Proadrenomedullin as a marker for abnormal platelet levels

11327,082

16/646798

September 13, 2018

The invention relates to a method for determining, diagnosis, prognosis, treatment guidance, treatment monitoring, risk assessment and/or risk stratification of patients with abnormal platelet levels comprising providing a sample of said patient, determining a level of proadrenomedullin (proADM) or fragment(s) thereof in said sample, wherein said level of proADM or fragment(s) thereof correlates with the abnormal platelet levels in said patient. In embodiments of the invention, a level of proADM or fragment(s) thereof of high severity indicates low platelet levels in the subject and subsequent initiating or modifying a treatment of the patient to improve said condition. In some embodiments of the invention the method comprises determining a level of one or more additional markers in a sample isolated from the patient, such as the level of platelets, the level of PCT or fragment(s) thereof, one or more markers of thrombocytopenia and/or one or more markers of an inflammatory response.

B.R.A.H.M.S GmbH (Hennigsdorf, DE)

B.R.A.H.M.S GmbH (Hennigsdorf, DE)

1. A method for reducing the risk of a patient developing thrombocytopenia, comprising a. receiving a sample of bodily fluid from said patient, b. determining a level of proadrenomedullin (proADM) or fragment(s) thereof in said sample, wherein said level of proADM or fragment(s) thereof indicates a risk of developing thrombocytopenia in said patient, and c. treating the patient to increase platelet levels, when the level of proADM or fragment(s) thereof in the patient sample is higher than or equal to a reference level (cut-off level) of proADM or fragment(s) thereof.

2. The method according to claim 1 , comprising in step b) a prognosis, risk assessment and optionally risk stratification of thrombocytopenia and/or disseminated intravascular coagulation (DIC), based on a level of proADM or fragment(s) thereof in said sample.

3. The method according to claim 1 , wherein the patient is, or has been diagnosed as, critically ill.

4. The method according to claim 3 , wherein the sample is isolated from the patient at or after the time point of diagnosis as being critically ill.

5. The method according to claim 1 , wherein the patient is diagnosed with an infectious disease.

6. The method according to claim 5 , wherein the patient is diagnosed with sepsis, severe sepsis or septic shock.

7. The method according to claim 1 , wherein the patient is diagnosed with one or more existing organ failure(s), and/or is a posttraumatic or postsurgical patient.

8. The method according to claim 1 , wherein the patient is diagnosed with disseminated intravascular coagulation (DIC).

9. The method according to claim 1 , wherein the level of proADM inversely correlates with the platelet level.

10. The method according to claim 1 , wherein the sample is selected from the group consisting of a blood sample, a serum sample, a plasma sample and a urine sample.

11. The method according to claim 1 , wherein determining a level of proADM or fragment(s) thereof comprises determining a level of midregion-proADM.

12. The method according to claim 1 , wherein a. a level of proADM or fragment(s) thereof below a high severity level is indicative of normal or high platelet levels, or b. a level of proADM or fragment(s) thereof equal to or above a high severity level is indicative of, or likelihood of developing thrombocytopenia and optionally disseminated intravascular coagulation (DIC), and c. wherein a high severity level of proADM or fragments thereof is a level above 6.5 nmol/l±20%.

13. The method according to claim 12 , wherein the level of proADM or fragment(s) thereof equal to or above the high severity level (cut-off value) indicates initiating or modifying a treatment of the patient to address the likelihood of developing thrombocytopenia and optionally disseminated intravascular coagulation (DIC).

14. The method according to claim 13 , wherein the treatment is selected from the group consisting of blood or platelet transfusion, transfusion of blood components, administering drugs promoting the formation of thrombocytes and performing a splenectomy.

15. The method according to claim 12 , wherein a level of proADM or fragment(s) thereof equal to or above a high severity level (or cut-off value) is indicative of an adverse event occurring.

16. The method according to claim 15 , wherein an adverse event comprises one or more of thrombocytopenia, DIC, infection, organ failure, organ dysfunction and/or mortality.

17. The method according to claim 12 , wherein the patients are intensive care unit (ICU)-patients, wherein a. the level of proADM or fragment(s) thereof below the high severity level (cut-off value) indicates discharging of said patient from ICU, and/or b. the level of proADM or fragment(s) thereof equal to or above the high severity level (cut-off value) indicates modifying the treatment of the patient in the ICU.

