Coagulants/Hematinics PHARMACOLOGY

Dr. Glenn V. Guevarra | November 8 2017

Transcribers: Choa, Chua C, Chua P, Chua S
Editor: Surname | 09262512345
3.04
OUTLINE II. IRON DEFICIENCY ANEMIA
 Most common cause of anemia
I. Anemia
 Causes:
A. Definitions
o Inadequate intake – infants less than 12
B. Types
months; malnourished
II. Iron Deficiency Anemia
o Increased demand – children, adolescents,
A. Iron Metabolism
pregnant females
B. Regulatory Mechanism
o Decreased absorption – Celiac disease,
C. Iron Requirements
inflammatory bowel secondary to sensitivity to
D. Values
gluten, decreased gastric acids due to intake of
E. Treatment
antacids, proton pump inhibitors (PPI), H2
F. Oral Iron Therapy
receptor blockers, gastrectomy
G. Oral Iron Preparations
o Increased blood loss – heavy menstruation
H. Contents
due to hormonal imbalance, trauma, parasitic
III. Hypoproliferative Anemia
infections like hookworm in children,
IV. Megaloblastic Anemia
menorrhagia, peptic ulcer disease,
A. Cobalamin (Vitamin B12)
undiagnosed colon cancer
B. Folic Acid (Vitamin B9)
Iron Metabolism
V. Impaired Hematopoesis
A. Colony Stimulating Factor (CSF)
B. Recombinant CSF
C. Recombinant Interleukin-11
D. Recombinant Thrombopoeitin
VI. Bleeding Disorders
A. Vitamin K Deficiency / Hemorrhagic
Disease of New Borns
B. Hemophilia A and B
C. Bleeding due to Trauma and Surgical
Procedure
VII. References
VIII. Quiz

LEGEND
Remember Book Lecturer Other Trans
Trans Comm

OBJECTIVES
Figure 1. Binding of iron and protoporphyrin to form heme.
At the end of the lecture, the student should be able to: Hemoglobin consists of heme and globin chains. Heme needs
1. Master shadow clone jutsu protoporphyrin and iron where the oxygen attaches to. Protoporphyrin
2. Learn how conquer the iron throne in Westeros accumulation means there is no iron available in the circulation. If there
is decreased iron, the oxygen carrying capacity of RBC is also
I. ANEMIA decreased.
Definition
 Decrease in the number of red blood cells (RBC) or quantity of
hemoglobin in the blood which leads to decreased ability of
blood to carry oxygen
 Causes:
o Decreased RBC formation or failure in maturation of RBCs
like iron deficiency anemia (IDA), blood loss, or increased
oxygen demand
o Increased RBC destruction as seen in patients suffering
from hemolytic anemia
Types
 Based on SIZE
o Microcytic – iron deficiency, anemia of chronic disease,
chronic kidney disease
o Macrocytic – megaloblastic anemia like pernicious anemia
caused by cobalamin deficiency, folic acid deficiency
o Normocytic – chronic infections/diseases like tuberculosis
and chronic renal failure; chronic inflammation like
rheumatoid arthritis
 Based on COLOR Figure 2. Absorption, transport, and storage of iron. [Fe2+: reduced
o Hypochromic iron, ferrous iron; Fe3+: oxidized iron, ferric iron; Heme iron:
o Hyperchromic present in food]
o Normochromic

