• View in gallery

    Representative fields (AC) of peripheral blood smear on admission showing numerous spherocytes and microspherocytes (arrows), anisocytosis, poikilocytosis, and rare schistocytes (arrowhead). Spherocytes are small, round, thick, densely staining red cells that appear to have a somewhat darker color and no central clear zone than the normal red cells. The red-cell changes indicate venom-induced spherocytic hemolytic anemia rather than microangiopathic hemolytic anemia as in disseminated intravascular coagulation or thrombotic microangiopathy.

  • 1.

    Frangides CY, Koulouras V, Kouni SN, Tzortzatos GV, Nikolaou A, Pneumaticos J, Pierrakeas C, Niarchos C, Kounis NG, Koutsojannis CM, 2006. Snake venom poisoning in Greece. Experiences with 147 cases. Eur J Intern Med 17: 2427.

    • Search Google Scholar
    • Export Citation
  • 2.

    Radonic V, Budimir D, Brataric N, Luksic B, Sapunar D, Vilovic K, 1997. Envenomation by the horned viper (Vipera ammodytes L.). Mil Med 162: 179182.

  • 3.

    Warrell DA, 2014. Venomous and poisonous animals. Farrar J, Hotez PJ, Junghanss T, Kang G, Lalloo D, White NJ, eds. Manson’s Tropical Diseases, 23rd edition. London, United Kingdom: Elsevier, 10961127.

    • Search Google Scholar
    • Export Citation
  • 4.

    Warrell DA, 2010. Snake bite. Lancet 375: 7788.

  • 5.

    World Health Organization, 2017. Report of the Tenth Meeting of the WHO Strategic and Technical Advisory Group for Neglected Tropical Diseases. Geneva, Switzerland: WHO.

    • Search Google Scholar
    • Export Citation
  • 6.

    Chippaux JP, 2012. Epidemiology of snake bites in Europe: a systematic review of the literature. Toxicon 59: 8699.

  • 7.

    Persson H, 2018. Pathophysiology and treatment of envenomation by European vipers. Gopalakrishnakone P, Vogel CW, Seifert S, Tambourgi D, eds. Clinical Toxinology in Australia, Europe, and Americas, Toxinology. Dordrecht, Germany: Springer, 357375.

    • Search Google Scholar
    • Export Citation
  • 8.

    Marinov I, Atanasov VN, Stankova E, Duhalov D, Petrova S, Hubenova A, 2010. Severe coagulopathy after Vipera ammodytes ammodytes snake bite in Bulgaria: a case report. Toxicon 56: 10661069.

    • Search Google Scholar
    • Export Citation
  • 9.

    Luksic B, Karabuva S, Markic J, Polic B, Kovacevic T, Mestrovic J, Krizaj I, 2018. Thrombocytopenic purpura following envenomation by the nose-horned viper (Vipera ammodytes ammodytes): two case reports. Medicine (Baltimore) 97: e13737.

    • Search Google Scholar
    • Export Citation
  • 10.

    Phillips RE, Theakston RD, Warrell DA, Galigedara Y, Abeysekera DT, Dissanayaka P, 1988. Paralysis, rhabdomyolysis and haemolysis caused by bites of Russell’s viper (Vipera russelli pulchella) in Sri Lanka: failure of Indian (Haffkine) antivenom. Q J Med 68: 691716.

    • Search Google Scholar
    • Export Citation
  • 11.

    Gillissen A, Theakston RD, Barth J, May B, Krieg M, Warrell DA, 1994. Neurotoxicity, haemostatic disturbances and haemolytic anaemia after a bite by a Tunisian saw-scaled or carpet viper (Echispyramidum”-complex): failure of antivenom treatment. Toxicon 32: 937944.

    • Search Google Scholar
    • Export Citation
  • 12.

    Schneemann M, Cathomas R, Laidlaw ST, El Nahas AM, Theakston RD, Warrell DA, 2004. Life-threatening envenoming by the Saharan horned viper (Cerastes cerastes) causing micro-angiopathic haemolysis, coagulopathy and acute renal failure: clinical cases and review. QJM 97: 717727.

    • Search Google Scholar
    • Export Citation
  • 13.

