# US 2008/0306346 A1 · Diagnostic tool detecting the degradation status of Von Willebrand Factor multimers

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- Number: US 2008/0306346 A1
- Document ID: US20080306346A1
- Status: Published application
- Kind: A1
- Application number: 11/713,863
- Filed: 2007-06-07
- Published: 2008-12-11
- Earliest claimed: 2007-06-07
- Inventors: Ralf A. Claus; Clemens Bockmeyer; Hans-Peter Deigner; Michaela Harz; Petra Roesch; Juergen Popp; Rainer Riesenberg
- Web page: https://patentgrep.com/patent/US20080306346A1

## CPC

- A61B 5/0059: {using light, e.g. diagnosis by transillumination, diascopy, fluorescence (photoacoustic A61B5/0093; optical measurement of heart rate A61B5/02416; optical measurement of blood flow A61B5/0261; optical measurement of analytes A61B5/1455)}
- A61B 5/412: {Detecting or monitoring sepsis}
- A61B 5/417: {the bone marrow}
- A61B 5/7275: {Determining trends in physiological measurement data; Predicting development of a medical condition based on physiological measurements, e.g. determining a risk factor}
- G01N 33/86: involving blood coagulating time {or factors, or their receptors}
- G16H 20/10: relating to drugs or medications, e.g. for ensuring correct administration to patients
- G16H 50/20: for computer-aided diagnosis, e.g. based on medical expert systems
- A61B 5/7264: {Classification of physiological signals or data, e.g. using neural networks, statistical classifiers, expert systems or fuzzy systems}
- G01N 2333/755: Factors VIII, e.g. factor VIII C [AHF], factor VIII Ag [VWF]
- Y02A 90/10: Information and communication technologies [ICT] supporting adaptation to climate change, e.g. for weather forecasting or climate simulation
- A61B: DIAGNOSIS; SURGERY; IDENTIFICATION (usefulness limited to only animals A61D)
- 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)
- G16H: HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

A method in which the cleavage profile and size distribution of von Willebrand factor (VWF) multimers is analyzed, includes: providing a sample medium of human body fluids comprising a plurality of VWF multimers of different size; enrichment or purification of the VWF multimers by cryoprecipitation or chromatography to obtain a separated preparation of the VWF multimers from said sample medium; exposing the separated preparation of VWF multimers to a light source to produce signals obtained by vibrational spectroscopy; detecting said signals; transformation by mathematical alogrithms; generation of patterns based on computing of data of original resonance spectra and determining the cleavage profile and the size distribution of said separated VWF multimers by chemometrics; and acquisition of a databank obtained from healthy individuals for identifying subjects at risk of developing at least one of the following diseases: sepsis, coagulopathy, thrombotic disease, infection, and inflammation.

## Claims

### Claim 1

A method of analyzing the cleavage profile and size distribution of von Willebrand factor (VWF) multimers, comprising: providing a sample medium or human body fluids comprising a plurality of VWF multimers of different size; enrichment or purification of VWF by cryoprecipitation or chromatography from said sample medium; exposing said separated preparation of VWF multimers to a light source to produce signals obtained by vibrational spectroscopy; detecting said signals; transformation by mathematical algorithms; generation of patterns based on computing of data of original resonance spectra and determining the cleavage profile and the size distribution of said separated VWF multimers by chemometrics and acquisition of a databank obtained from healthy individuals identifying subjects at risk of developing thrombotic disease and/or identifying subjects at risk of developing infection, inflammation in particular sepsis and/or coagulopathy.

### Claim 2 (depends on 1)

The method of claim 1 wherein analysis of the cleavage profile and size distribution of von Willebrand factor (VWF) multimers is used for therapeutically monitoring and decision making for these subjects.

### Claim 3 (depends on 1)

The method of claim 1 wherein analysis of the cleavage profile and size distribution of von Willebrand factor (VWF) multimers is used for screening of subjects at risk of developing thrombotic disease, infection, inflammation in particular sepsis and/or coagulopathy.

### Claim 4 (depends on 1)

The methods of claim 1 wherein analysis of the cleavage profile and size distribution of von Willebrand Factor (VWF) multimers from said samples is used for comparing spectra corresponding to a set of VWF abnormalities and/or disease for diagnostic approaches.

### Claim 5 (depends on 1)

The methods of claim 1 wherein analysis of the cleavage profile and size distribution of von Willebrand Factor (VWF) multimers from said samples is used for comparing spectra detecting the VWF-degrading activity of proteolytic enzymes, in particular of the ADAMTS13 protease.

### Claim 6 (depends on 1, 2, 3, 4, 5)

The methods of claims 1-5 wherein analysis of the cleavage profile and size distribution of von Willebrand Factor (VWF) multimers from said samples is used for early diagnosis and/or differential diagnosis and/or monitoring of the disease.

### Claim 7 (depends on 1, 2, 3, 4, 5, 6)

Methods of claims 1-6 wherein analysis of the cleavage profile and size distribution of von Willebrand Factor (VWF) multimers from said samples is used for correlational analysis with non-spectroscopic data.

### Claim 8 (depends on 1, 2, 3, 4, 5, 6, 7)

Methods of claims 1-7 wherein the plurality of signals of said sample is analysed by the use of non-supervised classification analysis, in particular comprising hierarchical clustering and principal component analysis.

### Claim 9 (depends on 1, 2, 3, 4, 5, 6, 7)

Methods of claims 1-7 wherein the plurality of signals of said samples is analysed by the use of supervised classification analysis, in particular comprising K-nearest neighbour analysis, nearest mean classifier, linear discrimination analysis, artificial neural networks, as well as support vector machines.

### Claim 10 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9)

Methods of claims 1-9 wherein analysis of the cleavage profile and size distribution of von Willebrand Factor (VWF) multimers from said samples is used for monitoring the administered therapeutically effective amount of a recombinant ADAMTS13 or genetic material comprising an ADAMTS13 gene or mutant or variant thereof.

### Claim 11 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10)

Methods of claims 1-10 wherein analysis of the cleavage profile and size distribution of von Willebrand Factor (VWF) multimers from said samples is used for monitoring the administered therapeutically effective amount of a therapeutically effective amount of ADAMTS13 protease such that the symptoms of the disease are alleviated, wherein the ADAMTS13 protease is selected from the group consisting: recombinant ADAMTS13; synthetic ADAMTS13; mutants, variants, fragments, and fusions of recombinant ADAMTS13; and mutants, variants, fragments, and fusions of synthetic ADAMTS13.

### Claim 12 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11)

Methods of claims 1-11 wherein analysis of the cleavage profile and size distribution of von Willebrand Factor (VWF) multimers from said samples is used for monitoring the efficiency of drugs or drug candidates for the treatment of thrombotic diseases, infection, inflammation and/or coagulopathy such that the application of the drug or the drug candidates influence the ADAMTS13 activity and/or the cleavage profile and size distribution of VWF multimers whereas alteration of ADAMTS13 activity and/or the cleavage profile and the size distribution of VWF after application of the drug or the drug candidate is used for indicating the efficiency of the drug or the drug candidate.

### Claim 13 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11)

Methods of claims 1-11 wherein analysis of the cleavage profile and size distribution of von Willebrand Factor (VWF) multimers from said samples is used for monitoring the treatment of diseases or altering physiological states characterized by decreased VWF-cleaving protease activity, and/or pathologic platelet aggregation whereas alteration of ADAMTS13 activity and/or the cleavage profile and the size distribution of VWF and/or parameters of platelet aggregation after application of the drug or the drug candidate is used for indicating the efficiency of the drug or the drug candidate.