Teaching TY Haematinics

Operational Obstetrics & Gynecology · Bureau of Medicine and Surgery · 2000 Slide 1

HAEMATINICS

TY CS& SC IMU 2012ME 1/11 SEM 3 12/3-17/3/2012


HAEMATINICS

These are the substances which are required for the formation of blood (erythropoiesis) and are used for the treatment of anaemia.

These are mainly IRON, FOLIC ACID & VIT B12


Case Scenario

A 26 year old lady with 22 weeks of pregnancy attends the 1st 1ntenatal booking visit. On enquiry she has had 3 normal full term deliveries and one caesarean section for a twin pregnancy at 38 weeks of pregnancy and one abortion at 19 weeks. She feels easily tired too and sleepy – She is really tiring to look after the children nowadays –this is also during the last week.On Examination She is anaemic. She is otherwise fit and well. Hb level 10.5 gm/dlMicrocytic hypochromic (MCV <80 fL)Macrocytic (MCV >100 fL)Treatment- Haematinics

fL = femto-litre = 10−15 L = 1 μm3


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Normal blood film Severe iron deficiency anaemia


Red cells – Macrocytosis


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White cells - Hypersegmented neutrophils


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Anaemia

• What is anaemia?– Haemoglobin level: The cut-off point for

the women by WHO 12 g/dl. Men 13 g/dl– Anaemia is a reduction in the number of

RBCs or the Haemoglobin content of blood below normal for age and sex of the individual

– Acute/ Chronic


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NUTRITION DISEASE RELATED

UNEXPLAINED

ALL ANAEMIA CASES


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IRON

FOLIC ACID

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B12

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FA & B12IRON FA & B12

ANAEMIA WITH NUTRI. DEFICIENCY


PATHOGENESIS

It is a condition in which the balance between production and destruction of RBCs is disturbed by:-

1. Blood Loss2. Impaired red cell formation3. Increased destruction of RBCs


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Types (Blood Picture)

• Normocytic (MCV 80-100 fL)

• Microcytic hypochromic / normochromic (MCV <80 fL)

• Macrocytic (MCV >100 fL)



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Diagnosis

• Peripheral blood film

• Flow cytometry – automatic counters



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Erythropoiesis

• Iron

• Vitamin B12

• Folic acid

• It is regulated by erythropoietin

- secreted by kidneys

- stimulates the bone marrow


IRON

Distribution in the Body:Total body iron in an adult is 2.5-5g. It is more in men 50 mg/kg than in women 38 mg/kg.

It is distributed into:--Hemoglobin – 66%Iron stores as ferritin, Haemosiderin 25%Myoglobin - 3%Parenchymal Iron (in enzymes) – 6%


Daily Requirement :-

Adult male - 0.5 – 1 mgAdult Female - 1 – 2 mgInfants - 60 g / kg

Children - 25 g / kgPregnancy - 3 – 5 mg


Dietary SourcesDiet contains 10 to 15 mg iron/day

RichLiver, Egg yolk, Oyster, Dry fruits, Wheat germs, yeast

MediumMeat, Chicken, Fish, Spinach, Banana, Apple

PoorMilk and its products, Root vagetables


IRON ABSORPTION

The average daily diet contain 10-15 mg of iron.5% to 10% absorbs dietary iron = 0.5 to 1 mg/dayAdequate for male and postmenopausal

Menstruating/pregnant woman require 1 to 3 mg/dayMenstrual loss is 30 mg/period.

Absorption occurs all over the intestine, but

magnify in the upper part.


To absorb- iron

Ferric to ferrous by acid reducing agent.From gut to Intestinal mucosal cells by1. Divalent metal transporter.From mucosa to plasma by 2. Ferroportin transporter

Absorbed ferrous to plasma by F transporter or oxidised to ferric form and ferric form +apoferritin= ferritin is stored in the mucosal cells.


GUT

Ferric

Ferrous

MUCOSAL CELLS PLASMA

Divalent metal transporter 1 Ferroportin

Ferrous– Ferric + Apoferritin – Ferritin

FerrousFerrous

Ferric

Transferrin+

Circulate in the plasma


Plasma Cells

Ferric + Transferrin

Released iron

Membrane+ Transferrin Receptors

Endocytosis


STORAGE

RE cellsLiver, Spleen, Bone-marrow, hepatocytes, myocytesas ferritin and haemosiderin


Plasma Iron from Old RBC 120 daysIron StoreIntestinal absorption

An Iron common pool

Erythrpoiesis, Other cells, Restorage


Iron Excertion:-

Iron is tenaciously conserved by the body. Daily excretion in adult male is 0.5 – 1mg.Mainly as exfoliated G.I mucosal cell, some RBC in bile.Other routes are desquamated skin, sweat and urine.In menstruating women, monthly menstrual loss may be averaged to 0.5 – 1 mg/day


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Causes of Iron Deficiency Anaemia

• Bleeding

– heavy menstruation– gastric (PU, cancer – occult bleeding) or piles– hookworm infestation – use of NSAIDs for pain /

inflammation


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• Increased Physiological Demand for Iron

– Pregnancy and Lactation

– Infancy, children and adolescents (rapid growth)


