• It is Contraindicated to use Fibrinolytics and Defibrotide concomitantly. • Drugs increasing the risk of Fibrinolytics associated Bleeding include… o Anticoagulants (Warfarin, Heparin, Enoxaparin, Dabigatran, etc) o Antiplatelet agents (Aspirin, Clopidogrel, etc) o Pentosan Polysulfate Sodium • Herbs increasing the risk of Fibrinolytics associated Bleeding include… o Fenugreek o Garlic o Ginkgo o Evening Primrose Oil o Clove Oil o Anise o Turmeric (Curcumin) o Licorice o Asafetida o Capsicum (Capsaicin) o Celery o Kava o Cat's claw o Medowsweet o Feverfew o Tan-shen

1. Clinically Important
Drug Interactions of
Fibrinolytics
Dr P.Naina Mohamed PhD
Pharmacologist

2. Introduction
 Fibrinolytics are the medications which breakdown the fibrin inside the
clot (Thrombus) but not the thrombus itself.
 Thrombolytics are the agents which can break down the whole
thrombus (Clot) itself. Heparin acts as an indirect thrombolytic agent.
 Anticoagulants are the drugs affecting blood coagulation factors and
used to prevent harmful blood clots which can cause serious conditions
like DeepVeinThrombosis (DVT), Pulmonary Embolism (PE), or a Stroke.
 Anticoagulants work before the thrombus formation and they cannot
dissolve the clot (Thrombus) once it is formed.
 Hence, Fibrinolytics (Thrombolytics) are administered following a Heart
attack, Stroke and Pulmonary embolism to dissolve the thrombus
blocking the blood vessels.
 Interaction between one or more coadministered medications leading to
change in their effectiveness or toxicity, is termed as “Adverse drug
interaction”.
 Fibrinolytic agents can interact with prescription drugs, Over-the-
counter (OTC) medications, Herbal products, Dietary supplements,
etc.

3. Fibrinolytics
Fibrinolytics include…
RecombinantTissue Plasminogen
Activators (rtPA)
Alteplase
Reteplase
Tenecteplase
Streptokinase
Urokinase

4. Recombinant
Tissue
Plasminogen
Activators
(rtPA)
 Recombinant tissue plasminogen activators (r-tPAs) include
Alteplase, Reteplase, andTenecteplase.
 Alteplase is approved to treat Heart Attack (ST-elevation Myocardial
infarction (STEMI)),Acute Ischemic Stroke (AIS),Acute
massive Pulmonary Embolism. It has a short half-life (~5 min).
 Reteplase is for Acute Myocardial Infarction (AMI). Reteplase produces
more faster thrombolysis thanAlteplase.
 Tenecteplase is also indicated in Acute Myocardial Infarction (AMI). It has
a longer half-life and greater binding affinity for fibrin.
 Overdose of RecombinantTissue PlasminogenActivators (rtPA)
can be treated with Aminocaproic acid.

5. Streptokinase
 Streptokinase is a Fibrinolytic agent and it is isolated and purified from
streptococci bacteria.
 Our body develops an immunity to Streptokinase, since it is a bacterial
product. Hence, it is not recommended to use Streptokinase again after
four days from the first administration. Further thrombotic events could
be treated withTissue plasminogen activators (tPA).
 Streptokinase is used in Acute Myocardial Infarction (AMI), Arterial and
VenousThrombosis and Pulmonary Embolism (PE).
 Due to the lack of fibrin specificity of Streptokinase, it produces more
fibrinogenolysis which makes it a less desirable thrombolytic drug than
tPA compounds.
 Overdose of Streptokinase can be treated with Aminocaproic acid.

6. Urokinase
 Urokinase is a Fibrinolytic agent and it was originally isolated from
human urine.
 Urokinase is also present in the blood and in the extracellular matrix of
many tissues.
 Urokinase used to treat DeepVenousThrombosis (DVT), Pulmonary
Embolism (PE) and Myocardial Infarction (MI).

7. Mechanism of
Action of
Fibrinolytics
 Ideally, thrombolytic drugs should be given within the first 2 hours of
Ischemic Stroke andAcute Myocardial Infarction.
Fibrinolytics
Bind to fibrin on
the surface of the
clot
Activation of fibrin-
bound
Plasminogen
Plasmin is cleaved
from fibrin-bound
Plasminogen
Plasmin breaks
cross-links
between fibrin
molecules
Dissolution of clot

8. Fibrinolytics &
Defibrotide
 Use of Fibrinolytic agents should be discontinued before initiating
Defibrotide.
http://reference.medscape.com/drug/activase-tpa-alteplase-342287#3
Fibrinolytics +
Defibrotide
Defibrotide
increases tissue
plasminogen
activator (tPA)
function, and
decreases the
activity of tissue
plasminogen
activator
inhibitor
Increased risk of
bleeding
Contraindicated

9. Fibrinolytics &
Anticoagulants
 Observe patients for external bleeding and be alert for signs and symptoms
of internal bleeding, if concomitant use of an anticoagulant and a fibrinolytic
agent is required.
https://www.ncbi.nlm.nih.gov/pubmed/11085346
Fibrinolytics +
Anticoagulants
(Warfarin, Heparin,
Enoxaparin, Dabigatran,
etc)
Additive
anticoagulation
Increased risk of
bleeding

