Ignite Creation Date:
2024-05-06 @ 7:34 PM
Last Modification Date:
2024-10-26 @ 3:09 PM
Study NCT ID:
NCT06050993
Status:
NOT_YET_RECRUITING
Last Update Posted:
2023-09-22
First Post:
2023-07-07
Brief Title:
Effects of Platelet Mimicking Nanoparticles in Patients With Cirrhosis
Sponsor:
Assistance Publique - Hôpitaux de Paris
Organization:
Assistance Publique - Hôpitaux de Paris
Study Overview
Official Title:
Exploration of Primary Haemostasis in Cirrhotic Patients With T-TAS System and Effects of Platelets Mimicking Nanoparticles
Status:
NOT_YET_RECRUITING
Status Verified Date:
2023-07
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
HEMCITAP
Brief Summary:
Haemostasis of cirrhotic patients is disturbed at different levels primary haemostasis coagulation and fibrinolysis leading to a new haemostatic balance Thrombocytopenia and thrombopathy are counterbalanced by elevation of Von Willebrand factor VWF and diminution of ADAMTS13 activity Exploration of primary haemostasis is difficult in the laboratory and non-interpretable in case of thrombocytopenia Moreover these tests are not performed under flow conditions The T-TAS01 system analyses the total haemostatic capacity in whole blood under shear stress with chips coated with type 1 collagen Platelets transfusion performs poorly in cirrhotic patients and is not recommended before invasive procedure Platelets mimicking nanoparticles PMNs have been developed by Pr Sen Gupta Case Western Reserve University Cleveland Ohio OH USA PMNs have been proven to collaborate with platelets and enhance haemostasis in different shear conditions in vitro and in different models of haemorrhage in vivo The assumption of this study is that the perfusions characteristics of cirrhotic patients in the T-TAS01 system will be different from those of non-cirrhotic patients and that platelets mimicking nanoparticles will improve these characteristics
Detailed Description:
Hepatic cirrhosis is accompanied by an alteration of the haemostatic balance primary haemostasis coagulation fibrinolysis With regard to primary haemostasis thrombocytopenia is usually moderate due to splenic or hepatic sequestration associated with portal hypertension Platelet synthesis is also reduced There are also autoimmune thrombocytopenia due to the presence of anti-platelet autoantibodies In addition there is a thrombopathy with functional alterations in platelet adhesion and aggregation In parallel with these abnormalities in platelet adhesion and aggregation the quantitative increase in the level of Von Willebrand factor VWF preserves the capacity for platelet aggregation even under conditions of circulating flow despite the reduction in the intrinsic functional capacity of VWF This increase can be explained by increased hepatic synthesis a larger endothelial surface area in the presence of collateral circulation and repeated endothelial aggression by endotoximia during infections as well as a decrease in clearance due to a decrease in the synthesis of ADAMTS13
Routine investigation of abnormalities in primary haemostasis is based almost exclusively on platelet counts as well as plasma VWF and ADAMTS13 assays Functional platelet tests PFA impedance aggregometry light transmission aggregation are more difficult to perform particularly in the case of thrombocytopenia and are not performed under circulating flow conditions The Total Thrombus Formation Analysis System T-TAS01 allows analysis of haemostatic capacity in whole blood and flow conditions Whole blood is deposited in a reservoir and then perfused onto a type I collagen-coated chip PL chip at a shear rate of 1500 s-1 mimicking blood flow in small arteries As the clot forms the pressure in the perfusion chamber increases until total occlusion occurs The parameters measured are
the time required to achieve a pressure within the perfusion chamber equal to 10 kilopascal kPa above the baseline pressure
the time required to reach a pressure of 60 kPa above the base pressure in the infusion chamber occlusion time
the area under the curve at 10 min The perioperative management of cirrhotic patients leads the clinician to ask the question of prophylactic platelet transfusion in the event of thrombocytopenia of less than 30 to 50 GL While this threshold value is based on a low level of evidence platelet transfusion has a poor performance in cirrhotic patients and is not without side effects Thus preventive platelet transfusion is not recommended In the event of bleeding management should consist of platelet transfusion combined with fibrinogen and antifibrinolytic administration Synthetic platelet mimicking particles SPs are made of a liposomal membrane and decorated with 3 different peptides collagen binding peptide CBP which binds to fibrillar collagen exposed at the subendothelium fibrinogen mimetic peptide FMP which can bind to the active form of platelet integrin αIIbβ3 and VWF binding peptide VBP which is derived from the C2 domain of factor VIII and can bind to the D-D3 domain of VWF
