Severe Coagulopathy After a Massasauga Rattlesnake Bite

PRACTICE | CASES CPD

Severe coagulopathy after a massasauga rattlesnake bite

Marissa Laureano MD, Mark Crowther MD n Cite as: CMAJ 2018 February 20;190:E191-4. doi: 10.1503/cmaj.170783

healthy 25-year-old man was bitten by an eastern massasauga rattlesnake (Sistrurus catenatus; Figure 1) on his KEY POINTS left great toe. He had been walking outside at night in • Local injury, pain or swelling is concerning for envenomation open-toedA sandals in the Eastern Georgian Bay region of Ontario. after a rattlesnake bite. He developed lower leg edema, and pain and swelling around his • Monitoring for coagulopathies is required after massasauga great toe, but he delayed seeking medical treatment for 22 hours rattlesnake bites. (Figure 2A). • Antivenom is the first-line treatment for envenomation. On initial examination, the patient had a hemorrhagic bleb • Additional doses of antivenom may be needed; thus, close two puncture marks 1.5 cm apart on his great toe. A 12 cm × 6 cm monitoring is required. hematoma was also present inferior to his left groin. Initial blood work showed an international normalized ratio of greater than 12.5 (normal range 0.9–1.1), partial thromboplastin time of He was monitored in the intensive care unit and given an addi- greater than 180 (normal range 20–40) s and fibrinogen of less tional 10 vials of antivenom because of his ongoing pain, swelling than 0.6 (normal range 5.1–11.8) µmol/L. His hemoglobin level and coagulopathy. This was followed by maintenance dosing and platelet count were within normal limits. with 12 vials of antivenom over 18 hours as his symptoms and In accordance with the West Parry Sound Health Centre algo- coagulopathy began to improve. rithm for rattlesnake bites, he received one vial of Antivipmyn, The patient did not have any severe bleeding, and after 40 followed by an additional nine vials.1 (Test doses are given to hours, the local swelling and erythema had improved substan- allow monitoring for anaphylaxis.) His international normalized tially (Figure 2B). His international normalized ratio normalized ratio and partial thromboplastin time 3.5 hours after administra- to 1.1 and his partial thromboplastin time was 31 seconds (Box 1). tion of antivenom improved to 2.4 and 45 seconds, respectively. Aside from antivenom, additional treatment (blood products or vitamin K) was not administered. He was discharged after four days of monitoring, during which time he received a total of 32 vials of Antivipmyn.

Discussion

The only venomous snake in Ontario, the massasauga rattlesnake resides mainly in the Eastern Georgian Bay area and the Bruce Peninsula (Figure 3).2 The Committee on the Status of Endangered Wildlife in Canada (COSEWIC) considers the snake to be threatened and it is protected under federal and provincial laws. Rattlesnake bites are uncommon, but potentially devastat- ing. Envenomation can result in hemorrhage, increased vascular permeability, tissue necrosis and, in the worst-case scenario, death from shock.3 In a case reported by the Arizona Poison and Drug Information Center, a massasauga rattlesnake bit a 62-year-

Tim Vicekrs/Wikimedia Commons old man on the right thumb. That patient’s fibrinogen decreased Figure 1: The massasauga rattlesnake is characterized by its blotching to less than 1.47 µmol/L, but there were no other abnormalities pattern throughout its gray to dark brown body. Its head is triangular and in coagulation laboratory work. He did not have any bleeding its vertical pupils differentiate it from other snakes in Ontario. and his fibrinogen levels normalized over two months.4

© 2018 Joule Inc. or its licensors CMAJ | FEBRUARY 20, 2018 | VOLUME 190 | ISSUE 7 E191 PRACTICE lingering, unneutralizedvenom. also bedepositedasadepotatthesiteofbite,resultingin serine proteases. teinases, eastern massasaugavenomshowedthepresenceofmetallopro- snake venomiscomplex,andaproteomic-basedanalysisof E192 the bite.Bythistime,24vialsofantivenomhadbeenadministered. after thebite.Figure2Bshowssubstantialimprovementinpatient’s erythemaandedema40hoursafter and erythemaofthelowerleftleg.Theimagein(A)wastakenbefore treatmentwithantivenom,12hours Figure 2:A25-year-oldmanwithahemorrhagicbleblocatedonthelefthallux withconcomitantswelling closed-toed bootsorshoeswhenhikinginareaswithrattle- To preventrattlesnakebites,itisimportanttowearankle-height, Management ofrattlesnakebites overactivation andfibrinogendegradation. with plateletdysfunction,vesselwallbreakdown,prothrombin of thehemostaticsystem,andsnakebiteshavebeenassociated Venom-related coagulopathycanaffectalmostanycomponent Pathophysiology venom. Themechanismisnotclearlyunderstood,butit subsequent reappearanceofthevenom’seffects. thought tobearesultoftheclearanceantivenomand †PTT normalrange 20–40s. *INR normalrange 0.9–1.1. Note: INR=international normalized ratio, PTT =partial thromboplastin time. administered No. Antivipmynvials PTT, s† INR* Time after bite, h Box 1:Results of thepatient’s coagulation laboratory testing over time Coagulopathy canrecurafterinitialtreatmentwithanti

