Blood And Blood Formation Flashcards
Total body distribution of iron
Total body iron in an adult is 2.5- 5 g (average 3.5 g) Men: 50 mg/kg Women: 38 mg/ kg It is distributed into: 1. Haemoglobin - 62% 2. Iron stores - 25% 3. Myoglobin - 7% 4. Parenchymal iron (in enzymes,etc) - 6%
To raise the Hb level of blood by 1g/dl about ___ of elemental iron is needed
200mg
Loss of 100 ml of blood (containing 15 g Hb) means loss of 50 mg elemental iron.
RDA of iron
Adult male: 0.5-1 mg
Adult female: 1-2 mg
Pregnancy: 3-5 mg
Infants: 60 μg/kg
Children: 25 μg/kg
Factors facilitating iron absorption
- Acid
- Reducing substances
- Meat: by increasing HCI secretion and providing haeme iron
Factors impeding iron absorption
- Alkalies: 2 reasons
- Phosphates: (rich in egg yolk)
- Phytates: (in maize, wheat)
- Tetracyclines
- Presence of other foods in the stomach.
In general, bioavailability of iron from cereal based diets is low.
Ferritin curtain and mucosal block
The gut has a mechanism to prevent entry of excess iron in the body.
Iron reaching inside mucosal cell is:
1. Transported to plasma
2. Oxidised and complexed with apoferritin to form ferritin
This ferritin generally remains stored in the mucosal cells and is lost when they are shed after 2-4 days
This is called the ‘Ferritin curtain’
Fate of free iron in plasma
Free iron is highly toxic.
On entering plasma:
1. Immediately oxidised enzymatically, then
2. Complexed with a glycoprotein transferrin (Tf)
(Total plasma iron content (~3 mg) is recycled 10 times everyday)
Oral iron preparations in brief
The preferred route of iron administration is oral.
Dissociable ferrous salts are:
1. Inexpensive
2. Have high iron content
3. Better absorbed than ferric salts, especially at higher doses.
Side effects of oral iron preparations
- Epigastric pain, heartburn, nausea, vomiting, bloating. staining of teeth, metallic taste, colic
- Constipation is more common (astringent action) than diarrhoea (irritant action)
- May be due to alteration of intestinal flora also
Tolerance to oral iron can be improved by initiating therapy at low dose and gradually increasing to the optimum dose
Types of simple oral iron preparations
- Ferrous sulfate:
(hydrated 20% iron, dried 32%)
Cheapest but metallic taste - Ferrous gluconate (12%)
- Ferrous fumarate (33% iron):
Less water soluble than ferrous sulfate and tasteless - Colloidal ferric hydroxide (50% iron)
- Carbonyl iron:
Metallic iron
Slow absorption and better gastric tolerance
Low bioavailability
Disadvantages of liquid iron formulations
Liquid formulations:
- May stain teeth
- Should be put on the back of tongue and swallowed
Maximum haematopoietic response is given when
A total of 200 mg elemental iron (infants and children 3-5 mg/kg) given daily in 3 divided doses
Prophylactic dose is 30 mg iron daily.
Absorption and side effects are more when given on a empty stomach
Iron therapy by injection is indicated when
- Oral iron is not tolerated
- Failure to absorb oral iron:
Chronic inflammation decreases absorption and rate at which iron is utilized. - Non-compliance
- In presence of severe deficiency with chronic bleeding.
- Along with erythropoietin in CKD patients
Parenteral iron therapy needs calculation of the total iron requirement of the patient for which several formulae have been devised. A simple one is:
Iron requirement (mg) = 4.4 x body weight (kg) x Hb deficit (g/dl)
Ionised salts of iron used oral cannot be injected because
- They have strong protein precipitating action
2. Free iron in plasma is highly toxic.
The organically complexed iron formulations for parenteral route are
1. lron-dextran has been in use for long Two relatively new ones: 2. Ferrous sucrose 3. Ferric carboxymaltose 4. Latest is Iron isomaltoside 1000. The newer formulations are less risky and have improved ease of administration.
