COX Inhibitors and
Blood Coagulation
PHM 142 – Tuesday September 16th, 2014
Chris Gallant
Edmond Chiu
Maggie Huynh
Bavithra Kumar
PHM142 Fall 2014
Instructor: Dr. Jeffrey Henderson
What is COX?
• Enzyme cyclooxygenase 1
• Responsible for the
formation of prostanoids1
• 3 main groups of
prostanoids include:
• prostaglandins
• prostacyclins
• thromboxanes
*These are all involved in
inflammatory responses/are
inflammatory mediators*
What is COX?
Two forms of
cyclooxygenase enzymes
exist:
COX-1 -> present in most tissues1
● e.g in GI tract it maintains the
normal lining of the stomach.
The enzyme is also involved in
kidney and platelet function. 2,3
COX-2 -> primarily present at sites
of inflammation1
What is Blood Coagulation?
Adapted from reference 5
COX’s Relationship to Blood
Coagulation
● COX plays a role in cessation of bleeding 4-6
● COX activates a chemical known as thromboxane A2
4-6
● The aggregation of platelets, in concert with the
clotting process, results in a fibrin clot which stops
bleeding and aids repair of the blood vessel. 7
What are COX inhibitors?
• A class of drugs that target the cyclooxygenase enzyme and act as
an effective treatment to pain and inflammation. Also known as
nonsteroidal anti-inflammatory drugs (NSAIDs).8
• Can be nonspecific (target both COX-1 and COX-2) or
specifically target COX-2.8
• COX-2 inhibition is desirable since this will reduce pain and
inflammation in certain areas, while COX-1 inhibition is associated
with side effects, such as stomach lining damage and gastric
ulcers.8
http://img.wikinut.com/img/297i4cfbldfkof_v/jpeg/0/Ibuprofen-Advil-tablets.jpeg
http://a.espncdn.com/photo/2007/1112/pg2_a_aleve_300.jpg
How COX Inhibitors Work
• Decrease the production of
prostaglandins, which promote pain,
inflammation and fever.9
• Prostaglandins also protect the lining of
the stomach and intestines, promote blood
clotting, and affect kidney function.9
• COX inhibitors are taken orally, and after
absorption into the bloodstream they bind
to the cyclooxygenase enzymes. COX-1 is
found in all tissues constitutively, while
COX-2 is induced by inflammation.9
• Binding can be reversible or irreversible.7
http://www.cheapmedicinechest.com/wp-content/uploads/2010/03/Figure-2-Nonselective-nonsteroidal-anti-inflammatory-drugs.png
http://publications.nigms.nih.gov/structlife/images/ch4_valine.gif
Aspirin and COX:
Mechanism of Action
•
•
•
Serine acetylation3
Non-selective3
Irreversible3
Adapted from reference 4
Issues with COX-2 specific inhibitors
• COX-2 inhibition
reduces prostacyclin
production, which is an
important prostaglandin
that prevents platelet
clumping.9
• Without prostacyclin,
platelets can build up
and clump, leading to
increased heart attacks
and strokes in patients.
Since COX-1 is
unaffected, thromboxane
A2 contributes to
thrombosis as well.9
• Examples are Vioxx and
Bextra, which have both
been discontinued.9
http://img.timeinc.net/time/covers/1101050228/map/viox.gif
Case Study
COX-2 inhibitors used to treat pain after
surgery 10,11
 Possible complications?

◦ Increased risk of thrombosis

Concern in Coronary-Artery Bypass
Grafting (CABG)?
Factors Considered

CABG increases thromboembolic events:
◦ Platelet activation
 Pre-exisiting cardiovascular conditions12
 Sheer stress from atherosclerosis
◦ Ischemia13
 During procedure14

COX-2 inhibitors increase risk of
thrombosis
Clinical Data
Figure adapted from reference 15
Conclusion of Study
Risk outweighs benefits16
 Advised to discontinue use of COX-2
specific inhibitors after CABG16

◦ Drug discontinued in 2005
Skit
To exemplify case study in clinical setting
 Enjoy!