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 Iron crosses the luminal membrane of the intestinal mucosal  Main regulatory mechanism is through hepcidin, which is
cell by two mechanisms: produced in the liver.
o active transport of ferrous iron by the divalent metal  Increased/adequate amount of iron = Increased hepcidin
transporter (DMT1) production. It decreases absorption of iron at the intestinal
o absorption of heme iron through heme transporter cells, increases formation of ferritin, and increases recycling in
(HCT1). which the aging RBC engulfed by macrophage.
 Once inside the intestinal cell, a portion of the absorbed iron
(Fe2+) attaches to the mucosal ferritin (storage form), but most Low hepcidin concentration = promotes iron release
of it are transported to the bloodstream via ferroportin. High hepcidin concentration = inhibits iron release
 In the blood, iron (Fe2+) is transported by transferrin to
erythroid precursors in the bone marrow for synthesis of
hemoglobin or to hepatocytes for storage as ferritin. Iron Requirements
Fe2+ must be converted to Fe3+ to be transported by transferrin.  RBC lifespan: 120 days (0.8-1% RBC/day)
 Fe3+ must be reduced to Fe2+ by ferrireductase before it can  1 ml RBC = 1 mg elemental iron
be absorbed by intestinal mucosal cells.  Daily iron requirements:
o Dietary iron: 10-20 mg/day (10-15% are absorbed)
NOTES: o Absorbed iron: Male: 1 mg; Female: 1.4 mg (2x in
 Ferrireductase is vitamin C-mediated, so to enhance pregnancy; 1.5x in children and adolescents
absorption, take ascorbic acid (Vitamin C) or citrus drinks
together with iron. Values
 Transferrin without iron is called apotransferrin.  Hematocrit – proportion of total blood volume that is
 Ferritin (storage form) decreases in iron deficiency anemia. composed of RBC
 Transferrin (transporter) increases in iron deficiency o Male: 47% (±7)
anemia. o Female: 42% (±5)
o In IDA: low
 Hemoglobin
o Male: 16 g/dL
o Female: 13 g/dL (menstruating); 14 g/dL (menopausal); 12
g/dL (pregnant)
o In IDA: low
 Erythropoietin – 10-25 U/L
 Mean Corpuscular Volume (MCV) – average volume of RBC;
determines size of RBC
 90 ± 8 fL (HCT x 10/RBC) (normal: 80-100 fL)
 Mean Corpuscular Hemoglobin (MCH) – average mass of
hemoglobin per RBC sample of blood
o 30 ± 3 pg (Hgb x 10/RBC)
 Mean Corpuscular Hemoglobin Concentration (MCHC) –
concentration of hemoglobin in a given volume of packed RBC
o 33 ± 2% (MCH/MCV)
 Serum iron – amount of circulating iron bound to transferrin;
can increase immediately on initiation of iron supplementation
o 9-27 umol/L (50-150 μg/dL)
o Children: 50-120 ug/dL, Newborn: 100-250 ug/dL (2019A)
Figure 3. Transferrin is the transporter in plasma and it binds to o In IDA: low
ferric (Fe3+) form of iron.  Total iron binding capacity (TIBC) – the most specific
Iron is absorbed in the duodenum and proximal jejunum, indicator when levels are high
although the more distal small intestine can absorb iron if o 54-64 μmol/L (300-360 μg/dL)
necessary. Iron absorption increases in response to low iron stores o In IDA: elevated; this is a compensatory mechanism
or increased iron requirements. (implies an increased need for iron)
 % transferrin saturation (SI x 100 / TIBC)
Regulatory Mechanisms o 25-50%
o In IDA: low
 Ferritin
o Male: ~100 μg/L
o Female: 30 μg/L
o In IDA: low

Table 1. Blood Laboratory Test Values

HEMOGLOBIN
Male 13.8 – 18 g/dL 8.5 – 11.17 mmol/L
Female 12.1 – 15.1 g/dL 7.51 – 9.37 mmol/L
Children 11 – 16 g/dL 6.83 – 9.93 mmol/L
Pregnant 11 – 14 g/dL 6.83 – 8.69 mmol/L
Figure 4. Erythropoietin Cycle. If there is low O2 tension, erythropoietin HEMATOCRIT
(Epo) production and secretion is increased  increased erythrocyte Male 45%
production Female 40%
RBC COUNT
 Iron is also stored (as ferritin) in macrophages in the liver, Male 4.7 – 6.1 million/L
spleen, bone, and in parenchymal liver cells. Female 4.2 – 5.4 million/L
RED CELL INDICES