Iron dextran
- Only preparation that can be injected IM and IV
- By IM route: absorbed through lymphatics, circulates without binding to transferrin and engulfed by RE cells where iron is made available
- Not excreted in urine or in bile. •Because dextran is antigenic, anaphylactic reactions are more common
IM iron dextran application
Given deeply in the gluteal region using Z track technique (to avoid staining of the skin).
Iron dextran can be injected 2 ml daily, or on alternate days, or 5 ml each side on the same day (local pain may occur with the higher dose).
But some part of the dose is locally bound. Thus, 25% extra needs to be added to the calculated dose.
Intravenous iron administration
- 2 ml containing 100mg iron is injected per day taking 10 min for the injection, or
- total calculated dose is diluted in 500 ml of glucose/saline solution and infused i.v. over 6-8 hours under constant observation.
•Injection should be terminated if the patient complains of giddiness, paresthesias or tightness in the chest.
•Resuscitation facilities should be available before any iron preparation is injected i.v
Why is test dose no longer prescribed while giving IV iron supplementation
The test dose prescribed earlier is no longer recommended, because the life threatening anaphylactic reaction can occur even when a previous dose or test dose has been well tolerated.
List of oral direct thrombin inhibitors
1. Ximelagatran: Side effect: hepatotoxic 2. Dabigatran: Dose reduction in patients with renal failure Used as DOAC/ NOAC
Oral factor Xa inhibitors
Xa ban: Apixaban Edoxaban Rivaroxaban Betrixaban
NOAC/ DOAC
Explain the properties
Novel Oral Anti Coagulants/ Direct acting …
Oral direct thrombin inhibitors + oral factor Xa inhibitors
• monitoring not required (like LMWH, Fondaparinaux)
Uses, ContraIndications and side effects of NOAC/ DOAC
Uses: 1. DVT (treatment and prophylaxis) 2. DoC for prophylaxis of thrombosis in non-valvular atrial fibrillation CI: 1. Mechanical valve thrombosis 2. Antiphospholipid antibodies causing thrombosis 3. Splanchnic vein thrombosis Side effects: bleeding
Anticoagulant drugs not requiring monitoring
Constituents of NOAC/ DOAC: 1. Dabigatran 2. Oral Xa inhibitors Others: 3. LMWH 4. Fondaparinaux
Antidote of anticoagulants
Against Dabigatran: anti dabigatran monoclonal antibody- Idarucezumab
Against oral Xa inhibitors: Ardexanet-alfa (Xa analogue)
Parenteral direct thrombin inhibitors
Hirudin Semi synthetic: Lepirudin Desirudin Synthetic: Bivalirudin Argatroban
The common property of ‘rudins’ of anticoagulants
In thrombin they block both catalytic and substrate recognition site
Bivalent direct thrombin inhibitors
(Unlike argatroban, which is a monovalent direct thrombin inhibitor, catalytic site only)
Side effects and contraindications of parenteral direct thrombin inhibitors
Side effect: bleeding
CI: renal failure except Argatroban (excreted by liver)
Monitoring of parenteral direct thrombin inhibitors
Monitoring aPTT is a must (except Argatroban: both PT and aPTT has to be monitored)
Uses of parenteral direct thrombin inhibitors
- Heparin induced thrombocytopenia (HIT)
DoC argatroban - DVT- desirudin
- STEMI-PCI: bivalirudin
Types of indirect thrombin inhibitors
- Unfractionated heparin UFH
- Low molecular weight heparin (enoxaparin, tinzaparin)
- Fondaparinaux
Properties of unfractionated heparin
Glycosaminoglycan= active pentasaccharide + very long chain heteropolysaccharide
From porcine intestinal mucosa
Low bioavailability due to affinity of heteropolysaccharide to various proteins
