Pharmacology

Pharmacology 3.2 1st Sem/A.Y. 2015-2016

Hematinics, Hemostatics and Coagulants

Glenn V. Guevara, MD September 11, 2015

OUTLINE

B. Anemia

C. Iron Deficiency Anemia D. Hypoproliferative Anemia E. Megaloblastic Anemia F. Myelopoiesis G. Megakaryopoiesis H. Hemostasis I. Summary

HEMATINICS, HEMOSTATICS AND COAGULANTS

A. Hematopoiesis

Figure 1: Hematopoiesis

 Formation of blood components o Erythropoiesis: formation of RBCs

o Myelopoiesis: formation of granulocytes and monocytes

o Megakaryopoiesis: formation of platelets  Derived from hematopoietic stem cells

B. Erythropoiesis

Figure 2: Erythropoiesis

 Erythropoietin: main regulator of erythropoiesis o Stimulate hematopoietic stem cells from the bone

marrow to form RBCs

o Released by kidneys in response to low O2 tension o Factors that decrease tissue oxygenation: low blood

pressure, anemia, low hemoglobin, poor blood flow, pulmonary disease

o Increased number of RBCs results to an increased O2 carrying capacity, inducing a negative feedback on EPO

Figure 3: Erythropoietin stimulation and inhibition

 Iron: needed for maturation of red blood cells o Each RBC contains several hundred hemoglobin

molecules which transport oxygen o Iron is needed for the production of heme  Cobalamin

 Folic Acid

B. ANEMIA

 Decrease in the amount of RBCs or hemoglobin in the blood

 Leads to lowered ability of blood to carry oxygen

Causes:

o Blood loss (most common cause): trauma, GI bleeding, abnormal menstrual bleeding o Decreased RBC production

 Nutrient deficiency (iron, cobalamin, folic acid); most common cause among decreased RBC production

 Thalessemia

 Bone marrow cancers  Kidney disease  Chronic infections

 Fluid overload- decrease in RBC production due to volume expansion

 Increased RBC breakdown- Sickle Cell Disease

Types of Anemia

o By size: normocytic, macrocytic, microcytic

o By color: normochromic, hypochromic, hyperchromic

Signs and Symptoms

Figure 4:

Shows a somewhat good looking man with a

creepy gaze. Also shown are the

Diagnostic Tests

o

o

RBC; also called "packed cell volume" or "erythrocyte volume fraction" (about 3x the Hgb concentration) o RBC Count – number of RBC

o Mean Corpuscular Volume (MCV)

 Average volume or size of RBC

 MCV = (Hct x 10) / RBC number in million  Normal MCV and decreased Hgb/Hct =

normocytic anemia; low MCV = microcytic and vice versa

o Mean Corpuscular Hemoglobin (MCH)

 Average mass of hemoglobin per RBC in a sample of blood

 Assess COLOR of the ANEMIA

 MCH = (Hgb x 10) / RBC number in million o Mean Corpuscular Hemoglobin Concentration

(MCHC)

 Concentration of hemoglobin in a volume of packed RBC – the HUE OF RBC

 MCHC = MCH/MCV x 100

 This is more sensitive for measuring the actual color because it considers both MCV and MCH o Blood Smear – morphology of RBCs

Table 1: Normal values for CBC

C. IRON DEFICIENCY ANEMIA  Most common cause of anemia

 Due to increased iron demand, iron loss or decreased iron intake

 More common in females (so take care and love your mom, sisters, daughters and girlfriends, boys.  There are a lot of illnesses associated with women.)

 Microcytic and hypochromic

Causes:

 Increased demand

o Growth and development – children, adolescents o Pregnancy  Blood loss o Parasitic infections o Menorrhagia o Peptic ulcers

o Patients on anticoagulants (aspirin, clopidogrel, etc)  Decreased intake

o Low iron diet: vegetarians, vegans 

o Malabsorption: intestinal resection, celiac disease, inflammatory bowel disease, decreased acidity of stomach (due to prolonged proton pump inhibitor use, e.g. omeprazole)

A. Diagnostic Tests

(Why do we need to know this? Kinda boring but just see yourself as House, Shepherd, Yang or Grey diagnosing your anemia patient. Wee!)

