1. Prof. Aboubakr Elnashar

2. Blood Clotting Vascular Phase Platelet Phase Coagulation Phase
Fibrinolytic Phase

3. 1. Vascular Phase
V.C
Exposure to tissues activate tissue factor and initiate coagulation
Tissue Factor

4. 2. Platelet phase
Blood vessel wall (endothelial cells) prevent platelet adhesion & aggregation
Platelets contain receptors for fibrinogen and von Willebrand factor.
After vessel injury: Platelets adhere & aggregate
Release permeability increasing factors (e.g. vascular permeability factor, VPF)
Loose their membrane & form a viscous plug

5. 3. Coagulation Phase 2 major pathways Both converge at a common point
Intrinsic pathway
Extrinsic pathway
Both converge at a common point
Clotting factors:
13 soluble
Biosynthesis is dependent on Vitamin K1& K2
Most are proteases
Normally inactive & sequentially activated

6. Extrinsic Pathway Intrinsic Pathway
Initiating factor is outside the blood vessels: tissue factor
Clotting: faster in Seconds PT
Intrinsic Pathway
All clotting factors are within the blood vessels
Clotting: slower
aPTT

7. Intrinsic Pathway Extrinsic Pathway Blood Vessel Injury Tissue Injury
Tissue Factor
XII
XIIa
Thromboplastin XI
XIa IX
IXa
VIIa
VII X Xa X
Prothrombin
Thrombin
Factors affected
By Heparin
Fibrinogen
Fribrin monomer
Vit. K dependent Factors
Affected by Oral Anticoagulants
Fibrin polymer
XIII

8. Thrombi Acc to location & composition
Venous
Occur primarily in the venous circulation
In response to venous stasis or vascular injury
Red
Composed
almost entirely of fibrin & erythrocytes
Associated with
Congestive Heart Failure, Cancer
Surgery.
Arterial
Occur in areas of rapid flow (arteries)
In response to an injured or abnormal vessel wall
White
Composed:
primarily of platelets, also fibrin & occasional leukocytes
Associated with MI
Stroke
ischemia

9. 4. Fibrinolysis Enhance degradation of clots
Activation of endogenous protease
Plasminogen (inactive form) is converted to Plasmin (active form)
Plasmin breaks down fibrin clots

10. Drugs used to reduce clotting
Drug Class Prototype Action Effect
1. Anticoagulant
Parenteral
Heparin
Inactivation of clotting
factors
Prevent DVT
Oral
Warfarin
Decrease synthesis of
clotting factors
Prevent DVT
Prevent arterial
thrombosis
2. Antiplatelet
Aspirin
Decrease platelet
aggregation
Breakdown of
thrombi
3. Thrombolytic
Streptokinase
Fibinolysis

11. I. Anticoagulants 1. Heparin Structure Mucopolysaccharide Metabolism
Partially in the liver by heparinase to uroheparin, which has only slight antithrombin activity.
20-50 % is excreted unchanged.
{The heparin polysaccharide chain is degraded in the gastric acid} administered IV or SC.
Heparin should not be given IM }danger of hematoma formation{.

12. Unfractionated heparin (UFH)
Mol weight:
Mechanism of action:
Primarily: interaction with antithrombin III: alters the molecular configuration of antithrombin III, making it 1,000 to 4,000 times more potent as an inhibitor of thrombin formation: limits conversion of fibrinogen to fibrin: prolongs aPTT
Also inhibits the effects of factor Xa on the coagulation cascade & limits platelet aggregation.
Half-life:
IV: 1 hr
SC: 3 hrs.

13. UFH inactivate factor IIa through formation of a tertiary complex (unlike LMWH).
UFH binds more to plasma proteins, endothelium and macrophages: reduced bioavailability & greater patient variability to a given dose.
UFH inactivates factors IIa and Xa & affects the aPTT (measure of anti-factor IIa activity).

14. Heparin-induced thrombocytopenia 20% .
Diagnosis: platelet count falls below the lower limits of normal or
by 50% but remains in the normal range.
Type 1
Mild, rarely dropping below 100,000 platelets/ML.
Platelet count monitoring is important, but therapy usually can continue {platelet count returns to normal even with continued use}.
{platelet activation & is not immune-mediated}.
b. Type 2
7 to 14 days after starting therapy.
Platelet counts frequently drop to 20,000/ML.
{an immune response caused by antibodies to the heparin-platelet factor 4 complex}.
It is related to: Mol wt, dose & duration of therapy.
immediate withdrawal of all forms of heparin is mandatory.
Platelet concentration should be monitored at least every 2 days.