L -amino acidoxidase,phospholipaseA2enzymesand 7 8 25241513121.1 1.2 1.3 1.5 2.4 > 12.5 oe1 02 832 28 24 20 10 None 8 53 63 31 33 26 37 45 > 180 22. 053. 3553.5 43.5 35.5 30.5 25.5 22 CMAJ | FEBRUARY 20, 2018 5,6 Thenatureof 8 Venomcan

| removed. Tetanusboostersshouldbegivenforprophylaxis. bility ofswelling,accessoriessuchasringsorwatchesshouldbe at venomremovalshouldbeavoidedand,becauseofthepossi- ics inthetreatmentofrattlesnakebites. Unless a wound infection is present, there is no role for antibiot- likely topenetrateleatherhikingbootsorlooseclothing. snakes. Themassasaugahasrelativelysmallfangs,whicharenot (± standarddeviation52.53)h ment producedinhorses.Ithasarelativelylonghalf-lifeof133 rotated through multiple facilities including municipal zoos, The envenomation canbetreatedwithAntivipmyn,aF(ab′) of snakesthatincludesrattlesnakes).Massasaugarattlesnake cious treatment for viper envenomation (pit vipers are a family in aboutone-thirdtoone-halfofpatients. lopathy hasbeenreportedaftertreatmentwithFabantivenom envenomation comparedwithotherproducts.Recurrentcoagu- way, breathingandcirculation. VOLUME 190 Antibodies tosnakevenoms(antivenom)arethemosteffica- Initial firstaidshouldfocusonsupportingthepatient’sair- | ISSUE 7

is present. should begivenwhenlocalinjury development ofcoagulopathy ation. there are no signs of envenom - charge fromhospitaltoensure should berepeatedbeforedis- assessment. Thesebloodtests should bemeasuredattheinitial ulation parametersandfibrinogen, delayed. signs of envenomation can be hours, and ideally 24 hours, as tored inhospitalforatleast8 patients shouldbecarefullymoni- ing acompletebloodcount,coag- taken andlaboratorywork,includ- limb circumferenceshouldbe require antivenom; about 25%ofbitesanddonot injected. “Drybites”comprise meaning that novenom was tory workmayhavea“drybite,” or abnormalitiesintheirlabora- provision ofantivenom. treatment andcanfacilitatethe can providedirectionregarding tlesnake envenomation,asthey centres shouldbeinvolvedforrat- the WestParrySoundHealth are knowntoreside.InOntario, where massasaugarattlesnakes Toronto and hospitals near areas Hospital forSickChildrenin venom Centre actsastheprovincialanti 10 11 Patients withoutpain,swelling Tourniquets,iceandattempts andreducedriskofrebound 14 depot. Local poison control Careful attention to the 14 9 Serialmeasurementsof 12,13 Antivenomis 10 1,9 these 2 frag- 1

PRACTICE

E193 95. . Species 801. 189- 103. 37: 93- 795- Crit Rev Toxicol 35: 20: 2001; 2009; 1991; 97. 383- Adapted from “Recovery 72: 21. 21. Available: www.wpshc.com/ Ann Emerg Med ; 2011; Ann Emerg Med 2011

Semin Thromb Hemost J Mol Evol

Deconstructing a complex molecular phenotype: pop- Venomous snakebites in the United States: manage- JE. Recurrence phenomena after immunoglobulin therapy for Effects of snake venoms on hemostasis. JG. Snake venom coagulopathy: use and abuse of blood products . LV. RC. ISSUE 7 ISSUE | , Chiucchi , 82. Procoagulant snake toxins: laboratory studies diagnosis, and under- Antivipmyn treatment package for eastern massasauga rattlesnake Antivipmyn treatment package for eastern massasauga rattlesnake H , Hancox T. 171- JL, Dart

GK. G , Stocker K

SA, Boyer

J 21: Lisle Gibbs Seifert 1991; Meier ment review and update. Am Fam Physician 2002;65:1367-74. Burgess Isbister rat- massasauga eastern in proteins venom individual in variation ulation-level tlesnakes (Sistrurus c. catenatus). snake envenomations: Part 1. Pharmacokinetics and pharmacodynamics of immunoglobulin antivenoms and related antibodies. in the treatment of pit viper envenomation. index.php/ontario-antivenom-depot-117 (accessed 2017 May 31). Recovery strategy for the massasauga (Sistrurus catenatus) in Canada Risk Act Recovery Strategy Series. Ottawa: Parks Canada Agency; 2012. Juckett standing snakebite coagulopathy. Fargher Massa- Ontario The Centre, Health Sound Parry West (ON): Sound Parry bites. Depot Antivenom Rattlesnake sauga

...... 2 3 1 7 6 5 8 4 VOLUME 190 VOLUME

References . |

1 To 1 1 FEBRUARY 20, 2018 FEBRUARY | CMAJ As symptoms and labora- 1 14 Upon discharge, patients should be counselled regarding rea- Antivenom should be administered to patients with signs and Antivenom should be administered to patients sons to seek medical attention. They should return to an emer- to return attention. They should seek medical sons to gency department if they have bleeding, worsening pain, swelling or signs of infection. Patients should avoid contact sports, elective surgery and dental work for two weeks after the bite. symptoms of envenomation. Therapy with antivenom should be antivenom Therapy with of envenomation. symptoms titrated to the patient’s pain, swelling and laboratory values. Laboratory work including a complete blood count, electrolytes, creatinine, urea, glucose, creatine kinase, international normal- transaminase alanine and transaminase aspartate ratio, ized should be measured two hours after each dose of antivenom.