CBC (see diagnostic tests of anemia) Serum iron

 It is the amount of circulating iron bound to transferrin  It can increase immediately on initiation of Fe

supplementation

Serum ferritin

 Most SENSITIVE indicator but is not reliable if within normal limits

 Remember that ferritin is the storage form of iron

Hematocrit (Hct) Male 45 % Female 40 % Hgb Count Male 13.8 to 18.0 g/dl (8.56-11.17 mmol/L) Female 12.1 to 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 (6.83-9.93 mmol/L) RBC Count Male 4.7-6.1 millions/uL Female 4.2-5.4 millions/uL MCV 80-100 fl (femtoliters) MCH 27-31 pg/cell (picograms) MCHC 32-36 g/dL or 19.9-22.3 mmol/L

Total Iron Binding Capacity (TIBC)

 Most SPECIFIC indicator (when levels are high)  It measures the blood capacity to bind iron with

transferrin. It is an indirect measure of transferrin  Transferrin is the transporter of iron in the blood. An

increase would point to an increased need for iron (2017B)

 It is usually elevated in IDA

Transferrin Saturation Index (Percent Saturation/ Iron Saturation)

 It is the percent saturation or iron saturation of transferrin

 How much iron is currently bound to transferrin (2017B)

 SI/TIBC x100

Table 2: Normal values

Serum Iron Male 65-176 μg/dL Female 50-170 μg/dL Children 50-120 μg/dL Newborn 100-250 μg/dL Serum Ferritin Male 18-270 ng/mL Female 18-160 ng/mL Children 7-140 ng/mL Newborn 25-200 ng/mL

Total Iron Binding Capacity 240-450 μg/dL

Transferrin Saturation Index

Male >15-50%

Female >12-50%

Still Possible 5-10%

Definitely Abnormal <5%

Table 3: Differentiating microcytic anemia causes via lab tests. These are the different diseases that can present with microcytic anemia but focus your attention on IDA. There’s a lower serum iron, % saturation, and serum ferritin but a higher TIBC. If you order for a smear in IDA patients, you’d see a microcytic & hypochromic morphology.

Tests Iron Deficiency

Inflammation Thalassemia Sideroblastic Smear Micro/hypo N/micro/hypo Micro/hypo w/

targeting

Variable

Serum Iron <30 <50 (N) to high (N) to high

TIBC >360 <300 (N) (N)

%saturation <10 10-20 (N) 30-80 30-80

Ferritin <15 30-200 (N) 50-300 50-300

Hemoglobin (N) (N) Abnormal (N)

Figure 5: Increasing severity of iron imbalance up to Iron Deficiency Anemia. Note the boxes in green, which indicate which stage would the first time the lab findings will appear (2017B). As the disease progresses, the other parameters that were normal become lower.

 With a Negative Iron Balance, bone marrow iron stores,

serum ferritin decrease while TIBC increases.

 With Iron Deficient Erythropoiesis, also SI, % saturation,

marrow sideroblasts decrease while RBC protoporphyrin increases.

 With IDA (which is severe), there is also morphological change in the RBC

Figure 6: Hemoglobin Synthesis. Protoporphyrin IX is the step before heme. When it binds to iron, then there is the formation of heme. If there is an increase in protoporphyrin if there is no iron available in circulation. Thus no heme is formed. In severe forms of iron deficiency anemia, you see a lot of immature RBC in the blood. Thus, you’ll need iron supplementation to normal it out.

B. Iron

 In 1 mL of RBC, you will get 1 mg iron

 Daily need: 15-20 mg/day (of elemental iron) due to 10-15% absorption of dietary iron

o M: 1 mg/day o F: 1.5 mg/day

o Higher requirement for:  Pregnant: 2-3x (5-6 mg)  Children/adolescents: 1.5x

 Vegetarian diet has 50% less iron absorption  High in Fe:

o red meat o egg yolk

o dark leafy greens (spinach) o dried fruit (raisins, prunes)

o iron enriched foods (cereals, grains) o mollusks (clams, oysters)

o beans (soybeans)

Different forms of Iron:

 Heme iron

o Red meat (Eww. Eat white meat to be healthy.) o absorbed directly through the heme transporter  FerrIc: IV supplement (e.g. Ferric Dextran)

o Why is it given parenterally?

This is because it must be first converted to ferrous by duodenal cytochrome B (a ferrireductase) to be absorbed in GIT.  FerrOus: Oral preparations (e.g. Ferrous gluconate)

o Why oral? Because it can be directly absorbed by the intestinal cell via DMT 1

Storage and Transport (Mentioned last year. From 2017 B)

 Inside the intestinal cell, iron is stored as ferritin.