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• Inadequate Absorption – post-gastrectomy – generalized malabsorption

(severe small bowel disease, Crohn’s disease / celiac disease)

• Inadequate Intake –

-- Rare for adult, but extreme poverty


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Normal blood film Severe iron deficiency anaemia


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Blood reports

• Hb is low

• MCV is low ( <80fL) – microcytes

• MCHC is low – hypochromic

• Ferritin is low

• Total iron binding capacity (TIBC) is increased

• Serum iron is low

• Transferrin saturation is < 19%


Indications for Iron therapy

Used for therapy and prophylaxis

1. Iron deficiency anaemia due to dietary lack or to chronic blood loss2. Pregnancy total 1000 mg(50 to 100mg elemental iron = 200 to 500 ug folic acid)3. Absorption is reduced. Mal absorption syndrome.4. Premature babies5. Severe pernicious anaemia with hydroxycobalamine6. 3.As an Astringent:- Ferric chloride is used in throat paint.


Excess Iron Required

1. In pregnancyExpansion of RBC massFoetusLoss during delivery

2. Lactating mother


Preparation and Doses

1. The preferred type of iron is ferrous salts. Ferrous form is inexpensive, high iron content and are better absorbed than ferric salts.

Sustained release preparations are more expensive but used for patient who cannot tolerate the standard forms.

The preferred route is the Oral Route.


2. Liquid formulation stain teeth. Less satisfactory.

200 mg elemental iron daily in 3 divided doses gives maximum haemopoietic response.Infant and children 3 to 5 mg/kg

30 mg/day is for prophylaxsisAbsorption is better taken in empty stomach. May have side-effects more.


Adverse Effect:- Oral Route

Are common at the therapeutic level.Related to elemental iron dose.Mainly Gastrointestinal symptomsConstipation are common.Blackens the face


Preparations & Doses 100 to 200 mg elemental iron/dayOral Route

1-Ferrous sulphate dried-200_300mg daily(60 to 100 mg Eiron)2-Ferrous gluconate – 1.2-1.8 g in divided daily doses(140 mg E iron)3. Ferrous Fumerate – 200 – 400 mg is divided daily dose.(140 mg E iron)4. Ferrous succinate and Ferrous glycine sulphate5. Colloidal ferric hydroxide – 200 – 400 mg daily


Parental Iron Therapy

IndicationsNot tolerated.Failure to absorb.No- complianceIn presence of severe deficiencyAlong with erythropoietin

Total Iron requirement = 4.4 x body wt kg x Hb deficit g/dl


Parental Iron Therapy

1. Iron dextran injection : Dose 1 ml 2. Iron sorbitol injection : 50 mg of iron/ml

Dose 1.5 mg of iron / kg


Adverse Effect:-

Local -* Pain at site of in injection. * Pigmentation of skin * Sterile abscess


Systemic –

* Fever, headache, joint pains, flushing, palpitation, chest pain, dyspnoea, lymph node enlargement * A metallic taste in mouth lasting for few hrs.* An anaphylactoid reaction resulting in vascular collapse & death.* Iron sorbital causes more immediate reaction than iron dextran, should be avoided in patients with kidney disease


ACUTE IRON POISIONING

High doses of iron salts by mouth can cause severe GI irritation and necrosis of mucous membrane. It occurs mostly in infants& children. It is very rare in adults.Manifestation are vomiting, abdominal pain, haematemesis, diarrhoea, lethargy, cyanosis,dehydration, acidosis, convulsions & finally shock , cardiovascular collapse & death.


TREATMENT:-

1. Chelate iron in the blood, stomach and intestine.2. To prevent further absorption of iron from gut.

A. Desferrioxamine 1 to 2 G I/M give urgently

B. Induce vomiting or perform gastric lavage with sodium bicarbonate solution to render iron insoluble.

C. Give egg yolk & milk orally compete iron.


D. Deferrioxamine 5-10 mg in 100 ml saline may be left in the stomach after lavage to prevent further iron absorption.

E. IV infusion desferrioxamine 80 mg/kg/24h or IM 2 g in sterile water every 12 hourly.


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Vitamin B12(Cyanocobalamine)


Vitamin B12(Cyanocobalamine)

Cobalamins - Active cellular co enzyme.Necessary for DNA synthesis. Formed from Cyanocobalamin and hydroxocobalamin.

Vitamin B12(Cyanocobalamine) is Extrinsic factor in the food. Principal sources - Meat (particularly liver), eggs and dairy products.


Absorption

Vitamin B12 absorption needs Intrinsic factor, glycoprotein secreted by parietal cells in the stomach, binds to vitamin B12 in the duodenum. This vitamin B12–intrinsic factor complex subsequently aids in the absorption of vitamin B12 in the terminal ileum. Then transported bound to plasma glycoprotein - transcobalamin II.

Excess B12 is stored in the liver (80%) and the rest in the kidney, adrenal, pancreas and other organs.


Vit B12 and folic acid are essential vitamins for normal DNA synthesis

Deficiency leads to impaired DNA synthesis; reduced cell division, but RNA and protein synthesis continue large (macrocytic) and fragile RBCs.