Lower bioavailability via subcutaneous route (binds proteins at the site of injection)
Mechanism of action of unfractionated heparin
- Active polysaccharide binds to AT-III ➡️ Xa breakdown
2. Heteropolysaccharide HPS binds to IIa ➡️ breakdown of IIa
Uses of unfractionated heparin
1. Subcutaneous: DVT prophylaxis 2. IV: Treatment of DVT Monitoring aPTT is required unlike other indirect thrombin inhibitors due to short t1/2
Low molecular weight heparin properties
Semi synthetic Short chain of heteropolysaccharide Smaller chain prevents binding to large number of IIa Xa> IIa inhibition Increased bioavailability
Low molecular weight heparin examples and uses
Enoxaparin Tinzaparin Uses (same as Fondaparinaux): Used via subcutaneous route for treatment and prophylaxis of DVT Monitoring not required for both
Fondaparinaux
Synthetic Only has active pentasaccharide Breakdown of Xa only Highest bioavailability Uses: same as low molecular weight heparin
Metabolism and dosage of indirect thrombin inhibitors
1. UFH: Metabolised by macrophages of RES (short t1/2) •Safe in renal failure •Dosage S/C-BD IV-QID 2. LMWH and Fondaparinaux: Excreted unchanged by kidney (longer t1/2) • CI in renal failure • S/C dosing- OD
DoC for poisoning of indirect thrombin inhibitors
Protamine sulphate
Binds to HPS chain and neutralises it
Activity decreases from UFH to Fondaparinaux
HIT
Ab that cross react to HPS (of heparin and is derivatives) are formed which increases the aggregation of Platelet factor-4 ➡️:
1. Thrombosis:
DoC anticoagulants like DTI, Fondaparinaux,…
2. Thrombocytopenia HIT:
not severe since it is due to consumption not destruction of platelets
More common in:
• females
• post surgical, cancer patients
DoC for prophylaxis and treatment of thrombosis
LMWH/ Fondaparinaux
For DVT, pulmonary embolism, MI, unstable angina, cancer patients
UFH unfractionated heparin is the DoC for
- Catheter induced thrombosis (factor XII)
2. Concurrent anti coagulation with thrombolysis
Side effects of heparin
A. Alopecia
H. Hyperkalemia, haemorrhage
O. Osteoporosis
T. Thrombocytopenia (HIT)
CI of heparin
T. Thrombocytopenia E. Endocarditis A. Alcoholics C. Cirrhosis H. HTN E. pEptic ulcer R. Renal failure
Warfarin
Inhibitor of VKOR (vitamin K oxidoreductase) which activates vitamin K
Delay in anticoagulant effect in 5 days
Warfarin and skin necrosis
Warfarin causes skin necrosis by the rapid fall of protein C and S (thrombotic effect) even before anticoagulant effect
Sequence of disappearance of clotting factors on warfarin
First to disappear: VII
Second to disappear: Protein C
Last to disappear: II
Antibiotics and warfarin
Antibiotics increases the effect of warfarin by reducing vitamin K synthesis
Uses of warfarin
- Prophylaxis and treatment of DVT:
Effective only after 5th day
LMWH given for first 5 days- ‘heparin bridge’ - DoC for prophylaxis of thrombosis (mechanical valve)- eg., atrial fibrillation
- Antiphospholipid Antibody syndrome
Side effects of warfarin
Bleeding Worsens HIT Alopecia Skin necrosis (M/C in breast of female) Teratogenic (nasal hypoplasia, stippled epiphyseal calcification)- decreased osteocalcin (vit K is decreased)
Warfarin in pregnancy
Warfarin is not used in pregnancy due to teratogenic effects (nasal hypoplasia, stippled epiphyseal calcification)- decreased osteocalcin (vit K is decreased)
Except for mechanical valve thrombosis:
Crosses placenta ➡️ Increases risk of intraventricular haemorrhage ➡️ stopped at 36th week ➡️ continue with LMWH
Monitoring of warfarin
Low therapeutic index ➡️ PT/INR is monitored
Normal INR: 0.9-1.3
Target: 2-3 for warfarin