 If iron is needed, it moves out as ferrous, becomes

converted to ferric, and ferric binds to transferrin -> circulates in blood

Katzung: Ferritin is a B-globulin that can bind 2 molecules of ferric iron.

C. Management

 Packed RBC Transfusion – for SEVERE ACUTE ANEMIA o Usually secondary to blood loss

o Supplementation can be started as adjunct but onset of effects will be delayed

 Oral iron  Parenteral iron

D. Oral Iron Preparations (Refer to Table 4)

 What you need to memorize in the table is the

elemental iron.

 Remember that the supplement is often iron + a base

salt (sulfate, fumarate). Sometimes they don’t show the elemental Fe in parenthesis and you have to compute from the dosage. (2017B)

 Elixirs are available for children and for patients who

cannot swallow.

 Ferrous gluconate- given to children with iron

deficiency anemia. It is usually prepared as an elixir

and combined with multivitamins.

 Extended release has excipients to prolong release

(2017B)

 Ferrous fumarate- usually combined with

multivitamins like folic acid and Vit-B complex  To reverse the anemia

o You need to give iron supplementation for

3-12 months.

o In Harrisons, they suggested giving

300mg/day elemental iron but according to WHO, you can start with 60 mg/day elemental iron for patients with mild-moderate anemia.

o Eg. If a patient needs 60mg/day of elemental

iron, you can give ferrous sulphate hydrated which has 65 mg. If you have a patient who needs 300mg/day of elemental iron, then you need to give 5 tablets of ferrous sulphate hydrated.

Benefits of Effective Iron Supplementation Programs

(Mentioned last year. From 2017 B)  Children/adolescents

o improved behavioral and cognitive development o improve child survival

 Pregnant women and their infants:

o decreased incidence of low birth weight babies and perinatal mortality

o decreased maternal mortality/obstetrical

complications

 All individuals

o improved fitness and work capacity o improved cognition

Table 4: Common Oral Iron Preparations

Generic Name Percent

Elemen tal Iron Tablet Elixir (5 ml) Properties Ferrous sulphate hydrated (dehydrate tetrahydrate) 20 % 325 (65) 300 (60) Commonly given due to tolerability, effectiveness and low cost More of the GI irritation effect 195 (39) 90 (18) Ferrous sulphate dessicated (monohydrate) 30-32% Extended Release ferrous sulfate 20% 525 (105) With incipients to prolong release Ferrous fumarate 33 % 325 (107) H% elemental iron; same effectiveness as sulfate 195 (64) 100 (33) Ferrous bisglycinate

20% 75 (15) Iron amino acid chelate; good absorption & high

Remember: Fair (Fer) ROD and RICky B ROD: FerRous, Oral, Direct, DMT 1

bioavailability Ferrous gluconate 12% 325 (39) 300 (35) Similar efficacy and tolerability as that of sulfate Polysaccharide iron (eg. Maltose iron) 100% 150 (150) 100 (100) Ferric complex with hydrolysed starch; less GI irritability; E. WHO Guidelines of Iron Supplementation (from lecturer’s lecture slides)

 The goal is to reverse anemia and provide 1g iron stores for up to 3-12 months.

 Patients under iron supplementation have to be evaluated every month (2017)

 Dosage: 60mg-300mg/day (300 is what Harrisons recommends but for mild to moderate anemia, start at 60 mg)



 Pregnant: 60 mg iron/400 μg folic acid for 6 months of pregnancy but may extend 3-6 months postpartum

o Start supplementation at the SECOND trimester (2017)

o Higher toxicity in 1st trimester (2017)

o Metallic taste exacerbates vomiting in the

mother in 1st trimester (2017)

 Child 6-24 months: 12.5 mg iron/50 μg folic acid

(N 6-12 months; LBW <2500g 2-24 months)  Child 2-5 yrs: 20-30mg iron

 Child 6-11 yrs: 30-60 mg

 Adolescents and adults: 60 mg

 Severe anemia

o Child <2 yrs: 25 mg iron + 100-400 μg folic acid x 3 months

o Child 2-12: 60 mg iron+ 400 μg folic acid x 3 months

o Adolescents, adults, pregnant women: 120 mg iron+ 400 μg folic acid x 3 months

F. Adverse Reactions & Precautions of Oral Iron

 Oral iron may cause GIT distress in 15-20% of patients o Most common complaint which can decrease compliance

since treatment lasts for months

o Abdominal pain, nausea, vomiting, constipation o You may switch to delayed release iron supplements

because they have less GIT adverse reactions

o This is often dose-related, another rationale to start low (Katzung)

