Method for diagnosing and monitoring hemostatic dysfunction, severe infection and systematic inflammatory response syndrome

• US 20030228625A1
• Filed: 02/27/2003
• Published: 12/11/2003
• Est. Priority Date: 02/27/2002
• Status: Active Grant

• Current Assignee: Biomerieux Incorporated (Compagnie Merieux Alliance SAS)
• Original Assignee: Biomerieux Incorporated (Compagnie Merieux Alliance SAS)
• Inventors: Jones, Gregory, Tejidor, Liliana, Toh, Cheng Hock, Neisheim, Mike
• Granted Patent: US 7,282,368 B2
• Time in Patent Office: Days
• US Class Current: 435/7.1
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 33/00 Antiparasitic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/04 Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: G01N 33/92 involving lipids, e.g. cholesterol , lipoproteins, or their receptors steroid hormones G01N33/743

Abstract

A method for diagnosing and monitoring subjects for hemostatic dysfunction, severe infection and systematic inflammatory response syndrome is provided whereby lipoproteins are examined for abnormalities, particularly for prothrominase enhancement, through quantitative and qualitative analysis.

Claims

1. A method for diagnosis and monitoring a host response to infection, SIRS and sepsis, said method comprising (a) obtaining a patient sample;

(b) measuring a lipoprotein fraction from said sample for an abnormality; and

(c) correlating said lipoprotein measurement to an abnormality found in patients having severe infection, SIRS or hemostatic dysfunction.

2. A method according to claim 1 wherein said lipoprotein abnormality is enhanced ability to support prothrombinase activity for patients with severe infection, SIRS and/or sepsis.

3. The method according to claim 1, wherein said lipoprotein fraction comprises beta lipopteins and said enhanced ability to support prothrombinase activity demonstrates at least a two-fold increase in prothrombin activity as compared with normal samples.

4. The method according to claim 1, wherein said step (b) is carried out by measuring rate of thrombin generation and said beta lipoprotein comprises an apoB containing lipoprotein.

5. The method according to claim 1, wherein said determining step is carried out in the absence of forming a complex between said betalipoprotein and C-reactive protein (CRP).

6. A method to predict an increased likelihood of system failure or mortality in said patient, said method comprising (a) obtaining a patient sample;

(b) measuring from said sample a lipoprotein fraction for PTase;

(c) comparing said prothrombin activation of said sample to a standard of normal patient samples or abnormal patient samples; and

(d) utilizing said comparison to predict the mortality of said patient wherein said lipoprotein for supporting PTase for patients with increased likelihood of system failure or mortality demonstrates at least a two-fold increase in PTase activity as compared with normal samples.

7. A method for predicting an increased likelihood of infection in a patient, said method comprising:

(a) obtaining a sample of very large density lipoproteins (VLDLs) from a patient; and

(b) determining the activity of VLDLs in said plasma or serum sample for activating prothrombin;

a greater activity of said VLDLs for activating prothrombin indicating an increased likelihood of infection in said patient.

8. A method according to claim 7 wherein said patient has a biphasic waveform.

9. A method according to claim 7 wherein a measurement of the activity of VLDL is carried out directly or indirectly.

10. A method according to claim 7 wherein said activity of VLDL is carried out by a method comprising measuring a rate of thrombin generation.

11. A method for diagnosing severe infection, SIRS or sepsis, said method comprising (a) obtaining a patient sample;

(b) subjecting the patient sample to a biphasic waveform screening test to obtain a normal or biphasic waveform result;

(c) subjecting said patient samples demonstrating said biphasic waveform result to a to determine PTase of the lipoproteins; and

(d) determining a relationship with those patients exhibiting increased PTase activities with a diagnosis of severe infection, SIRS or sepsis.

13. The method according to claim 11 wherein said relationship indicates that the patient has DIC.

12. The method according to claim 12, wherein said infection is sepsis.

14. A method for diagnosis and monitoring a host response to infection, SIRS and sepsis, said method comprising (a) obtaining a blood sample or serum sample from a patient;

(b) measuring said sample lipoprotein fraction for qualitative or quantitative properties of lipoproteins utlizing an anlaysis comprising NMR;

(c) comparing said properties of lipoproteins of said sample to a standard of normal patient samples or abnormal patient samples; and

(d) utilizing said comparison to diagnose and/or monitor a host response to infection, SIRS and sepsis.

15. A specific binding assay diagnosing and monitoring patients with severe infection, SIRS and sepsis said method comprising (a) obtaining a sample from a patient;

(b) contacting said sample with a specific binding agent to capture a lipoprotein containing an abnormality;

(c) quantitatively or qualitatively analzying said captured abnormal lipoprotein to obtain a result; and

(d) correlating said result with abnormal lipoproteins found in patients with severe infection, SIRS and hemostatic dysfunction.

16. An assay according to claim 15 wherein said specific binding agent is Annexin 5.

17. An assay according to claim 16 wherein said specific binding agent is an antibody specific to Annexin 5.

18. A method for treating a patient for severe infection, SIRS or sepsis, said method comprising administering an effective amount of Annexin 5 to block prothrombinase assembly.

19. A method according to claim 18 wherein said patient has DIC.

21. A method according to claim 18 wherein the abnormal lipoproteins are selected from the group consisting of VLDL, IDL and LDL.

20. A method for predicting the existence of sepsis in a patient, said method comprising:

a) obtaining a sample of lipoproteins from a patients, (b) determining whether the lipoproteins are abnormal as compared to lipoproteins from a normal patient sample, and (c) predicting the existence of sepsis in the patient based on detected abnormal lipoproteins.

22. A method for predicting the hemostatic dysfunction in a patient, said method comprising:

a) obtaining a sample of lipoproteins from a patients, (b) determining whether the lipoproteins are abnormal as compared to lipoproteins from a normal patient sample, and (c) predicting the existence of hemostatic dysfunction in the patient based on detected abnormal lipoproteins.

23. A method according to claim 23 wherein said step (b) is carried out by detecting an enhanced procoagulant aspect of the VLDL from patients with the biphasic waveform by measuring a shortening of clot time in a modified APTT assay or measuring clot formation or measuring increased rate of accelaration of clot formation in a dilute tissue factor based assay.

24. A method for diagnosis and monitoring a host response to infection, SIRS and sepsis, said method comprising (a) obtaining a patient sample;

(b) measuring a lipoprotein fraction from said sample for total surface area; and

(c) correlating said lipoprotein measurement to increased surface area lipoprotein abnormality found in patients having severe infection, SIRS and hemostatic dysfunction.

25. A method according to claim 24 wherein said lipoprotein surface area is increased at least about 45% as compared with normal patient samples.