Summary Slide
 COX is an enzyme cyclooxygenase responsible for the
formation of prostanoids which are involved in
inflammatory response
 COX plays a role in cessation of bleeding and activates a
chemical known as thromboxane A2 which relates to
blood coagulation and platelet aggregation
 COX inhibitors nonspecifically bind to COX-1 and COX-2
or specifically bind to COX-2. Binding to COX-2 is
desirable for reducing inflammation, pain and fever as it
also avoids gastric ulceration. This effect is caused by
reducing prostaglandin production.
 COX-2 inhibitors should be avoided when risk of
thromboembolic events is higher
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
Eustice, C. (2014, May 19). What Is Cyclooxygenase (COX)?. About Health . Retrieved September 15, 2014,
from http://osteoarthritis.about.com/od/osteoart
Lipsky, A. J. (n.d.). Clinical Considerations for Gastric Protection in the Presence of NSAID Therapy.
Medscape. Retrieved September 15, 2014, from http://www.medscape.org/viewarticle/4739
University, Department of Epidemiology and Preventative Medicine. (n.d.). How Aspirin Works. How Aspirin
Works. Retrieved September 15, 2014 from http://www.aspree.org/AUS/aspreecontent/aspirin/how-aspirin-works.aspx
Ophardt, Charles. "Prostaglandins." Virtual Chembook. N.p., n.d. Web. 15 Sept. 2014.
<http://www.elmhurst.edu/~chm/vchembook/555prostagland.html>.
"How The Blood Clots." How Does Blood Clot? Coagulation Explained, Diagram, Blood Clotting Process, Stages,
Hemostasis. N.p., 2010. Web. 15 Sept. 2014.
Rhoades, Rodney , and David Bell. "Blood Clotting." Inkling. Wolters Kluwer, n.d. Web. 15 Sept. 2014.
https://www.inkling.com/read/medical-physiology-rodney-rhoades-david-bell-4th/chapter-9/bloodclotting.
Stenina, Olga, and Edward Plow. "MET orchestrates cancer and blood coagulation." Nature.com. Nature
Publishing Group, n.d. Web. 15 Sept. 2014. <http://www.nature.com/nm/journal/v11/n4/fig_tab/nm0405376_F1.html>.
McGettigan, P. and Henry, D. (2000). Current problems with non-specific COX inhibitors. Curr Pharm Des,
6(17): 1693-1724.
Eustice, Carol. Cyclooxygenase: COX-1 and COX-2 explained. About Health,
http://osteoarthritis.about.com/od/osteoarthritismedications/a/cyclooxygenase.htm (accessed
September 10th, 2014).
References
10. Daniels, S. E., Grossman, E. H., Kuss, M. E., Talwalker, S., & Hubbard, R. C. (2001). A
double-blind, randomized comparison of intramuscularly and intravenously
administered parecoxib sodium versus ketorolac and placebo in a post—oral
surgery pain model. Clinical therapeutics, 23(7), 1018-1031.
11. Ng, A., Smith, G., & Davidson, A. C. (2003). Analgesic effects of parecoxib following total
abdominal hysterectomy†‡. British Journal of Anaesthesia, 90(6), 746-749.
12. Konstantopoulos, K., Grotta, J. C., Sills, C., Wu, K. K., & Hellums, J. D. (1995). Shearinduced platelet aggregation in normal subjects and stroke patients.Thrombosis
and haemostasis, 74(5), 1329-1334.
13. Park, J. L., & Lucchesi, B. R. (1999). Mechanisms of myocardial reperfusion injury. The
Annals of thoracic surgery, 68(5), 1905-1912.
14. Wan, S., LeClerc, J. L., & Vincent, J. L. (1997). Inflammatory response to
cardiopulmonary bypass mechanisms involved and possible therapeutic
strategies. CHEST Journal, 112(3), 676-692.
15. Nussmeier, N. A., Whelton, A. A., Brown, M. T., Langford, R. M., Hoeft, A., Parlow, J. L., ...
& Verburg, K. M. (2005). Complications of the COX-2 inhibitors parecoxib and
valdecoxib after cardiac surgery. New England Journal of Medicine, 352(11), 10811091.