    World Health Organization, 2010. Guidelines for the Prevention and Clinical Management of Snakebite in Africa. Brazzaville, Republic of Congo: WHO Regional Office for Africa.

    • Search Google Scholar
    • Export Citation
  • 14.

    World Health Organization, 2016. Guidelines for the Management of Snakebites, 2nd edition. New Dehli, India: WHO Regional Office for South-East Asia.

    • Search Google Scholar
    • Export Citation
  • 15.

    Behcet AL, Orak M, Aldemir M, Guloglu C, 2010. Snakebites in adults from the Diyarbakır region in southeast Turkey. Turk J Trauma Emerg Surg 16: 210214.

    • Search Google Scholar
    • Export Citation
  • 16.

    Luksic B, Culic V, Stricevic L, Brizic I, Poljak NK, Tadic Z, 2010. Infant death after nose-horned viper (Vipera ammodytes ammodytes) bite in Croatia: a case report. Toxicon 56: 15061509.

    • Search Google Scholar
    • Export Citation
  • 17.

    Saul FA, Prijatelj-Znidarsic P, Vulliez-le Normand B, Villette B, Raynal B, Pungercar J, Krizaj I, Faure G, 2010. Comparative structural studies of two natural isoforms of ammodytoxin, phospholipases A2 from Vipera ammodytes ammodytes which differ in neurotoxicity and anticoagulant activity. J Struct Biol 169: 360369.

    • Search Google Scholar
    • Export Citation
  • 18.

    Atanasov VN, Danchev D, Mitewa M, Petrova S, 2009. Hemolytic and anticoagulant study of the neurotoxin vipoxin and its components–basic phospholipase a2 and an acidic inhibitor. Biochemistry (Mosc) 74: 276280.

    • Search Google Scholar
    • Export Citation
  • 19.

    Jeyarajah R, 1984. Russell’s viper bite in Sri Lanka. A study of 22 cases. Am J Trop Med Hyg 33: 506510.

  • 20.

    Arthur CK, McCallum D, Loveday DJ, Collins A, Isbister JP, Fisher MM, 1991. Effects of taipan (Oxyuranus scutellatus) venom on erythrocyte morphology and blood viscosity in a human victim in vivo and in vitro. Trans R Soc Trop Med Hyg 85: 401403.

    • Search Google Scholar
    • Export Citation
  • 21.

    Condrea E, 1979. Hemolytic effects of snake venoms. Lee CY, ed. Snake Venoms. Handbook of Experimental Pharmacology: Continuation of Handbuch der Experimentellen Pharmakologie, Vol. 52. Berlin, Heidelberg: Springer, 448479.

    • Search Google Scholar
    • Export Citation
  • 22.

    Stoykova S, Goranova Y, Pantcheva I, Atanasov V, Danchev D, Petrova S, 2013. Hemolytic activity and platelet aggregation inhibitory effect of vipoxin’s basic sPLA2 subunit. Interdiscip Toxicol 6: 136140.

    • Search Google Scholar
    • Export Citation
  • 23.

    Warrell DA, 2005. Treatment of bites by adders and exotic venomous snakes. BMJ 331: 12441247.

  • 24.

    Isbister GK, Silva A, 2018. Addressing the global challenge of snake envenoming. Lancet 392: 619620.

 

 

 

 

Case Report: Spherocytic Hemolytic Anemia after Envenomation by Long-Nosed Viper (Vipera ammodytes)

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  • 1 Department of Clinical Hematology, Georgios Gennimatas Hospital, Athens, Greece;
  • 2 Department of Nephrology, Aghios Georgios Hospital, Chania, Greece;
  • 3 Department of Clinical Microbiology and Microbial Pathogenesis, Unit of Zoonoses and Geographic Medicine, School of Medicine, University of Crete, Heraklion, Greece

Snakebite envenoming is a major health issue in many parts of the world, especially in rural areas. Vipera ammodytes is the commonest cause of snakebite in Greece. We report our experience with a patient bitten by such a snake, who developed massive intravascular hemolysis characterized by a spherocytic rather than microangiopathic hemolytic picture. This case illustrates the potential of snakebite envenoming to cause spherocytic hemolytic anemia associated with hemoglobinuria and acute renal failure, and represents the first report of V. ammodytes in this context. Another important point is that antivenom was rapidly effective in reversing spherocytic hemolytic anemia, even though several hours had elapsed since the bite.