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MCV 80 – 100 fL
MCH 27 – 31 pg/cell  Iron toxicity
MCHC 32 – 36 g/dL 19.9 – 22.3 mmol/L o Acute – exclusive in young children (10 tablets) necrotizing
gastroenteritis, vomiting, abdominal pain, blood diarrhea,
Treatment shock, lethargy, dyspnea, coma and death
 Blood transfusion  Whole bowel irrigation, deferoxamine (IV iron-chelating
 Oral or parenteral iron therapy compound), supportive therapy
 Mild to moderate IDA: oral iron; if not tolerated, give parenteral o Chronic – hemochromatosis (iron overload) results when
 Severe IDA: blood transfusion + iron therapy excess iron deposits in heart, liver, pancreas etc; inherited
or acquired (treated with red cell transfusion)
Oral Iron Therapy  Intermittent phlebotomy, deferasirox (oral iron chelator)
 Goals of treatment: reverse anemia, replete iron stores
 Outcome measures:
III. HYPOPROLIFERATIVE ANEMIA
o In 3-5 days: increased reticulocytes
 Decrease in the overall RBC synthesis due to a chronic
o In 1 month: increased hemoglobin by 1g/dL
condition
 Increased absorption with concurrent intake of ascorbic acid,
 Usual observation of RBC: normocytic and normochromic
citrus drinks
 Decreased absorption with intake of tea, dairy, fish, agents that Table 3. Diagnosis of Hypoproliferative Anemia.
decrease gastric acidity (PPIs, H2 receptor blockers, antacids) Diagnosis of Hypoproliferative Anemia
 Drug interaction: decreased absorption with quinolones, Test Iron- Inflammation Renal Hypometabolic
tetracyclines, levodopa, levothyroxine, mycophenolate mofetil Deficiency Disease
o Caution when giving iron to patients with hypothyroidism Anemia Mild-severe Mild Mild-severe Mild
(taking levothyroxine) MCV 60-90 80-90 90 90
Morphology N / micro N N N
Table 2. Oral Iron Preparations (Note: Values enclosed in parenthesis SI <30 <50 N N
TIBC >360 <300 N N
are elemental iron absorbed in mg.)
%sat <10 10-20 N N
Generic Name Tablet size (mg) Elixir (5 ml)
Ferritin <15 30-200 115-150 N
Ferrous sulfate 325 (65) 300 (60)
Iron Stores 0 2-4+ 1-4+ N
195 (39) 90 (18)
Extended release 525 (105) -
Ferrous fumarate 325 (107) - Causes
195 (64) 100 (33)  Chronic Diseases
 Renal Diseases
Ferrous gluconate 325 (39) 300 (35)
 Metabolic Disease
Contents  Bone Marrow Depression
 Iron supplementation Anemia of Chronic Kidney Disease
o Pregnant women: 60 mg/day throughout pregnancy and up
 Due to a decrease in erythropoietin production
to 6 months after pregnancy
 Increased synthesis / release of hepcidin
o 6-24 months: 12.5 mg/day up to 12 months for infants with
normal body weight; up to 24 months for infants with low  Leads to a decreased erythropoiesis (shortened erythrocyte
body weight life span)
o 2-5 years: 20-30 mg/d; 6-11: 30-60 mg/d; adolescents and
adults: 60 mg/d
 Iron supplementation: with severe anemia
o <2 years: 25mg/day for 3 months
o 2-12 years: 60mg/day for 3 months
o >12 yrs (including pregnant women): 120mg/day for 3
months
 Adverse reactions:
o Abdominal cramps (must not be given to pregnant women
who are in the first trimester)
o Nausea and vomiting
o Diarrhea or constipation
o Black stools
 Parenteral Iron Therapy
o Indications: if the patient cannot tolerate oral iron,
condition is acute and severe, need iron continuously
o Iron dextran (anaphylaxis), ferric sucrose, ferric
carboxymaltose complex, sodium ferric gluconate complex,
ferumoxytol (paramagnetic ferric oxide)
o Used with recombinant Epo
o Risk of anaphylaxis
o Weight (kg) x 2.3 x (15-pt.’s hgb in g/dL) + 500 or 1000 Figure 5. Anemia of Chronic Disease
o Two ways:
1. Administer total dose required to correct deficit Endogenous Erythropoietin
and provide 500mg iron stores (infusion)  Also called hematopoietin, hemopoietin.
2. Give repeated small doses over protracted period  Produced in the kidney by interstitial fibroblasts (Fetus:
e.g. 100mg weekly x 10 weeks perisinusoidal cells of the liver)
 Controls erythropoiesis; stimulates progenitor proliferation and
maturation
 Normal level: 10-25 U/L