 Black stools are a side effect of oral iron. It has no significant clinical effect except possible masking of gastrointestinal bleeding in fecalysis. (Katzung)  Taking the following with oral iron can DECREASE

absorption:

o milk, caffeine, antacids, calcium supplements

 Vitamin C can INCREASE absorption. If you really need to

reverse anemia immediately, then you can give your iron supplements with Vit C.

G. Response to Treatment

 Reticulocyte count increases in 4-7 days after initiation of therapy and peaks at 1 ½ weeks

 After 4 weeks of treatment, you need to see a Hemoglobin levels > 20g/dL. Thus first follow up is after 1 month.  Absence of response may be due to poor absorption,

noncompliance to medication, or confounding diagnosis

 Iron tolerance test –this is for adverse reactions and the

response of a patient

o Give 2 iron tablets on an empty stomach

o Serum iron in 2 hours: If increase is at least 100 μg/dL, your treatment is adequate.

H. Parenteral Iron Therapy Indicated for:

 Poor tolerance to oral iron

 Acute condition (blood loss) AS ADJUNCT to packed RBC transfusion

 Most common use: Large demand for iron from patients

being treated with erythropoietin (which cannot be

satisfied by oral iron) especially hemodialysis patients or patients with kidney problems

Calculate the daily dose as follows:

 Body Weight (kg) x 2.3 x (15 – px Hgb in g/dL) + 500 or 1000 mg (depending on target iron stores)

Two ways to administer

 Administer total dose of iron required to correct deficit and provide at least 500 mg iron stores (can lead to more ADRs)  Give repeated small doses for certain period of time (most

commonly used by doctors) Forms of parenteral iron

 Iron dextran

o Contains 50 mg/mL elemental iron

o Not being used anymore high risk of anaphylaxis o Given <500mg IV/IM (half-life 6 hrs)

 Sodium Ferric Gluconate, Iron Sucrose, Ferumoxytol – newer drugs

o Given in chronic renal failure (CRF) o IV ONLY (Katzung)

o Ferritin levels between 500 and 1200 mg/mL and transferrin saturations of <25%

o Lower risk of anaphylaxis

Precautions (Katzung) (2017B)

 Monitor iron storage levels via SI or TIBC.

 Be careful in giving parenteral iron because overdose and toxicity can occur more easily as compared to the oral form.

o So, it is important to properly calculate the daily dose needed by the patient.

I. Iron Toxicity Acute

 Exclusively in young children who swallow 10 tablets or more

 Effects include necrotizing gastroenteritis, vomiting, abdominal pain, bloody diarrhea, shock, lethargy, dyspnea, coma and death

 Treatment includes: o Whole bowel irrigation

o Deferoxamine (iron chelating compound) o Supportive therapy

o According to Katzung, it is useless to give activated charcoal because it does not bind iron.

Chronic

 Seen in patients given iron for a prolonged period of time at

maximum dose

 Usually there is hemochromatosis aka iron overload results when there is excess iron deposition in heart, liver, pancreas etc

 May be inherited or acquired (mostly acquired) o Inherited hemochromatosis

o B-thalassemia leading to repeated RBC transfusions (Katzung)

 Treatment includes the ff:

o Intermittent phlebotomy (removes blood and therefore excess iron; 1 unit/week)

o Deferasirox: an oral iron chelator

 According to Katzung, phlebotomy is what is usually done because iron chelators are more complicated, expensive, and hazardous.

o It is only used as a last resort if a phlebotomy is not enough.

