Introduction
Snake bite envenomation leads to significant life threatening toxin mediated clinical syndromes.1, 2, 3, 4, 5 Early access to medical care is important and antivenom is the standard of care for envenomed patients. Many victims do not attend health care centers or hospitals but rely on traditional and native treatments, which in turn increase the burden of the disease by increasing the mortality. Available data shows 4.5 to 5.4 million people 6, 7, 8, 9 get bitten by snake annually. Of this 1.8 to 2.7 million severely affected. Snake bite is classified as category A neglected tropical disease by WHO. They affect over 1 billion people in resource limited setting carrying significant economic cost for low to middle income countries. There may be limited access to antivenom, blood products, specialized hospital and intensive care and ventilators. WHO set a global target for 50% reduction 10 in snake bite associated mortality and morbidity. Hemotoxic toxin syndrome,11 carry a high risk of hemorrhage and death. Snake venom have toxins that cause coagulopathy in a two different mechanism of actions. The snake toxins act as anticoagulant 12, 13, 14, 15, 16, 17 which inhibit clotting cascade or act as procoagulant 12, 13, 14, 15, 16, 17, 18 toxins which activate the clotting cascade and consume clotting factors. The consumption coagulopathy in snake bite is referred to as Venom Induced Consumptive Coagulopathy (VICC). 1, 19, 20, 21, 2, 22, 23, 24, 25, 26, 27 VICC is marked by prolonged clotting time and clotting factor deficiencies and an elevated ddimer. VICC has a rapid onset and resolves with inactivation of toxins and synthesis of new clotting factors. A subset of VICC develops Thrombotic Microangiopathy (TMA). 1, 19, 2, 28, 29, 30 TMA is different and poorly understood hemotoxic syndrome.
Materials and Methods
Participants
All consenting adult patients presenting to Thanjavur medical college with suspected or with clear snake bite history within 24 hours and Patients with thrombocytopenia less than 1.5 lakh in the first 3 days of hospital stay. 91 patients both males and females with history or suspected history of snake bite is taken for the study. Pre-existing kidney disease with serum creatinine more than 1.4 prior to snake bite and ultrasound evidence of chronic kidney disease are excluded.
Study procedure
After explaining the purpose, procedure, benefits and risks involved in the study, patient’s information study was handed over to the study subjects. After obtaining informed written consent, the patients with snakebite who fits into the eligibility criteria enter into the study. The study subjects were subjected to through clinical history examination and necessary laboratory investigations were done. Data was collected using pre- structured proforma.
Study variables
Admission characteristics- nature of bite, symptoms, signs
Clinical syndrome – local swelling, pure hemotoxicity, neurotoxicity and Acute Renal Failure Clinical findings- signs of bleeding, confusion, headache, aphasia, dysarthria, breath holding time, neck holding time, fever, jaundice, haematuria, oliguria
Laboratory parameters- complete blood count, prothrombin time, activated partial prothrombin time, platelets count, peripheral smear for schistiocytes, retic count, serum lactate dehydrogenase level, serum bilirubin, d- dimer.
Results
TMA spectrum disorders include isolated thrombocytopenia, thrombocytopenia with MAHA, thrombocytopenia, MAHA and renal failure. The most severe presentation is with thrombocytopenia, MAHA, schistiocytes and renal failure associated with significant mortality. TMA spectrum disorders affect predominantly the hematological system and renal system and the neurological finding are very low. Clinicians need to have a very high suspicion of TMA in snake envenomation syndromes. Easily available tests including complete blood count, platelet count, schistiocytes, hemoglobin, lactate dehydrogenase, creatinine, bilirubin and d-dimer should be monitored for first few days as the patient enters VICC. Early and appropriate administration of ASV helps in preventing the complications. And anticipation for the further evidence of TMA must be kept.
A total of 91 patients were taken for study. Blue bar diagram denotes absolute count and red bar diagram shows percent of patitents. 93.4% of studied population were given ASV within 1 hr of hospital admission.
Table 1
Various outcomes in snake bite cases among study population
Out of the studied population, approximately 49.5 % developed AKI. 31.9 % needed ICU stay same population need to undergo dialysis. 52.7 % had to undergo blood transfusion during the course of treatment and 40.7% developed venom induced DIC.
Discussion
In our study most of the patients have reached health care facility either primary or tertiary heath care centre within 24 hours. And in most of the patients the mean time between the time of bite and suspected history of bite is less than 1 hour. About 93.4% of patients (85 patients out 0f 91 patients studied) have received their antisnake venom within 1 hour of bite history. In a study conducted by ESLAMAIAN ET AL, it showed the mean time period between the bite and reaching first health care facility was about 6 hours. In the past, people used to rely on the natural medications and had superstitious believes which delay the arrival to health centre after bite. This mean hour of 1 hours shows that there is an increasing awareness among the people across the country.
Study by PADHIYAR ET AL, showed 62.5 % of patient had received.
ASV at primary health centre itself before arriving to the tertiary health care hospital. In my study the similar findings were observed. This shows the better availability of antisnake venom even at small health centres. This very much helps in preventing the mortality and the complications of snake bite that occurs due to delay in antisnake venom. The mean antisnake venom vials administered in my study is around 3 vials.