15. Dosing options.
Preoperative: 5,000U 2 hours before surgery. {The single preoperative dose seems to be as effective as multiple preoperative doses}.
Postoperative: 8 to 12 hrs after surgery & every 8 to 12 hrs until the patient is fully ambulatory.
Antidote:
Protamine sulphate
Monitor:
aPTT
Use in pregnancy :{does not cross the placenta} safe

16. Low-Molecular-Weight Heparin Molecular weight 1000-10000 Da.
Produced by
concentrating the low molecular component of UFH. Enzymatic or chemical controlled hydrolysis of UFH.
The mechanism of action
Primarily by inhibiting factor Xa, which is higher in the coagulation cascade than antithrombin: LMWH is more efficient than UFH.
{the molecular configuration of antithrombin III is not altered by LMWH} thrombin conversion is minimally inhibited and aPTT is not appreciably affected.

17. LMWH inhibits factor Xa and minimally affects factor IIa; thus aPTT is not used to measure its anticoagulant activity.

18. Mol Wt
Manufacturer
Trade
Generic
4500
Rhone-Poulence-Rorer
Lovenex, Clexane
Enoxaparin
4850
Novo
Logiparine
Tinzaparin
6370
Kabi
Fragmin
Dalteparin

19. Half-life:
4 hrs, by any route: longer dosing interval.
Bioavailability
More consistent than that of UFH: dosing is based on lean body mass & Less thrombocytopenia.
Use in pregnancy:
Does not cross the placenta: safe.
Dosing options.
Prophylaxis: Once a day
Therapy: Twice-daily.
Enoxaparin is an LMWH
Moderate risk: 20 mg/d
High risk: 40 mg/d.
Advantage
Decreased need for monitoring

20. LMWH UFH 1000-10000 3000-30000 Mol Wt range 4000-5000 12000-15000
Mo Wt average
2:1-4:1
1:1
AntiXa: antiIIa activity No
Yes
aPTT monitoring required
Inactivation by platelet factor 4
Capable of inactivation of platelet bound factor Xa ++
++++
Inhibition of platelet function
Increase vascular permeability +
Protein binding -
+++
Endothelial cell binding
Dose dependent clearance
2-5 times longer
50-20 min
Elimination half life

21. 2. Oral anticoagulants Coumarins - warfarin, dicumarol Structure:
small, lipid-soluble molecules, Structurally related to vitamin K, isolated from clover leaves
Mechanism:
Inhibits production of active clotting factors
blocks the Vitamin K-dependent glutamate carboxylation of precursor clotting factors e.g. FII, VII, IX , X
Metabolism:
Absorption: rapid
Binds to albumin
Clearance is slow: 36 hrs
Delayed onset: 8-12 hr {T1/2 of clotting factors in plasma}

22. blocks the Vitamin K-dependent glutamate carboxylation of precursor clotting factors

23. Use:
To prevent the formation, recurrence or extension of DVT & PE
Not used in pregnant women {cross placenta}
Not used for arterial thrombi {No effect on platelets} Toxicity:
bleeding
birth defects
Overdose:
Reversed by vitamin K infusion
Recovery needs synthesis of new clotting factors

24. Warfarin tablets, 5, 3 and 1mg

25. Category Mechanism Representative Drugs
Drugs that Increase
Warfarin Activity
Decrease binding to
Albumin
Inhibit Degradation
Decrease synthesis of
Clotting Factors
Aspirin
Sulfonamides
Cimetidine, Disulfiram
Antibiotics (oral)
Inhibition of platelets Aspirin
Inhibition of clotting Heparin
Factors Antimetabolites
Drugs that promote
bleeding
Induction of metabolizing Barbiturates
Enzymes Phenytoin
Promote clotting factor Vitamin K
Synthesis OC
Reduced absorption Cholestyramine
Colestipol
Drugs that decrease
Warfarin activity

26. Warfarin Heparin Oral Parentral only Absorption 7.6-13.9 L
Plasma vol (0.07 L/kg)
Vol of distribution
Hepatic
Hepatic metabolism & uptake by reticulo endothelial system
Also by thrombin & other clotting factors
Metabolism/Clearance
36-42 hr
50-90 min
Elimination t1/2
99.4% bound to albumin
Bound to antithrombin III & other serine proteases
Protein binding
1.5 mg/L
U/ml
Plasma concentration (therapeutic)
Bleeding
Skin necrosis
Drug interactions
Thrmbocytopenia
Osteoporosis
Side effects
Mild: hold 1-2 doses, observe, restart at lower dose
Severe: Vit K or fresh frozen plasma
Mild: Slow or stop infusion
Severe: Protamine 1 mg/100 u of estimated heparin remaining in body
Treatment of bleeding