D. HYPOPROLIFERATIVE ANEMIA

 At least 75% of all cases of anemia are hypoproliferative in nature

A. Types and Diagnoses

Table 5: Diagnosis of Hypoproliferative Anemia

Iron Deficiency anemia

 Most common type

Anemia of chronic disease

 Caused by chronic inflammation (rheumatoid arthritis), TB, tissue injury, and cancer

Anemia of renal disease

 Anemia results due to inadequacy of erythropoietin production secondary to impaired renal function

 Examples are chronic renal failure (CRF), uremia, PCKD

Anemia of metabolic disease

 Hypothyroidism and starvation

*Usual observation is that red cells are normocytic and

normochromic

B. Endogenous erythropoietin

 Produced in the kidney by intestinal fibroblasts; hypoxia stimulates its synthesis

 Involved in erythropoiesis; stimulates progenitor

proliferation and maturation

 Involved in wound healing; it stimulates angiogenesis and smooth muscle fiber proliferation

 Involved in the brain’s response to neuronal injury  Involved in vasocontriction-dependent hypertension  Increases iron absorption by suppressing hepicidin C. Recombinant Human Erythropoietin

Epoietin alfa or Darbopoietin alfa

 Increase Hct by 4 points and Hgb by 1g/dL in 2 weeks  Darbopoietin alfa has a half-life 3-4x longer than that of

epoietin alfa; it is a second generation erythropoiesis-stimulating agent

 Adverse effects known include, but are not limited to, allergic reactions, hypertension, migratory

thrombophlebitis, microvascular thrombosis, pulmonary embolism, thrombosis of retinal artery, temporal veins, renal veins, headache, tachycardia, edema, shortness of breath, GI upset (nausea, vomiting, diarrhea), stinging sensation at injection site, flu-like symptoms

 In light of this, iron supplementation and anticoagulants may be needed

Dosage for epoietin alfa (Guevarra, 2014):

o CRF: 50-150U/kg 3x/week IV or 80-120U/kg 1-3x/week IV /SQ (Hgb 10-12g/dL 4-6weeks; Hct 33-36% 2-4 months) ; maintained at 300U/kg

o AIDS: 100-300U/kg 3x/week IV/SQ

o Cancer: 150U/kg 3x/week; can reached 450-600U/kg 1x/week

o Surgery: 150-300U/kg OD for 10 days, day of surgery and 4 days after surgery

Dosage for darbopoietin alfa (Guevarra, 2014):

o CRF: 45µg/kg 1x/wk IV/SQ

o Carries an increased risk of cancer recurrence.

E. MEGALOBLASTIC ANEMIA

 Disorders characterized by presence of macrocytic red

cells in bone marrow

 Causes:

O Cobalamin/folate deficiency

O Abnormality (genetic/acquired) in cobalamin/folate metabolism

O DNA synthesis defects

Cobalamin

 A water soluble vitamin containing a cobalt molecule  Plays a role in regulating normal function of CNS, blood

formation, DNA synthesis, DNA regulation

 Synthesized by microorganisms mainly

 Coenzymes are methylcobalamin, a coenzyme involved in methionine, S-adenosylmethionine, and tetrahyrofolate production, and adenosylcobalamin

 Obtained via intake of fish, meat, dairy products

 We obtain 5-30 µg via diet, we lose 1-3 µg per day, a store of 2-3 mg is good for 4 years

 Passively absorbed in the buccal area, duodenum, and ileum; actively absorbed in the ileum in the presence of

gastric intrinsic factor

 Normal range is 150-600 pmol or 200-900 pg/ml Cobalamin deficiency can be caused by (Guevarra, 2014):

O Pernicious anemia due to IF loss secondary to

O Inadequate amount of intake O Gastric and/or ileal resection

O Decrease in gastric acid amount via proton pump

inhibitors and/or H2 blockers

O Alcoholism O Metformin intake O Malnutrition

Cobalamin deficiency results to (Guevarra, 2014): O Topic in question, megaloblastic anemia O Progressive swelling of myelinated neurons O Demyelination

O Neuronal cell death; these are seen in the spinal

column and cerebral cortex

O Hand and foot paresthesia

O Decrease in vibration and position sense, with associated unsteadiness

O Decrease in deep tendon reflexes O Confusion, moodiness, loss of memory O Loss of central vision

Vitamin B12 therapy (Guevarra, 2014)

O Given in cyanocobalamin and/or hydroxocobalamin, as these are the active medicinal forms

O If there is inadequate intake, give orally; if there is IF deficiency and/or gastric and ileal problems, give parenterally

O Cyanocobalamin is the first choice: give drug IM /

SQ (not IV as there is a risk of anaphylaxis; skin test needed), 1-1000µg 1-3x / week; supplementation is 80µg mixed w/ IF (not reliable; e.g. vegetarians) O An alternative is hydroxocobalamin, given 100 µg

