Coagulants, Hemostatics and Hematinics

7/29/2019 Coagulants, Hemostatics and Hematinics

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Page 1 of 8 NICOLE LALUCESKARLA LIGERALDEABBY MARALITMON PALMAVIRRA ROSALESVIN SANCHEZVINCENT REOLALASAURORA AUREA REYES

Hematinics

agents that tends to stimulate blood cell formation or toincrease the hemoglobin in the blood

Hemostasis and Hemostatics

finely regulated dynamic process of maintaining fluidity of the

blood, repairing vascular injury, and limiting blood loss while

avoiding vessel occlusion (thrombosis) and inadequate

perfusion of vital organs

dysregulated hemostasis include hereditary or acquired defects

in the clotting mechanism and secondary effects of infection or

cancer

agents that maintains hemostasis are called hemostatics

Coagulants

exogenous substances used to promote blood coagulation. The

endogenous blood coagulation factors are considered to be

coagulants only when administered as drugs

Blood

blood volume: 4-4.5L in females ; 4.5-5L in males

functions includes:

transport of various molecules (O2, CO2, nutrients,

metabolites, vitamins, electrolytes, etc.),

heat (regulation of body temperature)

transmission of signals (hormones)

buffering

immune defense

Red blood cells (RBCs) - transport O2 and pH regulation

White blood cells (WBCs) - divided into neutrophilic,

eosinophilic and basophilic, granulocytes, monocytes, and

lymphocytes. (Neutrophils play a role in nonspecific immune

defense; monocytes and lymphocytes participate in specific

immune responses)

Platelets (thrombocytes) hemostasis

Hematopoiesis

production from undifferentiated stem cells of circulating

erythrocytes, and platelets

produces over 200 billion new blood cells/d in the normal

person and more in conditions that cause loss or destruction of

blood cells

requires iron, folic acid, cobalamin and growth factors for

proliferation and differentiation of blood cells

Erythropoiesis

The young red cell is called a retlculocyte and normally takes

about 4 days to mature into an erythrocyte.

In health, erythropoiesis is regulatedand maintained within a

narrow range.


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G-CSF stimulates proliferation and differentiation of

progenitors already committed to the neutrophil lineage and

and prolongs their survival in the circulation

also has a remarkable ability to mobilize hematopoietic stem

cells, ie, to increase their concentration in peripheral blood

GM-CSFs biologic actions:

Multipotential hematopoietic groth factor that stimulates

proliferation and differentiation of early and late granulocytic

progenitor cells as well as erythroid and megakaryocyte

progenitors

stimulates the function of mature neutrophils together with interleukin-2 stimulates T-cell proliferation and

appears to be a locally active factor at the site of inflammation

it also mobilizes peripheral blood stem cells, but it is

significantly less efficacious than G-CSF in this regard

Iron

Iron absorption

Absorption, Transport and Storage of Iron:

Intestinal epithelial cells actively absorb inorganic iron andheme iron. Ferrous iron that is absorbed or released from

absorbed heme iron in the intestine is actively transported into

the blood or complexed with apoferritin and stored as ferritin

In the blood, iron is transported by transferrin to erythroid

precursors in the bone marrow for synthesis of haemoglobin or

to hepatocytes fro storage as ferritin

The transferrin iron complexes (TfR-Tf) bind to transferring

receptors in erythroid precursors and hepatocytes and are

internalized

After release of the iron, the TfR-Tf complex is recycled to the

plasma membrane and Transferrin is released

Macrophages that phagocytise senescent erythrocytes (RBC)

reclaim the iron from the RBC haemoglobin and either export it

or store it as ferritin

Iron storage and cycling

Anemia

There is a reduction in blood hemoglobin concentration due to

a decrease in the number of circulating erythrocytes and/or in

the amount of hemoglobin they contain.

It occurs when the erythropoietic tissues cannot supply enough

normal erythrocytes to the circulation.

In anemias due to abnormal red cell production, increased

destruction and when demand exceeds capacity, plasma

erythropoietin levels are increased.