10. Fibrinolytics &
Antiplatelet
agents
 Close monitoring for bleeding is recommended, if concomitant use of
Fibrinolytics andAntiplatelet agents such as Aspirin,Clopidogrel, etc. is
required.
http://www.neurology.org/content/79/13_Supplement_1/S68.long
Fibrinolytics +
Antiplatelet agents
(Aspirin,
Clopidogrel, etc)
Additive effects
Increased risk of
bleeding

11. Fibrinolytics &
Pentosan
Polysulfate
Sodium
 Monitor the patient closely for bleeding complications, if Fibrinolytics
and Pentosan polysulfate sodium are used concomitantly.
https://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiv
eid=8930#section-9

12. Thrombolytics
& Fenugreek
 Caution is advised if fenugreek and thrombolytic agents are used
concomitantly.
 Monitor the patients for signs and symptoms of excessive bleeding.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4949941/
Thrombolytics +
Fenugreek
Coumarins of
Fenugreek may
affect blood
coagulation
Increased risk of
bleeding

13. Thrombolytics
&Garlic
 Monitor for signs and symptoms of excessive bleeding, if excessive garlic
is consumed with concomitant use of thrombolytic agents.
 Garlic supplements should be discontinued at least 10 days prior to
elective surgery.
http://ijpho.ssu.ac.ir/article-1-32-en.pdf
Thrombolytics +
Garlic
Garlic may
reduce
thromboxane B2
Inhibition of
platelet
aggregation
Increased risk of
bleeding

14. Thrombolytics
&Ginkgo
 If both agents are taken together, monitor bleeding time and signs and
symptoms of excessive bleeding.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1490168/
Thrombolytics + Ginkgo
Ginkgolide B of Ginkgo
may inhibit Platelet
Activating Factor (PAF)
induced Platelet
aggregation
Increased risk of
bleeding

15. Thrombolytics
& Evening
PrimroseOil
 Caution is advised if evening primrose oil and thrombolytic agents are
used concomitantly.
 Monitor the patients for signs and symptoms of excessive bleeding.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2541068/pdf/bmj00459-
0008.pdf
Thrombolytics + Evening
Primrose Oil
Gamma-linolenic acid of
Evening primrose oil
inhibitsThromboxane B2
synthesis and increases
Prostacyclin synthesis
Additive anticoagulant
effect
Increased risk of
bleeding

16. Thrombolytics
&Clove oil
 Avoid concomitant use of clove oil with thrombolytic agents. If both are
taken together monitor the patient closely for signs and symptoms of
bleeding.
http://jpma.org.pk/full_article_text.php?article_id=4757
Thrombolytics +
Clove oil
Clove oil inhibits
Platelet
aggregation
Increased risk of
bleeding

17. Thrombolytics
&Anise
 Concomitant use warrants monitoring of the patients for signs and
symptoms of increased bleeding.
http://www.ajhp.org/content/57/13/1221.long
Increased risk of
bleeding
Coumarin of Anise
may increase the
anticoagulant
effect
Thrombolytics +
Anise

18. Thrombolytics
&Turmeric
(Curcumin)
 Caution is advised if curcumin and thrombolytic agents are used
concomitantly.
 Monitor for signs and symptoms of excessive bleeding.
http://www.sciencedirect.com/science/article/pii/0049384885902762?via%3Di
hub
Thrombolytics
+Turmeric
(Curcumin)
Curcumin
inhibits platelet
aggregation
Increased risk
of bleeding

19. Thrombolytics
& Licorice
 Monitor the patients for signs and symptoms of excessive bleeding.
http://www.sciencedirect.com/science/article/pii/S0049384803005425
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5345862/
Thrombolytics +
Licorice
Licorice may inhibit
Thrombin and
Platelet
aggregation
Increased risk of
bleeding

20. Thrombolytics
&Asafetida
 Monitor the patient closely for signs and symptoms of bleeding.
http://www.ajhp.org/content/57/13/1221.long
Thrombolytics +
Asafetida
Additive
anticoagulant
effects
increased risk of
bleeding

21. Thrombolytics
&Capsicum
(Capsaicin)
 Signs and symptoms of excessive bleeding should be monitored closely
if capsaicin and thrombolytic agents are taken concomitantly.
http://www.ajhp.org/content/57/13/1221.long
Increased risk of
bleeding
Capsaicin may inhibit
platelet aggregation
and enhance
fibrinolytic activity
Thrombolytics +
Capsicum (Capsaicin)

22. Thrombolytics
&Celery
 Monitor the patient closely for signs and symptoms of bleeding.
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0064255
Thrombolytics
+ Celery
Celery may
inhibit Platelet
aggregation
Increased risk
of bleeding

