ver the past decade , the use of synthetic cannabinoids / marijuana has increased . These products generally consist of plant material sprayed with chemicals that can interact with the cannabinoid receptor , leading to intoxication when smoked . Synthetic marijuana is a poorly regulated substance , and is routinely found in convenience stores , gas stations , and other retail outlets .

The appeal of such products is that they are inexpensive , available in states without legalized marijuana , and undetectable in urine drug screens . However , the risk to users can be substantial because synthetic marijuana does not routinely undergo any regulatory quality control , chemical content evaluation , or inspection . Certain products also may contain psychoactive substances .

The rising popularity of synthetic cannabinoids / marijuana is accompanied by reports of severe bleeding and coagulopathies among users . 1 The first cases occurred in Illinois in March 2018 ; more than 160 cases have now been reported . The outbreak has also been observed in eight other states . 2

Patients typically present with either severe bleeding or are found to have a coagulopathy when being evaluated for another condition . Most people with a coagulopathy have smoked the drug , but this condition also has been reported in patients who vaporized the drug or made it into a tea . To date , four deaths from severe bleeding have been linked to these products .

What Is Superwarfarin ? The cause of the synthetic cannabinoid – induced coagulopathy has been identified as contamination with brodifacoum , a potent vitamin K antagonist routinely used as a rodenticide . Like warfarin , brodifacoum blocks vitamin K epoxide reductase ( VKOR ), leading to lower levels of vitamin K – dependent coagulation proteins . 3 , 4

There are several differences between warfarin and brodifacoum that make brodifacoum a more ideal pesticide – and considerably more dangerous to humans who are exposed . First , the affinity of brodifacoum for VKOR is 10 times higher

than that of warfarin . Second , the half-life of brodifacoum can be extremely long , up to 20 to 30 days , leading to prolonged coagulopathy . This has also led to brodifacoum being referred to as a “ superwarfarin .”

The exact source of the contaminated synthetic cannabinoids , and whether the brodifacoum was added intentionally , is unknown .

Suspecting Synthetic Cannabinoid Coagulopathy Given this spreading outbreak , hematologists should have a high degree of suspicion for brodifacoum poisoning when evaluating patients who present with exceptionally abnormal results on coagulation testing . The use of synthetic cannabinoids is a key clinical clue , but some patients may be reluctant to divulge this history .

Laboratory testing will show a markedly elevated international normalized ratio ( INR )/ prothrombin time ( PT ). The activated partial thromboplastin time ( aPTT ) also is prolonged due to depletion of coagulation factors II , IX , and X . Factor testing will show low levels of vitamin K – dependent proteins , but preserved fibrinogen and other factors such as factors V and VIII .

Thromboelastography , if available , will show a significantly prolonged R time , or the time until the first evidence of a clot is detected . Qualitative and quantitative brodifacoum assays , as well as qualitative anticoagulant poisoning panels that test for several drugs including warfarin and brodifacoum , can be obtained via specialty laboratories to confirm the diagnosis .

Treating the Effects of Superwarfarin Poisoning Urgent treatment for brodifacoum poisoning consists of rapid identification and reversal of the coagulopathy . ( See the

TABLE for recommendations for managing coagulopathy in patients who use synthetic cannabinoids / marijuana .)

The specific antidote for brodifacoum poisoning is vitamin K , which needs to be administered with doses titrated to the INR . In the acute setting , up to 100 mg several times a day may be required .

A particular challenge with brodifacoum poisoning is the long half-life , which can lead to patients requiring

treatment for months with high-dose vitamin K . In a recent literature review , the mean daily dose of vitamin K required to correct the INR was 60 mg daily ( within a range of 15-600 mg daily ) for a median of 140 days . 4

The expense of oral vitamin K ( approximately $ 70 for 5 mg ) and the intensity of the required monitoring may pose considerable stress for health-care systems in the involved cities . Indeed , one of the reported brodifacoum-related deaths was in a patient who left the hospital against medical advice and then succumbed to uncontrolled bleeding .