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 Increased when Hgb level <100-120g/L (10-12g/dL) d. Adenosylcobalamin
 Clearance: 6-9 hours  fuel B12
 EPO release = 4-5x RBC production (1-2 weeks)  not often given for patients with neurologic
deficit and megaloblastic anemia
Treatment: often in combination with Methylcobalamin
 Blood transfusion - useful in DNA synthesis and mitochondrial
 Recombinant erythropoietin cobalamin biochemical reaction
 Stimulates proliferation and maturation of red cell 2. Supplementations:
progenitors; induces release of reticulocytes  Cobalamin IM / IV
 Indications: anemia observed in chronic kidney disease:  Better absorption than oral
other indications: AIDS, cancer chemotherapy, surgery,  1mg/week for 8weeks
prematurity, chronic inflammation  1mg/month for life
 Recombinant human erythropoietin (epoietin alfa) 2,000-  Cochrane review:
40,000 units/ml IV / SQ; HL 4-8hrs (once dosing)  1-2mg/d orally for 90-120days has similar
 Darbepoietin alfa extends half-life 24-36 hours serum improvement compared to IM
 Complications: IDA – start iron supplementation; injections regardless of etiology
thromboembolic events-start with anticoagulants  See appendix (A1 and A2)

IV. MEGALOBLASTIC ANEMIA Deficiency in cobalamin leads to pernicious anemia, neurologic

 Presence of distinctive morphological appearances problems and accumulation of Homocysteine. Homocysteine
(macrocytic) of developing RBC (genetic / acquired) contributes to cardiovascular diseases.
 Due to deficiency of cobalamin or folic acid
 Causes: Folic Acid
o Deficiency of either cobalamin (vitamin B12) or  Reduced forms are required for essential biochemical
folate reactions
o Decreased intake (not very common)  Key role in DNA synthesis
o Decreased absorption  Deficiency may lead to megaloblastic anemia, congenital
 Gastric / ileal resection – absence of malformation (neural tube defects) and cardiovascular
intrinsic factor and hydrogen ion to break disease (hyperhomocysteinemia)
down food  Average diet (as folates): 500-700g/day
 Decreased gastric acid from PPI H2 o 50-200g absorbed
blockers o Pregnant women: 300-400g absorbed
 Malnutrition  Sources: fresh vegetables, liver, yeast, fruits (90% destroyed
 Celiac disease by heating)
 Alcoholism  Daily requirement: 400g
o Genetic or acquired abnormalities affecting the o Pregnant women may reach as high as 500-600g
metabolism of these vitamins  Storage: 10mg
o Defects in DNA synthesis not related to cobalamin o megaloblastic anemia appears 1-6 months after
or folate stopping
 Serum: 9-45nmol (4-20ng/ml)
Cobalamin (Vitamin B12)
 Absorption: duodenum and proximal jejunum
 Water soluble vitamin
 See Appendix (A1)
 Synthesized by microorganisms
 Average diet contains 5-30μg/day (1-5μg) Folic Acid Supplementation
 Sources: meat, fish, dairy products
 Causes of deficiency
 Daily loss: 1-3μg
o Inadequate intake
 Daily requirement: 2μg o Increased demand (pregnancy, children)
 Storage: 3000-5000μg o Decreased absorption (celiac disease)
o good for 4 years o Medications (anti-folate drugs: co-trimoxazole,
o Megaloblastic anemia appears 5 years after sulfasalazine, methotrexate – see appendix A3)
stopping o Genetics
 Function: Key role in the normal functioning of the brain and Alcoholism
nervous system, and for the formation of blood; affects DNA Drugs that inhibit DHF reductase (methotrexate,
synthesis and regulation trimethoprim)
 Forms: Interfere in storage of folate in tissues (oral
a. Cyanocobalamin contraceptives)
 contains cyanide which the body needs to Megaloblastic anemia (faster and worse than B12
eliminate deficiency) – must distinguish from cobalamin deficiency;
 cheapest cobalamin deficiency has neurologic syndrome folate
 well tolerated by healthy patients deficiency does not
 not effective in smokers
Higher incidence in coronary artery and peripheral
 parenteral
vascular disease and for venous thrombosis
b. Hydroxocobalamin (hyperhomocysteinemia)
 good for patient with problems with methyl
 Dose:
transfer pathway
o Low risk: 400g/d 2-3mos before, during and up to
 not available in preparations
6mos after pregnancy
c. Methylcobalamin
o Moderate to high risk: up to 1mg/d
 more bioactive
 Folic acid - used for supplementation
 converted in the body to hydroxocobalamin
 parenteral and SL forms  Folinic acid (Leucovorin calcium - derivative of THF
 better for smokers antagonist)

