Fibrinolytics and antifibrinolytics

1. Moderator: Dr Ravichandra
Presenter: Dr Manjuprasad
FIBRINOLYTICS AND ANTIFIBRINOLYTICS
1

2. OVERVIEW
• Coagulation cascade
• Fibrinolytic system
• Fibrinolytic agents
• Antifibrinolytic agents
2

3. The agents commonly used for controlling blood
fluidity:
• Parenteral and oral anticoagulants
• Antiplatelets
• Antifibrinolytics
3

4. COAGULATION CASCADE
4

5. INITIATION OF COAGULATION
• Tissue factor exposed
• Form complex with VIIa
• This complex activates factor X and IX
5

6. intrinsic pathway activated when
• Factor XII, prekallikrein and higher molecular
weight kininogen interact with kaolin glass or
other surface to generate small amounts of
factor XIIa
6

7. ACTIVATION OF PROTHROMBIN
• By cleaving two peptide bonds on prothrombin,
factor Xa converts it to thrombin.
• presence of factor Va, a negatively charged
phospholipid surface, and Ca2+, factor Xa
activates prothrombin with 109-fold greater
efficiency.
7

8. CONVERSION OF FIBRINOGEN TO FIBRIN
- Fibrinogen is a dimer
- Each half has 3 pairs of polypeptide chain
(Aα, Bβ, γ)
- Disulphide bonds links the two chains
8

9. • Thrombin converts fibrinogen to fibrin
monomers by releasing fibrinopeptide A and
fibrinopeptide B
from amino terminus of Aα and Bβ
respectively.
• New amino terminus formed
• Fits into preformed holes on other fibrin
monomers to form fibrin gel
9

10. • Fibrin is a potent platelet agonist
• Amplifies platelet activation and aggregation
10

11. THROMBUS
1 . Arterial – Mainly by platelet
2 . Venous - Mainly by fibrin
11

12. FIBRINOLYSIS
• Plasminogen activator activates plasminogen
to plasmin
• Two types- t-PA
u-PA
• Plasminogen and plasmin binds to lysine
residues on fibrin - kringle domains
12

13. 13

14. PHYSIOLOGICAL INHIBITORS OF FIBRINOLYSIS
• Plasminogen activator inhibitor 1
• Plasminogen activator inhibitor 2
• ἀ2 – antiplasmin inhibits plasmin generated by
binding to first kringle domain
• Plasma carboxypeptidase removes the lysine
residue on fibrin at carboxyterminal
14

15. 15

16. • To prevent premature clot lysis factor XIIIa
mediates covalent cross linking of small
amounts of α2-antiplasmin onto fibrin
surface.
16

17. FIBRINOLYTIC DRUGS
PLASMINOGEN ACTIVATORS :
1ST generation : Streptokinase
Urokinase
2nd generation : Anistreplase
Alteplase
Reteplase
Tenecteplase
17

18. NEWER PLASMINOGEN ACTIVATOR
• Saruplase
• Monteplase
• Lanoteplase
NEWER FIBRINOLYTICS
• Desmoteplase
• Alfimerase
• BB 10153
18

19. Endopeptidases:
• Ancrod
• Fibrinolysin
Factor XIIIa inhibitors
• TRIDEGIN
• DESTABILASE
19

20. STREPTOKINASE
• Protein obtained from Group-C ß hemolytic
streptococci.
• No intrinsic enzyme activity.
• Forms a stable non covalent 1:1 complex with
plasminogen.
• Causes the conformational change in the
plasminogen.
• Exposes the active site and converts to plasmin.
20

21. Sk-plasminogen complex
Free and fibrin bound plasminogen
Plasmin
Systemic lytic state
• Half life 60-80 min
21

22. USES
• In acute MI
• In Pulmonary Thromboembolism
• A/E : Hemorrhage ,Allergic reaction like rash,
chills ,rigor ,fever.
rarely anaphylaxis
22

23. • To be avoided in patient
-with recent major streptococcal infection
-previous treatment by streptokinase
because antibodies diminishes efficacy
23

