David L. McGlasson, MS, MLS(ASCP)

Posted: September 26, 2019


Ok I admit it I am a child of the 1960’s. However, I spent the last three years in the Army 1966-1969 during the Vietnam War. After I got out of the military I spent a year doing veterinary pharmacology research and then headed back to San Antonio to finish my education. While there I experienced the effect of “Killer Weed, Wacky Tobacky, Mother Nature, Michoacan, Panama Red, whatever.” Unlike President Clinton I did inhale. I never thought about the issues that may be occurring in my coagulation system until I recently came upon some interesting articles that made me stop and think about the rapid legalization of cannabinoid products and their medicinal use. Even though I stopped imbibing after settling down and having kids and being drug tested at work since I was working in research for the United States Air Force, I am not making opinions on its use.

This weekend on the news a big news item was about “mysterious vaping-related illness” blamed in an Illinois death from an unknown respiratory disorder and in other parts of the country. In recent weeks, people aged 17 to 38 have been hospitalized across the state for respiratory symptoms including cough, shortness of breath and fatigue, and in some cases vomiting and diarrhea after vaping. This was according to the Illinois Department of Public Health. The department is also investigating 12 more individuals with these symptoms.

Dozens more in other states have also been hospitalized this summer, causing federal and state public health officials to warn of the danger of vaping or use of e-cigarettes- a practice on the rise.1,2  However, there is little information on the material that was being vaped.

This reminded me of a recent article that piqued my interest a few weeks ago that may lead indirectly to the above article. This article also took place in Illinois. It discussed an outbreak of synthetic cannabinoid-associated coagulopathy in an area around Peoria, IL. Since I’m originally from Illinois and I know the area very well where this problem occurred. I was drawn to the information immediately.

In March and April, of 2018 the authors described the problem of more than 150 patients that were presenting to area hospitals with coagulopathy and bleeding diathesis. The common thread seemed to be the use of synthetic cannabinoid use with the likely adulterating agent being a “super Warfarin called brodifacoum.2

Synthetic cannabinoids may go by a variety of names. The synthetic cannabinoids are human-made mind-altering chemicals that are sprayed on dried shredded plant material so they can be smoked or sold as liquids that can be vaporized and inhaled in e-cigarettes and other devices. They may be marketed as herbal or liquid incense.

These chemicals are called cannabinoids because they are similar to chemicals found in cannabis. Because of this similarity, synthetic cannabinoids are sometimes misleadingly called synthetic marijuana (or “fake weed”).

These synthetic cannabinoids are part of a group of drugs called new psychoactive substances (NPS). NPS are unregulated mind-altering substances that have become newly available on the market and are intended to produce similar effects as illegal drugs (in some states legal). Some of these substances have been around for years but have re-entered the public consumption arena in altered chemical forms, or due to renewed popularity of the cannabinoids.

In the Illinois outbreak cited in the article,3 a total of 34 patients were found to have a cannabinoid-associated coagulopathy during 45 hospitalizations. When confirmatory coagulation testing was run in 15 of the 34 subjects a superwarfarin poisoning was found in 15 of the cases tested. Anticoagulant testing revealed the presence of brodifacoum in 15 patients, difenacoum in 5, bromadiolone in 2 and warfarin in 1 patient.

Symptoms at presentation in the emergency center included gross hematuria in 19 subjects and severe abdominal pain in 15. Computed tomography was performed to evaluate abdominal pain and revealed renal abnormal issues in in 12 patients. Vitiamin K1 (phytonadione) was given orally in all of the 34 patients and was also given IV in 23 patients. Red blood cell transfusions were performed in 5 patients and fresh-frozen plasma transfusions were administered in 19. Four-factor prothrombin complex concentrates were used in 1 patient. One patient expired from spontaneous intracranial hemorrhage.