INTRODUCTION

There are five venomous snakes of the Viperidae family in Greece: Vipera ammodytes, Vipera berus, Vipera xanthina, Vipera ursinii, and Vipera schweizeri. Vipera ammodytes (long-nosed viper) is the commonest cause of snakebite in Greece. Unlike other snakes which are confined to specific geographic locations (V. berus to the border area of Greece and Bulgaria, V. xanthina to Thrace and northeastern Aegean islands, V. ursinii to Pindos Mountains, and V. schweizeri to Cyclades), Vipera ammodytes inhabits all parts of mainland Greece and most of the islands. Bites occur from March to October, peaking in June to August. Most victims are bitten at their rural occupation.1 Vipera ammodytes has two long, hinged front fangs; the average venom yield per bite is 20 mg. The adult viper averages 85 cm in length; has a single, elongated horn at the tip of its snout; and is marked with a dark, zigzag band running the length of the back. Its venom is a complex mixture exhibiting cytolytic, neurotoxic, hemorrhagic, and clotting activities.2 It is rich in proteins including enzymes that are proteolytic or hydrolytic (e.g., hydrolases, hyaluronidases, metalloproteinases, proteases, and phospholipases), nonenzymatic polypeptide toxins, and nontoxic proteins. It can stimulate the release of histamine or similar substances, and may contain Clostridium species that can cause tetanus and gas gangrene.1,2 We report a rare case of spherocytosis with severe intravascular hemolysis, hemoglobinemia, and hemoglobinuria after a V. ammodytes viper bite. We describe the clinical features, laboratory investigations, hematologic findings, and response to antivenom.

Case report.

A 53-year-old farmer from a rural area of Thessaly, Greece, was bitten by a snake on her left ankle while harvesting grass. The snake was identified by the patient as “ochia,” which is the Greek name for long-nosed viper (V. ammodytes). She attended a local hospital 1 hour after the bite and was noted to have swelling of her left foot. Treatment at her local hospital included corticosteroids, analgesics, antibiotics, and prophylactic tetanus antitoxin. However, she developed progressive swelling and ecchymosis of the bitten limb. Because of the lack of antivenom, she was transferred 9 hours later to Athens. Her past medical history was unremarkable.

On arrival, the patient was pale and complained of dizziness, nausea, and vomiting. Blood pressure was 96/55 mmHg, pulse 120 bpm, temperature 36.5°C, and pulse oximetry 93%. Below the left external malleolus were two fang marks; the left leg was markedly swollen. There was no evidence of gastrointestinal bleeding. Laboratory examinations revealed a white cell count of 15.73 × 109/L (4–10) with 88% neutrophils, hematocrit 21.4% (36.8–46), hemoglobin 6.8 g/dL (12–14), platelets 130 × 109/L (140–400), mean corpuscular volume 74.8 fL (79–98), reticulocytes 2.66% (0.5–2), total bilirubin 3 mg/dL (0.2–1.2), direct bilirubin 0.9 mg/dL (< 0.5), lactate dehydrogenase (LDH) 1,256 U/L (134–279), alanine aminotransferase 46 U/L (0–55), aspartate aminotransferase 32 (5–34), alkaline phosphatase 99 U/L (40–150), creatinine 2.7 mg/dL (0.6–1.1), fibrinogen 212 mg/dL (200–400), international normalized ratio (INR) 1.55 (0.8–1.2), activated partial thromboplastin time (aPTT) 33.5 seconds (26–39), and D-dimers 4.1 mg/L (< 0.5). Serum haptoglobin was undetectable, and a urine sample revealed severe hemoglobinuria. The urine sediment contained renal tubular cells, few erythrocytes, and no casts. A peripheral blood smear showed numerous spherocytes and microspherocytes numbering 18–19 per high-power field, anisocytosis, poikilocytosis, occasional nucleated erythrocytes, and rare schistocytes (Figure 1). Coombs test, cold agglutinins, a methyl-violet preparation for Heinz bodies, and flow-cytometric immunophenotyping for paroxysmal nocturnal hemoglobinuria were negative. The results of hemoglobin electrophoresis, G6PD and pyruvic kinase levels, and vitamin B12, folate, and ferritin levels were normal. The abdominal ultrasound showed no abnormalities.

