[ ISSN : 2573-3680 ]
Brodifacoum Toxicity; Coagulopathy; Synthetic Cannabinoids; Long Acting Warfarin; Rat Poison
A recent cluster of patients presenting with idiopathic, severe, coagulopathy was reported in Illinois and traced to contaminated cannabinoids. The contaminating substance was determined to be brodifacoum, a potent, long acting, rodenticide that inhibits vitamin K dependent clotting factor production. Since the original reports from the Midwest, multiple additional cases have been reported in at least 11 states. Brodifacoum toxicity has now reached the proportions of a public health crisis. Patients can present with bruising, epistaxis, oropharyngeal and gum bleeding, excessive menstrual bleeding, hematemesis, hematuria, flank pain, or abdominal pain mimicking an acute abdomen. We present a case of brodifacoum toxicity that was rapidly reversed with parenteral Vitamin K and K-centra, four factor clotting concentrate. The use of intermittent prothrombin complex concentrates has the ability to control life threatening hemorrhage and is a potential important adjunctive treatment to minimize use of large doses of vitamin K.
Case history
A 54 year old male in good health except for treated hypertension and remote history of nephrolithiasis. One week prior to admission he developed flu like illness with epigastric discomfort then intermittent nausea and vomiting. He denied fever, chills, hematemesis, hematochezia, melena, or diarrhea. He had mild polymyalgias. He took an over the counter antiemetic, emetrol. On day 4 he began to experience bilateral flank pain radiating to the groin then sudden onset of gross hematuria. He saw his primary care physician on day 6. Urine is positive for blood and bacteria. Hemoglobin 11.7 gm.
Cipro prescribed for presumed urinary tract infection vs prostatitis. Over the next 4 days, he developed profound weakness, orthostatic dizziness, a pounding sensation in his chest, lower extremity swelling, and spontaneous, non traumatic bruising. Past Medical History: Hypertension on Amlodipine 10 mg, renal stones, no surgery except laser treatment of central serous retinopathy. No history of peptic ulcer disease, hepatitis, yellow jaundice, malaria, mononucleosis, or inflammatory arthritis.
Allergy: penicillin as a child: desquamation of skin of hands and feet Family History: Parents and one female sibling healthy. No family history of bleeding disorders. Social History: Divorced. Works in a sheet metal factory. 2 healthy adult children.
Stopped smoking cigarettes in 1999. Drinks 6 beers daily. Denied drug use including cocaine, marijuana, and synthetic marijuana derivatives. Review of Systems: No headache or change in vision except for recent blurred vision when he stood up. Positive intermittent gum bleeding.
Well nourished Caucasian man in no distress. BP 108/52 pulse107 regular respiration 16 Temperature 98.3
HEENT:large port wine birthmark right neck and face. No mass, exudate, ulcer, hemorrhage in oropharynx.
No cervical, supraclavicular, axillary, or inguinal adenopathy Lungs clear to auscultation and resonant to percussion Regular cardiac rhythm; no murmur, gallop, or rub Abdomen soft, non tender, no mass, no organomegaly,
Genito-urinary: no flank tenderness; circumcised penis, no exudate
Extremities: 2+ pedal edema
Vascular: carotid pulses 2+, no bruits; dorsalis pedis pulses 2+ symmetric; no cyanosis
Neurologic: awake, alert, oriented x 3; cranial nerves grossly normal, motor strength 5/5, reflexes 2+ symmetric at biceps & patellae. Upper body coordination normal. Fundi: optic discs sharp, no hemorrhage or exudate
Skin: diffuse petecchial rash lower extremities. Multiple areas of soft tissue ecchymoses at recent venipuncture site, medial thighs bilaterally, soft tissue of calves extending to dorsum of foot on the left, and down to the heel (Figure 1).
Figure 1: Extensive soft tissue hematomas and ecchymoses.
Initial lab
Hemoglobin 5.3, Hematocrit 14.7, WBC 5,400, 72% neutrophils, 15 lymphocytes, 12 monocytes, Platelets 205,000, uncorrected reticulocyte count 1.6%.