24. ANISTREPLASE
• Anisolyated plasminogen streptokinase activator
complex (APSAC)
• Complex consist of purified human plasminogen &
streptokinase in which active site is masked with
anisoylation
• On administration acyl group hydrolyses
spontaneously releasing activated SK-plasminogen
complex
24

25. • Has a longer half life of 100min
• A/E : Hemorrhage
Allergic reaction
Hypotension
25

26. UROKINASE
• Two chain serine protease enzyme derived from
cultured fetal kidney cells
• Direct plasminogen activator which degrades both
fibrinogen and fibrin
• More fibrin specific than streptokinase
• Produces systemic lytic state
• t1/2 – 20 min
26

27. ALTEPLASE
• Recombinant form of single chain t-PA
• Rapidly activates plasminogen bound to fibrin
• Fibrin specific ,but not selective
• Not antigenic but anaphylactoid reaction in atopic
patient.
• t ½ 5-10 min
DUTEPLASE - Double chain recombinant t-PA
27

28. TENECTEPLASE
• Genetically engineered mutant form of alteplase
• Longer half life
• Resistance to inhibition by PAI 1
• .t1/2- 2hrs
• Dosage: single bolus dose of 50mg over 5sec
28

29. SARUPLASE
• Recombinant nonglycosylated form of single chain
urokinase type plasminogen activator
• Derived from genetically transformed E.coli
• Dose :20 mg infusion immediately followed by 60 mg
over 1hr
or Double bolus 40 mg 30 min apart
29

30. MONTEPLASE
• Mutant type of t-PA
• Independent of PAI
Uses:
• Myocardial infarction
• Pulmonary thromboembolism
• thrombolysis
• Endovascular thrombolysis for DVT
• Dose- 160x104 IU
30

31. LANOTEPLASE
• Recombinant t-PA
• long half life
• Single bolus dose 120 KU /kg
• Plasma activity lasts for 6 hrs compared to alteplase
4hrs
• Disadvantage - Intracranial hemorrhage rate higher
31

32. THERAPEUTIC INDICATIONS
 STEMI : Should be initiated within 30 minutes
Benefit most if Rx within 1-3 hrs
• In massive pulmonary thromboembolism reverses the
condition by
1. dissolving the thrombus obstructing
pulmonary artery
2. prevent the continued release of serotonin
and other neurohormonal factor which aggrevate
pulmonary HTN
3.lysis of much of source of thrombus in pelvic or
deep vein reduces recurrent PE
32

33. • Acute deep vein thrombosis
• Peripheral arterial thromboembolism
• Thrombosis on prosthetic material
• Acute ischemic stroke
• Clear the occluded cannula
33

34. CONTRAINDICATIONS
Absolute :
• Prior intracranial hemorrhage
• Known structural cerebral vascular lesion
• Known malignant intracranial neoplasm
• Ischemic stroke within 3 months
34

35. • Suspected aortic dissection
• Active bleeding or bleeding diathesis
• Significant closed head trauma or facial trauma
within 3 months.
35

36. Relative :
• - Uncontrolled hypertension (SBP>180,DBP>110mm of Hg)
• - Traumatic or prolonged CPR or major Surgery within 3
weeks
• -Pregnancy -Active peptic ulcer
• -Current use of warfarin and INR>1.7
.
36

37. ALFIMERASE
• Recombinant form of fibrolase (zinc metalloprotease
from venom of southern copper head snake)
• Degrades directly alpha chain of fibrin and fibrinogen
• Action independent of plasminogen concentration and
not inhibited by PAI 1
• Inhibited by ἀ2 macroglobulin limits systemic effects
37

38. Uses:
1.Catheter directed lysis of peripheral arterial
occlusion
2. Local delivery to restore flow in indwelling
catheter blocked by thrombus
38

39. DESMOTEPLASE
• Recombinant analogue of full length plasminogen
activator from saliva of vampire bat
• Binding via finger like domain and catalytic activity
enhanced in the presence of fibrin
• Use : Acute ischemic stroke but lacks efficacy
39

40. BB10153
• Variant form of plasminogen
• t1/2 4.4hrs
• Use: Acute ischemic stroke ,Peripheral arterial
occlusion
40

41. • TRIDEGIN – Isolated from giant amazon leech
• DESTABILASE-From leech
Not tested in humans
41