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o Circumvent inhibition of DHF reductase by o 100g/kg as single dose/chemotherapy cycle
methotrexate o cannot be mobilized if patient is being given stem
o Used for toxicity to anti-folates cell transplantation
o Not used for supplementation  Filgrastim – short acting
For most cases: no advantage over folic acid, more  PEG-filgrastim – long acting
expensive
Both should not be used for treatment of pernicious Growth Factors / Mobilizers
anemia because you only treat the megaloblastic  Lenograstim
anemia, not the the deficiency in cobalamin (it masks o Produced by hamster
signs and symptoms of cobalamin deficiency) o Recombinant human glycosylated G-CSF
Avoid multivitamin preparations unless there is clear o reverses neutrophil count by 30% compared to
deficiency of other vitamins filgrastim; mobilizes granulocytes (after PBSCT),
Well tolerated (even at 15mg/d) 150g/kg/d SQ or IV drip
Counteract effects of Phenobarbital, Phenytoin, and  Sargramostim
Primidone o Produced by yeast
o Recombinant human glycosylated GM-CSF
V. IMPAIRED HEMATOPOIESIS o 250g/kg/d SQ given 1-4 days after chemotherapy;
 Granulopoiesis – neutropenia, leukopenia mobilizes granulocytes (after PBSCT)
 Thrombopoiesis – thrombocytopenia o Half-life: 2-3hrs
 Causes o Slow infusion: 3-6 hours
o Immunosuppressive cancer chemotherapy (incl. o Adverse Effects:
those used in autoimmune diseases)  Bone pain
o Autologous stem cell transplantation – decreases  Malaise
blood cell lines  Flu-like symptoms
o Medication / immune related  Fever
Zidovudine induced bone marrow  Diarrhea
suppression in AIDS patients  Dyspnea
Kidney disease, chronic infection and inflammation,  Hypersensitivity reactions
malignancy, hypometabolic  Cutaneous necrotizing vasculitis
Hematopoietic Growth factors  Splenomegaly
o Glycoprotein hormones that regulate the
proliferation and differentiation of hematopoietic GM-CSF can cause more severe side effects, particularly at
progenitor cells in the bone marrow high doses
o Known hematopoietic growth factors:
 Erythropoietin (epoetin alfa and epoetin Recombinant Interleukin 11
beta)  Interleukin 11 - growth factor that stimulates megakaryocyte
 Granulocyte Colony Stimulating Factor (G- maturation; produced by fibroblasts and stromal cells in the
CSF) bone marrow
 Granulocyte-Macrophage Colony
Stimulating Factor (GM-CSF) Oprelvekin
 Interleukin-11 (IL-11)  Produced by Escherichia coli
 Recombinant human Interleukin 11
Colony Stimulating Factors (CSF)  Bacterially derived 19,000-Da polypeptide
 Glycoproteins that stimulate the proliferation and  Used in chemotherapy-related thrombocytopenia (<20,000
differentiation of blood cell lines
cells/l) - Goal is to reach at least to 100,000 cells/l
 First growth factors to be identified
 25-50g/kg/d SQ 5-9 days
 Produced naturally by fibroblasts, endothelial cells,
 Half-life: 7 hours
macrophages and T cells
 Adverse Effects:
 GM-CSF stimulates the proliferation, differentiation and
o Rash
function of a number of the myeloid cell lineages
o Paresthesias
 G-CSF is limited to neutrophils and their progenitors, o Fluid retention
stimulating their proliferation, differentiation and function o Dyspnea
o Tachycardia
Recombinant CSF o Palpitation
 Indications: o Blurred vision
o After immunosuppressive non-myeloid cancer
chemotherapy Recombinant Thrombopoietin
 High risk for post-chemo febrile  Thrombopoietin - growth factor that stimulates megakaryocyte
neutropenia (FN; >20%) production
 Prior episodes of FN
 For chronic thrombocytopenia
 Those that will not survive from FN
o After peripheral blood autologous stem cell
Romiplostim and Elthrombopag
transplantation
 Immediate mobilization of PBSCs resulting  Romiplostim - SQ, shorter T1/2; Elthrombopag - oral, longer
to reversal of granulocyte count T1/2
 Thrombopoietin agonists
Filgrastim, PEG-filgrastim  High affinity to human antibody Mpl receptor
 Produced by Escheichia coli  Used in chronic immune thrombocytopenia (ITP, TTP)
 Non-glycosylated recombinant human G-CSFs  Adverse Effects:
o 5g/kg/d SQ 1-3 days after chemotherapy until o Headache
o Dizziness
neutrophil count reaches 10,000cells/l (5-7days)
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o Dyspnea
o Arrhythmias
o Hypokalemia
o Hepatotoxicity
o Marrow fibrosis

VI. BLEEDING DISORDERS

 Vitamin K deficiency bleeding in the newborn (hemorrhagic
disease of the newborn)
 Hemophilia A and B
 Bleeding due to trauma and surgical procedures

Hemostasis
 Step 1- Vascular spasm
o Contraction of the smooth muscle produces the
vasoconstriction
 Step 2- Formation of the platelet plug
o Lesion of the endothelium exposes the collagen
fibers, platelet adhesion is triggered
o Platelets release mediators which further
favorize platelet aggregation; the platelet plug is
formed
 Step 3- The coagulation
o Fibrin filaments polymerize; red and white blood
cells get trapped and the blood clot is formed

This is the extrinsic pathway of the coagulation cascade. The

main aim of this is the tissue factor complex will lead to conversion
of your prothrombin to thrombin which will stimulate the production
of fibrin clot. After this, if there’s a stable plug, then there’s a trigger
for the activation of the plasminogen, through the enzyme t-PA
(tissue plasminogen activator). So the response will be plasmin
which will trigger fibrinolysis.