Figure 1.
Figure 1.

Representative fields (AC) of peripheral blood smear on admission showing numerous spherocytes and microspherocytes (arrows), anisocytosis, poikilocytosis, and rare schistocytes (arrowhead). Spherocytes are small, round, thick, densely staining red cells that appear to have a somewhat darker color and no central clear zone than the normal red cells. The red-cell changes indicate venom-induced spherocytic hemolytic anemia rather than microangiopathic hemolytic anemia as in disseminated intravascular coagulation or thrombotic microangiopathy.

Citation: The American Journal of Tropical Medicine and Hygiene 101, 6; 10.4269/ajtmh.19-0611

The patient received four vials of polyvalent antivenom (Imunoloski zavod-Zagreb European viper venom antiserum) with neutralizing activity against V. ammodytes, V. berus, V. aspis, V. xanthina, and V. ursinii intravenously. Before giving antivenom, methylprednisolone and histamine H1- and H2-receptor blockers were administered intravenously. Two units of packed red cells were transfused. Supportive measures to treat intravascular hemolysis included rehydration, sodium bicarbonate, and mannitol. There was no further clinical or laboratory evidence of continued hemolysis post-infusion of anti-snake venom so that no transfusions were necessary after the first hospital day. Spherocytes decreased markedly from the peripheral blood, numbering three per high-power field on the second hospital day, and, on the third day, the blood smear had returned almost entirely to normal. However, she required a surgical evaluation for potential intra-compartmental syndrome and, soon after admission, became oliguric. Her renal function deteriorated substantially with a urea of 183 mg/dL and creatinine of 6.5 mg/dL, and she was transferred to the renal unit for hemodialysis. She eventually made a full recovery.

DISCUSSION

Snakebite is an occupational disease of farmers, herders, and hunters in many parts of the world, especially in rural areas of tropical developing countries.35 Snakebite envenoming is included in the WHO’s list of high-priority neglected tropical diseases.5 The true rates of morbidity and mortality caused by snakebite are not known because of underreporting. The outcome of a bite depends on several factors such as the potency of the venom, the amount injected, the size and condition of the snake, the location and depth of bites, and the status of the patient bitten.1,3 The variation of venom composition not only from species to species but also within a single species throughout its geographic distribution or at different seasons of the year may explain the clinical diversity of snakebite.3

Vipera ammodytes, one of the most dangerous snakes of Europe, is distributed across south Austria, north Italy, southeast Europe, and Turkey.6 Vipera ammodytes is the only venomous snake in Thessaly. The presence of fang marks and the development of envenomation syndrome leave us in no doubt that our patient was bitten by a viper, that is, a long-nosed viper.

Although most V. ammodytes bites produce mild local and systemic manifestations, serious hemorrhagic, coagulopathy and local tissue complications have been observed.1,2,69 Intravascular hemolysis is a rare, life-threatening manifestation of snakebite envenomation, seen mainly after bites by exotic venomous snakes such as Indian and Sri Lankan Russell’s viper (Daboia russelii), South American Bothrops species, African-Asian “saw-scaled” vipers (Echis spp.), Sahara horned vipers (Cerastes cerastes), some Australasian elapids, and members of the colubrid genera Dispholidus, Thelotornis, and Rhabdophis.3,1014 These cases are characterized by numerous triangular, helmet-shaped, and fragmented red blood cells (schistocytes) consistent with microangiopathic hemolytic anemia secondary to disseminated intravascular coagulation (DIC) or thrombotic microangiopathy.