27. II. Antiplatelet Drugs
Activation and aggregation of platelets is a major component of thrombosis especially in arteries
Targets for platelet inhibitory drugs: (a) inhibition of prostaglandin metabolism through inhibition of cyclooxygenase (aspirin)
(b) inhibition of ADP-induced platelet aggregation (ticlopidine)

28. Platelet Activation:
Endothelial damage of vessel: exposes collagen
Activated platelets release ADP, serotonin (5-HT)& thromboxane A2 (TXA2-) from arachidonic acid: platelet aggregation by causing the appearance of binding sites for fibrinogen on platelet membrane
Fibrinogen is involved: platelet to platelet adhesion (aggregation)
Thrombin causes further platelet activation by releasing platelet ADP & stimulating PG synthesis
prostacyclin (PGI2) - synthesized within vessel walls inhibits thrombogenesis by increasing platelet cAMP. Nitric oxide (NO) - released by endothelium - increases cAMP

29. (a) NSAIDS Aspirin - prototype Mechanism:
inhibits cyclooxygenase (COX)
COX is a key enzyme involved in the synthesis of thromboxane 2 (prostaglandins). Inhibits platelet aggregation
long acting because new proteins must be synthesized
other NSAIDS: shorter duration because of reversible competitive inhibitory action
potency varies, e.g. Naproxen, meclofenamic acid, Ibuprofen, Indomethacin, phenylbutazare
Contraindication:
Patients with glucose 6-PO4 dehydrogenase deficiency

30. 335 mg/day: reduced the risk of heart attack in patients over 50 Use:
Dose:
Low dose daily (180 mg/day): Prevents ischemic attack (ministroke) and MI
335 mg/day: reduced the risk of heart attack in patients over 50
Use:
Prevention of recurrent infarcts in patients with myocardial infarction, also reduces the incidence of first infarcts
low-dose aspirin, compared with placebo, reduces by 36% the risk of VTE after orthopaedic surgery
Meta-analysis of trials in surgical and medical patients: significant reduction in DVT and PE with antiplatelet prophylaxis. (Pulmonary embolism prevention (PEP) Trial . Prevention of PE and DVTwith low dose aspirin: Lancet 2000; 355:1295–302.)

31. (b) Ticlopidine decrease platelet aggregation by inhibiting ADP pathway of platelets
no effect on PG metabolism
used as alternative for patients intolerant to aspirin
expensive
(C) Other antiplatelet drugs:
Dipyridamole, sulfinpyrazone

32. III. Thrombolytic Agents
Agents which reduce the formation of arterial platelet thrombi
Mechanism:
Rapid lysis of thrombi by catalyzing the formation of plasmin from plasminogen
Endogenous plasmin breaks down fibrin promoting clot dissolution
Use:
Emergency treatment of coronary artery thrombonís in M.I.
IV or intracoronary injection
DVT: rapid recanalization of occluded vessels  
Toxicity:
Bleeding (intracranial, G.I.)
Allergic reactions (i.e. streptokinase)  

34. Streptokinase:
Purified from bacteria
Continuous use: immune reaction
Forms a complex with plasminogen & catalyzes it: rapid conversion to plasmin
Urokinase:
From cultured human kidney cells
No immune response
Directly converts plasminogen to plasmin
tPA:
Produced by recombinant techniques
No immune reaction - EXPENSIVE
Promotes conversion of plasminogen (that is found to fibrin) to plasmin
In theory, selective for formed clots

35. Dosing administration Average dose Potential antigenicity
Cost
Dosing administration
Average dose
Potential antigenicity
Fibrin specificity
Enzymatic efficiency for clot lysis
Low
1 hr IV infusion
1.5 MU
Yes
Minimal
High
Streptokinase
Moderate
2-5 min IV infusion
30 u
high
Antistreplase
15 mg IV bolus, 50 mg over 30 min, then 35 mg over 60 min
100 mg No
Tissue plasminogen activator
1 mu IV bolus,
1 mu over 60 min
2 mu
moderate
low
Urokinase

36. Thank you
Aboubakr Elnashar