Impaired Hemostasis
Test Value Normal
Platelet count <50,000 cells/µL 150,000-450,000
cells/µL)

Bleeding time >10 mins 1-9 mins

(Platelet function)
Prothrombin time >13.5 secs 11-13.5 secs
(Extrinsic pathway)
Partial thromboplastin >35 secs 25-35 secs
time (Intrinsic
pathway)
Table. Normal and abnormal values of different tests

Vitamin K Deficiency / Hemorrhagic Disease of Newborns

Vitamin K
 Fat soluble vitamin
 Needed for synthesis of prothrombin (II), VII, IX, X
 For manipulation of calcium in bones
 Requirement is low (synthesized by bacteria in SI),
deficiency uncommon
 Deficient in poor diet, resection of SI, celiac disease,
parenteral nutrition, recent surgery, multiple antibiotic
therapy, uremia
 Newborns: 30-60% clotting factors compared to adults
and sterility of gut leads to 1% risk of bleeding due to vit.
K deficiency

Vitamin K Supplementation
 Natural forms:
o K1 (Phytonadione; found in food)-

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 Available clinically in oral and o In practice: 500-1000 mg qid for 4-5 days
parenteral  AE: clotting problems (thrombosis, retinal occlusion,
 Used for vitamin K deficiency or embolism, infarct, seizures), hypotension, myopathy, GI
depressed prothrombin observed in discomfort, nausea, diarrhea, hypersensitivity reactions
excess warfarin (nasal stuffiness, rash)
o K2 (Menaquinone; found in tissues)  CI: DIC, upper GU bleeding (potential for excessive
o K3 (Menadione) clotting)
 Not used as therapy
 Synthetic : TPA activates your plasminogen to produce plasmin which
 Toxic increases fibrinolysis of a stable fibrin clot. Para siyang blood
 RDI: Males- 120 µg/day; Females- 90 µg/day; infants- 10 thinners. So if you inhibit it (TPA inhibitors), it acts as
µg/day procaogulant.
 To prevent newborn vitamin K deficiency bleeding:
Vitamin K1- 0.5-1mg IV/IM ( most common is 0.5 mg) Off label indications of TPA inhibitors:
 Vitamin K1 is currently administered to all newborns  Patients with trauma in which you can’t control
to prevent the hemorrhagic diseases of vitamin K bleeding
deficiency, which is common in premature infants  After operation or surgical procedure in which there
 IV administration of vitamin K1 should be slow, is still profuse bleeding
because rapid infusion can produce dyspnea, chest and
back pain, and even death.
 To prevent osteoporosis in menopausal women: Serine Protease Inhibitors
Vitamin K2- 45 mg/day  Aprotinin
 To reverse warfarin effect prior to operation: Vitamin o Inhibits fibrinolysis by free plasmin and may
K1 1-2.5 mg have other antihemorrhagic effects
o Inhibits plasmin-streptokinase complex
Hemophilia A and B o Reduce bleeding especially involving
Plasma Fractions extracorporeal circulation for open heart
 Bleeding occurs in setting with deficient coagulation procedures and liver transplantation