IM; this has a more sustained effect, lasting 3 months O Treatment usually lasts for 6-12 months, as a long

term treatment; cyanocobalamin is given monthly in the form of 100 µg injections

O Also given for cases of neuropathies such as trigeminal neuralgia and multiple sclerosis, psychiatric disorders, poor growth and/or nutrition, as a tonic for patients suffering from tiredness and/or easy fatigue

Folic acid

 Vitamin that is obtained from fresh green vegetables, fruits, liver, and yeast; 90% of vitamin is destroyed in the heat of cooking

 Normally we obtain 50-500 µg of it per day; vegetarians

only obtain roughly 2 mg/day

 We usually require 400 µg per day; pregnant women require 500-600 µg per day; they must have an intake of at least 400 µg per day to prevent defects in the neural tube  Absorbed in duodenum and proximal jejunum (proximal

small intestine), transported while bound to a plasma-binding protein

 Normal range is 9-45 nmol or 4-20 ng/mL Deficiency (Guevarra, 2014)

O Causes are alcoholism, diseases of the proximal small intestine, inhibitors of dihydrofolate reductase such as

methotrexate and trimethoprim, drugs that interfere

in folate storage in tissues such as oral

contraceptives

O Deficiency of folic acid can result to higher incidences of defects in the neural tube (anencephaly,

encephaloceles, spina bifida), the topic in question

(megaloblastic anemia), coronary artery and

peripheral vascular diseases, venous thrombosis or hyperhomocysteinemia

Therapy (Guevarra, 2014):

O Given as folic acid, orally or parenterally or part of

MV prep

O Given as a prophylaxis in pregnant women, (dose of 400-500 µg per day); for hemolytic anemia it is given at a dose of 1 mg per day

O Can be given as folinic acid (leucovorin calcium), a derivative of tetrahydrofolate

O Folinic acid circumvents DHF reductase inhibition (ex. Resulting from methotrexate intake); it is an antidote for folate antagonist toxicity (ex. Resulting from trimethoprim and pyrimethamine intake)

O Has no advantage over folic acid; it is actually more

expensive

O Avoid multivitamin preparations; do multivitamin

preparations only if there is evidence of vitamin deficiency

O Folic acid is well tolerated by the body, even at doses

as high as 15 mg per day

O Folic acid can decrease, even counteract effects of drugs like phenobarbital, phenytoin, primidone

F. MYELOPOIESIS

 Myeloid growth factors are glycoproteins that stimulate the proliferation and differentiation of one or more myeloid cell lines

 Enhance the function of mature granulocytes and monocytes


 Produced naturally by a number of different cells, including fibroblasts, endothelial cells, macrophages, and T cells
  GM-CSF is capable of stimulating the proliferation,

differentiation, and function of a number of the myeloid cell lineages


 G-CSF is restricted to neutrophils and their progenitors,

stimulating their proliferation, differentiation, and function

A. Conditions that affect Myelopoiesis

 Autologous bone marrow transplantation


 Intensive myelosuppressive cancer chemotheraphy  Zidovudine induced neutropenia in AIDS patients
  Severe congenital neutropenia

B. Recombinant GM-CSF (Sargramostim)

 Produced by yeast 
  125-500μg/m2

/d SQ (Half-life: 2-3hrs) [Katzung says: Serum T_{1/2 of 2-7 hours after IV or SQ administration}

 Slow infusion: 3-6 hours 


 Lower doses mainly affects neutrophils; larger doses affect monocytes/eosinophils 


 Adverse Effects: bone pain, malaise, flu-like symptoms, fever, diarrhea, dyspnea and rash, transient

supraventricular arrhythmia, elevation of serum creatinine, bilirubin and hepatic enzymes 


C. Recombinant G-CSF (Filgrastim/Pegfilgrastim)

 Filgrastim

o produced by Escherichia coli


o Stimulates CFU-G to increase neutrophil production; stimulation of CFU-G to increase neutrophil production 


o 1-20μg/kg/d IV infusion for 30 mins 


o Patient on cancer chemotherapy: 5μg/kg/d; daily administration for 14-21 days 


 Pelfigrastim

o gene through conjugation of a 20,000-Da 
polyethylene glycol moiety to the G-CSF glycoprotein produced by E. coli

o Longer half-life

o 6mg SQ

G. MEGAKARYOPOIESIS



megakaryopoiesis. It is produced by the liver, marrow stromal cells, and many other organs. It is the primary

regulator of platelet production.

