# US 9,435,813 B2 · Biomarkers of hemorrhagic shock

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- Number: US 9,435,813 B2
- Document ID: US9435813B2
- Status: Granted
- Kind: B2
- Application number: 13/696,530
- Filed: 2011-05-11
- Published: 2013-06-13
- Granted: 2016-09-06
- Earliest claimed: 2010-05-11
- Assignees: The General Hospital Corporation
- Applicants: Hasan B. Alam; Yongqing Li
- Inventors: Hasan B. Alam; Yongqing Li
- Web page: https://patentgrep.com/patent/US9435813B2

## CPC

- G01N 33/6893: {related to diseases not provided for elsewhere}
- G01N 33/92: involving lipids, e.g. cholesterol {, lipoproteins, or their receptors (steroid hormones G01N33/743)}
- G01N 2800/32: Cardiovascular disorders
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

Methods for the use of keratinocyte chemoattractant (KC)/human growth-regulated oncogene (GRO) (KC/GRO), apolipoprotein A2 (APOA2), angiotensinogen r (AGT), thyroglobulin (TG), disintegrin and metalloproteinase domain-containing protein 17 (ADAM17), anionic trypsin-1 (PRSS1), complement C4 (C4A), zona pellucida sperm-binding protein 1 (ZP1), neuropilin-2 (NRP2), solute carrier family 13 member 2 (SLC13A2), glucagon-like peptide 2 receptor (GLP2R), lipoma high mobility group protein isoform I-C (HMGIC) fusion partner-like protein 4 (LHFPL4), and claudin-3 (CLDN3) as biomarkers for diagnosis and prognosis, and for monitoring the efficacy of treatment, in hemorrhagic shock (HS).

## Claims

### Claim 1

A method of predicting and improving prognosis of a subject suffering from hemorrhagic shock (HS), the method comprising:
obtaining a sample comprising serum from the subject;
determining expression levels of keratinocyte chemoattractant (KC)/human growth-regulated oncogene (GRO) (KC/GRO), zona pellucida sperm-binding protein 1 (ZP1), and apolipoprotein A2 (APOA2) in the sample to obtain test values;
comparing the test values to respective reference values that represent threshold levels of KC/GRO, ZP1, and APOA2;
identifying the subject as having an increased risk of mortality due to HS if the test values are above the reference values, or identifying the subject as having an increased chance of survival if the test values are below the reference values, and
administering an effective amount of a vasopressor to the subject identified as having an increased risk of mortality due to HS, thereby improving prognosis of the subject.

### Claim 2 (depends on 1)

The method of claim 1, wherein the sample comprises plasma or whole blood.

### Claim 3 (depends on 1)

The method of claim 1, wherein the method further comprises:
determining an expression level of claudin-3 in the sample to obtain a test value;
comparing the test value to a reference value that represents a threshold level of claudin-3; and
identifying the subject as having an increased risk of mortality due to HS if the test value is above the reference value, or identifying the subject as having an increased chance of survival if the test value is below the reference value.

### Claim 4 (depends on 1)

The method of claim 1, wherein the subject is a human.

### Claim 5 (depends on 1)

The method of claim 1, wherein the method further comprises:
determining an expression level of angiotensinogen r (AGT), thyroglobulin (TG), disintegrin and metalloproteinase domain-containing protein 17 (ADAM17), anionic trypsin-1 (PRSS1), complement C4 (C4A), neuropilin-2 (NRP2), solute carrier family 13 member 2 (SLC13A2), glucagon-like peptide 2 receptor (GLP2R), or lipoma high mobility group protein isoform I-C (HMGIC) fusion partner-like protein 4 (LHFPL4) in the sample to obtain a test value;
comparing the test value to a respective reference value that represents a threshold level of AGT, TG, ADAM17, PRSS1, C4A, NRP2, SLC13A2, GLP2R, or LHFPL4; and
identifying the subject as having an increased risk of mortality due to HS if the test value of ADAM17, PRSS1, C4A, NRP2, SLC13A2, GLP2R, or LHFPL4 is above its respective reference value or the test value of AGT or TG is below its respective reference value; or identifying the subject as having an increased chance of survival if the test value of ADAM17, PRSS1, C4A, ZP1, NRP2, SLC13A2, GLP2R, or LHFPL4 is below its respective reference value or the test value of AGT or TG in the subject is above its respective reference value.

### Claim 6 (depends on 5)

The method of claim 5, wherein the method comprises determining expression levels of KC/GRO, APOA2, AGT, TG, ADAM17, PRSS1, C4A, ZP1, NRP2, SLC13A2, GLP2R, and LHFPL4; and comparing the test values to respective reference values.

### Claim 7 (depends on 1)

The method of claim 1, wherein the levels of KC/GRO and APOA2 are determined by quantitative immunoassay.

### Claim 8 (depends on 7)

The method of claim 7, wherein the quantitative immunoassay is selected from the group consisting of enzyme linked immunosorbent assay (ELISA), immunoprecipitation, immunofluorescence, enzyme immunoassay (EIA), radioimmunoassay (RIA), and Western blot analysis.

### Claim 9

A method of predicting and improving prognosis of a subject suffering from HS, the method comprising:
obtaining a sample comprising serum from the subject;
determining expression levels of KC/GRO, ZP1, and APOA2 in the sample to obtain test values;
comparing the test values to respective reference values that represent threshold levels of KC/GRO, ZP1, and APOA2;
identifying the subject as having an increased risk of mortality due to HS if the test values are above the reference values, or identifying the subject as having an increased chance of survival if the test values are below the reference values; and
administering an effective amount of a histone deacetylase 1 (HDAC1) inhibitor to the subject identified as having an increased risk of mortality due to HS, thereby improving prognosis of the subject.

