WO2022178177A4 - Freeze-dried platelet derivative compositions for treating antiplatelet-induced coagulopathy - Google Patents
Freeze-dried platelet derivative compositions for treating antiplatelet-induced coagulopathy Download PDFInfo
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- WO2022178177A4 WO2022178177A4 PCT/US2022/016866 US2022016866W WO2022178177A4 WO 2022178177 A4 WO2022178177 A4 WO 2022178177A4 US 2022016866 W US2022016866 W US 2022016866W WO 2022178177 A4 WO2022178177 A4 WO 2022178177A4
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- 239000000203 mixture Substances 0.000 title claims abstract 101
- 206010053567 Coagulopathies Diseases 0.000 title claims abstract 18
- 208000015294 blood coagulation disease Diseases 0.000 title claims abstract 9
- 239000003146 anticoagulant agent Substances 0.000 title claims abstract 4
- 230000000702 anti-platelet effect Effects 0.000 title claims 2
- 229940127218 antiplatelet drug Drugs 0.000 claims 26
- 230000000740 bleeding effect Effects 0.000 claims 25
- 230000002159 abnormal effect Effects 0.000 claims 14
- 239000000556 agonist Substances 0.000 claims 12
- 230000002776 aggregation Effects 0.000 claims 9
- 238000004220 aggregation Methods 0.000 claims 9
- 230000035602 clotting Effects 0.000 claims 9
- 238000011156 evaluation Methods 0.000 claims 9
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 claims 8
- 239000003795 chemical substances by application Substances 0.000 claims 7
- 102000002938 Thrombospondin Human genes 0.000 claims 6
- 108060008245 Thrombospondin Proteins 0.000 claims 6
- 239000003550 marker Substances 0.000 claims 6
- 230000010118 platelet activation Effects 0.000 claims 6
- 230000000284 resting effect Effects 0.000 claims 6
- 108010047303 von Willebrand Factor Proteins 0.000 claims 6
- 102100036537 von Willebrand factor Human genes 0.000 claims 6
- 229960001134 von willebrand factor Drugs 0.000 claims 6
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 claims 5
- 108090000190 Thrombin Proteins 0.000 claims 5
- 229960000446 abciximab Drugs 0.000 claims 5
- 229960001138 acetylsalicylic acid Drugs 0.000 claims 5
- 229960004072 thrombin Drugs 0.000 claims 5
- HWEOXFSBSQIWSY-MRXNPFEDSA-N 3-[(6r)-6-[(4-chlorophenyl)sulfonylamino]-2-methyl-5,6,7,8-tetrahydronaphthalen-1-yl]propanoic acid Chemical compound N([C@H]1CC2=CC=C(C(=C2CC1)CCC(O)=O)C)S(=O)(=O)C1=CC=C(Cl)C=C1 HWEOXFSBSQIWSY-MRXNPFEDSA-N 0.000 claims 4
- KYWCWBXGRWWINE-UHFFFAOYSA-N 4-methoxy-N1,N3-bis(3-pyridinylmethyl)benzene-1,3-dicarboxamide Chemical compound COC1=CC=C(C(=O)NCC=2C=NC=CC=2)C=C1C(=O)NCC1=CC=CN=C1 KYWCWBXGRWWINE-UHFFFAOYSA-N 0.000 claims 4
- QWKAUGRRIXBIPO-UHFFFAOYSA-N Atopaxar Chemical compound N=C1C=2C(F)=C(OCC)C(OCC)=CC=2CN1CC(=O)C(C=C(C=1OC)C(C)(C)C)=CC=1N1CCOCC1 QWKAUGRRIXBIPO-UHFFFAOYSA-N 0.000 claims 4
- LMHIPJMTZHDKEW-XQYLJSSYSA-M Epoprostenol sodium Chemical compound [Na+].O1\C(=C/CCCC([O-])=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 LMHIPJMTZHDKEW-XQYLJSSYSA-M 0.000 claims 4
- 108010056764 Eptifibatide Proteins 0.000 claims 4
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- COWWROCHWNGJHQ-OPKBHZIBSA-J cangrelor tetrasodium Chemical compound [Na+].[Na+].[Na+].[Na+].C1=NC=2C(NCCSC)=NC(SCCC(F)(F)F)=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)C(Cl)(Cl)P([O-])([O-])=O)[C@@H](O)[C@H]1O COWWROCHWNGJHQ-OPKBHZIBSA-J 0.000 claims 4
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- RRGUKTPIGVIEKM-UHFFFAOYSA-N cilostazol Chemical compound C=1C=C2NC(=O)CCC2=CC=1OCCCCC1=NN=NN1C1CCCCC1 RRGUKTPIGVIEKM-UHFFFAOYSA-N 0.000 claims 4