42. FIBRINOLYSIN
• Enzyme derived from plasma of bovine origin or extracted
from the culture of certain bacteria
• Used along with desoxyribonuclease which destroys DNA
• Acts locally by inactivating fibrin molecule
• Uses: Superficial wound , minor burn, ulcer
• CI: Hypersensitivity
• A/E: Increased pain, Burning sensation
42

43. ANCROD
• Proteolytic enzyme derived from the venom of Malayan pit viper
• Action through fibrinogen degraded product ,acts as a cofactor
for t-PA induced plasminogen activation
• Reduction in blood viscosity
• Use : Atherosclerotic disease
43

44. • t ½ 3-5 hrs
• Eliminated renally
• Administered parenterally
• A/E: Hypersenstivity , thrombophlebitis of injected vessel
44

45. ANTI FIBRINOLYTIC DRUGS
LYSINE ANALOGUES:
• EPSILON AMINO CAPROIC ACID
• TRANEXAMIC ACID
SERINE PROTEASE INHIBITOR
• APROTININ
45

46. EPSILON AMINO CAPROIC ACID
• Competes for lysine binding site on plasminogen and plasmin ,
blocks the interaction of plasmin with fibrin
• Rapidly absorbed orally
• Removed by kidney
• Dose : 5 g orally 4 times a day
IV – 5 g loading dose infusion over 30 min
1-1.25 g/ hr – till bleeding stopped
46

47. • Therapeutic uses:
- Over dose of thrombolytic agent t-PA , Streptokinase
- Post surgical bleeding – GIT , cardiac , orthopedic, prostatic
- Adjuvant treatment in hemophilia
- Prophylaxis for rebleeding from intracranial hemorrhage
- Bladder hemorrhage secondary to radiation
- Hereditary angioneurotic edema
47

48. • A/E:
• Nausea
• Hypotension
• Myopathy
• Muscle necrosis
• Abdominal discomfort
• Nasal stuffiness
• Intravascular thrombosis.
48

49. TRANEXAMIC ACID
• Analogue of aminocaproic acid
• More potent than EACA
• t1/2 : 2hrs
• Less protein bound
• Excreted in urine
• Dose : oral 1 to 1.5 g , 2 to 3 times /day
I.V inj 10 mg/kg tid
49

50. Therapeutic uses:
• Treatment and prophylaxis of hemorrhage with excessive
fibrinolysis
• Prevention of bleeding after surgery or trauma
-Tooth extraction in patient with hemophilia
-Cervical conisation
-Prostatic surgery
-Cardiac surgery
50

51.  Primary or IUD induced hemorrhage
 Heavy bleeding associated with fibroid
 Prevent rebleeding in ruptured intracranial
hemorrhage
 Dentistry 5% mouth rinse
 Hereditary angioneurotic edema
 Treatment of recurrent epistaxis
51

52. 52
• A/E:
GIT distress
Hypersensitivity skin reaction
Musculoskeletal pain
DVT
Ocular and visual disturbance
Post operative convulsion

53. APROTININ
53
• Monomeric globular polypeptide derived from bovine lung
tissue
• Inhibits several serine protease –
trypsin, chymotrypsin, plasmin, kallikrein
• t ½ 5 – 10 hrs
• 2KIU bolus then 2 to 5 KIU IV every 4hr slow infusion

54. 54
USES:
• Reduce bleeding from open heart surgery
• Liver transplantation
• Blood loss in obstetric patient
• Prostate surgery
• Ruptured intracranial aneurysm
• Prevention of post operative DVT
• Acute pancreatitis
• Topical use in neurosurgery

55. 55
• A/E:
Acute renal failure
Heart attack
Stroke
Encephalopathy
Anaphylaxis
Thrombosis
DIC

56. REFERENCES
56
• Goodmann and Gilman’s The pharmacological basis of
therapeutics 12th edition
• Principles of pharmacology HL Sharma KK Sharma 2nd edition
• Textbook of medical pharmacology – Padmaja udaykumar
• Basic clinical pharmacology Katzung 11th edition

57. 57