factors (<5-10%) o Associated with increased risk of renal failure,
 Most common are VIII (Classic hemophilia or Hemophilia heart attack, and stroke
A) and IX (Christmas or Hemophilia B)
 Concentrated plasma fractions are given. Risk of VII. SUMMARY
transmission of infection diminished by pasteurization  Anemia
o Iron- elemental iron
 Combined factor treatment are recommended:
o Cobalamin- supplementation and biochemical
o Prothrombin complex concentrates-
reactions
when most of the clotting factors are o Folic acid- supplementation and biochemical
deficient, more expensive reactions
o Factor VIII plasma fractions-for Hemophilia A o Supportive therapy- for anemia of chronic disease
o Factor IX plasma fractions- for Hemophilia B  Erythropenia (Erythopoietin)
o Humate P ( von Willebrand factor and VIII o Erythopoeitin alfa- short acting
concentrate)- for von Willebrand disease o Darbepoietin- long acting
Desmopressin acetate increases the factor VIII activity  Neutropenia/ Leukopenia
of patients with mild hemophilia A or von Willebrand disease. It o rHu G CSF- more frequently used
 FIlgastrim
can be used in preparation for minor surgery such as tooth
 Pegfilgrastim- long acting
extraction without any requirement for infusion of clotting
 Lenograstim- mobilizer
factors if the patien has documented adequate response. o rHu GM CSF
 Sagramostim
 Recombinant Factor VIIa is approved for treatment of  Thrombocytopenia
inherited or acquired hemophilia A or B with inhibitors, o Interleukin 11 (oprelvekin)- for thrombocytopenia
treatment of bleeding associated with invasive procedures in due to chemotherapy
congenital or acquired hemophilia, or factor VII deficiency. In o Thrombopoietin agonists (romiplostim,
the European Union, the drug is approved for treatment of elthrombopag)- for chronic thrombocytopenia (ITP
Glanzmann’s thrombasthenia. and TTP)
 Hemolysis
o Vitamin K supplementation- phytonadione for
Bleeding due to Trauma and Surgical Procedure newborns
Fibrinolysis/ TPA Inhibitors o Plasma fractions (VIII, IX)- for hemophilia A, B
 Indications: o TPA inhibitors (aminocaproic acid, tranexamic
o Minimize or prevent post-surgical bleeding acid)- for patients with excessive bleeding
(prostatic and orthopedic surgery)
o Minimize bleeding after tooth extraction III. REFERENCES
(especially hemophiliacs) 1. Katzung
 Aminocaproic acid- inhibitor of fibrinolysis (similar to 2. 2019 A and C trans
lysine) 3. Lecture Notes
o Inhibits plasminogen activation by competing 4. Recordings
for lysine binding sites in plasminogen 5. Powerpoint
o Blocks interaction of plasmin with fibrin
o IV 5g LD for 30 mins; 1-1.25 g/hr PO for 8 hrs IV. QUIZ
 Tranexamic acid- analog of ACA; same indication 1. TRUE or FALSE: DMT1 cotransporter carries ferric iron in the
o Administered orally/IV 15 mg/kg LD followed by gut.
30 mgkg q6