In our patient, the rapid fall in the hematocrit, along with hyperbilirubinemia, hemoglobinuria, absent haptoglobin, and marked increase in LDH were consistent with intravascular hemolysis. However, the hematologic picture was not consistent with a microangiopathic (fragmentation) hemolysis but with a spherocytic hemolysis that, to our knowledge, has not previously been reported in V. ammodytes envenomation. Radonic et al.2 did not report spherocytosis or intravascular hemolysis among 389 victims of bites by V. ammodytes. Also, spherocytic hemolysis was not described in large series of snakebites from Greece and Turkey.1,15 Luksic et al.16 reported a 45-day-old boy who developed intravascular hemolysis, thrombocytopenia, and DIC after a V. ammodytes viper bite, but they did not comment on the blood smear or type of hemolysis.

The occurrence of a prolonged INR in our patient, but normal aPTT and fibrinogen level, is more likely due to the anticoagulant activity of venom than consumption coagulopathy from DIC (V. ammodytes venom contains well-characterized toxins that inhibit the prothrombinase complex by binding to procoagulant phospholipids and factor Xa, thereby prolonging INR).4,17,18 Mild thrombocytopenia, as seen in this patient, often accompanies viper bites, caused by platelet activation/inhibition from venom phospholipases and/or platelet sequestration in the bitten limb.3,13,14

The finding of spherocytes in the present case and their rapid disappearance after antivenom therapy are intriguing. Varying degrees of spherocytosis and sphero-echinocytosis have been reported after Russell’s viper bites in Sri Lanka and after a bite by Taipan in Australia.19,20 Spherocytosis may be caused by phospholipase A2 (PLA2) in snake venom, an enzyme that catalyzes the hydrolysis of phospholipids.21 Phospholipase A2 cleaves a fatty acid from lecithin to produce lysolecithin, disrupting the red-cell membrane in this process. The most severely damaged erythrocytes undergo intravascular hemolysis; erythrocytes that have been insufficiently injured to undergo lysis assume a spherical shape. The hemolytic effect is enhanced by the product lysolecithin, which, itself, causes further disruption of the membrane. There is a correlation between the amount of lysolecithin produced by viperid-venom PLA2 and red-cell shape (attachment of 10−11 μmol lysolecithin/cell produces crenated bidiscoids,1.3 × 10−11 μmol/cell crenated spheres, and > 2 × 10−11 μmol/cell smooth spheres).21 Once formed, spherocytes are less deformable and are retained in the spleen, where further destruction occurs.

A wide range of factors may influence the degree of hemolysis, including the amount of lysolecithin attached to the red cell and the duration of the attachment (which depend on the amount of venom injected, the initial plasma lecithin concentration, and the rate of plasma lysolecithin clearance), the level of plasma proteins known to protect sphered red cells from destruction, and the functional state of the spleen.21 Vipera ammodytes venom is rich in PLA2, which may explain its hemolytic effect in our patient.18,22

The course of snakebite envenomation requires close monitoring of the patient and careful clinical decision-making. The most important clinical decision is whether or not to give antivenom because only a minority of patients need it, it may cause anaphylaxis, it is expensive, and it is frequently in short supply. In European viper bites, antivenom is recommended for patients with clinical or laboratory evidence of systemic (e.g., hemostatic abnormalities, hypotension, neurotoxicity, and renal failure) and/or severe local (i.e., progressive local edema extending beyond the bitten segment of the limb) envenoming.3,7,23 It is said that if several hours have elapsed since the bite, the antivenom may be less successful in preventing toxin effects and potentially reversing some effects.24 Our patient’s clinical course shows the effectiveness of antivenom in arresting venom-induced spherocytic hemolysis even when given 10 hours after the bite, and teaches us that for reversing systemic effects, it is actually never too late for administration of antivenom.3,13 However, timelier administration could have halted the hemolytic process and, thus, prevented any further renal damage due to massive hemoglobinuria. If, by the time the patient is admitted to hospital, there is irreversible tubular damage, antivenom will not prevent renal failure.