However, anemia can also be caused by defective production of

erythropoietin as, for example, in renal disease

a deficiency in oxygen-carrying erythrocytes, is the most

common and can easily be treated

includes iron deficiency anemia, megaloblastic anemia,

hemolytic anemia, hemoglobinopathies etc

treatment: supplementation of iron, folic acid, cobalamin,

growth factors and transfusion

megaloblastic anemia

typical finding is macrocytic anemia, often with associated

mild or moderate leucopenia or thrombocytopenia (or

both), a characteristic hypercellular bone marrow with an

accumulation of megaloblastic erythoid and other

precursor cells

group of disorders characterized by the presence of

distinctive morphologic appearances of the developing red

cells in the bone marrow

cause is deficiency of either cobalamin (vitamin B12) orfolate or genetic or acquired abnormalities affecting the

metabolism of these vitamins or defects in DNA synthesis

not related to cobalamin or folate

Neurologic syndrome associated with Vit B12 deficiency

usually begins with paresthesias and weakness in

peripheral nerves and progress to spasticity, ataxia, ans

other CNS dysfunctions

Once a diagnosis of megaloblastic anemia has been made,

it must be determined whether Vit B12 or Folic Acid

deficiency is the cause can be accomplished by

measuring serum levels of the vitamins.

The Schilling test, which measures absorption and urinary

excretion radioactively labeled VitB12, can be used tofurther define the mechanism of VitB12 malabsorption

when this is found to be the cause of the megaloblastic

anemia

Pernicious Anemia results from defective secretion of IF

by the gastric mucosal cells

The Schilling test shows diminished absorption of

radioactively labeled Vit B12, which is corrected when IF is


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administered with radioactive B12, since the vitamin can

then be normally absorbed

COBALAMINMechanism of action:

(cobalamin) serves as a cofactor for the enzyme methylmalonyl CoA mutase

(mecobalamin or methylcobalamin) serves as a cofactor for the enzyme

methionine synthase

Necessary for the transfer of methyl groups

Name of Drug Pharmacokinetics Indication/Dosage Additional NotesCyanocobalamin Injection

Hydroxycobalamin

Mecobalamin

average diet contains 5-30 g of vit

B12 daily

1-5 g of which is usually absorbed

Storage: liver 3000-5000 g

Complexes with intrinsic factor

(produced by parietal cells);

complex is absorb in the distal

ileum by a receptor-mediated

transport system

daily requirement: 2 g

Vit B12 deficiency results from

malabsorption due to either lack

of IF or to loss or malfunction of

the specific absorptive mechanism

in the distal ileum

bound to a plasma glycoprotein,

transcobalamin II

excess vitamin B12 is transported to

the liver for storage

Oral preparations: 500-

1000 g

parenteral injection is

available as

cyanocobalamin or

hydroxocobalamin

100-1000 g of vitamin B12

IM daily or every other day

for 1-2 weeks then

maintenance therapy

consists of 100-1000 g IM

once a month for life

if neurologic abnormalities

are present, maintenance

should be given every 1-2

weeks for 6 months before

switching to monthly

injections

oral cobalamins are not

used to treat Vit B12

deficiency with neurologic

manifestations but can be

used for pernicious anemia

(500g BID)

Megaloblastic anemia GIT-

glosstits, dyspepsia due to

gastric mucosa atrophy

Neurological abnormalities

Optic atrophy

Mental disturbances

serves as a cofactor for

several essential

biochemical reactions in

humans

consists of a porphyrin-

like ring with a central

cobalt atom attached to a

nucleotide

deoxyadenosylcobalamin

and methylcobalamin are

the active forms

Cyanocobalamin and

hydroxocobalamin and

other cobalamins found in

food sources are

converted to the active

forms

ultimate source of vitamin

B12 is from microbial

synthesis

Sources: certain

microorganisms that grow

in soil, water, or in the

intestinal lumen of

animals, legumes which

are contaminated by

bacteria producing

Vitamin B12

Metabolic functions:

oEssential for normal

maturation of

erythroblasts and

epithelial cells

oPropionate catabolism


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Clinical Pharmacology:

Folate deficiency results in megaloblastic anemia that is

microscopically indistinguishable from the anemia caused by Vit

B12 deficiency

Folic acid deficiency is often caused by by inadequate dietary of

intake of folates.