18. The method according to claim 1 , comprising determining a level of one or more additional markers in a sample isolated from the patient.

19. The method according to claim 18 , wherein the one or more additional markers comprises the level of platelets in a blood sample.

20. The method according to claim 18 , wherein the one or more additional markers comprises PCT or fragment(s) thereof.

21. The method according to claim 18 , wherein the one or more additional markers comprise one or more markers for disseminated intravascular coagulation (DIC).

22. The method according to claim 21 , wherein the one or more markers for disseminated intravascular coagulation (DIC) are selected from the group consisting of membrane microparticle, sCD14-ST, prothrombinase, antithrombin and/or antithrombin activity, cationic protein 18 (CAP18), von Willebrand factor (vWF)-cleaving proteases, lipoproteins in combination with CRP, fibrinogen, fibrin, B2GP1, GPIIb-IIIa, non-denatured D-dimer of fibrin, platelet factor 4, histones and a prothrombin time (PT) Assay.

23. The method according to claim 1 , comprising a. receiving a sample of bodily fluid from said patient, b. determining a level of proadrenomedullin (proADM) or fragment(s) thereof in said sample, and c. determining a level of procalcitonin (PCT) or fragment(s) thereof in said sample, d. wherein when a level of procalcitonin (PCT) or fragment(s) thereof of is >0.5 ng/ml it indicates the presence of, or increased risk of acquiring, sepsis, and wherein when a proADM level or fragment(s) thereof of is >2.75 nmol/L it indicates the presence of, or increased risk of acquiring, thrombocytopenia, and e. treating the patient wherein treating the patient comprises a treatment to increase platelet levels and a treatment of sepsis.

24. The method according to claim 23 , wherein treating the patient comprises administering one or more agents selected from the group consisting of corticosteroids, a blood or platelet transfusion, a transfusion of blood components and drugs promoting the formation of thrombocytes, and additionally administering an antibiotic and/or anti-infective agent.

25. The method according to claim 1 , wherein the treatment in step c) is a treatment of disseminated intravascular coagulation (DIC) comprising administering one or more agents selected from the group consisting of Factor V, Factor XII 1-AP, shingosine-1-phosphate (S1 P), thombomodulin, antibodies against tissue factor or tissue factor pre-mRNA splicing, reactive nitrogen inhibiting peptide (RNIP) fragment, TAFIa(i), Procoagulant Phospholipid, and thrombin inhibitor.

26. The method according to claim 1 , wherein the treatment is selected from the group consisting of antibiotic treatment, invasive mechanical ventilation, non-invasive mechanical ventilation, renal replacement therapy, vasopressor use, fluid therapy, corticosteroids, blood or platelet transfusion, splenectomy, direct thrombin inhibitors (such as lepirudin or argatroban), blood thinners (such as bivalirudin and fondaparinux), discontinuation of heparin in case of heparin-induced thrombocytopenia, lithium carbonate, folate, extracorporal blood purification and organ protection.

27. The method according to claim 1 , wherein the treatment comprises administering one or more agents selected from the group consisting of corticosteroids, a blood or platelet transfusion, a transfusion of blood components and drugs promoting the formation of thrombocytes, or performing a splenectomy.

28. The method according to claim 1 , wherein a high severity level is equal to or above a cut-off value in the range of 6.5 nmol/l±20% to 12 nmol/l±20%.

29. The method according to claim 1 , wherein a high severity level is equal to or above 10.9 nmol/l±20%, when the patient has been diagnosed with sepsis, severe sepsis or septic shock.