Ex vivo in the absence of endothelial injury these SPs do not induce platelet aggregation in the absence of agonist but enhance aggregation in the presence of agonist These SPs do not trigger thrombin formation on their own but in the presence of tissue factor SPs increase thrombin generation and fibrin formation In perfusion chambers these nanoparticles allow platelets to adhere to a collagen-coated surface and to aggregate with each other In vivo SPs collaborate with platelets to restore effective haemostasis in thrombocytopenic mice undergoing tail-clipping Their haemostatic efficacy has also been demonstrated in various animal models of traumatic injury including a mouse model of liver laceration a porcine model of traumatic arterial haemorrhage and a rodent model of liver resection
The assumption of this study is that the characteristics of infusions with the T-TAS01 system will be altered in cirrhotic patients reflecting impairment of primary haemostasis compared to control patients and that platelet-mimicking nanoparticles PMNs will correct these alterations
Routine investigation of abnormalities in primary haemostasis is based almost exclusively on platelet counts as well as plasma VWF and ADAMTS13 assays Functional platelet tests PFA impedance aggregometry light transmission aggregation are more difficult to perform particularly in the case of thrombocytopenia and are not performed under circulating flow conditions The Total Thrombus Formation Analysis System T-TAS01 allows analysis of haemostatic capacity in whole blood and flow conditions Whole blood is deposited in a reservoir and then perfused onto a type I collagen-coated chip PL chip at a shear rate of 1500 s-1 mimicking blood flow in small arteries As the clot forms the pressure in the perfusion chamber increases until total occlusion occurs The parameters measured are
the time required to achieve a pressure within the perfusion chamber equal to 10 kilopascal kPa above the baseline pressure
the time required to reach a pressure of 60 kPa above the base pressure in the infusion chamber occlusion time
the area under the curve at 10 min The perioperative management of cirrhotic patients leads the clinician to ask the question of prophylactic platelet transfusion in the event of thrombocytopenia of less than 30 to 50 GL While this threshold value is based on a low level of evidence platelet transfusion has a poor performance in cirrhotic patients and is not without side effects Thus preventive platelet transfusion is not recommended In the event of bleeding management should consist of platelet transfusion combined with fibrinogen and antifibrinolytic administration Synthetic platelet mimicking particles SPs are made of a liposomal membrane and decorated with 3 different peptides collagen binding peptide CBP which binds to fibrillar collagen exposed at the subendothelium fibrinogen mimetic peptide FMP which can bind to the active form of platelet integrin αIIbβ3 and VWF binding peptide VBP which is derived from the C2 domain of factor VIII and can bind to the D-D3 domain of VWF
Ex vivo in the absence of endothelial injury these SPs do not induce platelet aggregation in the absence of agonist but enhance aggregation in the presence of agonist These SPs do not trigger thrombin formation on their own but in the presence of tissue factor SPs increase thrombin generation and fibrin formation In perfusion chambers these nanoparticles allow platelets to adhere to a collagen-coated surface and to aggregate with each other In vivo SPs collaborate with platelets to restore effective haemostasis in thrombocytopenic mice undergoing tail-clipping Their haemostatic efficacy has also been demonstrated in various animal models of traumatic injury including a mouse model of liver laceration a porcine model of traumatic arterial haemorrhage and a rodent model of liver resection
The assumption of this study is that the characteristics of infusions with the T-TAS01 system will be altered in cirrhotic patients reflecting impairment of primary haemostasis compared to control patients and that platelet-mimicking nanoparticles PMNs will correct these alterations
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 2023 -A00064-41 | OTHER | IDRCB | None |