Folic acid deficiency can be caused by drugs. Methotrexate, and

to a lesser extent, trimethoprim and pyrimethamine, inhibit

dihydrofolate reductase and may result in a deficiency of folate

cofactors and ultimately in megaloblastic anemia.

Long term therapy with phenytoin can also cause folate

deficiency, but only rarely causes megaloblastic anemia

FOLIC ACID

Mechanism of action:

provide precursors for the synthesis of amino acids, purines, and DNA

Name of drug Pharmacokinetics Indication Additional notes

Folic acid average diet contains 500-700 g of

folates daily,

50-200 g of which is usually absorbed in

proximal jejunum (5-20 mg of folates are

stored in the liver and other tissues)

pregnant women may absorb as much as

300-400 g of folic acid daily

sources: yeast, liver, kidney, and green

vegetables.

Excretion: urine and stool

folic acid deficiency and megaloblastic

anemia can develop within 1-6 months

after the intake of folic acid stops

megaloblastic anemia

oral preparations:

400 g folic acid

daily for adults

are satisfactory

600 g for

pregnant women

500 g for nursing

mothers

Metabolic function:

thymydilate synthesis

Iron deficiency anemia

most common cause of chronic anemia and one of the most

prevalent forms of malnutrition

Stages:

negative iron balance

iron-deficient erythropoiesis

iron deficiency anemia

clinical manifestation: pallor, fatigue, dizziness, exertional dyspnea,

other generalized symptoms of tissue hypoxia, tachycardia,

increased cardiac output, vasodilation


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DRUGS FOR ANEMIA

IRON PREPARATIONS

Mechanism of action:

forms the nucleus of the iron-porphyrin heme ring, which together with globin chains forms hemoglobin

Adverse effects: Hypersensitivity reactions. Acute toxicity, NEC< nausea, vomiting, bloody diarrhea, nausea, epigastric discomfort, abdominal

cramps, constipation, and diarrhea, black stools


IRON Absorption takes place in the

duodenum and the proximal

jejunum

absorption: 1mg/day; 2 mg in

menstruation, birth andpregnancy (3-15% in a normal

person and ~25% in iron

deficient states)

iron needed in body: 10-20 mg

/day (women>children>men)

In a iron-deficient individual,

about 50-100mg of iron can be

incorporated into hemoglobin

daily, about 25% of oral iron

given as ferrous salt can be

absorbed

iron deficiency anemia

Available preparations

Ferrous Salt

Preparation

Elemental Iron

Content

Ferrous sulfate

Hydrated 20%

Dessicated 30%

Ferrous gluconate 12%

Ferrous fumarate 33%

Ferrous lactate 19%

200-400 mg of elemental iron should be

given daily to correct iron deficiency most

rapidly

Patients unable to tolerate such large doses

of iron can be given lower daily doses of

iron, which results in slower but still

complete correction of iron deficiency

Treatment should be continued for 3-6

months after correction of the cause of the

iron loss

Hemoglobin reversibly

binds oxygen and

provides the critical

mechanism for oxygen

delivery from the lungsto other tissues.

In the absence of

adequate iron, small

erythrocytes with

insufficient hemoglobin

are formed

PARENTERAL IRON

Mechanism of action: forms the nucleus of the iron-porphyrin heme ring, which together with globin chains forms hemoglobin


Iron dextran iron deficiency anemia

IV infusion or IM injection

give total dose of iron required to

correct the hemoglobin deficit

and provide the patient with 500

mg of iron stores; second is to

give repeated small doses of

parenteral iron over a protracted

period

formula: kg x 2.3x 15 hgb in g/dl

+ 500mg

dilute in D5 0.9 NaCl; given 60-90mins

IV administration eliminates the

local pain and tissue staining that

often occur with the IM route and

allows delivery of the entire dose

or iron necessary to correct the

iron deficiency at one time

reserved for patients with documented iron

deficiency who are unable to tolerate or

absorb oral iron and for patients with

extensive chronic blood loss who cannot be

maintained with oral iron alone

headache, light-headedness, fever,

arthralgias, nausea and vomiting, back pain,

flushing, urticaria, bronchospasm, and,

rarely, anaphylaxis and death (48-72H)