CONCLUSION

Snakebite is a complex medical problem often faced by farmers in many parts of the world. Vipera ammodytes viper bite is a potentially serious event that requires immediate hospital care. We describe here, for the first time, a case of acquired spherocytic hemolytic anemia caused by V. ammodytes envenomation and resulting in rapid intravascular hemolysis, hemoglobinuria, and renal failure. Spherocytic hemolysis must be distinguished from fragmentation hemolysis because of the quite different diagnostic significance (spherocytic hemolysis results from enzymatic attack on membrane by circulating venom PLA2, whereas fragmentation hemolysis indicates DIC or thrombotic microangiopathy). An important point in this case is that antivenom was rapidly effective in arresting spherocytic hemolysis, even though it was given 10 hours after the bite.

REFERENCES

  • 1.

    Frangides CY, Koulouras V, Kouni SN, Tzortzatos GV, Nikolaou A, Pneumaticos J, Pierrakeas C, Niarchos C, Kounis NG, Koutsojannis CM, 2006. Snake venom poisoning in Greece. Experiences with 147 cases. Eur J Intern Med 17: 2427.

    • Search Google Scholar
    • Export Citation
  • 2.

    Radonic V, Budimir D, Brataric N, Luksic B, Sapunar D, Vilovic K, 1997. Envenomation by the horned viper (Vipera ammodytes L.). Mil Med 162: 179182.

  • 3.

    Warrell DA, 2014. Venomous and poisonous animals. Farrar J, Hotez PJ, Junghanss T, Kang G, Lalloo D, White NJ, eds. Manson’s Tropical Diseases, 23rd edition. London, United Kingdom: Elsevier, 10961127.

    • Search Google Scholar
    • Export Citation
  • 4.

    Warrell DA, 2010. Snake bite. Lancet 375: 7788.

  • 5.

    World Health Organization, 2017. Report of the Tenth Meeting of the WHO Strategic and Technical Advisory Group for Neglected Tropical Diseases. Geneva, Switzerland: WHO.

    • Search Google Scholar
    • Export Citation
  • 6.

    Chippaux JP, 2012. Epidemiology of snake bites in Europe: a systematic review of the literature. Toxicon 59: 8699.

  • 7.

    Persson H, 2018. Pathophysiology and treatment of envenomation by European vipers. Gopalakrishnakone P, Vogel CW, Seifert S, Tambourgi D, eds. Clinical Toxinology in Australia, Europe, and Americas, Toxinology. Dordrecht, Germany: Springer, 357375.

    • Search Google Scholar
    • Export Citation
  • 8.

    Marinov I, Atanasov VN, Stankova E, Duhalov D, Petrova S, Hubenova A, 2010. Severe coagulopathy after Vipera ammodytes ammodytes snake bite in Bulgaria: a case report. Toxicon 56: 10661069.

    • Search Google Scholar
    • Export Citation
  • 9.

    Luksic B, Karabuva S, Markic J, Polic B, Kovacevic T, Mestrovic J, Krizaj I, 2018. Thrombocytopenic purpura following envenomation by the nose-horned viper (Vipera ammodytes ammodytes): two case reports. Medicine (Baltimore) 97: e13737.

    • Search Google Scholar
    • Export Citation
  • 10.

    Phillips RE, Theakston RD, Warrell DA, Galigedara Y, Abeysekera DT, Dissanayaka P, 1988. Paralysis, rhabdomyolysis and haemolysis caused by bites of Russell’s viper (Vipera russelli pulchella) in Sri Lanka: failure of Indian (Haffkine) antivenom. Q J Med 68: 691716.

    • Search Google Scholar
    • Export Citation
  • 11.

    Gillissen A, Theakston RD, Barth J, May B, Krieg M, Warrell DA, 1994. Neurotoxicity, haemostatic disturbances and haemolytic anaemia after a bite by a Tunisian saw-scaled or carpet viper (Echispyramidum”-complex): failure of antivenom treatment. Toxicon 32: 937944.

    • Search Google Scholar
    • Export Citation
  • 12.

    Schneemann M, Cathomas R, Laidlaw ST, El Nahas AM, Theakston RD, Warrell DA, 2004. Life-threatening envenoming by the Saharan horned viper (Cerastes cerastes) causing micro-angiopathic haemolysis, coagulopathy and acute renal failure: clinical cases and review. QJM 97: 717727.

    • Search Google Scholar
    • Export Citation
  • 13.