Prothrombin time: >90 seconds, INR>10; PTT: >200 seconds Na 130, glucose 139, BUN 17, creatinine 1.2 AST 15, ALT 12, bilirubin 0.7, 0.2 direct, LDH 123, Total Protein 4.9, Albumin 3.0, calcium 8.5.
Urine: yellow, clear, large positive hemoglobin, 0-5 RBCs, 0-5 WBCs, negative protein, negative nitrite.
Imaging: non-contrast CT abdomen and pelvis with renal stone protocol showed extensive blood in retroperitoneum and renal collecting system (Figure 2).
Figure 2: (a) CT abdomen and pelvis: hemorrhage into the renal collecting system. (b) CT abdomen and pelvis: Extensive hemorrhage throughout the bilateral retro and extra peritoneal spaces.
Fibrinogen 503 mg%; d-dimer 1.0 (lab normal up to 0.48), COOMB’s direct antiglobulin test negative; Haptoglobin 217 Review of peripheral blood film: normochromic normocytic red cells, no spherocytes, schistocytes, polychromasia or inclusions, mature neutrophils, no toxic granulations, no early myeloid forms, mature lymphocytes, some of the monocytes appeared immature but not blastic, platelets normal in number and morphology.
Clinical course
PT/PTT repeated to exclude lab error and was reproducibly abnormal.
Sample sent to University hospital lab for plasma mixing studies and factor VIII level to rule out factor deficiency vs inhibitor to coagulation.
itamin K 10 mg IV administered. K-Centra 4 factor prothrombin complex concentrate given 25 units/kg.
Red cell transfusion given.
Repeat coagulation tests about 2 hours after K-centra showed near complete correction consistent with factor deficiency subsequently confirmed by plasma mixing studies and a factor VII level of 2% of control. Oral vitamin K continued daily. In less than 24 hours following K-centra, PT & PTT were rising and hemoglobin falling.
Additional K-centra and transfusions given hospital day 4. A thrombin time was done to exclude dysfibrinogenemia and was normal.
Factor VII returned at 2%; factor II,44%(50-154); factor V, 112% (70-150); factor X, 51%; factor VIII 310% (80-150).
On hospital day 5, patient again confronted re use of synthetic cannabinoid products which he denied on admission interview and now admitted to use on day before and day of appearance of his initial GI symptoms. Diagnosis was confirmed by a brodifacoum drug level of 27.1 microgram/ml sent to the Wisconsin State Laboratory of Hygiene, U of Wisconsin, Madison, WI. Daily vitamin K, 10 mg was continued.
Serial PT/INR and factor VII lab testing done. PT/INR normalized by day 28 after ingestion. The patient was kept on 10 mg of Vitamin K daily. On day 8 there was stabilization of his PT/INR at 22.9 seconds, INR 2.0. A factor VII level was up to 21%. By day 15, there was further improvement with PT/INR nearly normal and a concomitant factor VII level of 34%.
Vitamin K is an essential cofactor for the enzyme gamma glutamyl carboxylase. Carboxylation of glutamate residues on a number of proteins, most importantly, some of the coagulation factors, results in their activation. Vitamin K antagonists inhibit the synthesis of Vitamin K dependent clotting factors II, VII, IX, and X. Their anticoagulant effect is due to interference in the cyclic conversion of Vitamin K 2,3-epoxide back to the reduced form of Vitamin K by Vitamin K epoxide reductase (VKOR). Partially carboxylated and decarboxylated proteins have reduced procoagulant activity. In 1940, Dicoumarol was shown to be the agent in sweet clover that induced hemorrhage in cattle. Warfarin, 4-hydroxy3(3-oxo-1-phenylbutyl) coumarin was developed as a more potent anticoagulant and initially used as a rodenticide until 1954 when it was approved for use as an anticoagulant in humans. Superwarfarins are chemically modified forms of warfarin developed when resistance to warfarin began to develop in rodents. Two derivatives with the highest toxicity are difenacoum and brodifacoum. Brodifacoum was found to be highly lethal in rats and other animals. It is estimated that a 15 mg amount would be lethal for a 60 kilogram human. In addition to being 100 times more potent in inhibiting vitamin K dependent clotting factors, with a tenfold higher affinity for the VKORC enzyme system, the addition of substituted phenyl rings significantly increases their hydrophobicity leading to enhanced tissue accumulation and retention and a prolonged half life of 30 days or greater compared with 36-42 hours for warfarin. This compound can stay in the system for months. The increased hydrophobicity is also felt to be associated with coagulant independent toxicities related to changes in capillary permeability and morphology. This may be particularly important with respect to nephrotoxicity and may result in glomerular hemorrhage, red cell cast formation and acute kidney injury. Accidental and intentional brodifacoum toxicity has been reported in thousands of people. One estimate is over 16,000 cases per year in the United States alone. Diffuse, multisystem bleeding is the common presenting manifestation including mucocutaneous sites, gastrointestinal, spontaneous hematomas, soft tissue and intramuscular hemorrhage, and rarely, intracranial bleeding [1-9].