Daily requirement- 2.4 ug. 2.6 ug for pregnant mother

Average adult stores ~ 3000 - 5000g


Red cells – Macrocytosis


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White cells - Hypersegmented neutrophils


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Causes of B12 deficiency

• Partial or total gastrectomy• Diseases of distal ileum• Nutritional deficiency: very rare but possible

in strict vegetarians after many years without meat, egg or dairy products

• Fish tapeworm (sequestration of B12 by the worms)

• Prolonged exposure to N2O anaesthesia (N2O inactivates the vitamin)


Therapy

• Since almost all cases of B12 deficiency are due to malabsorption, parenteral treatment is needed, and for life.

• Hydroxycobalamin (produces higher and more sustained blood level) or cyanocobalamin.


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Toxicity

• Vit. B12 and folic acid have no known toxic effects even in high doses which are excreted in the urine and faeces

• Rare (allergic) effects: itching, fever, nausea, dizziness, anaphylaxis (especially hydroxycobalamin)


Folic acid (Pteroyl glutamic acid)


Folic acid (Pteroyl glutamic acid)

Folates are co-factors in the synthesis of purines and pyrimidines which are essential for DNA synthesis

To be effective folates must be in the tetrahydro (FH4) form. The enzyme dihydrofolate reductase reduces dietary folic acid to FH4 (tetrahydrofolate)

Folates are found in the green vegetables (heat labile), liver (more heat stable), yeast, nuts, cereals, fruits


• Folic acid is readily and completely absorbed in the duodenum and proximal jejunum

• Is subsequently transported into the blood stream by active and passive transport.

• Since body stores are relatively low and daily requirement high, deficiency (and anaemia) can occur within 1-6 months

• Excreted in urine and stool and destroyed by catabolism


• The average daily diet contains 500 -700g of folate of which 50 - 200g is absorbed.

• Daily requirement 400 ug. per day• Pregnancy- 600 to 800 ug. per day


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Causes of folate deficiency

• Often by dietary insufficiency (poverty, elderly)

• For alcoholics and liver disease, poor diet and very low liver storage

• Pregnancy (deficiency associated with neural tube defect)

• Haemolytic anaemia• Dialysis Patients


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•Mal- absorption (e.g. coeliac disease or tropical sprue)

•Drugs that interfere with folate absorption e.g. Phenytoin, Oral contraceptives and Isoniazid

•Methotrexate, Pyrimethamine, Trimethoprim can interfere with metabolism


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Therapy

• Parenteral administration is rarely needed because folic acid is well absorbed even in mal-absorption syndromes

• Don’t use in undiagnosed megaloblastic anaemia.

• 600 to 800 micrograms of folate for pregnant mothers


ERYTHROPOINTIN

In 1906, Paul Carnot, a professor of medicine in Paris, France, and his assistant, DeFlandres, proposed the idea that hormones regulate the production of red blood cells.


Erythropoietin is produced in the kidney and liver, and is involved in the production and differentiation of erythrocytes.


Erythropoietin


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Clinical use

• Anaemia of chronic renal failure(epoietin is given i.v., s.c., or i.p.)

• Anaemia in AIDS patients• Cancer (chemotherapy) related anaemia• Surgery and autologous blood transfusion

(orthopaemic, cardiac procedures)• Myelodysplasia


Abuse: sportsman to enhance performance

Side effects:

– Flu-like symptoms, – Hypertension, – Encephalopathy with headache, – Disorientation convulsion blood viscosity (due to RBC mass)


Colony Stimulating Factors (CSF)

Cytokinase stimulate growth, differentiation and functional activitty of colonies of myeloid cells

Some have been developed for clinical use.

FilgrastimLenograstimMolgramostim


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G-CSF – Filgrastim (NEUPOGEM)

• Recombinant human G-CSF

• Produced in E.coli


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Clinical Uses

• severe neutropenia after autologous hematopoietic stem cell transplantation and high-dose cancer chemotherapy

• reduces morbidity secondary to bacterial and fungal infections

• neutropenia of AIDS patients receiving zidovudine


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• Filgrastim is administered by subcutaneous injection or intravenous infusion over at least 30 minutes

• half-life of 3.5 hours

Adverse reactions • mild to moderate bone pain• skin reactions following subcutaneous injection• rare cutaneous necrotizing vasculitis


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Lesson Outcomes

1. Discuss the iron metabolism and pharmacokinetics of iron

2. Explain the indications of use for different types of iron preparation in the treatment of iron deficiency anaemia

3. Discuss different types of iron therapy, indications & adverse effects (contraindications)

4. Discuss the iron toxicity & its treatment5. Discuss the pharmacokinetics, indications of use,

therapy and adverse effects for Vitamin B12 & Folic acid

6. Describe the outline of erythropoietin & G-CSF therapy


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Contents

• Treatment of Iron deficiency (oral and parental preparations of iron)

• Management of iron overload • Treatment of B12 deficiency (oral and parental

preparations of B12) • Treatment of Folic acid deficiency• Erythropoietin & G-CSF therapy


THANK YOU

TY CS & SC IMU

Teaching TY Haematinics

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