Acute Thrombotic Microangiopathic Kidney Injury Due to Echis Coloratus Envenomation Case No
Acute thrombotic microangiopathic hemolytic anemia due to Echis coloratus envenomation
Tzvi-Ran Ilan Rahmani, Taysir Nasasra, Lior Fuchs, Yaniv Almog, Yael Lurie & Ori Galant
Israel Poison Information Center, Rambam Health Care Campus; The Rappaport Faculty of Medicine, Technion, Haifa, Israel. Department of Medicine; Medical Intensive Care Unit, Soroka University Medical Center; Faculty of Health Sciences, Ben Gurion University of the Negev, Beer-Sheva, Israel.
Cerastes cerastes
Atractaspis engaddensis
Cerastes gasperettii Walterinnesia aegyptia Cerastes Pseudocerastes vipera fieldi Echis coloratus The most common venomous snake in the southern part of Israel In Israel: Jordan In rocky desert areas- On the Arabian The Negev desert, the Dead Sea area, Peninsula: and along the Jordan valley up to the In Saudi Gilboa mountain. Arabia, Yemen, and Oman. In eastern Egypt
Distribution of four Echis species in Africa and the Middle East. Key: E. ocellatus – blue, E. pyramidum – red, E. coloratus – green, E. carinatus – purple. Distributions mapped according to the WHO venomous snake distribution database and a recent study of the genus Echis. PLoS Negl Trop Dis. 2010 Oct 26;4(10):e851 Clinical manifestations of E. coloratus bite
• Local: local pain, hematoma, bullae, swelling • Systemic: Impaired coagulation, bleeding tendency (PT and PTT prolongation, low fibrinogen level, thrombocytopenia) • Usually reversed following antivenom administration (Echis Coloratus monovalent antiserum, equine source, Kamada, Israel) Acute thrombotic microangiopathic kidney injury due to Echis coloratus envenomation Case No. 1 Case No. 2 • A previously healthy 39-year old man presented • A 70-year old man presented to the Soroka to the Soroka Medical Center 2.5 hours after Medical Center after Echis Coloratus bite Echis coloratus bite • Vital signs were within normal limits. Physical • Vital signs were within normal range, and examination revealed mild local swelling. physical examination revealed mild local • Laboratory tests on presentation: swelling. Non-clotting blood; Platelets: 101,000/µL, • Laboratory tests on presentation: creatinine 1.7 mg/dL Non-clotting blood; Platelets: 170,000/µL • Treatment: Blood products – FFP and • Treatment: Blood products - fresh frozen cryoprecipitate; E. coloratus anti-venom. plasma (FFP) and cryoprecipitate; Normalization of coagulation tests. E. coloratus anti-venom (50 ml) 4 h after the bite. Normalization of coagulation tests.
Typical clinical presentation following Echis Coloratus Bite During the following days: • Anemia (Hb= 6.4 & 9 mg/dL), thrombocytopenia (26 & 30,000/µL), and intravascular hemolysis: - elevated lactate dehydrogenase (LDH), indirect bilirubin, - schistocytes on peripheral blood smear, - multiple red blood cell casts on urine microscopy. • Severe oliguric kidney injury (creatinine 10.4 & 7.6 mg/dL)
• The combination was consistent with thrombotic microangiopathy Treatment and outcomes
• Hemodialysis (due to severe oliguric renal failure) • Plasma exchange (PLEX) (4 - 6 courses) • During the following days, renal function gradually normalized • Markers of hemolysis subsided • Discharged on day 15 and 11 after the envenomation. Discussion
• Coagulopathies are important complication of snake bites by many viper species, including Echis Coloratus. • Coagulopathies vary among snake species due to the specific toxins, but almost all cause activation of the coagulation cascade and consumption of clotting factor: Venom Induced Consumption Coagulopathy (VICC) • The toxins are procoagulants in vitro (resulting in rapid clot formation) but in vivo, they lead to severe consumption of clotting factors and therefore an increased bleeding risk. Snake venom induced coagulopathy
• Echis species contain prothrombin activators. • Clinical effects: range from minor bleeding (e.g., oozing at the bite site) to major life-threatening hemorrhage • Coagulation tests abnormalities: prolonged and often unrecordable PT, PTT, low or undetectable fibrinogen, elevated D-dimer. In some cases thrombocytopenia • Treatment - Antivenom: to bind and neutralize the toxin(s) - Clotting factor replacement, mainly Fresh Frozen Plasma (FFP) Thrombotic microangiopathy (TMA)
• A proportion of patients who develop VICC will also develop an venom-related thrombotic microangiopathy: microvascular thrombosis and non-immune hemolysis due to intravascular red blood cell fragmentation. • Characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury, which may continue beyond the resolution of VICC. • Clinical syndromes consistent with TMA have been reported for decades, but it was recognized as such only in 2007
(Isbister GK et al. Thrombotic microangiopathy from Australian brown snake (Pseudonaja) envenoming. Intern Med J 2007;37:523–528) Thrombotic microangiopathy (Cont.) • Thrombotic microangiopathy has been documented after bites with many viper species and Australasian elapids. • Ours are the first well-documented cases of TMA after E. Coloratus envenomation. • Is it really a new syndrome? • In a review of 68 cases of E. coloratus envenomation Clinical and laboratory manifestations Number of patients (%) The authors hypothesized that Anemia (< 10 g/dL) 9 (14%) renal failure was caused by DIC Thrombocytopenia (< 100,000) 25 (40%) with microthrombi in the renal parenchyma, but did not report acute nonoliguric renal failure 1 (1.5%) any signs of hemolytic anemia. Major bleeding 12 (18%) (Toxicon. 1992;30(1):25-32.) Treatment of snakebite-associated TMA
• It is unclear whether approaches used in other TMAs are appropriate (e.g., plasma exchange for thrombotic thrombocytopenic purpura, TTP) . • Antivenom should be administered early with the onset of systemic signs and symptoms, e.g. VICC Plasma exchange (PLEX) • ADAMTS13 is a plasma protease responsible for cleavage of von-Willebrand factor (vWF). Its activity is reduced in autoimmune thrombotic thrombocytopenia purpura (TTP), often due to anti- ADAMTS13 autoantibodies. • In autoimmune TTP, PLEX is assumed to replace ADAMTS13 and remove anti-ADAMTS13 autoantibodies and the ultra-large vWF pro-coagulant multimers. • It is unknown if these mechanisms are relevant to snakebite-induced TMA. In one of our patients, ADAMTS13 activity was normal and anti- ADAMTS13 autoantibodies were absent. Plasma exchange (cont.)
• PLEX may remove antivenom! • PLEX did not appear to change the time course or severity of TMA in a small series of six patients following Australian brown snake (Pseudonaja) bite. (Internal Medicine Journal 37 (2007) 523–528) Summary • Echis coloratus envenomation may cause severe thrombotic microangiopathy. • Snake bite victims should be closely followed for signs of TMA (microangiopathic hemolysis, thrombocytopenia, acute kidney injury) • Comprehensive investigations of coagulation and immune pathways in snake bite victims could provide a better understanding of the pathophysiology.
Thank you!