On March 8, 2018, a cluster of cases of unexplained severe coagulopathy were reported in Illinois. (10,11,12).They were traced to synthetic cannabinoids found to be laced with brodifacoum. It is not certain whether the brodifacoum was added to enhance the euphoric effects of the cannabinoid or just purely for malicious reasons. The cannabinoid component is not detected on routine urine drug screening. These cannabinoids are not federally regulated and can be bought over the counter. A number of synthetic cannabinoids have been marketed under various names including K2, spice, yellow giant, black giant, and blue giant. They are usually sprinkled on herbal material and smoked but can also be obtained in a liquid form [10-13]. This patient purchased the material in a local Quickstop convenience store. This was the third reported case in North Carolina.
The same week that this patient was admitted to the hospital, the FDA issued a warning statement on July 19, 2018 [14]. This followed an initial clinical alert from the CDC posted on April 23. Since the initial reports, additional cases, now numbering over 150, have been reported in multiple states with at least 8 deaths. The North Carolina Department of Health and Human Services issued an alert for our state on 7/31/18 [15].
Brodifacoum contaminated cannabinoids present a major health hazard which can lead to prolonged coagulopathy and death. In some instances up to 100 mg of Vitamin K daily for weeks to months has been necessary to sustain clotting factor production. The average price of 5 mg of Vitamin K is approximately $70. One estimate of a 2 week course of treatment is $8,000 [10,11].
Although Brodifacoum inhibits the same vitamin K dependent clotting factors as warfarin and can be reversed with Vitamin K [16- 18], vitamin K may take a number of hours to reach its full effect and require repetitive, large doses, particularly when being used to reverse a long acting warfarin derivative. Prolonged use and high volumes of fresh frozen plasma are impractical. A four factor Prothrombin Complex concentrate (PCC) with increased levels of factor VII compared with previous PCCs became available in 2013 and has the capacity to rapidly reverse warfarin toxicity [19,20]. The availability of K-centra presents an important adjunct to Vitamin K therapy for the rapid reversal of severe warfarin related coagulopathy and is now the recommended product of choice per 2016 CHEST guidelines [21]. Optimal dosing is not established. Preliminary data suggests lower doses may be as effective as higher doses. We are looking at this prospectively at our institution. We chose a low dose regimen of 25 units per kilogram which proved to be highly effective and was only repeated one additional time.
A 54 year old man presented with acute soft tissue, genitourinary tract, and retroperitoneal bleeding. Prothrombin and Partial thromboplastin times were markedly elevated. Coagulopathy was rapidly and completed reversed with the initial use of both vitamin K and K-Centra four factor clotting concentrate then maintained with oral Vitamin K. Brodifacoum toxicity was suspected and subsequently confirmed.
This case illustrates the importance of a high clinical level of suspicion and prompt evaluation of an unexplained coagulopathy in persons who may have ingested a brodifacoum contaminated cannabinoid product and extends the use of K-centra 4 factor clotting concentrate as a rapid, although temporary, antidote when faced with life threatening hemorrhage.
9. Sharma P, Bently P. Of rats and men: superwarfarin toxicity. Lancet. 2005; 365: 552-553.
17. Thigpen JL, Limdi NA. Reversal of oral anticoagulation. Pharmacotherapy. 2013; 33: 1199-1213.
Granfortuna J. Brodifacoum Coagulopathy from Tainted Synthetic Cannabinoids. SM J Clin Med. 2018; 4(3): 1038.
