INR trends and pharmacologic interventions are depicted for 4 select patients in Fig. 3. Patients 4 and 8 received oral and intravenous vitamin K at doses and administration frequencies closely matching the treatment protocol (Fig. 1). Patients 8 and 10 both presented with hematemesis and hematuria after synthetic cannabinoid exposure, and received FFP with oral and intravenous vitamin K administration. However, the graph for patient 10 depicts INR elevation during a period of delayed vitamin K administration. Upon resumption of vitamin K 50 mg administered orally every 8 hours, his INR normalized. The INR trend and interventions for patient 13, the patient described in Box 1 (see Box 1, http://links.lww.com/MD/D211, Supplemental Content, which illustrates the case report of patient 13 including 2 images of her head computed tomography [CT] scan). No patients in this cohort experience adverse effects as a result of high dose vitamin K exposure.
Clinical outcomes included 1 death due to intracerebral hemorrhage (ICH) (patient 13), 3 self-discharges against medical advice, 1 administrative discharge, and 11 discharges in stable clinical condition. The median length of stay was 4 days (IQR = 3–6). The average cost of pharmacologic hospital treatment was $5300 USD (range $2241–$8086 USD).
Of this cohort, synthetic cannabinoid use was confirmed via patient and family interviews in 14 (88%) patients, with 8 patients (57%) reporting the last use within 48 hours prior to hospital admission. Thirteen patients (81%) had confirmatory brodifacoum testing, and brodifacoum levels returned detectable levels in 12 cases (92%). Although the brodifacoum assay returned negative for 1 patient, he was treated for superwarfarin toxicity due to his lack of concomitant comorbidities and presence of coagulopathy on presentation refractory to standard doses of vitamin K.
Fourteen patients (87.5%) were prescribed vitamin K at discharge. Patients without discharge vitamin K prescriptions included the patient with fatal intracranial hemorrhage, and the patient who left against medical advice. Eight patients were scheduled for ongoing INR monitoring with vitamin K adjustment at the outpatient hematology anticoagulation clinic. Of the 8 patients that followed in the hematology anticoagulation clinic, the duration of follow-up was 35 days on average (range, 13–84). Five patients required an increase in their outpatient dose of vitamin K at the first follow-up visit to maintain an INR below 2. All 8 patients were lost to follow-up despite multiple attempts from the anticoagulation clinic team to re-establish care using various forms of communication. Two episodes of re-bleeding occurred after discharge secondary to poor medication adherence in the outpatient setting.
4 Discussion and conclusions
In this series we provide clinical outcomes of a cluster of patients presenting with LAAR coagulopathy and expert based approach to treatment of such patients at our academic center. In this cohort, patients most commonly presented with hematuria and/or epistaxis. Twelve patients (75%) achieved at least one INR value below 2 within 24 hours of the first INR measurement. Three of the 4 patients without an INR value below 2 within 24 hours of the first INR measurement underwent a treatment approach inconsistent with recommendations outlined in the treatment protocol. Of note, the 3 patients with protocol non-adherence and inadequately reversed INRs within 24 hours of presentation received insufficient vitamin K doses. The one fatality was in a patient presenting with intracerebral hemorrhage with brain herniation at the time of emergency department presentation. We believe that rapid diagnosis of these coagulopathies, and initiation of a vitamin K based treatment regimen that is continued for a prolonged period is essential to avoidance of severe clinical complications. Therefore, detection of clinical symptoms of LAAR-induced coagulopathy must be recognized in a variety of settings.
Our protocol was developed with a multi-disciplinary team of hematologists and clinical pharmacists after the first LAAR-toxicity case at our health system. Recommendations were compiled based on knowledge of superwarfarin action and after an extensive literature review of existing data describing LAAR-toxicity management.[10–23] This information was then disseminated to clinicians and pharmacists at our institution. A treatment protocol assists with expediting care in across all setting of our health system.