    World Health Organization, 2010. Guidelines for the Prevention and Clinical Management of Snakebite in Africa. Brazzaville, Republic of Congo: WHO Regional Office for Africa.

    • Search Google Scholar
    • Export Citation
  • 14.

    World Health Organization, 2016. Guidelines for the Management of Snakebites, 2nd edition. New Dehli, India: WHO Regional Office for South-East Asia.

    • Search Google Scholar
    • Export Citation
  • 15.

    Behcet AL, Orak M, Aldemir M, Guloglu C, 2010. Snakebites in adults from the Diyarbakır region in southeast Turkey. Turk J Trauma Emerg Surg 16: 210214.

    • Search Google Scholar
    • Export Citation
  • 16.

    Luksic B, Culic V, Stricevic L, Brizic I, Poljak NK, Tadic Z, 2010. Infant death after nose-horned viper (Vipera ammodytes ammodytes) bite in Croatia: a case report. Toxicon 56: 15061509.

    • Search Google Scholar
    • Export Citation
  • 17.

    Saul FA, Prijatelj-Znidarsic P, Vulliez-le Normand B, Villette B, Raynal B, Pungercar J, Krizaj I, Faure G, 2010. Comparative structural studies of two natural isoforms of ammodytoxin, phospholipases A2 from Vipera ammodytes ammodytes which differ in neurotoxicity and anticoagulant activity. J Struct Biol 169: 360369.

    • Search Google Scholar
    • Export Citation
  • 18.

    Atanasov VN, Danchev D, Mitewa M, Petrova S, 2009. Hemolytic and anticoagulant study of the neurotoxin vipoxin and its components–basic phospholipase a2 and an acidic inhibitor. Biochemistry (Mosc) 74: 276280.

    • Search Google Scholar
    • Export Citation
  • 19.

    Jeyarajah R, 1984. Russell’s viper bite in Sri Lanka. A study of 22 cases. Am J Trop Med Hyg 33: 506510.

  • 20.

    Arthur CK, McCallum D, Loveday DJ, Collins A, Isbister JP, Fisher MM, 1991. Effects of taipan (Oxyuranus scutellatus) venom on erythrocyte morphology and blood viscosity in a human victim in vivo and in vitro. Trans R Soc Trop Med Hyg 85: 401403.

    • Search Google Scholar
    • Export Citation
  • 21.

    Condrea E, 1979. Hemolytic effects of snake venoms. Lee CY, ed. Snake Venoms. Handbook of Experimental Pharmacology: Continuation of Handbuch der Experimentellen Pharmakologie, Vol. 52. Berlin, Heidelberg: Springer, 448479.

    • Search Google Scholar
    • Export Citation
  • 22.

    Stoykova S, Goranova Y, Pantcheva I, Atanasov V, Danchev D, Petrova S, 2013. Hemolytic activity and platelet aggregation inhibitory effect of vipoxin’s basic sPLA2 subunit. Interdiscip Toxicol 6: 136140.

    • Search Google Scholar
    • Export Citation
  • 23.

    Warrell DA, 2005. Treatment of bites by adders and exotic venomous snakes. BMJ 331: 12441247.

  • 24.

    Isbister GK, Silva A, 2018. Addressing the global challenge of snake envenoming. Lancet 392: 619620.

Author Notes

Address correspondence to Konstantinos Liapis, Department of Clinical Hematology, Georgios Gennimatas Hospital, Leoforos Mesogion 154, Athens 115 27, Greece. E-mail: kosliapis@hotmail.com

Disclaimer: This manuscript contains original material that has not been published elsewhere or submitted to another journal.

Authors’ addresses: Konstantinos Liapis, Department of Clinical Hematology, Georgios Gennimatas Hospital, Athens, Greece, E-mail: kosliapis@hotmail.com. Evangelia Charitaki, Department of Nephrology, Aghios Georgios Hospital, Chania, Greece, E-mail: evacharitaki@hotmail.com. Anna Psaroulaki, Department of Clinical Microbiology and Microbial Pathogenesis, Unit of Zoonoses and Geographic Medicine, School of Medicine, University of Crete, Heraklion, Greece, E-mail: psaroulaki@uoc.gr.

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