The purpose of this statement is none other than to highlight the importance of ethical standards and quality required in basic and applied research currently being done so we can subsequently inform health care professionals of new developments that are taking place in this area.
Ma. Esperanza Rodríguez-van Lier*
Chemotherapy is commonly used in cancer treatment. So far, chemotherapy agents can be categorized into three types: classical chemotherapeutic drugs, molecular target agents and cellular machineries target drugs.
Ziyou Wang1,2 and Zunnan Huang1,2*
Blood transfusion can cause some transfusion adverse reactions. In order to understand the incidence of adverse transfusion reactions, we performed a meta-analysis in Chinese hospitals. Of 809 literatures, seven studies involving a total of 211, 050 patients with blood transfusion treatment were included in this meta-analysis. Meta-analysis showed that the total incidence of adverse reactions was 0.4% [95% CI (0.2, 0.9), P < 0.0001]. Further subgroup analysis showed that the incidence of febrile and allergic reactions was 0.2% [95% CI (0.1, 0.5), P < 0.0001] and 0.2% [95% CI (0.1, 0.3), P < 0.0001], respectively. The common blood components caused adverse reactions were red blood cell, plasama, and platelet in clinical practice.
Yulu Gao1 , Qinyun Li2 , Zongshuai Gao2 , Yunxia Zhu4 , Yanqiu Liao5 , Changtai Zhu2 *# , Yongning Sun3 *#
Background: CT scanning remains one of the most routinely used diagnostic tools in a setting of Interstitial Lung Disease (ILD). New and improved technologies, such as High Resolution Computer Tomography (HRCT) have revolutionized the quality of imaging, leading to a prominent increase in number of incidental findings that may or may not be of any clinical significance. The aim of this study was to evaluate the prevalence of incidental findings on thoracic CT and their clinical significance.
Methods: Retrospective analysis was conducted on a cohort of 84 patients referred to our academic center as cases of ILD. Patients were referred for further evaluation between January 2000 and January 2014 and were followed over the disease course. CT scans were done annually as part of clinical management and patients were screened for any incidental findings. All incidental findings were reviewed, recorded in a clinical database and followed up on subsequent visits.
Results: 25 (30%) patients were found to have incidental findings. Liver abnormalities were found in 12 (14.29 %) patients. 11(13.10 %) patients were reported to have coronary artery calcifications. 5 (5.95 %) and 3 (3.57%) patients had thyroid abnormalities and renal cysts, respectively. A malignant lesion was found in 1 patient each in liver and thyroid abnormality subgroup.
Conclusion: Incidental findings are common on thoracic CT scans providing valuable and unexpected findings which warrant investigation by health care providers to exclude malignant processes.
Sonu Sahni1,2*, Sameer Verma1,2, Reeju S Thomas1 , Barbara Capozzi3 and Arunabh Talwar1,2
Hepatitis C Virus infection (HCV) is an increasing public health concern with an estimated 184 million people infected worldwide and approximately 350.000 yearly deaths from HCV-related complications.
Nesrine Gamal and Pietro Andreone*
We report a case of large cell undifferentiated lung carcinoma in a middle aged patient with previously treated tuberculosis and scarring. 20 pack years of smoking history was noted. He presented with metastasis at multiple sites including trochanter, liver and acute bilateral lateral rectus palsy. Chest radiography showed fibrosis of right upper zone with homogenous opacity. Sputum examination for AFB was negative. Computerized tomography of the thorax showed an irregular heterogeneously enhancing mass involving right upper lobe with cavitation, necrosis along with lymph node involvement and the erosion of the 4th rib with liver metastasis. Radiography of hip joint was suggestive of lesser trochanteric metastasis. MRI brain was suggestive of mass at base of brain in parasellar area. Fine needle aspiration cytology and CT guided biopsy confirmed undifferentiated large cell carcinoma of lung. Tuberculosis and smoking may increase the risk of lung scarring and malignancy and pulmonary scarring may be associated with increased lung carcinoma in ipsilateral lung. Clinician needs to be more sensitive to look for malignancy association particularly in patient with or previously treated for tuberculosis and even more emphasis to be laid if scarring of lung is observed.