7915002 March 2011 Bergmann
7939639 May 2011 Cullilla et al.
7972799 July 2011 Bergmann
8507210 August 2013 Bergmann et al.
8772239 July 2014 Tsuruta
9229013 January 2016 Bergmann et al.
9541549 January 2017 Bergmann et al.
2006/0029589 February 2006 Weiler
2008/0261258 October 2008 Smith
2010/0292131 November 2010 Kas et al.
2011/0086831 April 2011 Bergmann et al.
2012/0094314 April 2012 Bahrami et al.
2012/0142120 June 2012 Bergmann et al.
2013/0203612 August 2013 Graf et al.
2013/0302841 November 2013 Struck et al.
2015/0011017 January 2015 Bergmann et al.
2015/0118699 April 2015 Ishikura
2017/0010286 January 2017 Bergmann
2017/0370949 December 2017 Struck et al.
2018/0348235 December 2018 Vigué et al.
2019/0178894 June 2019 Ziera et al.
2019/0376985 December 2019 Bergmann et al.
2021/0156850 May 2021 Anderberg et al.
1488209 December 2005
2320237 August 2016
9707214 February 1997
0242770 May 2002
04090546 October 2004
2004090546 October 2004
08012019 January 2008
WO09062948 May 2009
10128071 November 2010
2010128071 November 2010
10139475 December 2010
12059477 May 2012
13086359 June 2013
14147153 September 2014
17089474 June 2017
18007588 January 2018
18029214 February 2018