Brodifacoum and other superwarfarins are LAARs that interfere with hepatic synthesis of vitamin K-dependent coagulation factors (II, VII, IX, X). Coagulopathy reversal for LAARs is achieved with similar strategies to warfarin reversal, (PCC or FFP administered with vitamin K). PCCs reverse warfarin and LAARs by increasing levels of vitamin K-dependent coagulation factors (II, VII, IX, X, protein C and S). Since the vitamin K-dependent coagulation factors in PCC have a limited half-life, it is essential to treat patients with LAAR exposure with concomitant vitamin K and PCC to provide the liver with sufficient vitamin K to resume synthesis of functional vitamin K-dependent coagulation factors. While 10 mg or less of phytonadione is sufficient to reverse warfarin anticoagulation, large daily doses of phytonadione (25–600 mg/d) are required to overcome the effects of brodifacoum due to its greater potency.[1,15–23] Additionally, treatment with high dose vitamin K is required for weeks to months due to the long half-life of LAARs. These factors, combined with available literature, were taken into consideration when developing the LAAR toxicity treatment protocol at our health system.
Vitamin K doses ranging from 25 to 600 mg/d have been required to reverse LAAR-induced coagulopathy in the published literature.[1,15–23] In our treatment protocol, we suggest vitamin K 50 mg every 6 or 8 hours initially depending on whether the patient presented with bleeding symptoms, with further up- or down-titration of the dose based on clinical response. However, we found 50 mg every 8 hour oral dosing to be inadequate in patients 5 and 10, and vitamin K 50 mg orally every 6 hours resulted in inadequate INR lowering in patient 9. This highlights the importance of aggressive vitamin K dosing at the time of presentation and subsequent dose reduction as tolerated. When preparing for discharge, the cost of vitamin K was an additional obstacle. Multiple contacts were made to insurance companies and state agencies in order to be able to obtain sufficient oral vitamin K for each patient to complete their course of treatment.
According to human pharmacokinetic data oral vitamin K administration is associated with a half-life of 6 hours. Additionally, although vitamin K is lipid soluble, there is minimal toxicity associated with administration of high doses. Therefore, we recommend vitamin K 50 mg every 6 hours be initiated on presentation for patients with clinically significant bleeding and initial INRs greater than or equal to 1.4, regardless of the degree of initial INR elevation. The contribution of the frequency and duration of LAAR exposure to the severity and refractoriness of LAAR-induced coagulopathy is unclear. However, because of the lipophilicity and long half-life of LAARs, patients with higher degrees of exposure may require more aggressive initial vitamin K dosing. Although some case reports cite the use of phenobarbital, a potent cytochrome P450 enzyme inducer, to increase LAAR elimination, phenobarbital was not included in our protocol due to the prolonged time to onset of enzyme induction effects, adverse effects, and abuse potential.[1,19]
Further complicating the treatment of LAAR-induced coagulopathy is the lack of readily available laboratory assays to detect and quantify the degree of toxicity. The recent epidemic of LAAR-induced coagulopathy has been primarily due to brodifacoum-tainted synthetic marijuana. Only one reference laboratory in the United States offers a brodifacoum assay (NMS Laboratories; Willow Grove, PA), which is qualitative and takes several days to result. Although a readily available quantitative assay would be helpful for clinical management, an undetectable serum level does not exclude the possibility of brodifacoum toxicity. Due to the lipophilicity and resultant hepatic sequestration of brodifacoum, concentrations in the liver can remain significantly elevated in the setting of undetectable plasma concentrations.[1,20,23] Therefore, we included one patient with a negative serum brodifacoum level, with a clinical presentation and social history consistent with LAAR-induced coagulopathy. We also cannot exclude the possibility that this patient or other patients in our cohort may have been exposed to non-brodifacoum LAARs. In light of these challenges, awareness of the typical demographics and clinical presentations of patients with LAAR-induced coagulopathy is critical to ensure appropriate identification and treatment.
Outpatient management of LAAR-induced coagulopathy is particularly challenging due to the long half-life of these substances and requirement for prolonged treatment. To ensure appropriate transitions of care and longitudinal management of vitamin K dosing, we developed a referral program for LAAR-induced coagulopathy. With this model, patients were scheduled to see a clinical pharmacist in our hematology anticoagulation clinic after discharge. As with other reports, long-term management of this patient population proved challenging even with these arrangements. All patients were lost to follow-up during their outpatient course prior to completing an adequate course of treatment with vitamin K.