Sreenivasa Rao Sudulagunta1 *, Shyamala Krishnaswamy Kothandapani2 , Mahesh Babu Sodalagunta3 , Hadi Khorram2 , Mona Sepehrar4 and Zahra Noroozpour1
Systemic Sclerosis (SSc) is a connective tissue disease characterized by fibrosis of the skin and internal organs, pronounced alterations in the microvasculature and frequent cellular and humoral immunity abnormalities. The rheumatic involvement of SSc is polymorphic and can reveal the disease or may appear during the course of its progression. Musculoskeletal involvement is dominated by non specific arthralgia, polyarthritis, and bony resorption especially acro-osteolysis. The diagnosis of these rheumatic manifestations is generally based on x rays examination. Musculoskeletal involvement in SSc is generally relieved with Non Steroidal Anti-Inflammatory Drugs (NSAID) or low dose of corticotherapy. The immunosuppressive therapy is used in corticoid-resistant or corticoid-dependent forms such us méthotrexate. The aim of our review is to presents an overview of the different osteoarticular and muscular involvement in SSc, their diagnosis and management.
Nessrine Akasbi*, Fatima Ezzahra Abourazzak and Taoufik Harzy
Sedigheh Mirhashemi1 , Mohammad Hosein Kalantar Motamedi1 *, Amir Hossein Mirhashemi2 and Hamid Reza Rasouli1
We encountered two autopsy cases of huge cardiomegaly with over 1000g in weight. Histochemical characteristics were examined using conventional staining including HE and Azan stains and immunohistochemical staining using antibodies against Complement Component 9 (CC9), RNA Binding Protein Motif 3(RBM3), Endothelial Type NO Synthase (eNOS) and Hypoxic Inducible Factor1α (HIF1). The reactive area with anti CC9 antibody, which presumed to be a marker of hypoxic change of myocardium, overlapped with eosinophilic area by HE and basophilic one by Azan. Although the reactive area with anti CC9 antibody showed relatively weak in the cytoplasm by anti eNOS antibody and no in the nucleus of cardiocytes with anti RBM3 antibody, outside of the reactive area with anti CC9 antibody there were intensive reactivity with anti eNOS antibody in cytoplasm and in a nucleus with anti RBM3 antibody. Anti HIF1 antibody showed weak reactivity with cytoplasm of endocardial cardiocytes and no with cytoplasm of cardiocytes in another area. The results obtained from the present cases revealed that the hypoxic change was equivalent even though the cause of cardiomegaly was deferred between two cases, and conventional staining such as HE and Azan utilized to detect hypoxic change in the heart and immunohistochemical studies seemed to be a useful tool for clarifying the cascade of hypoxic changes in the myocardium.
Satoshi Furukawa1,2*, Mayumi Kataoka1 , Satomu Morita1,2, Akari Uno2 , Masahito Hitosugi2 , Hiroshi Matsumoto1,3 and Katsuji Nishi1,2
A 45-year-old woman with multiple sclerosis was admitted to our hospital after out of hospital cardio-pulmonary resuscitation. The first ECG showed ventricular fibrillation. Following direct current defibrillation and mechanical reanimation, spontaneous circulation was restored and the ECG unremarkable without any signs of ischemia. Coronary angiography showed unobstructed coronary arteries Figure 1, (Panel A). Left ventriculography revealed apical wall obstruction, suggestive of apical aneurysm (Panel B, supplementary videos). Transthoracic echocardiography and Cardiac Magnetic Resonance Imaging (CMR) eventually lead to the diagnosis of a rare case of Apical Hypertrophic Cardiomyopathy (AHC) with ace of spades-form (Panel C,D). The patient underwent Cardioverter-Defibrillator Implantation (ICD) and amiodarone medical therapy for secondary prophylaxis. Patient’s family history and screening for HCM were unsuspicious.
Wiedemann S# *, Heidrich FM# , Speiser U and Strasser RH