Snakebite-induced Coagulopathy
Ponlapat Rojnuckarin, MD, PhD Chulalongkorn University Elapid Viper Neurotoxin Hematotoxin
Un-clotted blood Russell’s viper (Daboia siamensis)
Rojnuckarin p Malayan Pit Viper (Calloselasma rhodostoma)
Rojnuckarin p Green Pit Vipers in Bangkok
Trimeresurus albolabris Trimeresurus macrops
Rojnuckarin p Symptoms & signs of viper bites
Local Systemic: –Systemic bleeding –Hemolysis –Renal failure Teeth Marks Fang Marks
Non-venomous snake Venomous snake Mahasandana S Local effects I
Ecchymosis
Edema Mahasandana S Local effects II
Blister Necrosis
Mahasandana S Clinical syndromes 1. Consumptive coagulopathy Factor X/V activators: True vipers (Daboia russelli) Prothrombin activators: True vipers (Echis sp.), Australian elapids (Pseudonaja sp, Oxyurenus sp, Notechis sp), Colubrids (Rhabdophis sp.) Thrombin-like enzymes: most pit vipers 2. Anticoagulant syndrome: Australian elapids (Pseudoechis sp, Acanthophis sp., Austrelaps sp) 3. Thromboembolism: Bothrops lanceolatus, B. caribbaeus 4. Thrombotic microangiopathy: Doaboia russelli, Cerastes cerastes, Protheris superciliaris, Pseudonaja sp, Dispholidus typhus
Rojnuckarin P. Toxins and Hemostasis: from Bench to Bedside 2010. Clotting factor activators
Extrinsic Tenase TF FVIIa
FIXa FVIIIa Intrinsic Tenase
Prothrombinase Factor X Factor V activators FXa FVa activators PLASMINOGEN
Plasminogen activators PROTHROMBIN THROMBIN Prothrombin PLASMIN activators
Fibrinogenolysis FIBRINOGEN FIBRIN FDP Thrombin-like enzymes Rojnuckarin P. Toxins and Hemostasis: from Bench to Bedside 2010. Snake venoms activate the common pathway of coagulation.
Russell’s viper
Russell’s viper Pit vipers Red-necked Keelback Thrombin-like enzymes
Fibrinopeptide A Fibrinopeptide B Fibrinogen
Thrombin D E D
D E D
D E D D E D D E D
Firm clot Thrombin-like enzymes
Fibrinogen Fibrinopeptide A
D E D Thrombin- like
D E D
D E D Mitrakul C, et al D E D D E D Am J Clin Path 1973 Friable clot Fibrinolysis Green pit viper bites (N = 46)
Rojnuckarin et al. Toxicon 1999; 37: 743. Fibrinogenolysis
Fibrinopeptide A Fibrinogenolysis Fibrinogen
D E D Thrombin- like
D E D D E D
D E D
D E D D E D Friable clot Fibrinolysis Fibrinolytic activation t-PA release Fibrin deposition
PAI-1 Plasminogen Plasmin
Venom Plasminogen Activator alborhagin Alboagg B Activators Alboagg A Gp VI Gp Ib/IX/V
GpIIb/IIIa albolabrin Inhibitor Systemic bleeding from viper bites
Hypofibrinogenemia – Thrombin-like enzymes clot fibrinogen in vitro – Activation of fibrinolysis in vivo – Defibrination syndrome Thrombocytopenia – Platelet activation and agglutination in vitro – Activated platelets are cleared from circulation. Metalloproteases damage vessel wall
Toxicon 1999; 37: 743, Toxicon 2005; 45: 977 Laboratory
– Thrombocytopenia – Hypofibrinogenemia causing prolonged Whole blood clotting time, thrombin time and prothrombin time – Elevated fibrin degradation products (FDPs): Usually not tested Whole blood clotting time
Sribunruang S Partially clotted may be mistaken as un-clotted VCT.
Slow recovery of fibrinogen (HL 4 days) Venous clotting time (VCT)
Available in community hospitals
Therapeutic laboratory – Not too sensitive – Require antivenom, if prolonged
WHO recommends 20 min WBCT – One tube and tilted only once at 20 min Prothrombin time
Automated and Better standardized Study in Green pit viper bite (N=97) Fibrinogen < 100 mg/dL (Gold standard) Sensitivity Specificity INR>1.2 85.7% 95.6% WBCT 20 85.7% 95.8% (N=55) VCT> 30 57.0% 94.4%
Pongpit and Limpawittayakul, et al. TRSTMH 2012; 106; 415 20min WBCT is not sensitive in Russell viper bites
•Compared with INR > 1.5 •WBCT has only 40% sensitivity Sensitive to fibrinogen •INR prolongation due to Common pathway defects? •PT is better than WBCT.
Isbister GK et al. QJM 2013 20min WBCT done by trained personnel is still not sensitive.
•RV and Hump nose viper •N = 987 •8% Coagulopathy •Compared with INR > 1.4 •WBCT had 82% sensitivity 98% specificity
Thromb Haemost 2017; 117: 500 POC-INR is not useful in Australian snakebites (N = 15).
False Negative
False Positive
3 = Afibrinogenemia Thromb Res 2013; 132: 610 Slow Onset of Toxicity (n=213)
54.9% 84% 94.4% 95.8% 98.6% 100% 120 100 80 >90% 60 within 3 days 40 20 0
24 48 72 96 120 144 Hours
Rojnuckarin P, et al. J Hematology Trans Med 1996 GPV venom kinetics (Individual patients, n = 27) ng/ml Rojnuckarin & Bunchongkit Trop Doct 2007; 37: 207 18 16 14 Long half life 12 Some Detectable venom on d14 Wait for spontaneous recovery: Not recommended 10 8 6
Venom4 levels 2 0 0 1 2 3 4 5 6 7 8 Tim e after bites ( d a y ) SYSTEMIC BLEEDING (GPV; n=37)
GUM HEMATEMESIS HEMATURIA PETECHIAE HEMOPTYSIS PER VAGINA MELENA HEMATOCHEZIA SUBCONJUNCTIVA EPISTAXIS Multiple sites 54.1% Rojnuckarin P, et al. Thai J Hematology Trans Med 1996 Hemolysis in Russell’s viper bites from Phospholipases
J Nat toxins 1998; 7: 73-85, Toxin and Hemostasis 2010 Russell’s viper venom: Nephrotoxicity
Decreased renal blood flow (hypotension, renal vasoconstriction) Thamaree, et al. Nephron 1994;67:209 Tungthanathanich, et al. Toxicon 1986;24:365 Thamaree, et al. J Nat Toxins 2000;9:43 Microthrombi in glomerulus Suntravat et al. Toxicon 2011; 58: 230 Direct nephrotoxicity Ratcliffe, et al. Am J Trop Med Hyg 1989;40:312 Interstitial nephritis Sitprija V, et al. Am J Trop Med Hyg 1982;31:408 Geographical variations of Russell’s viper bites Sri Lanka India Myanmar Thailand Coagulation + ++ ++ ++ Renal failure ++ + ++ + Pituitary - + ++ - infarction Hemolysis ++ + - + Neurotoxicity ++ + - - Edema - - ++ - Shock - + ++ -
Variations of preys Trans Royal Soc Trop Med Hyg 1989; 83: 732 First Aids: Pressure immobilization
Not practical for general uses. Do if not delay transportation to hospitals Sribunruang S Management (Viper)
Initial evaluation – Physical exam: local & systemic effect – WBCT or PT, platelet count If normal: Follow-up coagulopathy for 3 days (At least twice on the first day) Russell’s Viper : Hydration & force diuresis to prevent renal failure Antivenom is the key treatment .
Antivenom to all patients – For rapidly fatal toxin or irreversible damages – Cost and side effects – Only for Malayan kraits Antivenom only to symptomatic patients – 50% are dried bites. – Coagulopathy is promptly reversed. – Antivenom is not helpful for local tissue damages. – All other snakes QSMI Polyvalent Antivenoms
Immunize single horse with multiple venoms. For patients with weakness or coagulopathy, respectively Equally effective as monovalent antivenoms but more difficult to produced If not available, may combine multiple monovalent antivenom (More protein load) Queen Soavabha Memorial Institute (QSMI), Thai Red Cross Society Cross-neutralization
QSMI Hemato-polyvalent antivenom – C. rhodostoma (Malaysia and Indonesia) – C. purpureomaculatus – D. siamensis (Myanmar) – NOT Tropidolaemus wagleri QSMI Neuro-polyvalent antivenom – Effectively neutralized venoms from many Southeast Asian cobras, kraits and king cobra but less effective for Indian cobra venoms Polyvalent antivenom may recognize common epitopes?
Acta Trop 2014; 132: 7. PLOS Neglect Trop Dis 2012; 6: e1672. INDICATIONS for VIPER ANTIVENOM
1. Whole blood clotting time > 20 min. or PT INR > 1.2 2. Systemic Bleeding 3. Severe thrombocytopenia (?50x 109/L) 4. Impending compartment syndrome
Repeat q 6 hours until WBCT or PT normal or bleeding stopped Effects on renal failure after RV bites: Still unknown Antivenom Dose Requirement (N=212)
Doses 1 Dose = adequate to neutralize a simulated bite 1 dose every 6 h until normal coagulation time Thiansookon & Rojnuckarin. Acta Trop 2008; 105 203-5 Treatment of local effects
Corticosteroid has no benefit (Nuchprayoon I) Antibiotic prophylaxis is not recommended (5% infection rate*) Pt with blister: higher risk Tetanus toxoid when normal coagulogram Antivenom – Helpful for severe edema – Not helpful to prevent/treat necrosis
*Rojnuckarin P, et al. Am J Trop Hyg 1998 Antivenom can reduce edema.
Chuntawibun & Rojnuckarin, TRSTMH 2006; 100: 879 Compartment syndrome
Correct coagulopathy with antivenom Consider fasciotomy ? Conservative treatment may be helpful (limb elevation). Characteristics No Antivenom Antivenom P-values (N=163) (N=80)
Hours after bite 4.2 7.7 7.6 10 0.004
Edema over 2 joints 18.9% 56.4% 0.000
Ecchymosis 12.2% 37.2% 0.000
Blister 7.9% 21.8% 0.040
Systemic bleeding 0.6% 10% 0.001
Un-clotted VCT 1.8% 98.7% 0.000
Platelet count (x109/L) 264.8 94.2 160.6 96.3 0.135
Necrosis 7.3% 8.9% 0.895
Chotenimitkun and Rojnuckarin, Clin Toxicol 2008; 46:122 Adverse reactions
Early adverse reactions (within hrs) – Incidence 3.5-85% – Rash, fever, urticaria, bronchospasm, hypotension, may be fatal. – Major limitation of antivenom Late adverse reactions (Days-wk) – Incidence 4.9-56% – Serum sickness Clin Toxicol 2016; 54: 27 Incidence of early adverse reactions Saovabha F(ab’)2/Caprylic antivenom – 3.5% (9/254) reactions – 2.3 in vipers vs. 12.5% in cobras (p=0.016) ? Related to higher protein load in cobra antivenom (10 vs. 3 vials) 1.2% Hypotention All were skin test negative.
Thiansookon & Rojnuckarin. Acta Trop 2008; 105 203-5 CURRENT ANTIVENOM
Reactions: Nonspecific protein aggregation Skin test is NOT recommended, but patient observation is required. Pre-medication depends on the incidence. More liberal uses of antivenom
Thiansookon & Rojnuckarin Acta Trop 2008; 105 203-5 Conclusion/Future direction
PT should be used for viper bites 20-min WBCT when PT is not available. Polyvalent antivenoms are available. Due to lower incidence of reactions: Early antivenom to prevent slow- recovering systemic effects (Neurotoxin or Nephrotoxin) How to prevent and manage local necrosis? Acknowledgments
Queen Saovabha Chulalongkorn University Memorial Institute King Chulalongkorn Memorial Hospital
Chuanchom Muanpasitporn Walee Chanthawibun Lawan Chanhome Rung Settapiboon Sukit Bunjongkit Jureeporn Noiphrom Pon Singhamatr Runyawan Chotenimitkun Orawan Khow Jaradpong Arpijantarangoon Aegachai Thiansukhon Narumol Pakmanee Anuwat Pinyachat Supat Chamnachanan Visith Sithprija Panchalee Jangprasert Pornthip Mekchai Paweenrat Limpawitayakul Jamrus Pongpit Benjaporn Akkawat Jumlong Juntiang Paweena Pradniwat Robbin Klieverik
Suebsan Mahasandana Tanin Intragumtornchai