1. Between 3-10 and asymptomatic ➡️ stop warfarin ➡️ restart when INR is normal
2. >10 and asymptomatic ➡️ stop warfarin and give vit K (2.5-5 mg oral)
3. Symptomatic➡️ stop warfarin ➡️ start FFP + IV Vitamin K (5-10 mg)
Streptokinase
- Binds to plasminogen ➡️ uncovers tpa binding site ➡️ increases plasmin
- High dose requirement because of streptococcus antibodies
- Clot non specific drug ➡️ high risk of bleeding
- Transient hypotension (bradykinin)
tpa analogues
Alteplase Reteplase Duteplase Tenecteplase - maximum clot specificity (rather than plasma fibrin) Lesser risk of bleeding
Uses of tpa analogues or fibrinolytics
- Thrombolysis:
STEMI, ischemic stroke - Massive pulmonary embolism (more powerful)
- Local route for peripheral thrombosis
CI of tpa analogues
B. Brain tumour/ aneurysm R. Recent stroke/ trauma A. Aortic dissection I. Intracranial haemorrhage history N. Non competitive vascular punctures
Side effects of fibrinolytics
Bleeding
DoC for fibrinolytic induced bleeding: EACA- an antifibrinolytic (Epsilon amino caproic acid)
Transexemic acid (anti fibrinolytic) can also be used
Uses of anti fibrinolytics like EACA
- DoC for fibrinolytics induced bleeding
- Gastric ulcer bleed
- Variceal esophagial bleed
Transexemic acid is also an anti fibrinolytic
Factors involved in platelet aggregation which are utilised pharmaceutically
- GPIIb/IIIa: adhesion of platelets
- TxA2
- ADP stimulates P2Y12 receptor
- Phospholipids activates coagulation system
Aspirin as an antiaggregant
Irreversible inhibitor of COX-2 ➡️ decreases TxA2
Low dose ➡️ 50-325 mg OD
Side effects: bleeding
Continued in case of surgery (unlike clopidogrel)
Uses of aspirin
- Acute coronary syndrome (MI, unstable angina)
2. 2° prophylaxis of MI and stroke
Classification of ADP/ P2Y12 receptor inhibitors
1. Irreversible (prodrugs): Clopidogrel Ticlopidine Prasugrel 2. Reversible: Competitive: Cangrelor Non competitive:Ticagrelor
Hit and run drugs
Drugs acting longer than t1/2 due to irreversible binding to their target
Eg., clopidogrel
Clopidogrel
ADP/ P2Y12 receptor inhibitor
Uses (like aspirin):
1. 2° prophylaxis of MI and stroke (along with aspirin for stent placement post MI)
2. Acute coronary syndrome- MI/ unstable angina
Ticlopidine
Most toxic ADP/ P2Y12 receptor inhibitor Not preferred Effects: 1. GIT upset- nausea, vomiting 2. Agranulocytosis 3. Thrombocytic purpura - haemolytic uremic syndrome complex
Prasugrel
Fastest and most effective ADP/ P2Y12 receptor inhibitor
CI:
High risk of intracranial bleed ➡️ CI in cerebrovascular diseases
Uses (similar to Cangrelor):
STEMI - percutaneous intervention (PCI)
Cangrelor
Adenosine analogue Competitive inhibitor of ADP/ P2Y12 receptor t1/2 is 3-6 min only IV short acting Uses: STEMI - PCI (same as prasugrel)
Ticagrelor
Long acting ADP/ P2Y12 receptor inhibitor
Can be given orally
Uses:
Acute coronary syndrome- MI, unstable angina (along with aspirin/ clopidogrel)
Varapaxar
Protease activated receptor (involved in aggregation) inhibitor
Side effect:
Risk of cranial bleed ➡️ CI in cerebrovascular disorders (like prasugrel)
Uses:
1. 2° prophylaxis of acute coronary syndrome (along with aspirin/clopidogrel)
2. Prophylaxis of peripheral arterial disease
GP IIb/ IIIa inhibitors examples and uses
- Abciximab
- Tirofiban
- Eptifibatide
Uses: - Acute coronary syndrome
- Acute attack of stroke (ischemic)
Abciximab
GP IIb/ IIIa and vitronectin inhibitor ➡️ more effective
Side effect:
bleeding and thrombocytopenia
Shortest t1/2 but has maximum affinity so longest acting
Eptifibatide
GP IIb/ IIIa inhibitor
Longest t1/2 (minimum affinity)
Shortest acting