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2. TRUE or FALSE: Hepcidin levels increase when iron levels
are adequate.
3. Which of the following medications will help normalize low
leukocyte levels (neutropenia)?
a. Iron
b. Darbepoietin
c. Folic acid
d. Filgrastim
4. Which of the following medications is a recombinant
interleukin-11 used to prevent thrombocytopenia?
a. Oprelvekin
b. Sargramostim
c. Darbepoietin
d. Filgrastim
3. What distinct morphological appearance can be seen on
developing RBCs of a patient with megaloblastic anemia?
a. Microcytic
b. Hypochromic
c. Macrocytic
d. Hyperchromic
4. What form of vitamin K is administered to newborns to
prevent vitamin K deficiency bleeding?
a. K1
b. K2
c. K3
d. K4

Answer key: FALSE, TRUE, D, A, C

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APPENDIX

Figure A1. Cobalamin (blue square) and Folic Acid (red square) Biochemical Reaction. Cobalamin is needed to convert Homocysteine to Methionine,
which leads to DNA Methylation/Synthesis. If there is no cobalamin, there would be a decrease in production of methionine and decrease in DNA
synthesis.

Figure A2. Cobalamin Biochemical Reaction. Two bioactive forms of cobalamin – (1) Methylcobalamin and (2) Adenosylcobalamin. Contributes to
energy in the mitochondria and health in myelin sheath. But most neurologic problems are because of methylcobalamin.

Figure A3. Inhibition of Folic Acid Synthesis by Sulfonamides and Methotrexate.

Table A1. Clinical Uses of Hematopoietic Growth Factors and Agents that mimic their actions.

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Table 2. Therapeutic products for the treatment of coagulation disorders.

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