Guclu et al. “Effect of severe sepsis on platelet count and their indices” African Health Sciences 2013 13:333-338 (Year: 2013). cited by examiner
Lale et al. “Dengue fever and thrombocytopenia: A dealy duo” Blood 2006 108: 3978 (Abstract) (Year: 2006). cited by examiner
Michels et al. (II) “Platelet function alterations in dengue are associated with plasma leakage” Thrombosis and Haemostasis 2014 112:352-362 (Year: 2014). cited by examiner
Sharma (Anaesth Intensive Care 2007 35:874-880). (Year: 2007). cited by examiner
Annane (Annals of Intensive Care 2011 1:7, total 7 pages). (Year: 2011). cited by examiner
De La Torre-Prados (Minerva Anestesiologica 2016 82: 760-766 (Year: 2016). cited by examiner
Levi Hematology 2005 10 Suppl. 1:129-131 (Year: 2005). cited by examiner
International Search Report for PCT/EP2018/074725 dated Oct. 9, 2018. cited by applicant
Michels, M. et al., “High plasma mid-regional pro-adrenomedullin levels in children with severe dengue virus infections,” Journal of Clinical Virology, Journal of Clinical Virology, 2011, vol. 50, pp. 8-12. cited by applicant
Kalayanarooj, S., “Clinical Manifestations and Management of Dengue/DHF/DSS,” Tropical Medicine and Health, 2011, vol. 39, No. 4 Supplement, pp. 83-87. cited by applicant
Thanachartwet, V. et al., “Serum procalcitonin and peripheral venous lactate for predicting dengue shock and/or organ failure: a prospective observational Study,” PLOS Neglected Tropical Diseases, Aug. 26, 2016, 19 pages. cited by applicant
Anadaluz-Ojeda D. et al. : “Superior accuracy of mid-regional proadrenomedullin for mortality prediction in sepsis with varying levels of illness severity”, Intensive Care, vol. 7, Feb. 10, 2017, Article No. 15, pp. 1-8. cited by applicant
Angeletti S. et al. : “Diagnostic and prognostic role of procalcitonin (PCT) and MR-pro-Adrenomedullin (MR-proADM) in bacterial infections”, APMIS, vol. 123, No. 9, Jun. 8, 2015 (Jun. 8, 2015), pp. 740-748. cited by applicant
Angeletti S. et al: “Procalcitonin and mid-regional pro-adrenomedullin test combination in sepsis diagnosis”, Clinical Chemistry and Laboratory Medicine, De Gruyter, DE, vol. 51, No. 5, Apr. 30, 2013 (Apr. 30, 2013), pp. 1059-1067, XP009502330, ISSN: 1434-6621, DOI: 10.1515/CCLM-2012-0595. cited by applicant
Bruno Viaggi et al: “Mid regional pro-adrenomedullin for the prediction of organ failure in infection. Results from a single centre study”, PLOS ONE, vol. 1 3, No. 8, Aug. 13, 2018 (Aug. 13, 2018), p. e0201491, XP055535888, DOI: 10137 1/journal.pone.0201 491. cited by applicant
Cairon Pietr-et al: “Circulating Biologically Active Adrenomedullin such statement (bio-ADM) Predicts Hemodynamic support Requirement and Mortality During Sepsis”, CHEST, vol. 152, No. 2, Aug. 1, 2017 (Aug. 1, 2017), pp. 312-320, XP55430860. cited by applicant
Caroline Guignant et al: “Assessment of pro-vasopressin and proadrenomedullin as predictors of 28-day mortality in septic shock patients”, Intensive Care Medicine, vol. 35, No. 1 1, Aug. 7, 2009 (Aug. 7, 2009), pp. 1859-1867, xP055535903, DE ISSN: 0342-4642, DOI: 10.1 007is001 34-009-1 610-5. cited by applicant
Charles P.-E. et al.: “MR-ProADM elevation upon ICU admission predicts the outcome of septic patients and is correlated with upcoming fluid overload”, Shock, vol. 48, No. 4, Oct. 2017, pp. 418-426. cited by applicant
Christ-Crain M el al: “Biomarkers in respiratory tract infections: diagnostic guides to antibiotic prescription, prognostic markers and mediators”, European Respiratory Journal, Munksgaard International Publishers, Copenhagen, DK, vol. 30, No. 3, Aug. 31, 2007 (Aug. 31, 2007), pp. 556-573, XP00950261 1. cited by applicant
Christ-Crain M.: “Procalcitonin Guidance of Antibiotic in Community-acquired Pneumonia: A Randomized Trial”, American Journal of Respiratory Critical Care Med-cine, vol. 174, No. (Jan. 1, 2006), pp. 84-93, XP055021 728, ISSN: 1 073-449X, DOI: 10.11 64/rccm.200512-1 9220C. cited by applicant
Christ-Crain Mirjam et al: “Mid-regional proadrenomedullin as a prognostic marker in sepsis: an study”, Critical Care, Biomed Central London, GB, vol. 9, No. 6, Nov. 15, 2005 (Nov. 15, 2005), pp. R81 6-R824, XP021 012417, ISSN: 1364-8535, DOI: 10.11 86/CC3885. cited by applicant
De Jong Evelien el al: “Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment—n critically patients: a randomised, controlled, open-label trial”, Lancet Infectious Diseases, Elsevier Lid, US, vol. 16, No. 7,Mar. 2, 2016 (Mar. 2, 2016), pp. 819-827, XP02961 8593. cited by applicant
De La Torre-Prados Maria V et al: “Mid-regional proadrenomedullin as prognostic biomarker in septic shock”, Minerva Anestes—Olog—Ca G—Ornale Italiano Di Anestesia E D—Analg, Societa Italiana Di an Estesiolog Ia, IT, vol. 82, No. 7, Jul. 1, 2016 (Jul. 1, 2016), pp. 760-766, XP0091 92235,ISSN 1827-1596. cited by applicant
Elke G. et al.: “The use of mid-regional proadrenomedullin to identify disease severity and treatment response to sepsis-a secondary analysis of a large randomised controlled trial”, Crit. Care, vol. 22, No. 1, 79, Mar. 21, 2018 (Mar. 21, 2018), pp. 1-12, XP55556348. cited by applicant