Peninsula, Wainfleet Bog and Ojibway Prairie Complex. The patient in this case was bitten in the Eastern Georgian Bay area. Peninsula, Wainfleet Bog and Ojibway Prairie Complex. ) in Canada,” Parks Canada Agency, 2015. Strategy for the massasauga (Sistrurus Catenatus , Bruce , Bruce in Ontario. Four major areas have been highlighted: Eastern Georgian Bay Figure 3: Geographic distribution of the massasauga rattlesnake tory values improve, maintenance dosing of antivenom can be tory values improve, maintenance dosing of antivenom can be given and the frequency of bloodwork can be decreased. Persistent pain or swelling, thrombocytopenia and coagulopathy Persistent pain or swelling, thrombocytopenia are indications for further treatment. assess for late coagulopathy, a follow-up visit with bloodwork assess for late coagulopathy, a follow-up visit with bloodwork should be scheduled two to three days and five to seven days after discharge. PRACTICE E194 12. 10. 11. 9 .

tion ofCanada,LEOPharmaandBayerfor projects fromtheHeartandStrokeFounda- care) have received funding for research (McMaster UniversityandStJoseph’sHealth- search employees).Hisinstitutions which is used to support the salary of re search atMcMasterUniversity(incomefrom Pharma ChairinThromboembolismRe- Foundation of Ontario; and held the LEO vestigator awardfromtheHeartandStroke Bayer andLEOPharma;receivedaCareerIn- for projectsinvolvingAKPAmerica,Daiichi, mittees, orotherresearch-relatedactivities Portola; participatedinstudysteeringcom- Ingelheim, Janssen,Pfizer,LEOPharmaand boards forOctapharma,Bayer,Boehringer months, MarkCrowtherhassatonadvisory Competing interests:Withinthelast48 tion, firstaid,andclinicalmanagement. Junghanss Boyer in healthyhumanvolunteers. Gold lowing pitviperenvenomation.ArchInternMed1999;159:706-10. Garza-Ocanas

BS, Dart LV, Seifert SA, Clark RF, Clark SA, Seifert LV, T M Bodio , RC, Barish L , Alagon A . RA. Medically importantvenomousanimals:biology,preven- , E Tamez delaO Bites ofvenomoussnakes. Toxicol Lett et al. Recurrent andpersistentcoagulopathyfol- Clin InfectDis 2011; , Pharmacokinetic of Antivipmyn et al.PharmacokineticofAntivipmyn 205( CMAJ - Suppl):S87. N EnglJMed 2006; | (Laureano), andPathologyMolecular Affiliations: DepartmentsofMedicine The authorshaveobtainedpatientconsent. This articlehasbeenpeerreviewed. interests weredeclared. dentiality arrangements.Noothercompeting and thattheseactivitiesareboundbyconfi- or otheraspectsofhematologicalpractice, relating tothrombosis,anticoagulantdrugs, participated invariousmedicolegalactivities Bayer, Celgene,ShireandCSLBehring, BMS-Pfizer Alliance, LEO Pharma, AbbVie, from Alexion,OrthoClinicalDiagnostics,the educational materialsandpresentations has alsoreceivedfundingforpreparationof work in which Mark Crowther is involved. He FEBRUARY 20, 2018 43: 1309- 2002; 17. 347: 347 - 56. | 14. 13. VOLUME 190

Lavonas venom forpitviperenvenomation:aprospective,blinded,multicenter,ran domized clinicaltrial.ClinToxicol(Phila)2015;53:37-45. Bush informed consensusworkshop. agement ofcrotalinesnakebiteintheUnitedStates:resultsanevidence- Denver HealthandHospitalAuthority.

SP, Ruha SP,

EJ, Ruha EJ, | ISSUE 7 A-M, Seifert A-M, W Banner A-M,

[email protected] Correspondence to:MarissaLaureano, massasauga rattlesnakebites. and expertiseontheuseofAntivipmynfor Dr. TerenceFargher,whoprovidedinsightinto Acknowledgement: Theauthorsthank the work. agreed tobeaccountableforallaspectsof approval oftheversiontobepublishedand important intellectualcontent,gavefinal drafted themanuscript,reviseditcriticallyfor the conceptionanddesignofwork, Contributors: Bothauthorscontributedto ilton, Ont. Health Sciences,McMasterUniversity,Ham- Medicine (Laureano,Crowther),Facultyof

SA, BMC EmergMed , et al. et al.; Unified treatmentalgorithmfortheman- Rocky Mountain Poison and Drug Center, Rocky Mountain Poison and Drug Center, Comparison ofF(ab’) 2011; 11:2. 2 versusFabanti -