Levels of brodifacoum should be checked weekly . Once the levels become undetectable , clinicians can start a cautious trial of tapering vitamin K . However , this must be done carefully because the high affinity of brodifacoum for VKOR and enterohepatic recirculation can lead to persistent coagulopathy , even if brodifacoum levels are undetectable .

For brodifacoum-ingesting patients who present with life-threatening bleeding , urgent intervention is critical . If patients present with central nervous system bleeding or potential exsanguination , infusion of four-factor prothrombin complex concentrates ( 50 units / kg ) is recommended . Standard supportive care , including platelet or blood transfusions as needed , appropriate attention to the source of bleeding , and vitamin K supplementation as outlined above should also be undertaken .

Regardless of how widespread the outbreak of brodifacoum poisoning becomes , hematologists need to be on the front lines of both diagnosis and treatment . Considering synthetic marijuana use in the differential of patients who present with unexplained bleeding and coagulopathy is important , particularly in areas heavily affected by the outbreak . Rapid identification and treatment of brodifacoum poisoning can prevent significant morbidity and potentially save lives . ●

Joseph Shatzel , MD , is a fellow and Thomas G . DeLoughery , MD , is professor of medicine , pathology , and pediatrics in the Division of Hematology and Medical Oncology at Oregon Health and Science University Knight Cancer Institute in Portland .

TABLE . Managing Coagulopathy in Patients Who Use Synthetic Cannabinoids / Marijuana

Suspecting the Diagnosis Clinical bleeding History of synthetic cannabinoids use Markedly abnormal INR and aPTT Normal platelets and fibrinogen Establishing the Diagnosis

Factor levels of both vitamin K and nonvitamin K – dependent factors ( e . g ., factors II , V , VIII , and X )

Specific brodifacoum assays

Urgent Treatment for Severe / Life-Threatening Bleeding

Four-factor prothrombin complex concentrates 50 units / kg

Intravenous vitamin K 100 mg , checking INR every 4-6 hours and repeating dose if INR > 1.5

Blood transfusion if hemodynamically unstable

Long-Term Therapy

Oral vitamin K 50-100 mg , titrating to daily dosing to keep INR < 1.5

Weekly brodifacoum levels , and initiate cautious trial of lowering vitamin K when levels become undetectable

references

1 . Centers for Disease Control and Prevention . COCA clinical action : outbreak alert update : potential life-threatening vitamin K-dependent antagonist coagulopathy associated with synthetic cannabinoids use . Accessed May 23 , 2018 , from https :// content . govdelivery . com / accounts / USCDC / bulletins / 1eb9503 .

2 . Illinois Department of Public Health . Synthetic cannabinoids . Accessed May 23 , 2018 , from http :// dph . illinois . gov / topics-services / prevention-wellness / medical-cannabis / synthetic-cannabinoids .

3 . Feinstein DL , Akpa BS , Ayee MA , et al . The emerging threat of superwarfarins : history , detection , mechanisms , and countermeasures . Ann N Y Acad Sci . 2016 ; 1374:111-22 .

4 . King N , Tran MH . Long-acting anticoagulant rodenticide ( superwarfarin ) poisoning : a review of its historical development , epidemiology , and clinical management . Transfus Med Rev . 2015 ; 29:250-8 .

High Hopes : Hematology Patients Turn to Cannabis for Relief

CONTENTS

The Editorial Board Offers Improvements to CRO Practices

Kenneth Anderson on Hematology as a Labor of Love

Advice from the ASH Mentor Award Winners

Managing Blood Clots in Pregnant Women

Practicing Hematology in Limited-Resource Areas

GUN VIOLENCE : A PUBLIC HEALTH ISSUE

pASHions :

Data Stream : David Williams Shows ASH Annual

Demystifying the Lab : Gene Editing With

For more information and perspectives on the use of medical marijuana in hematologic patients , read the feature “ High Hopes ,” from our December 2017 issue at ashclinicalnews . org / feature / high-hopes .