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- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 claims 4
- LGSDFTPAICUONK-UHFFFAOYSA-N elinogrel Chemical compound O=C1C=2C=C(F)C(NC)=CC=2NC(=O)N1C(C=C1)=CC=C1NC(=O)NS(=O)(=O)C1=CC=C(Cl)S1 LGSDFTPAICUONK-UHFFFAOYSA-N 0.000 claims 4
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- 229960001123 epoprostenol Drugs 0.000 claims 4
- 229960004468 eptifibatide Drugs 0.000 claims 4
- GLGOPUHVAZCPRB-LROMGURASA-N eptifibatide Chemical compound N1C(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CCCCNC(=N)N)NC(=O)CCSSC[C@@H](C(N)=O)NC(=O)[C@@H]2CCCN2C(=O)[C@@H]1CC1=CN=C2[C]1C=CC=C2 GLGOPUHVAZCPRB-LROMGURASA-N 0.000 claims 4
- 229960001680 ibuprofen Drugs 0.000 claims 4
- 229960001006 picotamide Drugs 0.000 claims 4
- 150000003180 prostaglandins Chemical class 0.000 claims 4
- 229950005789 sarpogrelate Drugs 0.000 claims 4
- FFYNAVGJSYHHFO-UHFFFAOYSA-N sarpogrelate Chemical compound COC1=CC=CC(CCC=2C(=CC=CC=2)OCC(CN(C)C)OC(=O)CCC(O)=O)=C1 FFYNAVGJSYHHFO-UHFFFAOYSA-N 0.000 claims 4
- 238000001356 surgical procedure Methods 0.000 claims 4
- 229950001286 terutroban Drugs 0.000 claims 4
- 229960002528 ticagrelor Drugs 0.000 claims 4
- OEKWJQXRCDYSHL-FNOIDJSQSA-N ticagrelor Chemical compound C1([C@@H]2C[C@H]2NC=2N=C(N=C3N([C@H]4[C@@H]([C@H](O)[C@@H](OCCO)C4)O)N=NC3=2)SCCC)=CC=C(F)C(F)=C1 OEKWJQXRCDYSHL-FNOIDJSQSA-N 0.000 claims 4
- 229960003425 tirofiban Drugs 0.000 claims 4
- COKMIXFXJJXBQG-NRFANRHFSA-N tirofiban Chemical compound C1=CC(C[C@H](NS(=O)(=O)CCCC)C(O)=O)=CC=C1OCCCCC1CCNCC1 COKMIXFXJJXBQG-NRFANRHFSA-N 0.000 claims 4
- IQKAWAUTOKVMLE-ZSESPEEFSA-M treprostinil sodium Chemical compound [Na+].C1=CC=C(OCC([O-])=O)C2=C1C[C@@H]1[C@@H](CC[C@@H](O)CCCCC)[C@H](O)C[C@@H]1C2 IQKAWAUTOKVMLE-ZSESPEEFSA-M 0.000 claims 4
- 229960001726 treprostinil sodium Drugs 0.000 claims 4
- 229960005044 vorapaxar Drugs 0.000 claims 4
- ZBGXUVOIWDMMJE-QHNZEKIYSA-N vorapaxar Chemical compound C(/[C@@H]1[C@H]2[C@H](C(O[C@@H]2C)=O)C[C@H]2[C@H]1CC[C@H](C2)NC(=O)OCC)=C\C(N=C1)=CC=C1C1=CC=CC(F)=C1 ZBGXUVOIWDMMJE-QHNZEKIYSA-N 0.000 claims 4
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 claims 3
- 239000005528 B01AC05 - Ticlopidine Substances 0.000 claims 3
- 239000005465 B01AC22 - Prasugrel Substances 0.000 claims 3
- 229960003009 clopidogrel Drugs 0.000 claims 3
- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 claims 3
- 230000007423 decrease Effects 0.000 claims 3
- 239000011859 microparticle Substances 0.000 claims 3
- 229960004197 prasugrel Drugs 0.000 claims 3
- DTGLZDAWLRGWQN-UHFFFAOYSA-N prasugrel Chemical compound C1CC=2SC(OC(=O)C)=CC=2CN1C(C=1C(=CC=CC=1)F)C(=O)C1CC1 DTGLZDAWLRGWQN-UHFFFAOYSA-N 0.000 claims 3
- 238000012032 thrombin generation assay Methods 0.000 claims 3
- PHWBOXQYWZNQIN-UHFFFAOYSA-N ticlopidine Chemical compound ClC1=CC=CC=C1CN1CC(C=CS2)=C2CC1 PHWBOXQYWZNQIN-UHFFFAOYSA-N 0.000 claims 3
- 229960005001 ticlopidine Drugs 0.000 claims 3
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 claims 2
- 101001078143 Homo sapiens Integrin alpha-IIb Proteins 0.000 claims 2
- 102100025306 Integrin alpha-IIb Human genes 0.000 claims 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims 2
- -1 abciximab Chemical compound 0.000 claims 2
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 claims 2
- 239000000504 antifibrinolytic agent Substances 0.000 claims 2
- 239000000872 buffer Substances 0.000 claims 2
- 229950003499 fibrin Drugs 0.000 claims 2