There are notable differences between the two published geographic case series of synthetic cannabinoid-induced coagulopathy.[25,26] Kelkar et al described a single tertiary care hospital's experience with managing 34 cases of LAAR-toxicity secondary to synthetic cannabinoid use. Most bleeding events were mild in both series, though the types of bleeding presentations differed slightly; intracerebral hemorrhage, bruising, melena, and menorrhagia were more frequent in the Illinois outbreak. Fewer patients in the Illinois cohort achieved an INR value below 2 within 24 hours of the first INR measurement than with our population, perhaps due to differences in treatment protocols.
Another recent case series published by Armstrong et al discusses the clinical course of 6 patients presenting with multi-organ failure from synthetic cannabinoids exposure. Psychological disturbance, acute kidney injury, severe rhabdomyolysis, compartment syndrome, shock, and liver failure were observed in this cohort, highlighting the wide variability in symptoms and severity after use of synthetic cannabinoids. In this case series, patients were not tested for brodifacoum and interventions to reduce LAAR-coagulopathy and resultant INRs were not described. While these findings were different from ours and the Illinois experience, future studies could consider correlation between LAAR toxicity, symptom type, and symptom severity when reporting outcomes.
Rapid reduction of INR is a clinical priority and therefore we recommend the more aggressive vitamin K dosing strategy utilized in our protocol, with careful de-escalation of dosing according to response. Because the physiology of LAAR-induced coagulopathy is similar to warfarin-induced coagulopathy, we feel it is reasonable to extrapolate from available data demonstrating superiority of PCC administration to FFP for life threatening warfarin-induced hemorrhage to the treatment of LAAR-induced life-threatening bleeding. We did not include recombinant factor VIIa as a treatment option in the Johns Hopkins protocol because of limited available data for this agent for warfarin reversal and high adverse event rates. Additionally, administration of recombinant factor VIIa may lower the INR in patients with LAAR-induced coagulopathy, but due to the short half-life, this effect is likely to be for limited duration, and does not address the underlying deficiency of other vitamin-K dependent clotting factors.
There are several limitations to this paper, the majority of which relate to the small sample size in this cohort. We cannot provide adjustment for comorbidities or analysis within bleeding types due to the small sample size.
Suspected LAAR exposure warrants an expedited approach to clinical assessment and treatment. This case series underscores the need for heightened awareness of this increasingly prevalent etiology for severe bleeding including ICH in emergency departments and system readiness. Targeted and expeditious public health education regarding avoidance of synthetic cannabinoids potentially contaminated with brodifacoum is essential. Health care providers should consider vitamin K-dependent coagulopathy in patients with unexplained bleeding and reported or suspected synthetic cannabinoid use. Geographic areas with increased prevalence of LAAR-induced coagulopathy should consider the development and implementation of a standardized treatment protocol. Although this protocol was developed because of an epidemic of coagulopathy associated with exposure to LAAR-contaminated cannabinoids, it would be appropriate to utilize this protocol for the management of other etiologies of brodifacoum toxicity. Utilization of the Johns Hopkins protocol for LAAR-induced coagulopathy resulted in adequate INR reduction within 24 hours of presentation in 75% of patients and only one fatality.
Conceptualization: Mona N. Bahouth, Peggy Kraus, Kathryn Dane, Holly Schmidlin, Satish Shanbhag.
Data curation: Kathryn Dane, Manuela Plazas Montana.
Formal analysis: Kathryn Dane, Manuela Plazas Montana, Jagar Jasem.
Investigation: Peggy Kraus, Kathryn Dane, Manuela Plazas Montana, William Tsao, Burton Tabaac, Jagar Jasem, Evan Einstein, Michael B. Streiff.
Methodology: Mona N. Bahouth, Satish Shanbhag.
Project administration: Manuela Plazas Montana.
Supervision: Peggy Kraus.
Validation: Mona N. Bahouth.
Writing – original draft: Mona N. Bahouth.
Writing – review & editing: Mona N. Bahouth, Peggy Kraus, Kathryn Dane, Manuela Plazas Montana, William Tsao, Burton Tabaac, Jagar Jasem, Holly Schmidlin, Evan Einstein, Michael B. Streiff, Satish Shanbhag.
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brodifacoum; coagulopathy; K2; long-acting anticoagulant rodenticides; synthetic cannabinoids; treatment algorithm; vitamin K
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