 Interleukin-11 (IL-11) was cloned based on its activity to promote proliferation of an IL-6-dependent myeloma cell line Stimulates hematopoiesis, intestinal epithelial cell growth, and osteoclasto-genesis and inhibits adipogenesis。 Enhances megakaryocyte maturation in-vitro; in-vivo increases peripheral blood platelet counts 


Recombinant Interleukin-11 (Oprelvekin)

o Bacterially derived 19,000-Da polypeptide 
 o 25-50 μg/kg/d SQ; Half-life: 7 hours 
 o Administered daily; response in 5-9 days 


o Used for chemotherapy induced thrombocytopenia

in non-myeloid malignancies (20,000/μL). Aim:

platelet count reaches 100,000/μL 


o Adverse Effects: Fluid retention and associated cardiac symptoms, such as tachycardia palpitation, edema, shortness of breath, blurred vision, injection site rash or erythema, and paresthesias. 


Recombinant Thrombopoietin

o Recombinant Human Megakaryocyte Growth and Development Factor (rHuMGDF) and Recombinant Human Thrombopoietin (rHuTPO) – mixed results on

efficacy

o Mimics of recombinant thrombopoietin – used

exclusively for ITP

 Romiplostim – small peptide that binds with high

affiity to the thrombopoietin receptor


 Safe and efficacious in patients with ITP
  Platelet ct >50,000/μL in 8 weeks of study  1-10 μg/kg/d SQ

 Eltrombopag – 6 week course of 50-75mg/d orally

o Well-tolerated

H. HEMOSTASIS

A. Elements of Hemostasis

 Primary Hemostasis

o Affected by: aspirin and NSAIDs

o Adequate vascular response, platelets, levels of Von Willebrand factor

 Secondary Hemostasis

o Affected by: warfarin and heparin o Involve the extrinsic factors

o Adequate level of clotting factors, vitamin K

B. Bleeding Disorders

 Causes

o Inherited coagulation disorders  clotting factor deficiency  hemophilia

o Hemorrhagic diathesis of liver disease o surgical procedures / multi-organ injuries o vitamin K deficiency

C. Diagnostic Tests

 platelet count: 150,000-400,000/m2 


 bleeding time (measure platelet function): 1-9 mins 
  prothrombin time (measure extrinsic pathway; used for


 warfarin): 11-13.5 sec 


 partial thromboplastin time (measure intrinsic pathway; used for heparin): 25-35sec

D. Vitamin K

 cause of bleeding disorder  fat soluble

 needed for complete synthesis of certain proteins that are 
 required for blood coagulation (II, VII, IX, X) - 1972
  also used to manipulate binding of calcium in bone and

other tissues 


RDI

 Infants: 10–20μg/day


 Children & adolescents: 15–100μg/day  Males: 120 μg/day


 Females: 90 μg/day (lower than males)

Vitamin K Deficiency

o Uncommon 
 o Causes: 


 Resection of SI


 Malabsorption syndrome


 Prolonged use of broad spectrum antibiotics  Diet low in vit. K


 CKD
  Alcoholics  Liver disease
  Anticoagulants
  Salicylates
  Barbiturates  Cefamandole

o Usually occurs in newborns right after birth  clotting factors are 30 to 60% of adult values
  due to reduced synthesis of precursor proteins and

the sterility of their guts

 Vit. K deficiency bleeding in 1st week of the infant's life is 0.25 to 1.7%

F. Tissue Plasminogen Activator (TPA) Inhibitors

 Used to control bleeding in patients  Seen in the final stage of thrombin formation  Inhibitors of fibrinolysis

 Plasmin has a role in the lysis of clot made by secondary hemostasis

Aminocaproic acid

 Competes for lysine binding sites on plasminogen and

plasmin, blocking the interaction of plasmin with fibrin
  A very potent inhibitor of fibrinolysis (thrombi that formed

during treatment with the drug are not lysed)

 Used to reduce bleeding after prostatic surgery or after

tooth extractions in haemophiliacs

 also used to prevent bleeding after surgical procedures (ability to treat a variety of bleeding disorders has been unsuccessful)

 Loading dose: 4-5g IV/PO during the 1st hour then 1-1.25g PO q1Hour ; continuous IV infusion at 1g/Hr (continue for 8 hours or until bleeding is controlled, not to exceed 30g/day)

Tranexamic acid


 Like aminocaproic acid, competes for lysine binding sites on plasminogen and plasmin, thus blocking their interaction with fibrin

 Safer than aminocaproic acid


 Can be used for the same indications as aminocaproic acid and can be given IV or orally Usually given 1g 4x/day for 4 days (500mg 3x/day for 4-7days)

*Adverse effects of both drugs: hypersensitivity reactions, nausea, vomiting, diarrhea, clotting problems (loss of vision, infarct, embolism) 


I. SUMMARY

 Erythropoietin stimulates erythropoiesis. (without it there will be no erythropoiesis that will happen) 


 Iron is needed for maturation of RBC. 


