A Fatal Case of Traumatic Brain Injury With Severe Coagulopathy Due to Rhabdophis Tigrinus (Yamakagashi) Bites, A Case Report


 Background

Yamakagashi venom is a prothrombin activator, leading to disseminated intravascular coagulation. We report a fatal case of severe coagulopathy from head trauma assumed to be caused by a yamakagashi bite.
Case Presentation:

An 80-year-old man fell and developed systemic tonic–clonic convulsions. Head computed tomography revealed brain contusion and acute subdural hematoma. Physical examination revealed two bite marks with persistent bleeding on the right lower leg. The patient stated that he had been bitten by some creature 3 days prior, but the bite was left untreated. Laboratory tests showed fibrinogen levels below the detection limit. Even though 18 units of fresh frozen plasma were administered for coagulopathy, fibrinogen levels did not improve. He died approximately 13 hours after admission.
Conclusion

In this case of a yamakagashi bite with active bleeding due to trauma, early administration of Yamakagashi antivenom should be considered to control coagulopathy.


Abstract Background
Yamakagashi venom is a prothrombin activator, leading to disseminated intravascular coagulation. We report a fatal case of severe coagulopathy from head trauma assumed to be caused by a yamakagashi bite.

Case Presentation:
An 80-year-old man fell and developed systemic tonic-clonic convulsions. Head computed tomography revealed brain contusion and acute subdural hematoma. Physical examination revealed two bite marks with persistent bleeding on the right lower leg. The patient stated that he had been bitten by some creature 3 days prior, but the bite was left untreated. Laboratory tests showed brinogen levels below the detection limit. Even though 18 units of fresh frozen plasma were administered for coagulopathy, brinogen levels did not improve. He died approximately 13 hours after admission.

Conclusion
In this case of a yamakagashi bite with active bleeding due to trauma, early administration of Yamakagashi antivenom should be considered to control coagulopathy.

Background
Although the exact number is still unknown, there have been 37 cases in 40 years, making these cases relatively rare. 1 Only one fatal case has been reported since 2000 due to the early administration of yamakagashi antivenom in severe cases. Here, we report a fatal case of severe coagulopathy from head trauma assumed to be caused by a yamakagashi bite.

Case Presentation
An 80-year-old man visited a neighboring hospital complaining of back pain. He accidentally fell in the waiting room and subsequently developed systemic tonic-clonic convulsions. Head computed tomography (CT) revealed a single cerebral contusion in the left frontal lobe and a left subacute subdural hematoma (Fig. 1A), and the patient was transferred to our hospital. His vital signs appeared normal; however, mild disturbance of consciousness was observed (Glasgow Coma Scale E4V4M6). The light re ex was prompt on both sides and there was no anisocoria. Physical examination revealed two swollen and continuously bleeding bite marks on the right lower leg (Fig. 2). The patient stated that he had been bitten by a creature 3 days prior and left his bite untreated. No other physical or trauma-related changes were observed, and no abnormalities except coagulopathy were noted on laboratory tests ( Table 1). The patient showed a prolonged prothrombin and activated partial thromboplastin time, and brinogen levels were below the detection limit. Follow-up head CT revealed a single brain contusion and a small amount of acute subdural hematoma in the left frontal lobe (Fig. 1B). Accordingly, the patient was diagnosed with a head injury accompanied by severe coagulopathy and admitted to the intensive care unit. The neurosurgeon found no indications for surgery. For coagulopathy, 18 units of fresh frozen plasma (FFP) were administered ~ 8 hours after admission, but brinogen levels showed little improvement (Fig. 1).
Head CT performed 7 hours after the injury revealed gradual worsening of intracranial hemorrhage ( Fig. 1C). Furthermore, his state of consciousness deteriorated over time. However, surgical intervention was not indicated because of severe coagulopathy. The patient died 3 days after the bite, approximately 13 hours after hospital admission.

Discussion
In this case, a de nite diagnosis of a yamakagashi bite could not be made. However, the patient had two bite wounds on the right lower leg, and the bleeding persisted 3 days after the injury, coagulopathy with brinogen levels < 50 mg/dL was present, and brinogen levels remained below detectable levels despite FFP administration. Therefore, the severe head injury caused by coagulopathy likely resulted from a yamakagashi bite.
Yamakagashi is found throughout Russia and eastern Asia, including China, Taiwan, Korea, and Japan (excluding the Ryukyu region). 2 They have two kinds of venom. 3 Cervical gland venom is released from ~ 10 pairs of glands under the skin of the neck when the neck is strongly compressed and the glands rupture, and it causes corneal ulceration and iritis when it enters the eye. Duvernoy's gland venom, in contrast, is released from the hind-region of the maxilla through conduit openings in front of the two pairs of fangs located on the back teeth of the maxilla. Because these fangs are short (< 2 mm) and no muscles are needed to squeeze the Duvernoy's gland, a momentary bite is often not enough to release the venom. If back teeth are involved in the bite, this venom can enter the body and cause serious bleeding.
Yamakagashi venom is a prothrombin activator. It causes strong blood coagulation and has a weak thrombin-like effect, 4 leading to disseminated intravascular coagulation (DIC) with a brinolytic phenotype. 5 Disseminated brin formation occurs, and brinolysis is activated, causing hypo brinogenemia and increased levels of brinogen degradation products. 1 Therapies for DIC due to yamakagashi venom include serotherapy (de nitive therapy) and recombinant thrombomodulin (rTM) therapy (alternative therapy). Yamakagashi antivenom can only be administered in clinical trials. Although Yamakagashi antivenom has an equine source, anaphylaxis rates are 0%. 6 In one study, compared to the antivenom non-administered group (n = 15), the antivenom administered group (n = 19) had a better prognosis (p = 0.03) and lower incidence of renal failure requiring dialysis (p = 0.03). 1 Since Yamakagashi antivenom is used off-label in Japan, 2 we need to participate in a clinical research group to use it. 5 Additionally, considering that Yamakagashi venom causes DIC with a brinolytic phenotype, rTM preparations are expected to be effective, 7 and their applications are being investigated. rTM can inhibit thrombin production, thus reducing bleeding symptoms and organ damage caused by DIC. 8 However, rTM is contraindicated in the early phase of trauma because it may promote bleeding, and the patient in our case had an active intracranial hemorrhage. To our knowledge, there have been no reported cases of complications in cases of traumatic intracranial hemorrhage after yamakagashi bites due to rTM administration. Moreover, only one report of rTM use in the diagnosis of DIC due to trauma exists, and the e cacy of rTM has not been reported, 9 although no life-threatening bleeding events have been observed in patients who die. Yamakagashi bites can cause DIC with a brinolytic phenotype; however, rTM may not be used in cases of yamakagashi bites with active bleeding due to trauma.
In this case, the possibility of a yamakagashi bite was not considered, and a large dose of FFP was administered to improve trauma-related severe coagulopathy. However, the intracranial hematoma worsened, with little improvement in brinogen levels, causing death. Even if we diagnosed the yamakagashi bite, owing to active bleeding caused by trauma, there would be no de nitive treatment except yamakagashi antivenom.

Conclusion
In this case of a yamakagashi bite with active bleeding due to trauma, there could be no de nitive treatment except for yamakagashi antivenom. . B Two hours after the injury, the left subacute subdural hematoma was not signi cantly changed, but the brain contusion worsened. C Seven hours after the injury, the hematoma in the left frontal lobe was markedly enlarged and had perforated into the ventricle. When FFP administration was started, PT-INR and APTT showed a transient improvement, but Fib remained almost below the detection limit.