- 230000023597 hemostasis Effects 0.000 claims 2
- 239000000106 platelet aggregation inhibitor Substances 0.000 claims 2
- 239000012313 reversal agent Substances 0.000 claims 2
- 150000003839 salts Chemical class 0.000 claims 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 claims 1
- 108010039627 Aprotinin Proteins 0.000 claims 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 claims 1
- 108010049003 Fibrinogen Proteins 0.000 claims 1
- 102000008946 Fibrinogen Human genes 0.000 claims 1
- 239000007995 HEPES buffer Substances 0.000 claims 1
- 101001015004 Homo sapiens Integrin beta-3 Proteins 0.000 claims 1
- 102100032999 Integrin beta-3 Human genes 0.000 claims 1
- 208000007536 Thrombosis Diseases 0.000 claims 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims 1
- 230000009471 action Effects 0.000 claims 1
- 229960005305 adenosine Drugs 0.000 claims 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims 1
- 229960003375 aminomethylbenzoic acid Drugs 0.000 claims 1
- QCTBMLYLENLHLA-UHFFFAOYSA-N aminomethylbenzoic acid Chemical compound NCC1=CC=C(C(O)=O)C=C1 QCTBMLYLENLHLA-UHFFFAOYSA-N 0.000 claims 1
- 238000004458 analytical method Methods 0.000 claims 1
- 229940127219 anticoagulant drug Drugs 0.000 claims 1
- 229960004405 aprotinin Drugs 0.000 claims 1
- 159000000007 calcium salts Chemical class 0.000 claims 1
- 150000001720 carbohydrates Chemical class 0.000 claims 1
- 210000000170 cell membrane Anatomy 0.000 claims 1
- 230000001010 compromised effect Effects 0.000 claims 1
- 238000002297 emergency surgery Methods 0.000 claims 1
- 229940012952 fibrinogen Drugs 0.000 claims 1
- 230000036541 health Effects 0.000 claims 1
- 238000000338 in vitro Methods 0.000 claims 1
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 claims 1
- 238000009533 lab test Methods 0.000 claims 1
- 159000000003 magnesium salts Chemical class 0.000 claims 1
- 230000007246 mechanism Effects 0.000 claims 1
- 239000003960 organic solvent Substances 0.000 claims 1
- 230000008520 organization Effects 0.000 claims 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 claims 1
- 159000000001 potassium salts Chemical class 0.000 claims 1
- 108020003175 receptors Proteins 0.000 claims 1
- 102000005962 receptors Human genes 0.000 claims 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims 1
- 235000017557 sodium bicarbonate Nutrition 0.000 claims 1
- 159000000000 sodium salts Chemical class 0.000 claims 1
- 229960000401 tranexamic acid Drugs 0.000 claims 1
- GYDJEQRTZSCIOI-LJGSYFOKSA-N tranexamic acid Chemical compound NC[C@H]1CC[C@H](C(O)=O)CC1 GYDJEQRTZSCIOI-LJGSYFOKSA-N 0.000 claims 1
- 229940127090 anticoagulant agent Drugs 0.000 abstract 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/14—Blood; Artificial blood
- A61K35/19—Platelets; Megacaryocytes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- Health & Medical Sciences (AREA)
- Hematology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Biotechnology (AREA)
- Virology (AREA)
- Biomedical Technology (AREA)
- Immunology (AREA)
- Developmental Biology & Embryology (AREA)
- Cell Biology (AREA)
- Zoology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Provided herein are methods and compositions for treating a coagulopathy in a subject. Such methods can include administering to the subject in need thereof, for example because they have been administered an anticoagulant agent, an effective amount of a composition including platelets, or in illustrative embodiments platelet derivatives, and in further illustrative embodiments freeze-dried platelet derivatives (FDPDs). Various properties of exemplary embodiments of such methods and platelet derivatives used therein, as well as numerous additional aspects and embodiments are provided herein.
Claims
1. A composition comprising freeze-dried platelet derivatives (FDPDs) for treating a coagulopathy in a subject that is being administered or has been administered an antiplatelet agent, wherein the treating comprises:
(a) determining in a pre-administering evaluation, that the subject has an abnormal value for one or more clotting parameters; and
(b) after (a), administering to the subject in need thereof an effective amount of the composition comprising FDPDs such that the bleeding potential of the subject is reduced, thereby treating the coagulopathy.
2. A composition comprising freeze-dried platelet derivatives (FDPDs) for treating a coagulopathy in a subject having an increased potential for bleeding as a result of being administered or having been administered an antiplatelet agent, wherein the treating comprises: administering to the subject having the increased potential for bleeding, an effective amount of the composition comprising FDPDs such that the bleeding potential of the subject is reduced, wherein the composition comprising FDPDs comprises a population of FDPDs having a reduced propensity to aggregate such that no more than 10% of the FDPDs in the population aggregate under aggregation conditions comprising an agonist but no platelets, thereby treating the coagulopathy.
3. The composition of claim 2, wherein the treating further comprises before the administering, determining that the subject was administered an antiplatelet agent.
4. A composition comprising freeze-dried platelet derivatives (FDPDs) for treating a coagulopathy in a subject, wherein the treating comprises: administering to the subject in need thereof an effective amount of the composition comprising FDPDs such that the bleeding potential of the subject is reduced, wherein the subject was administered an antiplatelet agent and a second agent that decreases platelet function, and wherein the subject is in need thereof because of an increased potential for bleeding as a result of being administered the antiplatelet agent and the second agent, thereby treating the coagulopathy.
5. The composition of claim 4, wherein the treating further comprises before the administering the composition comprising FDPDs, determining that the subject was administered the antiplatelet agent and the second agent that decreases platelet function.
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6. The composition of any one of claims 2 to 5, wherein the treating further comprises determining that the subject has an abnormal value for one or more clotting parameters in a pre-administering evaluation before the administering of the composition comprising freeze-dried platelet derivatives.
7. The composition of claim 4, wherein the antiplatelet agent is a first antiplatelet agent and the second agent is a second antiplatelet agent.
8. The composition of claim 7, wherein the first antiplatelet agent and the second antiplatelet agent are each different antiplatelet agents selected from aspirin, cangrelor, ticagrelor, clopidogrel, prasugrel, eptifibatide, tirofiban, abciximab, terutroban, picotamide, elinogrel, ticlopidine, ibuprofen, vorapaxar, atopaxar, cilostazol, prostaglandin El, epoprostenol, dipyridamole, treprostinil sodium, and sarpogrelate.
9. The composition of claim 7, wherein the first antiplatelet agent and the second antiplatelet agent have different mechanisms of action.
10. The composition of claim 9, wherein the first antiplatelet agent and the second antiplatelet agent are each different antiplatelet agents selected from aspirin, cangrelor, ticagrelor, clopidogrel, prasugrel, eptifibatide, tirofiban, abciximab, terutroban, picotamide, elinogrel, ticlopidine, ibuprofen, vorapaxar, atopaxar, cilostazol, prostaglandin El, epoprostenol, dipyridamole, treprostinil sodium, and sarpogrelate.
11. The composition of any one of claims 1 to 5, wherein the antiplatelet agent is selected from aspirin, cangrelor, ticagrelor, clopidogrel, prasugrel, eptifibatide, tirofiban, abciximab, terutroban, picotamide, elinogrel, ticlopidine, ibuprofen, vorapaxar, atopaxar, cilostazol, prostaglandin El, epoprostenol, dipyridamole, treprostinil sodium, and sarpogrelate.
12. The composition of any one of claims 1 to 5, wherein the antiplatelet agent is selected from cangrelor, ticagrelor, abciximab, terutroban, picotamide, elinogrel, ibuprofen, vorapaxar, atopaxar, cilostazol, prostaglandin El, epoprostenol, dipyridamole, treprostinil sodium, and sarpogrelate.
13. The composition of any one of claims 1 and 3 to 5, wherein the composition comprising FDPDs comprises a population of FDPDs having a reduced propensity to aggregate such that no more
157
than 10% of the FDPDs in the population aggregate under aggregation conditions comprising an agonist but no platelets.
14. The composition of any one of claims 1 to 5, wherein the FDPDs have a potency of at least 1.5 thrombin generation potency units (TGPU) per 106 platelet derivatives.
15. The composition of any one of claims 1 to 5, wherein at least 50% of the FDPDs are CD 41- positive FDPDs, wherein less than 5% of the CD 41-positive FDPDs are microparticles having a diameter of less than 0.5 pm, and wherein the FDPDs have a potency of at least 1.5 thrombin generation potency units (TGPU) per 106 platelet derivatives.
16. The composition of claim 15, wherein the antiplatelet agent targets a CD41/CD61 complex.
17. The composition of claim 16, wherein at least 75% of the FDPDs are CD41 -positive FDPDs.
18. The composition of claim 16, wherein the antiplatelet agent is selected from one or more of abciximab, eptifibatide, and tirofiban.
19. The composition of any one of claims 1 to 5, wherein the composition comprising FDPDs comprises a population of FDPDs having a reduced propensity to aggregate such that no more than 10% of the platelet derivatives in the population aggregate under aggregation conditions comprising an agonist but no platelets; and having one or more characteristics of a super-activated platelet selected from
A) the presence of thrombospondin (TSP) on their surface at a level that is greater than on the surface of resting platelets;
B) the presence of von Willebrand factor (vWF) on their surface at a level that is greater than on the surface of resting platelets; and
C) an inability to increase expression of a platelet activation marker in the presence of an agonist as compared to the expression of the platelet activation marker in the absence of an agonist.
20. The composition of any one of claims 1 to 5, wherein the composition comprising FDPDs comprises a population of FDPDs comprising CD 41 -positive platelet derivatives, wherein the population comprises FDPDs having a reduced propensity to aggregate such that no more than 10% of the FDPDs in the population aggregate under aggregation conditions comprising an agonist but no platelets,
wherein the FDPDs have an inability to increase expression of a platelet activation marker in the presence of an agonist as compared to the expression of the platelet activation marker in the absence of the agonist, wherein the FDPDs have a potency of at least 1.5 thrombin generation potency units (TGPU) per 106 platelet derivatives; and wherein less than 5% of the CD 41 -positive FDPDs are microparticles having a diameter of less than 0.5 pm.
21. The composition of any one of claims 1 to 5, wherein the composition comprising FDPDs comprises a population of FDPDs having a reduced propensity to aggregate such that no more than 10% of the platelet derivatives in the population aggregate under aggregation conditions comprising an agonist but no platelets, and further having one or both of: the presence of thrombospondin (TSP) on their surface at a level that is greater than on the surface of resting platelets; and the presence of von Willebrand factor (vWF) on their surface at a level that is greater than on the surface of resting platelets.
22. The composition of any one of claims 1 to 5, wherein the composition comprising FDPDs comprises a population of FDPDs comprising a population of platelet derivatives comprising CD 41 -positive platelet derivatives, wherein less than 5% of the CD 41-positive platelet derivatives are microparticles having a diameter of less than 0.5 pm, and comprising platelet derivatives having: a reduced propensity to aggregate such that no more than 10% of the platelet derivatives in the population aggregate under aggregation conditions comprising an agonist but no platelets; an inability to increase expression of a platelet activation marker in the presence of an agonist as compared to the expression of the platelet activation marker in the absence of the agonist; the presence of thrombospondin (TSP) on their surface at a level that is greater than on the surface of resting platelets; the presence of von Willebrand factor (vWF) on their surface at a level that is greater than on the surface of resting platelets; and a potency of at least 1.5 thrombin generation potency units (TGPU) per 106 platelet derivatives.
23. The composition of any one of claims 1 to 5, wherein the FDPDs comprise the receptor targeted by the antiplatelet reversal agent that was administered or is being administered to the subject.
24. The composition of any one of claims 1 to 5, wherein the effective amount of the composition comprising FDPDs is between 1.0 X 107 to 1.0 X 10n/kg of the subject.
25. The composition of any one of claims 1 to 5, wherein the effective amount of the composition comprising FDPDs is between 1.6 X 107 to 5.1 X 109/kg of the subject.
26. The composition of any one of claims 1 to 5, wherein the effective amount of the composition comprising FDPDs is an amount that has a potency between 250 and 5000 TGPU per kg of the subject.
27. The composition of any one of claims 1 to 5, wherein the treating the coagulopathy decreases the bleeding potential of the subject such that normal hemostasis is restored in the subject.
28. The composition of any one of claims 1 to 5, wherein the composition comprising FDPDs has the property that it is capable of reducing the bleeding potential of the subject, independent of whether a post-administering evaluation of bleeding potential if performed would yield a normal or abnormal result.
29. The composition of any one of claims 1 to 5, wherein the composition comprising FDPDs has the property that it is capable of reducing the bleeding potential of a subject having an abnormal value for one or more clotting parameters in an in vitro laboratory test, such that normal hemostasis is restored in the subject, independent of whether a post-administering evaluation of bleeding potential if performed would yield a normal or abnormal result.
30. The composition of any one of claims 4 to 5, wherein the second agent is not an anticoagulant.
31. The composition of any one of claims 1 to 5, wherein administration of the antiplatelet agent is stopped upon administration of the composition.
32. The composition of any one of claims 1 to 5, wherein administration of the antiplatelet agent is continued for at least 1 day after administration of the composition.
33. The composition of any one of claims 1 to 5, wherein the subject is identified as having an abnormal result for one or more pre-administering evaluations of clotting parameters during surgery.
34. The composition of claim 33, wherein the surgery is an emergency surgery.
35. The composition of claim 33, wherein the surgery is a scheduled surgery.
36. The composition of any one of claims 6, wherein the one or more clotting parameters includes an evaluation of bleeding.
37. The composition of claim 36, wherein the evaluation of bleeding is performed based on the World Health Organization (WHO) bleeding scale.
38. The composition of claim 37, wherein before the administering, the subject has bleeding of grade 2, 3, or 4 based on the WHO bleeding scale.
39. The composition of claim 38, wherein after the administering, the subject has bleeding of grade 0 or 1 based on the WHO bleeding scale.
40. The composition of claim 37, wherein after the administering, the subject has bleeding of one grade less, based on the WHO bleeding scale, than before the administering.
41. The composition of claim 37, wherein after the administering, the subject has bleeding of two grades less, based on the WHO bleeding scale, than before the administering.
42. The composition of claim 37, wherein after the administering, the subject has bleeding of three grades less, based on the WHO bleeding scale, than before the administering.
43. The composition of claim 6, wherein the evaluation of the one or more clotting parameters includes thromboelastography (TEG), and wherein an abnormal result for TEG is obtained.
44. The composition of claim 43, wherein the abnormal result for TEG comprises a maximum amplitude (MA) of less than about 50 mm.
45. The composition of claim 44, wherein after the administering, the subject has an increase in MA of at least 5, 10, 15, 20, or more, mm.
46. The composition of claim 44, wherein after the administering, the subject has a normal MA.
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47. The composition of claim 43, wherein the abnormal result for TEG comprises a percent aggregation (in the presence of 1 mmol/L arachidonic acid) of less than about 85%.
48. The composition of any one of claims 1 to 5, wherein after the administering, the subject has an increase in percent aggregation (in the presence of 1 mmol/L arachidonic acid) of at least 2, 3, 5, 8, 10, 12, or more, percentage points.
49. The composition of any one of claims 1 to 5, wherein after the administering, the subject has a normal percent aggregation (in the presence of 1 mmol/L arachidonic acid).
50. The composition of claim 43, wherein the TEG is used to evaluate adenosine diphosphate- induced platelet-fibrin clot strength.
51. The composition of claim 43, wherein the TEG is used to evaluate arachidonic acid-induced platelet-fibrin clot strength.
52. The composition of claim 6, wherein the evaluation of one or more clotting parameters is measured using a P2Y12 Reaction Units (PRU) and/or an Aspirin Reaction Units (ARU) test and an abnormal PRU and/or an abnormal ARU is obtained.
53. The composition of claim 52, wherein the abnormal result of the P2Y12 reaction unit test is a PRU of less than about 195, or less than about 180.
54. The composition of claim 53, wherein after the administering, the subject has an increase in PRU of at least 25, 50, 75, 100, or more.
55. The composition of claim 53, wherein after the administering, the subject has a normal PRU.
56. The composition of claim 52, wherein the abnormal result of the Aspirin Reaction Unit test is an ARU of less than about 550, or less than about 500.
57. The composition of claim 56, wherein after the administering, the subject has an increase in ARU of at least 25, 50, 75, 100, or more.
58. The composition of claim 56, wherein after the administering, the subject has a normal ARU.
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59. The composition of claim 6, wherein the one or more clotting parameters is thrombin generation measured using a thrombin generation assay (TGA) and an abnormal TGA result is obtained.
60. The composition of claim 6, wherein the one or more clotting parameters is analysis of total thrombus-formation.
61. The composition of any one of claims 1 to 5, wherein the use further comprises administering to the subject an additional antiplatelet agent reversal agent.
62. The composition of any one of claims 1 to 5, wherein the composition further comprises an anti- fibrinolytic agent.
63. The composition of claim 62, wherein the anti -fibrinolytic agent is selected from the group consisting of e-aminocaproic acid (EACA), tranexamic acid, aprotinin, aminomethylbenzoic acid, fibrinogen, and a combination thereof.
64. The composition of any one of claims 1 to 5, wherein administering comprises administering intravenously.
65. The composition of any one of claims 1 to 5, wherein the composition comprises trehalose.
66. The composition of claim 65, wherein the composition further comprises an incubating agent comprising one or more salts and a buffer.
67. The composition of claim 66, wherein the incubating agent comprises one or more salts selected from phosphate salts, sodium salts, potassium salts, calcium salts, magnesium salts, and a combination of two or more thereof, wherein the buffer comprises HEPES, sodium bicarbonate (NaHCCl·,). or a combination thereof, and wherein the composition comprises one or more additional saccharide.
68. The composition of claim 67, wherein the composition further comprises polysucrose.
69. The composition of claim 67, wherein the composition comprises an organic solvent.
70. The composition of any one of claims 1 to 5, wherein the antiplatelet agent is present in the subject at the time the composition comprising the FDPDs is administered at a level that increases the bleeding potential of the subject.
163
71. The composition of claim 70, wherein the antiplatelet agent is present at a Cmax within 1 hour of the time the composition comprising the FDPDs is administered to the subject.
72. The composition of any one of claims 1 to 5, wherein the FDPDs are surrounded by a compromised plasma membrane.
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Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2022221719A AU2022221719A1 (en) | 2021-02-17 | 2022-02-17 | Freeze-dried platelet derivative compositions for treating antiplatelet-induced coagulopathy |
| JP2023549556A JP2024507362A (en) | 2021-02-17 | 2022-02-17 | Freeze-dried platelet derivative composition for treating antiplatelet-induced coagulopathy |
| CA3211079A CA3211079A1 (en) | 2021-02-17 | 2022-02-17 | Freeze-dried platelet derivative compositions for treating antiplatelet-induced coagulopathy |
| EP22710793.5A EP4294411A1 (en) | 2021-02-17 | 2022-02-17 | Freeze-dried platelet derivative compositions for treating antiplatelet-induced coagulopathy |
| PCT/US2022/079280 WO2023081804A1 (en) | 2021-11-04 | 2022-11-04 | Platelet derivative compositions, and methods of making and using such compositions |
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| US202163150338P | 2021-02-17 | 2021-02-17 | |
| US63/150,338 | 2021-02-17 | ||
| US202163275937P | 2021-11-04 | 2021-11-04 | |
| US63/275,937 | 2021-11-04 | ||
| US202163276420P | 2021-11-05 | 2021-11-05 | |
| US63/276,420 | 2021-11-05 | ||
| US202163264227P | 2021-11-17 | 2021-11-17 | |
| US63/264,227 | 2021-11-17 | ||
| US17/673,773 | 2022-02-16 | ||
| US17/673,773 US20220168353A1 (en) | 2019-08-16 | 2022-02-16 | Freeze-dried platelet derivative compositions for treating antiplatelet induced coagulopathy |
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| WO2022178177A1 WO2022178177A1 (en) | 2022-08-25 |
| WO2022178177A4 true WO2022178177A4 (en) | 2022-10-20 |
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| EP3887404A4 (en) | 2018-11-30 | 2022-11-02 | Cellphire, Inc. | Platelets loaded with anti-cancer agents |
| EP3886879A4 (en) | 2018-11-30 | 2022-12-07 | Cellphire Inc. | Platelets as delivery agents |
| SG11202112054WA (en) | 2019-05-03 | 2021-11-29 | Cellphire Inc | Materials and methods for producing blood products |
| BR112022002892A2 (en) | 2019-08-16 | 2022-05-24 | Cellphire Inc | Thrombosomes as an antiplatelet agent reversal agent |
| WO2021158622A1 (en) | 2020-02-04 | 2021-08-12 | Cellphire, Inc. | Anti-fibrinolytic loaded platelets |
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| US7811558B2 (en) | 2004-08-12 | 2010-10-12 | Cellphire, Inc. | Use of stabilized platelets as hemostatic agent |
| AU2005272821B2 (en) | 2004-08-12 | 2010-09-09 | Cellphire, Inc | Methods for preparing freeze-dried platelets, compositions comprising freeze-dried platelets, and methods of use |
| US8097403B2 (en) | 2006-12-14 | 2012-01-17 | Cellphire, Inc. | Freeze-dried platelets, method of making and method of use as a diagnostic agent |
| AU2016317642A1 (en) | 2015-08-28 | 2018-08-16 | Cellphire, Inc. | Products and methods using a platelet-derived hemostatic agent for controlling bleeding and improving healing |
| EP3887404A4 (en) | 2018-11-30 | 2022-11-02 | Cellphire, Inc. | Platelets loaded with anti-cancer agents |
| EP3886879A4 (en) | 2018-11-30 | 2022-12-07 | Cellphire Inc. | Platelets as delivery agents |
| SG11202112054WA (en) * | 2019-05-03 | 2021-11-29 | Cellphire Inc | Materials and methods for producing blood products |
| BR112022002892A2 (en) * | 2019-08-16 | 2022-05-24 | Cellphire Inc | Thrombosomes as an antiplatelet agent reversal agent |
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