Snakebites and microvesicles: Popping bubbles

Snakebite envenoming is estimated to cause 95 000125 000 deaths and up to 400 000 permanent injuries or disabilities worldwide on an annual basis. This serious health threat has been recognized by the World Health Organization, and snakebite envenoming is classified as a category A neglected tropical disease.1 In May of 2018, the World Health Assembly adopted a resolution on snakebite envenoming,2 thereby providing a mandate to develop a comprehensive plan to effectively control the burden of envenoming and reduce its debilitating impact. The multisectoral strategy that is required to achieve this will address socioeconomic, environmental, and healthcare challenges. Targeted actions to raise awareness have culminated in, among others, a recent international scientific conference where many essential stakeholders united in the fight against snakebite envenoming.3 While the highest health burden from venomous snakebites falls on south Asia and subSaharan Africa,4 exact information on the number of envenomings, clinical effects of snakebites, and effective treatments are lacking on a global scale. In an effort to address this, the Australian Snakebite Project registry has compiled information on a substantial proportion of all Australian snakebites since 2005.5,6 This study clarified that the most commonly observed clinical envenoming phenotype in Australia is venominduced consumptive coagulopathy (VICC),5 an unbridled activation and consumption of the coagulation system. This is due to the venom composition of the snakes that are most commonly involved in these envenomings5; Pseudonaja species contain procoagulant factor XaValike and Notechis species factor Xalike enzymes.7-9 Once injected into the blood stream of the prey, the Notechis factor Xalike protease interacts with prey factor V(a),10 and the circulating venom factor XaValike enzymes are capable of converting prothrombin of the prey into thrombin.10,11 Action of thrombin induces VICC, which is characterized by a (complete) consumption of fibrinogen and factors V and VIII, elevated Ddimer levels, and an international normalized ratio >3.12,13 From the envenomed individuals that developed VICC as reported in the Australian Snakebite Project, approximately 10% presented with microangiopathic hemolytic anemia (MAHA),5 resulting from intravascular red cell fragmentation with schistocytosis and thrombocytopenia. Most MAHA cases were observed following taipan (Oxyuranus species, 26% MAHA cases) and brown snake (Pseudonaja species, 14% MAHA cases) envenoming, while bites from Notechis and Hoplocephalus species each led to MAHA in 7% of envenomed individuals. Interestingly, this correlates with the venom composition of these snakes, with both Oxyuranus and Pseudonaja venom comprising factor XaValike prothrombin activators, while a factor Xalike protease is found in the venom of Notechis and Hoplocephalus snakes.7-9 Also, the onset of VICC appears to proceed more rapidly following envenoming by Pseudonaja snake bites relative to those of Notechis snakes,14 and MAHA only seems to occur following VICCassociated snakebites.5 Despite these indirect observations, the exact pathophysiology of venomassociated MAHA remains unclear. To gain insight into the venommediated damage to the endovascular system, in their recent article in Research and Practice in Thrombosis and Haemostasis, Enjeti and colleagues have focused on the role of microvesicles (MVs) in snakebite patients.15 Microvesicles are shed by outward blebbing of the plasma membrane and typically function to transfer cargo, such as proteins and ribonucleic acids, from a donor cell to an acceptor cell, leading to behavioral changes in the acceptor cell. Microvesicles may be shed by platelets, endothelial cells, megakaryocytes, and tumor cells, and the diameter of these vesicles ranges from 30 to 1000 nm.16,17 Elevated levels of MVs in the circulation are often associated with pathophysiological conditions such as sepsis, diabetes mellitus, cardiovascular diseases, and cancer,18-22 and MVs may even impact progression of disease. In their study, Enjeti and colleagues primarily studied MVs generated by platelets, red blood cells, and endothelial cells. Compared to control subjects, platelet MVs were significantly higher in the blood of snakebite patients that did not suffer from MAHA, while paradoxically red blood cell–derived MV levels were