For patients who are treated chronically

with parenteral iron, it is important to

periodically monitor iron storage levels to

avoid the serious toxicity associated with

iron overload. Unlike oral iron therapy,

which is subject to the regulatory

mechanism provided by the intestinal

uptake system, parenteral administration,

which bypasses this regulatory system,

can deliver more iron than can be safely


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stored in intestinal cells and macrophages

in the liver and tissues

Iron sucrose complex Less likely to cause anaphylactic reactions

Iron sodium gluconate

complex

acute iron toxicity

seen in children

include necrotizing gastroenteritis, with vomiting,

abdominal pain, and bloody diarrhea followed by shock,lethargy, and dyspnea; complications include severe

metabolic acidosis, coma, and death

treated with Deferoxamine, a potent iron-chelating

compound, can be given systemically to bind iron that has

already been absorbed and to promote its excretion in urine

and feces

chronic iron toxicity

secondary to iron overload (hemochromatosis)

results when excess iron is deposited in the heart, liver,

pancreas, and other organs

leads to organ failure and death

can be treated by intermittent phlebotomy and Deferasirox

by reducing liver iron concentrations

Anemia of Chronic Disease

encompasses inflammation, infection, tissue injury, and

conditions (such as cancer) associated with the release of

proinflammatory cytokinesis one of the most common

forms of anemia seen clinically and probably the most

important in the differential diagnosis of iron deficiency

low serum iron, increased red cell protoporphyrin, a

hypoproliferative marrow, transferrin saturation in the

range of 1520%, and a normal or increased serum ferritin

Decrease EPO response interleukin, TNF

Hepcidin found in liver in chronic inflammation

decreases iron uptake and metabolism

HEMATOPOIETIC GROWTH FACTOR

ERYTHROPOIETIN originally purified from the urine

of patients with severe anemia

recombinant human

erythropoietin (rHuEPO, epoetin

alfa) is produced in a mammalian

cell expression system

(Chronic Renal Failure) CRF: usual dose is

50150 U/kg 3x/week IV

hemoglobin levels of 1012 g/dL are

usually reached within 46 weeks if iron

levels are adequate; 90% of these

patients respond

4-13H half life; Darbepoetin alfa with a

longer half life

Toxicity

rapid increase in

hematocrit and

hemoglobin and

include hypertension

and thrombotic

complications

MYELOID GROWTH FACTORS (G-CSF & GM-CSF)

Filgrastim

Sargramostim

originally purified from cultured

human cell lines

recombinant human G-CSF (rHuG-

CSF; filgrastim) is produced

through bacterial expression and

recombinant human GM-CSF

(rHuGM-CSF; sargramostim) is

produced in a yeast expression

serum half-lives of 2-7 hours after IV

or SQ; longer for pegfilgrastim

uses:

myelosuppressive chemotherapy

producing neutropenia

in autologous stem cell

transplantation

AE:

G-CSF causes bone pain

GM-CSF can cause fever,

malaise, arthralgias,

myalgias, and a capillary

leak syndrome

characterized by

peripheral edema and

pleural or pericardial

effusions; allergic

reactions

MEGAKARYOCYTE

GROWTH FACTORS

(INTERLEUKIN 11)

A 65-85kDa protein produced by

fibroblasts and stromal cells in the

bone marrow Oprelvekin, the recombinant form

of IL-11 is produced by expression

in E.coli

Half-life: 7-8 hours when the drug

is injected subcutaneously

Thrombopoietin a 65-85kDa

glycosylated protein is expressed

by a variety of organs and cell

It is approved for the secondary

prevention of thrombocytopenia

in patients receiving cytotoxicchemotherapy for treatment of

nonmyeloid cancers

Give by subcutaneous injection at a

dose of 50mcg/kg/d

It is started 6-24 hours after

completion of chemotherapy and

continued fro 14-21 days or until

the platelet count passes the

AE:

Fatigue, headache,

dizziness, and CV effects(including anemia due to

hemodilution, dyspnea

due to fluid

accumulation in the

lungs, and transient

atrial arrhythmias)

