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Snakes: Pathophysiology

It is important to note that, since children have smaller limbs, less subcutaneous tissue, and smaller body mass, they can potentially receive more venom per kilogram of body weight and therefore have more clinical severity than adults.6

Crotaline Venom

Crotaline venom is a complex solution of various proteins, peptides, lipids, carbohydrates, and enzymes, including ribonuclease, deoxyribonuclease, kinins, leukotrienes, histamine, phospholipase, serotonin, hyaluronidase, acetylcholinesterase, collagenase, and metallic ions.15,16 These components allow the snake to kill prey quickly and begin the process of digestion. Specific components cause direct tissue injury, capillary leakage, coagulopathy, and neurotoxicity. Crotaline bites usually cause severe pain from the time of envenomation and swelling that can progress at variable rates due to the lymphatic transport of venom.

Tissue damage at the site of the bite is the most common complication following envenomation by North American crotaline snakes. The etiology of this effect is only partially understood because snake venom varies with the different species of snakes, the individual members of the species, the season, and the nutritional status, location, and age of the snake. It is therefore difficult to predict the extent of local tissue damage that can develop following snakebites.2

After a bite, the area may become edematous and tense. Ecchymosis can be prominent. Fluid filled or hemorrhagic bullae can form at the site of the bite and necrosis may eventually become evident. Local reactions to envenomations are secondary to increased blood vessel permeability and direct tissue necrosis caused by the venom with additional tissue damage due to ischemia and swelling. Generalized rhabdomyolysis may occur in the absence of impressive muscular swelling in the case of envenomation by the canebrake rattlesnake (Crotalus horridus atricaudatus).17

Venom metalloproteinases (VMPs) are important in the pathogenesis of tissue necrosis at the site of the bite because they cleave protumor necrosis factor alpha (pro-TNF alpha) and release activated TNF alpha, a mediator of the inflammatory response and inducer of macrophage differentiation. TNF alpha is also responsible for neutrophil degranulations, leukocyte migration, release of mediators of inflammation (i.e., interleukins), as well as its own synthesis and release by macrophages. It also stimulates the production of endogenous human metalloproteinases (HMPs). These HMPs subsequently cleave more pro- TNF alpha, further amplifying the inflammatory reaction. In addition, HMPs injure tissue directly by degrading extracellular matrix proteins. This selfinducing cycle causes an inflammatory response that is further augmented by other enzymes.2,18

Envenomation is a dynamic process which can progress unpredictably to serious local or systemic involvement. The full extent of symptoms may not be evident for hours. However, as a general rule, if there are no symptoms within six to eight hours, the patient can be considered medically cleared.6

Hematological abnormalities are common in crotaline envenomations. Coagulopathies were reported in over 40% of victims envenomated by all North American crotalines.19 In another series, coagulopathy was present in 60% of rattlesnake envenomation victims, hypofibrinogenemia was present in 49%, and thrombocytopenia was present in 33%.1 Hypofibrinogenemia results from fibrinolysins and thrombin-like enzymes in the crotaline venom. These specific components cause depletion of fibrinogen and elevation of fibrin and fibrinogen degradation products which cause elevation of prothrombin. Crotaline snake venom also contains nonspecific proteases that degrade clotting factors or activate the coagulation cascade, further prolonging clotting times.1,2

There are different mechanisms responsible for the thrombocytopenia that results from crotaline envenomation. Platelet destruction may be mediated by the action of phospholipases which damage platelet membranes. In addition, the rapid rise in platelet count seen following administration of antivenom suggests that platelets are sequestered in the local microvasculature and subsequently released after antivenom treatment.1,2

Thrombocytopenia is particularly common and often severe following the bite of the Timber Rattlesnake (Crotalus horridus horridus). Timber Rattlesnake venom contains the protein crotalocytin which causes platelet aggregation and is thought to be partially responsible for thrombocytopenia.20

The venom of water moccasins or cottonmouths produces less severe local and systemic pathology than rattlesnakes. Furthermore, copperhead envenomations tend to be less serious than water moccasins.4,21 Copperhead envenomations cause significant soft tissue edema but usually do not cause significant coagulopathy, systemic symptoms, or extensive tissue destruction; they usually require only conservative local treatment. However, with the availability of CroFab® (Crotalidae Polyvalent Immune Fab), a sterile, nonpyrogenic, purified, lyophilized preparation of ovine Fab, more copperhead snakebites are being treated with antivenom.10,22

An important exception to these general observations regarding crotaline envenomations is that of the Mojave Rattlesnake (Crotalus scutalatus scutalatus), whose venom contains a potent neurotoxin. A patient bitten by a Mojave Rattlesnake can present with cranial nerve dysfunction, muscle fasciculations, and weakness, with delayed onset of paralysis and respiratory failure similar to coral snake envenomations. Mojave Rattlesnake bites can present with or without the local tissue effects, depending on the geographic location of the snake.6,23

In addition to the Mojave Rattlesnake, neurotoxic effects are described following Southern Pacific Rattlensnake (C. viridis helleri), Western Diamondback Rattlesnake (C. atrox), and Timber Rattlesnake (C. horridus horridus) envenomations.24,25 Mojave toxin (venom A) may cause muscle paralysis by inhibition of acetylcholine release at the presynaptic neuromuscular junction, whereas muscle fasciculations may be caused by altered calcium binding on the nerve membrane. Successful treatment of fasciculations secondary to Mojave Rattlesnake and Western Diamondback Rattlesnake envenomations with CroFab® has been reported.25 However, fasciculations secondary to Southern Pacific Rattlesnake envenomation may be refractory to CroFab® treatment.26 Although CroFab® incorporates Mojave Rattlesnake venom into its production process, the neurotoxic proteins in other North American rattlesnake venoms may not have sufficient immunogenic similarity to be neutralized by CroFab®.26

Elapid Venom

Coral snake venom has various toxins which produce systemic neurotoxicity, resulting in the loss of muscle strength and death by respiratory paralysis. Coral snake envenomations may present with serious systemic toxicity with little symptomatology at the actual site of the envenomation due to the venom's lack of cytotoxicity.

M. fulvius venom contains phospholipase A2 and alpha neurotoxin. The cardiotoxic or myotoxic phospholipase A2 has been theorized to depolarize the muscle fiber membrane. The alpha neurotoxins block motor endplate acetylcholine receptors, decreasing neuron activity. Onset of clinical effects following envenomation occurs between one and seven hours but can be delayed up to 18 hours. The neurological abnormalities may include slurred speech, paresthesias, ptosis, diplopia, dysphagia, stridor, muscle weakness, fasciculations, and respiratory paralysis. Coral snake envenomations have the potential to cause high morbidity with respiratory failure, neurological dysfunction, and cardiovascular collapse, requiring airway and respiratory management lasting several weeks.13,27

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Last Modified: 05/26/2017
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