### Claim 10 (depends on 9)

The method of claim 9, wherein the sample comprises plasma or whole blood.

### Claim 11 (depends on 9)

The method of claim 9, wherein the method further comprises:
determining an expression level of AGT, TG, ADAM17, PRSS1, C4A, NRP2, SLC13A2, GLP2R, or LHFPL4 in the sample to obtain a test value;
comparing the test value to a respective reference value that represents a threshold level of AGT, TG, ADAM17, PRSS1, C4A, NRP2, SLC13A2, GLP2R, or LHFPL4; and
identifying the subject as having an increased risk of mortality due to HS if the test value of ADAM17, PRSS1, C4A, NRP2, SLC13A2, GLP2R, or LHFPL4 is above its respective reference value or the test value of AGT or TG is below its respective reference value; or identifying the subject as having an increased chance of survival if the test value of ADAM17, PRSS1, C4A, ZP1, NRP2, SLC13A2, GLP2R, or LHFPL4 is below its respective reference value or the test value of AGT or TG in the subject is above its respective reference value.

### Claim 12 (depends on 11)

The method of claim 11, wherein the method comprises determining expression levels of KC/GRO, APOA2, AGT, TG, ADAM17, PRSS1, C4A, ZP1, NRP2, SLC13A2, GLP2R, and LHFPL4; and comparing the test values to respective reference values.

### Claim 13 (depends on 9)

The method of claim 9, wherein the method further comprises:
determining an expression level of claudin-3 in the sample to obtain a test value;
comparing the test value to a reference value that represents a threshold level of claudin-3; and
identifying the subject as having an increased risk of mortality due to HS if the test value is above the reference value, or identifying the subject as having an increased chance of survival if the test value is below the reference value.

### Claim 14 (depends on 9)

The method of claim 9, wherein the subject is a human.

### Claim 15 (depends on 9)

The method of claim 9, wherein the HDAC1 inhibitor comprises valproic acid (VPA).

### Claim 16 (depends on 9)

The method of claim 9, wherein the levels of KC/GRO and APOA2 are determined by quantitative immunoassay.

### Claim 17 (depends on 16)

The method of claim 16, wherein the quantitative immunoassay is selected from the group consisting of ELISA, immunoprecipitation, immunofluorescence, EIA, RIA, and Western blot analysis.

### Claim 18

A method of predicting and improving prognosis of a subject suffering from HS, the method comprising:
obtaining a sample comprising serum from the subject;
determining expression levels of KC/GRO, ZP1, and APOA2 in the sample to obtain test values;
comparing the test values to respective reference values that represent threshold levels of KC/GRO, ZP1, and APOA2;
identifying the subject as having an increased risk of mortality due to HS if the test values are above the reference values, or identifying the subject as having an increased chance of survival if the test values are below the reference values; and
administering a treatment for HS to the subject identified as having an increased risk of mortality due to HS, wherein the treatment comprises fluid resuscitation or transfusion of blood or a blood product, thereby improving prognosis of the subject.

### Claim 19 (depends on 18)

The method of claim 18, wherein the sample comprises plasma or whole blood.

### Claim 20 (depends on 18)

The method of claim 18, wherein the method further comprises:
determining an expression level of AGT, TG, ADAM17, PRSS1, C4A, NRP2, SLC13A2, GLP2R, or LHFPL4 in the sample to obtain a test value;
comparing the test value to a respective reference value that represents a threshold level of AGT, TG, ADAM17, PRSS1, C4A, NRP2, SLC13A2, GLP2R, or LHFPL4; and
identifying the subject as having an increased risk of mortality due to HS if the test value of ADAM17, PRSS1, C4A, NRP2, SLC13A2, GLP2R, or LHFPL4 is above its respective reference value or the test value of AGT or TG is below its respective reference value; or identifying the subject as having an increased chance of survival if the test value of ADAM17, PRSS1, C4A, ZP1, NRP2, SLC13A2, GLP2R, or LHFPL4 is below its respective reference value or the test value of AGT or TG in the subject is above its respective reference value.

### Claim 21 (depends on 20)

The method of claim 20, wherein the method comprises determining expression levels of KC/GRO, APOA2, AGT, TG, ADAM17, PRSS1, C4A, ZP1, NRP2, SLC13A2, GLP2R, and LHFPL4; and comparing the test values to respective reference values.

### Claim 22 (depends on 18)

The method of claim 18, wherein the method further comprises:
determining an expression level of claudin-3 in the sample to obtain a test value;
comparing the test value to a reference value that represents a threshold level of claudin-3; and
identifying the subject as having an increased risk of mortality due to HS if the test value is above the reference value, or identifying the subject as having an increased chance of survival if the test value is below the reference value.

### Claim 23 (depends on 18)

The method of claim 18, wherein the subject is a human.

### Claim 24 (depends on 18)

The method of claim 18, wherein the levels of KC/GRO and APOA2 are determined by quantitative immunoassay.

### Claim 25 (depends on 24)

The method of claim 24, wherein the quantitative immunoassay is selected from the group consisting of ELISA, immunoprecipitation, immunofluorescence, EIA, RIA, and Western blot analysis.