Their data indicated the super warfarin adulterants of synthetic cannabinoids led to the clinically significant bleeding disorders discovered in the patients that presented with common symptoms. In their patient group in most of the subjects presenting with the similar bleeding diathesis the issues were contained with the use of Vitamin K1, and replacement therapy. The specific synthetic cannabinoid compounds were not known.

Two recent cases of interaction of Coumadin therapy being affected by the use of cannabis by oral ingestion and smoking were reported in two journals.

The first case involved a 35-year old Middle Eastern male subject who had been on a long-term treatment regimen with Coumadin that resulted in an elevated international normalized ratio (INR) without bleeding complication. The patient had been on Coumadin from 2010-2018 with a relatively stable INR in the 2.0-3.0 INR range until the INR suddenly increased to 7.2 following a 1-month time use of edible cannabis ingestion and cannabis smoking. The subject had no symptoms of bleeding. No other suspicious causes of the elevation of the INR were evident. The patient was advised to hold 2 doses of Coumadin and discontinue cannabis use. The INR dropped below 4.0 upon discontinuation of cannabis with dose adjustments to Coumadin.

This elevation in the INR was explained by the inhibition of CYP2C9 by cannabis use which caused the decreased metabolism of Coumadin. The failure of the Coumadin to maintain the patient in the therapeutic range was due to the interaction of the drug caused by the cannabis intake. This was determined by the use of the Horn Drug Interaction Probability Scale.

To date the authors had found no other case reports describing the interaction with Coumadin by edible use of cannabis. They suggested that patients on Coumadin therapy who were using

Cannabis for medicinal or recreational reasons be monitored for proper Coumadin anticoagulation management.4

However, second case involved a 56-year old white male who had been receiving Coumadin therapy for 11 years after a mechanical heart valve replacement. He was admitted to the hospital with a diagnosis of upper GI bleeding. His INR upon admission was at a supra-therapeutic level of 10.41, with a decreased hemoglobin level of 6.6 g/dl. He was given 4 units of FFP and one 10-mg dose of oral vitamin K; his INR the next day had dropped to 1.8. He was discharged 7 days after admission. Fifteen days after being discharged he was readmitted with a constant nosebleed and increased bruising. This admission his INR value was 11.55. After receiving treatment he was discharged with a sub-therapeutic INR result of 1.14. The patient smoked marijuana more frequently during the time of these 2 hospital admissions due to his depression. He was counseled by the pharmacy on the potential interaction of Coumadin and marijuana. The patient stopped smoking marijuana after three counseling sessions. During the subsequent 9 months that he did not smoke marijuana, his INR values ranged from 1.08 to 4.40 with no significant bleeding issues. Again, the Horn Drug Interaction Probability Scale was used in determining the interaction of marijuana and the Coumadin therapy as being the cause of his bleeding issues.5

In a brilliant article by Zakrzeska A et al, the authors discussed the genetic interaction of cannabinoids and hemostasis. They stated: Elements of the endocannabinoid system (cannabinoid receptors CB1, CB2, CBPT and CBED, endocannabinoids, enzymes involved in the synthesis and metabolism of endocannabinoids) are located on the structures involved in the process of hemostasis.

An increasing level of endocannabinoids was also observed in some pathological conditions, which may occur in disorders of hemostasis. At the same time, disconcertingly, there are an increased number of reports about incidents of cardiovascular events in smokers of marijuana. Experimental and clinical studies demonstrated multidirectional, often contradictory, effects of cannabinoids on hemostasis, including effects of the compounds on platelets, vascular endothelium, fibrinolysis, and plasma coagulation systems.

The mechanisms of action of cannabinoids on homeostasis depend on the cannabinoid receptors CB1, CB2, CBPT and CBED, receptors of other systems stimulated by endocannabinoids, as well as metabolites of endocannabinoids and nitrogen oxide.