Hypokalemia has also

been seen in some


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types

Hepatocytes major source of

human thrombopoietin, and

patients with cirrhosis and

thrombocytopenia have low

serum thrombopoietin levels

nadir and rises to > 50,000

cells/microliter

patients

COAGULANTS/HEMOSTATICS

A. Classification:

1. Systemic Coagulants:a. Fat-soluble Vitamin K and its Analogues

1. Phytonadine or Vitamin K1 (Aqua-Mephyton)

2. Menadione U.S.P. or Vitamin K3

b. Anti-fibrinolytic Agents

1. Traneximic acid + (Cyclokapron)

2. Paraaminomethylcarboxylic acid (Hemostan)

3. Aminocaproic acid (Amicar)

c. Serine Protease Inhibitor

1. Aprotinin (Trasolyl)

d. Plasma Fractions

1. Factor VIII available in the following preparations:

a. Cryoprecipitate

b. Lyophilized Factor VIII

2. Factor IX3. Fibrinogen

e. Others

1. Absorbable Gelatin Sponge (Gelfoam)

2. Oxidized Cellulose (Oxygel, surgical)

3. Thrombin

4. Thromboplastin

5. Fibrin form

2. Prototype: Vitamin K Analogue

a. Source: Phytonadine is a fat-soluble vitamin found in green, leafy vegetables and oils, such as soybean, canola, and olive oil

1. K1 phytonadione derived from plants

2. K2 menaquinone produced by intestinal flora

3. K3 synthetic water-soluble form

b. Pharmacokinetics:

1. Requires bile salts for intestinal absorption

2. Effect delayed up to 6 hours after ingestion but is complete after 24 hours

c. Adverse effects: hypersensitivity

d. Preparation: Phytonadine 10mg/ml amp

Name of Drug Pharmacokinetics Indication/Dosage Additional Notes

VITAMIN K found primarily in leafy green

vegetables

dietary requirement is low,

synthesized by bacteria that

colonize the human intestine

2 natural forms exist: vitamins K1

and K2. Vitamin K1

(phytonadione) is found in food

and Vitamin K2 (menaquinone) is

found in human tissues and is

synthesized by intestinal bacteria

vitamins K1 and K2 require bile

salts for absorption from the

intestinal tract

vitamin K1 is available in oral

and parenteral forms

effect delayed for 6 hours but

the effect is complete by 24

hours when treating

depression of prothrombin

activity by excess warfarin or

vitamin K deficiency

IV administration should be

slow( rapid infusion can

produce dyspnea, chest and

back pain, and even death.)

vitamin K repletion is best

achieved with intravenous or

oral administration,

administered to all newborns

to prevent the hemorrhagic

disease of vitamin K deficiency,

which is especially common in

premature infants.

FIBRINOLYTIC INHIBITORS:

AMINOCAPROIC ACID AND

TRANEXAMIC ACID

adjunctive therapy in hemophilia

therapy for bleeding from

fibrinolytic therapy

prophylaxis for rebleeding from

intracranial aneurysms

postsurgical bleeding and bladder

hemorrhage secondary to

radiation- and drug-induced

cystitis.

Aminocaproic acid

oral dosage is 6 g QID; IV at a

5 g loading dose should be

infused over 30 minutes to

avoid hypotension

CI: in patients with DIC or

GU bleeding of the upper

tract, eg, kidney and ureters

because of the potential for

excessive clotting

AE: intravascular

thrombosis from inhibition

of plasminogen activator,

hypotension, myopathy,

abdominal discomfort,

diarrhea, and nasal

stuffiness.


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Tranexamic acid

similar to lysine; synthetic

inhibitor of fibrinolysis

competitively inhibits

plasminogen activation

analog of aminocaproic acid

rapidly absorbed orally and

cleared by the kidney

orally with a 15 mg/kg

loading dose followed by 30

mg/kg/day QID

SERINE PROTEASE

INHIBITORS: APROTININ

Aprotinin

serine protease inhibitor

inhibits fibrinolysis by free

plasmin

inhibits the plasmin-streptokinase complex in

patients who have received

that thrombolytic agent

reduce bleeding by as much as

50% from many types of

surgery

increased risk of myocardial

infarction, stroke, and renal

damage in aprotinin-

treated patients

association withanaphylaxis has been

reported in

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Coagulants, Hemostatics and Hematinics