Clinical trial NCT06304714: Effects of Bothrops Spp. Snake Envenomation on Willebrand Factor Activity in Martinique and French Guiana
Official title: Abnormalities of Plasma Willebrand Factor Activity Induced by Bothrops Snakebites Endemic to Martinique and French Guyana
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Snake Envenomation
Thrombi
Coagulopathy
Hemorrhage
Keywords: Snakebite envenomation
French Caribbean (Martinique, French Guiana)
Bothrops species
Von Willebrand Factor
endothelial activity
haemostasis
Lead sponsor: University Hospital Center of Martinique
Sponsor class: OTHER
Collaborators: name: University Hospital, Lille
First posted: 2024-03-12
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_ONLY
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: The study population will be patients hospitalized in the emergency and intensive care units of the Martinique University Hospital or the Cayenne University Hospital (French Guiana).

Patient recruitment will be organized by center throughout the 18-month study period.

Initial data collection (D0) will be carried out on admission to the hospital ward, using a blood sample taken as part of the treatment and for research purposes, to collect indicators relating to plasma Willebrand factor activity and the endothelial response induced by Bothrops bites. These indicators collected on D0 will constitute the reference data specific to each individual. At D1 and D8, these indicators will be collected again.

Brief summary: In 2017, the World Health Organization placed snakebites at the top of its list of neglected tropical diseases in an effort to facilitate funding for prevention programs, improve access to anti-venom, and stimulate new research in this area. Between 5 and 25 cases per 100 000 inhabitants are reported per year in French Guiana and Martinique. Before the era of anti-venom immunotherapy, envenomations by Bothrops snake bites in French Guiana and Martinique could quickly become life-threatening with a mortality rate close to 30%. Today, the administration of fragments of Fab or (Fab')2 immunoglobulins gives anti-venoms an excellent capacity to neutralise venom toxins, which has reduced mortality to less than 1% in the case of early hospital treatment In French Guiana, envenomation by Bothrops bites is characterized by local signs such as intense pain, rapidly expanding oedema, haemorrhagic phlyctenes and sometimes muscle necrosis. The local inflammatory and haemorrhagic damage is related to the enzymatic activities of the toxins contained in the venom (metallo-proteinases, disintegrins, and phospholipases A2, in particular). At the systemic level, venom serine proteases and metalloproteinases activate the coagulation cascade by multiple mechanisms (activation of coagulation factors X and V and of protrombin, thrombin-like and fibrinogenolytic enzymatic properties) and are responsible for the collapse of coagulation factors making the blood incoagulable. The metalloproteinases "hemorrhagins" destroy the vessel wall and are the cause of locoregional and systemic hemorrhage.

Envenomations by bites of Bothrops lanceolatus in Martinique have particular characteristics. Despite the genetic similarity with their congeners in French Guiana, envenomation by bites of Bothrops lanceolatus is characterized by the development of very intense local inflammatory signs (little haemorrhage) and the occurrence of thrombotic complications such as cerebral, pulmonary or myocardial infarction. The mechanisms behind this thrombotic presentation are not known. The large amount of metalloproteinases in the composition of Bothrops lanceolatus venom is believed to be responsible for destruction of vascular endothelium and pro-thrombotic state. Bothrops lanceolatus bite envenomations have been reported to be frequently complicated by generalized infections, disseminated intravascular coagulation and the occurrence of multi-visceral failure syndrome. This observation suggests abnormalities in endothelial function in which changes in Willebrand factor expression have been implicated.

The investigators hypothesize that plasma Willebrand factor (VW) activity and the intensity of endothelial activation are different depending on the Bothrops snake species involved in the bites in Guyana and Martinique. Due to the specific properties of the venoms of each Bothrops species, the activity of the Willebrand factor (VW) and the consequences in terms of endothelial activation would be different and responsible for the clinico-biological characteristics according to the geographical origin of the snakes.

The investigators will demonstrate that the accumulation of Willebrand factor (VW) and the increase in its activity are responsible for the endothelial activation and micro-thrombosis observed during envenomations by Bothrops lanceolatus bites, whereas the decrease in its activity induced by the venoms of endemic Bothrops from Guyana is responsible for haemorrhagic phenomena.

This study will highlight the importance of changes in Willebrand factor activity on endothelial activation and the initiation of micro-thrombosis in the case of Bothrops lanceolatus envenomations and on primary haemostasis and bleeding disorders in the case of endemic Bothrops in Guyana. This new knowledge is important insofar as individualised therapeutic management can be proposed. Indeed, several studies have shown that adjuvant treatment of thrombotic microangiopathies, such as thrombotic thrombocytopenic purpura, with blood products (fresh frozen plasma) or plasma exchange, improves endothelial dysfunction and the prognosis of patients.


Eligibility criteria: Inclusion Criteria:

* Men or Women, at least 18 years old
* Be admitted to the Emergency Department of the Martinique University Hospital or the Cayenne University Hospital
* Be the victim of a confirmed Bothrops snake bite in Martinique or French Guyana. The formal identification of the snake by the patient or his entourage is imperative.
* Have a confirmed diagnosis of stage III envenomation (regional oedema of the limb and/or moderate general symptoms such as moderate hypotension, malaise, vomiting, abdominal pain, diarrhoea) and stage IV (extensive oedema reaching the trunk and/or severe general symptoms such as prolonged hypotension, shock, anaphylactoid reaction, visceral damage)
* Be able to receive and understand information related to the research
* Be able to freely give verbal consent to participate in the proposed research
* Be able to freely give written informed consent to participate in the plasmathèque
* Be affiliated to the general social security system

Exclusion Criteria:

* Pregnant or breastfeeding woman
* People who have been treated for snakebite with Bothrops anti-venom Bothrofav® or Antivipmyn-tri®.
* Known disorders of haemostasis such as haemophilia A (factor VIII deficiency), haemophilia B (factor IX deficiency), vitamin K deficiency, hepato-cellular insufficiency, presence of circulating anticoagulant factors
* Disseminated intravascular coagulation (DIC)
* Constitutional and acquired Von Willebrand disease
* Constitutional and acquired thrombopathies
* Idiopathic thrombocytopenic purpura
* Person under legal protection (guardianship, curatorship, safeguard of justice), and person deprived of liberty.

Primary outcomes:
measure: Plasma Willebrand factor (VW:Act) activity prior to administration of the anti-venom (Bothrofav® or Antivipmyn-tri®).
timeFrame: Day 0 (initail hospital admission)
Secondary outcomes:
measure: Plasma VW factor activity (VW:Act/VW:Ag ratio)
timeFrame: Day 1 and day 8
Other outcomes:
measure: Hemostasis abnormalities
timeFrame: Day 0, day 1 and day 8
measure: Plasma levels of high-molecular-weight VW factor multimers assessed by electrophoresis technique
timeFrame: Day 0, day 1 and day 8
measure: Plasma concentrations of soluble forms of the endothelial adhesion molecules
timeFrame: Day 0, day 1 and day 8
Locations:
city: Fort de France
country: Martinique
facility: University Hospital Center of Martinique
Study officials:
affiliation: University Hospital of Martinique
name: REMI NEVIERE, Professor
role: STUDY_DIRECTOR
affiliation: University Hospital of Martinique
name: DABOR RESIERE, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital of Cayenne, FRENCH GUIANA
name: HATEM KALLEL, Professor
role: PRINCIPAL_INVESTIGATOR
References: