Antithrombotic compounds, methods and uses thereof

1. A method of binding a phosphate containing biological macromolecule, the method comprising administering a Universal Heparin Reversal Agent (UHRA) polymer to a subject in need of having phosphate containing biological macromolecules bound, wherein the UHRA polymer comprises: a) a dendritic polyglycerol core having 5-33 randomly distributed tetra-amine groups, wherein the tetra-amines have the following structure

and wherein the molecular weight of the polymer in kDa per tetra-amine group does not exceed 4.5; and (b) an outer shell, wherein the outer shell is a hydrophilic polymeric system, wherein the hydrophilic polymeric system is selected from the group consisting of polyether, polyalcohol, polyglycerol, linear polyglycerol, oligosaccharide, poly(N-isopropylacrylamide (PNIPAM), polyacrylamide (PAM), poly(2-oxazoline), poly(ethylene glycol), methoxy(polyethylene glycol), poly(ethylene oxide), poly(vinyl alcohol) (PVA), and poly(vinylpyrrolidone) (PVP), and combinations thereof, and wherein the UHRA polymer is selected from the group consisting of UHRA-1, UHRA-2, UHRA-5, UHRA-6, UHRA-7, UHRA-8, UHRA-9, UHRA-10, UHRA-11, UHRA-13, UHRA-14 and UHRA-15.

2. The method of claim 1 , wherein the outer shell is selected from one or more of:

or

wherein

n is 0-100, x is 0-100 and y is 0-100;

n is an integer between 1 and 20, x is an integer between 1 and 20 and y is an integer between 1 and 20;

n is an integer between 3 and 10, x is an integer between 3 and 10 and y is an integer between 3 and 10;

n is an integer between 4 and 9, x is an integer between 4 and 9 and y is an integer between 4 and 9;

or

n is an integer between 5 and 8, x is an integer between 5 and 8 and y is an integer between 5 and 8.

3. The method of claim 1 , wherein the binding of the phosphate containing biological macromolecule results in neutralization.

4. The method of claim 1 , wherein the phosphate containing biological macromolecule is polyphosphate or a nucleic acid.

5. The method of claim 4 , wherein the binding to polyphosphate disrupts the interaction between thrombin and polyphosphate.

6. The method of claim 1 , wherein the polyglycerol core has between 7-24 randomly distributed tetra-amine groups or wherein the polyglycerol core has between 11-24 randomly distributed tetra-amine groups.

7. The method of claim 1 , wherein the molecular weight of the UHRA polymer in kDa per tetra-amine group is between 0.9 and 4.5 or wherein the molecular weight of the UHRA polymer in kDa per tetra-amine group does not exceed 3.6.

8. The method of claim 1 , wherein the UHRA polymer has an IC 50 (nM) for inhibition of thrombin binding to polyphosphate is equal to or less than 50 nM.

9. The method of claim 1 , wherein the polyglycerol core has a degree of branching: in the range of about 0.05 to about 0.95; or in the range of about 0.40 to about 0.65.

10. The method of claim 1 , wherein the subject is administered the UHRA polymer to treat stroke, acute coronary syndrome, pulmonary embolism, atrial fibrillation, venous or arterial thromboembolism, disseminated intravascular coagulation (DIC), deep-vein thrombosis (DVT), peripheral artery disease, trauma-induced coagulopathy, extracorporeal circulation, cancer-associated thrombosis, sepsis, septic shock, Systemic Inflammatory Response Syndrome (SIRS), and inflammation.

11. The method of claim 10 , wherein the UHRA polymer is administered in a dose range of 1 mg/kg to 1000 mg/kg.

12. The method of claim 10 , wherein the UHRA polymer is administered in a dose range of 50-100 mg/kg.

13. The method of claim 10 , wherein the subject is human.

14. The method of claim 10 , wherein the subject is non-human.

15. The method of claim 14 , wherein the subject is a non-human mammal.

16. The method of claim 14 , wherein the subject is a mouse, a rat, a pig, a dog, a cat, a horse, a sheep, a cattle, a goat or a chicken.

17. The method of claim 1 , wherein shell polymer is between about 10 to about 90 wt % of the UHRA polymer.