23. Thrombolytics
& Kava
 Monitor the patient closely for signs and symptoms of bleeding.
https://www.thieme-connect.com/products/ejournals/pdf/10.1055/s-2006-
957597.pdf
Thrombolytics +
Kava
Kava may inhibit
Cyclooxygenase
(COX)
Inhibition of
Platelet
aggregation
Increased risk of
bleeding

24. Thrombolytics
&Cat's claw
 Monitor the patient closely for signs and symptoms of bleeding.
http://www.ajhp.org/content/66/11/992.long
Thrombolytics +
Cat's claw
Rhynochophylline
of Cat's claw may
inhibit Platelet
aggregation
Increased risk of
bleeding

25. Thrombolytics
&
Meadowsweet
 Monitor the patient closely for signs and symptoms of bleeding.
http://onlinelibrary.wiley.com/doi/10.1046/j.1365-2710.2002.00444.x/full
Increased risk of
bleeding
Salicylate content
of Meadowsweet
Possess Antiplatelet
activity
Thrombolytics +
Meadowsweet

26. Thrombolytics
& Feverfew
 Caution is advised if feverfew is taken with thrombolytic agents. Monitor
the patient closely for signs and symptoms of bleeding.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3210009/
Thrombolytics +
Feverfew
Parthenolide of
Feverfew reduce
Thromboxane A2
production
Inhibition of
platelet
aggregation
Increased risk of
bleeding

27. Thrombolytics
&Tan-shen
 Avoid concomitant administration of thrombolytic agents withTan-shen.
http://www.sciencedirect.com/science/article/pii/S0003497598006249
Thrombolytics +
Tan-shen
Tan-shen may
inhibit cAMP
phosphodiesterase
Additive
antiplatelet effects
Increased risk of
bleeding

28. Alteplase &
ACE inhibitors
 Use caution when administering Alteplase to patients who takeACE inhibitors.
 Patients receiving alteplase infusion should be monitored closely for signs of
orolingual angioedema. Appropriate therapy should be initiated (ie, antihistamines,
steroids or epinephrine) if orolingual angioedema occurs and discontinuation of
alteplase infusion should be considered.
http://onlinelibrary.wiley.com/doi/10.1111/ene.12472/full
Alteplase + ACE
inhibitors (Captopril,
Lisinopril, Perindopril,
etc)
Alteplase can increase
the Bradykinin
production & ACE
inhibitors decrease the
Bradykinin breakdown
Accumulation of
Bradykinin
Increased risk of
Orolingual Angioedema

29. Alteplase &
Nitroglycerin
 If possible, concomitant use of nitroglycerin and alteplase should be
avoided.
 The lowest effective dose of nitroglycerin should be used, if
coadministration of Alteplase and Nitroglycerin is necessary.
http://onlinelibrary.wiley.com/doi/10.1592/phco.20.5.380.35057/epdf
Alteplase +
Nitroglycerin (GTN)
Nitroglycerin
enhances the hepatic
blood flow
Increased catabolism
of Alteplase
Less coronary artery
reperfusion, longer
time to reperfusion,
and more coronary
artery reocclusion

30. Streptokinase
&Antiplatelet
agents
 Close monitoring for bleeding is recommended, if concomitant use of
Fibrinolytics andAntiplatelet agents such as Aspirin,Clopidogrel, etc. is
required.
http://www.neurology.org/content/79/13_Supplement_1/S68.long
Streptokinase +
Antiplatelet agents
(Aspirin, Dipyridamole,
Clopidogrel, etc)
Additive effects
Increased risk of
bleeding

31. Conclusion
 Drug interactions can result in significant morbidity and
mortality and thus minimizing the risk for drug interactions
should be a goal in drug therapy.
 The risk of adverse effects could be reduced by healthcare
professionals through the screening, education, and follow
up on suspected drug interactions.
 If possible, the patients are recommended to fill all their
prescriptions at one pharmacy.
 Pharmacists can play a crucial role in identifying possible
drug interactions by asking patients on Fibrinolytics about
their herbal and other alternative medicine product use.

32. References
oStockley’s Drug Interactions, 9e
Karen Baxter
oGoodman & Gilman's:The Pharmacological Basis ofTherapeutics, 12e
Laurence L. Brunton, Bruce A. Chabner, Björn C. Knollmann
oBasic & Clinical Pharmacology, 12e
Bertram G. Katzung, Susan B. Masters, Anthony J.Trevor
oA Manual of Adverse Drug Interactions
J.P.Griffin, P.F. D'Arcy
oClinical Manual of Drug Interaction Principles for Medical Practice
Gary H.Wynn, Jessica R. Oesterheld, Kelly L. Cozza,Scott C. Armstrong

33. References
 http://www.micromedexsolutions.com
 https://link.springer.com/article/10.2165/00003088-199528040-
00004#enumeration
 https://www.ncbi.nlm.nih.gov/pubmed/8578491
 http://reference.medscape.com/drug-interactionchecker
 https://www.drugs.com/drug_interactions.html
 http://www.webmd.com/interaction-checker/
 http://www.rxlist.com/drug-interaction-checker.htm
 http://umm.edu/health/medical/drug-interaction-tool
 http://ukhealthcare.uky.edu/Library/DrugReference/Druginteractionchec
ker/