The range of biological functions of endo- and plant cannabinoids, expanded to include the process of hemostasis, may constitute a condition for their recognition as a new factor responsible for thromboembolism in smokers of marijuana, in pathological disorders with increased levels of endocannabinoids and in individuals with polymorphisms of FAAH C385A and A385A. On the other hand, there are compelling explanations for the anti-hemostatic action of the cannabinoids.6

The effects of cannabis on platelet function were previously reported in an article published in 2004 by Deusch E, et al. They determined that the delta-9-tetrahydrocannabinol (THC) portion of the cannabis plant effects using Western blotting and flow cytometry for the detection of platelet surface activation markers. Previous reports have indicated an association of chronic THC intake and myocardial infarction as well as the juvenile onset of thromboangitis obliterans (Buerger disease). However, there have been contraindicating reports on the effects of THC on platelets.

The researchers investigated the effects of THC on human platelets and the expression of cannabinoid receptors on their cell membranes in this in vitro study. The effects of THC (final concentrations 0.1 – 10 μM) on the expression of activated platelet fibrinogen receptor (glycoprotein IIb-IIIa) and P-selectin were characterized by flow cytometry. Western blotting was performed with platelet membrane preparations to determine the surface expression of cannabinoid receptors on human platelets. THC increased the expression of glycoprotein IIb-IIIa and P-selectin on human platelets in a concentration-dependent manner. The two known cannabinoid receptors (CB1and CB2) were both detected on the cell membrane of human platelets. Their functional results suggested a receptor-dependent pathway of THC-induced platelet activation.

However, further in vivo studies are warranted to evaluate the role of cannabinoid receptors in mediating the demonstrated procoagulatory effects of THC. This is necessary to determine if there are potential cardiovascular and coagulation side effects of THC in seriously ill patients. Until then, health care workers should be conscious of the potential adverse effects of THC.7

Going back a few years to 1980 an article was published in Thrombosis Research by a group of researchers that determined that marijuana might impair blood coagulation. THC was given orally to 12 healthy males in a dose of 210 mg/day for 12-16 days (they had no problem getting volunteers [sic]). They monitored platelet count, platelet adhesion, platelet aggregation, bleeding time, and factors V, VII, and VIII.

No clinical changes were observed, although a minimal increase in FVII (p=0.05) was observed. However, they hypothesized that due to the possible alteration in FVII and the observation that THC is significantly bound to albumin that THC might interfere with use of Coumadin-type anticoagulants as do many drugs with sedative hypnotic properties.8

Wow, way back in 1980, almost 40 years ago this team of scientists made a prophecy that might be part of the issues we are facing today with the interference of the cannabinoids with contaminated Vitamin K agonists or subjects who are on targeted Coumadin therapy legally.

 

References

 

  1. Thayer K. Mysterious vaping-related illness blamed in Illinois death. Chicago Tribune, August 24, 2019.
  2. Tran Minh-Tran, Perea-Alvarez I, Swaroop B. Synthetic cannabinoids: an unexpected cause of coagulopathy. Transfusion 2018 58. Letter to the editor.
  3. Kelkar AH et al: An Outbreak of Synthetic Cannabinoid Associated Coagulopathy in Illinois. N Engl J Med 2018;379:1216-23.
  4. Hsu A, painter NA. Probable Interaction Between Warfarin and Inhaled and Oral Administration of Cannabis. J Pharm Pract. 2019 EPub ahead of Print Jul 18.
  5. Yamreudeewog W, Wong HK, Brausch LM, Pulley KR. Probable Interaction between warfarin and marijuana smoking. 2009;43(7):1347-53.
  6. Zalrzesla A et al: Cannabinoids and haemostasis. Postepy Hig Med Dosw (online) 2016; 70(0):760-74.
  7. Deusch E, et al: The Procoagulatory Effects of Delta-9-Tetrahydrocannabinol in Human Platelets. Anesth Analg 2004;99:1127-30.
  8. Heiden D, Rodvien R, Jones R, Mielke CH. Effect of Oral Delta-9-Tetrahydrocannabinol on Coagulation. Thromb Res. 1980;17:885-889.

 

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