McGraw Hill Education, 2018.
c) It contains only RBCs and WBCs, but no viable platelets or (3) ASMPH Batch 2022. 2017. Trans Format.
coagulation factors. (4) Purdue University. “MLA Formatting and Style Guide.” Purdue Owl,
d) None. All of the above are correct. [https://owl.purdue.edu/owl/research_and_citation/mla_style/mla_f
8. A 12-year old boy presents with a low platelet count and ormatting_and_style_guide/mla_formatting_and_style_guide.html]
hemoconcentration (dengue). Warning signs for hemorrhagic fever . Accessed 30 July 2018.
are not yet present. Among the following treatments, what will be
the best course? Note: only among the choices, not necessarily the
best for the disease. IMPORTANT LINKS
a) Iso-osmotic IV fluid
b) Platelets stored for 7 days at 19 deg. Celsius Trans feedback: https://tinyurl.com/AcadsTransFeedback
c) 3-day old platelet bag stored at room temperature Errata submission: https://tinyurl.com/ContentErrataSubmission
d) Whole blood transfusion Errata tracker: https://tinyurl.com/ErrataTracker
9. T/F. Much like in anemia from chronic diseases, it is also advisable
to give Epoetin to those with aplastic anemia.
10. After having experienced continuous side effects such as pain,
nausea, black stools, your patient comes back to you asking for

APPENDIX

Table 5. Summary of hematopoietic drugs

Drug Class Drug Mechanism of Action
Erythropoiesis-Stimulating Epoetin alfa Stimulate proliferation and maturation of committed
Agents (ESAs) Darbepoietin alfa erythroid progenitors to increase RBC production

Myeloid Growth Factors GM-CSF (Sargrastim) Stimulate proliferation and differentiation of 1 or more
G-CSF (Filgrastim) myeloid cell lines, and enhance the function of mature
Pegylated recombinant G-CSF granulocytes and monocytes
(Pegfilgrastim)
Thrombopoietic Growth Factors IL-11 (Oprelvekin) Enhance megakaryocyte maturation and increases
peripheral blood platelet counts
Romiplostim Activate thrombopoietic receptor which stimulates
Eltrombopag megakaryopoiesis

Table 6. Summary of blood components and their common uses

Blood components
Component Description/ Uses
Whole Blood • Contains only RBCs and WBCs but no viable platelets or coagulation factors
• Provides both oxygen-carrying capacity and volume expansion
• Only used for exchange transfusion in neonates
• *Fresh whole blood: Contains all the components but is only used in emergencies due to difficult
storage conditions

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Red Blood Cells • Corrects acute anemic conditions (e.g. bleeding)
Fresh Frozen Plasma • Contains stable coagulation factors and plasma proteins: fibrinogen, antithrombin, albumin, and
proteins C and S
• Corrects deficiencies in coagulation factors
• Treats shock due to plasma loss from burns or massive bleeding
• Cryosupernatant:
→ Derived from FFP
→ Contains factors II, VII, IX, X, XIII and fibronectin
→ Used for plasma exchange in TTP
Cryoprecipitate • Derived from FFP
• Source of fibrinogen, factor VIII, and vWF
Transfusion products
Product Description/ Uses
Irradiated Packed RBC/ Platelets • For patients undergoing immunosuppressive therapy
Leukodepleted Packed RBC • For prevention of febrile transfusion reactions and transmission of cytomegalovirus (CMV)
• Used to avoid possible alloimmunization
Washed Packed RBC • For patients with antibodies to plasma proteins or previous severe allergic reaction to blood
transfusion
Cryopreserved Red Cell • For replenishing stem cell stores (e.g. chemotherapy)
Concentrates / Platelets / Stem • For patients with rare blood types (e.g. Bombay phenotype)
Cells

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