 Defective RBCs are formed in patients with Vit. B12 and B9 
 are deficient. 


 GM-CSF, G-CSF, IL-11 and thrombopoietin are helpful in 
 certain conditions that produce neutropenia or


 thrombocytopenia

 Vit. K supplementation can be given to patients with certain 
 bleeding disirders.

 TPA inh. can be given to patients suffering bleeding from 
 trauma, surgery, etc.

GUIDE QUESTIONS

1. All of the following substances delay absorption of ingested iron EXCEPT:

A. caffeine B. milk

C. sodium ascorbate D. calcium ascorbate

2. Which of the following parenteral iron preparations has a higher incidence of anaphylactic reactions?

A. ferric gluconate B. ferric sucrose C. ferric dextran D. ferric oxide

3.Lexi, a 32-year-old female, diagnosed with iron deficiency

anemia, needs 60mg a day of elemental iron. To minimize the incidence of adverse reactions, you decided on a “once

a day” dosing regimen for the patient. Which of the following drugs will be best suited for the patient?

A. ferric-maltose complex 150 mg B. ferrous sulfate dessicated 325 mg C. ferrous fumarate 200mg

D. ferrous gluconate200 mg

4. Which of the following iron preparations is usually found in multivitamin medicated syrups because of its low elemental iron content?

A. ferrous gluconate B. ferrous sulfate dessicated C. ferrous fumarate

D. ferric-maltose complex

5. Which of the following conditions associated with cobalamin deficiency will benefit most from oral cyanocobalamin?

A. atrophic gastritis

B. inflammatory bowel disease C. chronic alcoholism

D. ileal resection

6. The conditions that will least likely benefit from epoeitin alfa treatment

A. massive traumatic blood loss B. chronic renal failure

C. cancer D. AIDS

57. Which of the following will most likely happen when correcting cobalamin deficiency with folic acid

supplementation?

A. lower incidence of homocysteinemia and venous thrombosis B. lower incidence of megaloblastic anemia

C. decreased risk for nerve degeneration D. increased risk for neural tube defects

8. In a patient with neutropenia, which of the following agents will be least beneficial?

A. sargamostim B. Romiplostim C. filgrastim D. perfilgrastim

9. Thrombocytopenia from immunosuppressive chemotherapy can be treated with the following medications EXCEPT:

A. elthrombopag B. romiplostim C. sargramostim D. Oprelvekin

10. Which of the following available vitamin K preparations is toxic for humans?

A. phylloquinone B. menaquinone C. menatetrenone D. menadione Answers: 1)C 2)C 3)C 4)A 5)C 6)A 7)B 8)B 9)C 10)D

OBJECTIVES

REFERENCES

APPENDIX

Vitamin K1 Vitamin K2

Form Phylloquinone,

Phytomenadione, Phytonadione,

Menaquinones, Bacteria in SI can convert vit .K1 to K2

Source Leafy green vegetables:

dandelion greens, spinach, lettuce , cabbage, cauliflower, broccoli, and brussels sprouts

Fruits:

avocado, kiwifruit and grapes

Animal Meat:

chicken, beef, their fat, livers, and organs Fermented or aged cheese, eggs
 Bacteria in SI can convert K1 to K2

Absorption Small intestine Small intestine

Signs and Symptoms of Deficiency

Anemia, bruising, bleeding gum or nose, heavy menstrual bleeding

Deficiency Osteoporosis, Coronary heart disease, Severe aortic calcification

Therapy At birth:

 IV: 0.5 to 1.0 mg Newborns:

 Human milk (1–4 μg/L)  Vit. K formula-derived milk

(100 μg/L)

Menopausal women:  Orally (45 mg daily)  To prevent osteoporosis

Rapid reversal from warfarin for pre-op:  Orally (1-2.5 mg)

Figure 2: Factors that favor and inhibit thrombosis