Almost more than 50 studies have been carried out in various countries across the world to bring out the prevalence of thrombotic Microangiopathy (TMA) spectrum disorders that occurs following snake bite. These cases are predominantly distributed in countries like India, Srilanka followed by Australia and from few other countries. The species studied are mainly Vipers, Elapids and few others.
In our study 33% of patients had, deranged INR at presentation and around 40% of patients had platelets count less than 1 lakh 50000 cells/cu.mm at presentation. Among this 40.7% of patients developed venom induced consumptive coagulopathy and 53.7% of patients have received blood and blood products transfusion and around 3.9% patients had ICU stay. In a study done by Demple et al, showed normalization of coagulation profile occurs within 48 hours of antisnake venom administration.
Another study by Aggarwal et al, showed 51 patients out of 53 studied showed who had abnormal coagulation profile at presentation after 12 hours of intravenous antisnake venom administration their coagulation profile become normal. In our study this time interval between the normalization of coagulation profile and antisnake venom administration was difficult to analyse.
The majority of the studies that are done prior to the systemic review, suggested that thrombotic Microangiopathy spectrum disorders are uncommon. However the systemic review of the previous studies published in December 8, 2020 by TINN NOUTOUSE et al found that there is a significant incidence of TMA spectrum disorders following snakebite. Our study also supports the fact, that TMA1, 19, 2, 28, 29, 30 disorders following snakebite usually occurs in the background of coagulopathy in the presence of thrombocytopenia is significant. In most of the cases the platelet count is usually between 50,000 cells/cu.mm to 1, 00,000 cells/cu.mm and in severe cases it is less than 50,000cells/cu.mm.
Mechanism of coagulation are typically in favour of venom induced consumptive coagulopathy, with coagulation factor consumption as evidenced by prolonged INR and APTT. Anemia and thrombocytopenia present in almost in many cases as seen in other TMAs such as hemolytic uremic syndrome (HUS). 1, 4, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 In our study the full spectrum of illness Microangiopathy haemolytic anemia, thrombocytopenia and renal failure was seen in 2.2 % of study patients. Thrombocytopenia and acute kidney injury was observed in 29.7 % of patients. Thrombocytopenia, Microangiopathy haemolytic anemia, schistiocytes, end organ damage seen in 13.2%. Out of this 67.6% developed acute kidney injury and about 45(% had the need for dialysis. These patients were intensively treated with hemodialysis and transfusion, out of which around 14.3% developed acute kidney injury managed conservatively without the need for renal replacement therapy.
Around 64.8% needed renal replacement therapy and recovered. And 14.3 % patients were put on maintenance hemodialysis and was on further follow up. And around 6.6% of patients expired in spite of effective treatment.
The predominant clinical organ affected is renal system. AKI occurring in almost more than 90% of cases with TMA. And the majority of cases required dialysis for AKI and recovered over days to weeks. Very few cases were put on maintenance HD. The clinical studies available has provided little evidence whether timing of antivenom has benefit against TMA prevention. In animal studies the antivenom administered before envenomation developed few complications. And supported the hypothesis that fewer manifestation such as TMA, VICC occurs following the timely administration of ASV within the critical period. This study also shows non correlation the time of ASV administration and the clinical course particularly TMA.
The platelet count at admission, the presence of schistiocytes and the development of VICC, the need for dialysis and outcome are very much interrelated and has effect. The aetiology of TMA following snake bite remains unclear. The pattern of end organ renal injury TMA in the previous studies are mostly in the pattern of HUS than TTP as evidenced by lack of neurological manifestation. It is found that the development of full spectrum disorder was associated with higher antisnake venom dose, blood products, dialysis, ICU stay, longer duration of hospital stay and mortality. The treatment modality used in the patients with TMA were blood and blood products transfusion and dialysis.
The main limitation of this study is we could not able to do renal biopsy and the clinical correlation of severity with it. Herein, from this study it is found that there is a reasonable risk in the development of TMA spectrum disorders following snakebite. Antivenom in the corner stone in the management of snakebite, and it is found that there is no evidence for ASV protective effect against the development of TMA after snake bite. Further studies has to be carried out to show the benefit of plasma exchange for TMA spectrum disorders that occur following snake bite. This will helps to formulate the protocol for the management of TMA and its complications following bite.
Conclusion
TMA spectrum disorders include isolated thrombocytopenia, thrombocytopenia with MAHA, thrombocytopenia, and renal failure. The most severe presentation is with thrombocytopenia, MAHA, schistiocytes and renal failure associated with significant mortality. TMA spectrum disorders affect predominantly the hematological system and renal system.
Easily available tests including complete blood count, platelet count, schistiocytes, hemoglobin, lactate dehydrogenase, creatinine, bilirubin and d-dimer should be monitored for first few days as the patient enters VICC.
Early and appropriate administration of ASV helps in preventing the complications. Patients with full blown TMA should be managed adequately with good supportive care and individualized transfusions with blood and blood products has to be done if needed.