Gille Jochen et al: “MR-proADM: A New Biomarker for Early Diagnosis of Sepsis in Burned Patients”, Journal of Burn Care & Research, Williams & Wilkins, US, vol. 38, No. 5, Aug. 31, 2017 (Aug. 31, 2017), pp. 290-298, XP009502061. cited by applicant
Hartmann Oliver et al: “Time-dependent Cox regression: Serial measurement of the cardiovascular biomarker proadrenomedullin—mproves survival prediction in patients with—ower resp-ratory infection”, International Journal of Cardiology, vol. 161, No. 3, Sep. 24, 2012, p. 166-173, XP028959234. cited by applicant
Michels M et al: “High plasma mid-regional pro-adrenomedullin—evels in children with severe dengue virus—fections”, Journal of Clinical Virology, Elsevier, Amsterdam, NL, vol. 50, No. 1, Jan. 1, 2011 (Jan. 1, 2011), pp. 8-12, XP027588087. cited by applicant
Munirah Al Shuaibi et al: “Pro-adrenomedullin as a Novel Biomarker for Predicting Infections and Response to Antimicrobials in Febrile Patients With Hematologic Malignancies”, Cli n ical I nfectious Diseases, vol. 56, No. 7,Jan. 3, 2013 (Jan. 3, 2013), pp. 943-950, xP055535801, US ISSN: 1 058-4838, DOI: 10.1 O93icidicis1 029. cited by applicant
Pereira J.M. et al: “Mid-regional proadrenomedullin: An early marker of response in critically community-acquired pneumonia?”, Revista Portugu Esa De Pneumologia (English Edition), vol. 22, No. 6, Nov. 1, 2016 (Nov. 1, 2016), pp. 308-314, XP0554451 19, ISSN: 2173-5115, DOI: 10.1016/j.rppnen.2016 .03.012. cited by applicant
Rossella Marino et al: “Plasma adrenomedullin is associated with short-term mortality and vasopressor requirement in patients admitted with sepsis”, Critical Care, Biomed Central Ltd., London, GB, vol. 18, No. 1,Feb. 17, 2014 (Feb. 17, 2014), p. R34, XP021179720, ISSN: 1364-8535, DOI: 10.1 186/CC13731. cited by applicant
Saeed K. et al.: “The early identification of disease progression in patients with suspected infection presenting to the emergency department: a multi-centre derivation and validation study”, Crit. Care, vol. 23, No. 1, 40, Feb. 8, 2019 (Feb. 8, 2019), pp. 1-15, XP55556343, the whole document. cited by applicant
Schuetz Philipp el al: “Blood biomarkers for personalized treatment and patient management decisions in community-acquired pneumonia”, Current Opinion on Infectious Diseases., vol. 26, No. 2, Apr. 1, 2013 (Apr. 1, 2013), pp. 159-167 , XP055439092. cited by applicant
Sebastian Decker et al: Immune-Response Patterns and Next Generation Sequencing Diagnostics for the Detection of Mycoses in Patients with Septic Shock-Results of a Combined Clinical and Experimental Investigation, International Journal of Molecular Sciences, vol. 18, No. 8, Aug. 18, 2017 (Aug. 18, 2017), p. 1796, XP055417185,DOI: 10.3390/ijm518081796. cited by applicant
Shuaibi M. Al et al: “Pro-adrenomedullin as a Novel Biomarker for Predicting Infections and Response to Antimicrobials in Febrile patients With Hematologic Malignancies”, Clinical Infectious Diseases, vol. 56, No. 7,Jan. 3, 2013, p. 943-950, XP055418326. cited by applicant
Siripen Kalayanarooj: “Clinical Manifestations and Management of Dengue/DHF /DSS”, Tropical Medicine and Health, vol. 39, No. 4SUPPLEMENT, Jan. 1, 2011 (Jan. 1, 2011), pp. S83-S87, XP055511310. cited by applicant
Thanachartwet Vipa el al: “Serum Procalcitonin and Peripheral Venous Lactate for Predicting Dengue Shock and/or Organ Failure: A Prospective Observational Study”, PLOS Neglected Tropical Diseases, vol. 10, No. 8, Aug. 26, 2016 (Aug. 26, 2016), p. e0004961, XP055511330. cited by applicant
Ueda et al: “Increased plasma levels of adrenomedullin in patients with systemic inflammatory response syndrome”, Amer. J Resp. Crit. Care Med., vol. 160, No. 1, Jul. 1, 1999, pp. 132-136, XP055052609. cited by applicant
Wang R L et al: “Prediction about severity and outcome of sepsis by pro-atrial natriuretic peptide and pro-adrenomedullin”, Chin J. Traumatol, NL, vol. 13, No. 3, Jun. 1, 2010, pp. 152-157, XP027087080. cited by applicant
Bello et al. Prognostic power of proadrenomedullin in community-acquired pneumonia is independent of aetiology. Eur Respir J 2012; 39: 1144-1155. cited by applicant
Cavallazzi et al. Midregional proadrenomedullin for prognosis in community-acquired pneumonia: a systematic review. Respiratory Medicine (2014) 108, 1569e1580. cited by applicant
Courtais et al. Proadrenomedullin, a useful tool for risk stratification in high Pneumonia Severity Index score community acquired pneumonia. American Journal of Emergency Medicine (2013) 31, 215-221. cited by applicant
Curbelo et al.Inflammation biomarkers in blood as mortality predictors in community-acquired pneumonia admitted patients: Importance of comparison with neutrophil count percentage or neutrophil-lymphocyte ratio. PLOS ONE | https://doi.org/10.1371/journal.pone.0173947 Mar. 16, 2017 (pp. 1-14). cited by applicant
Debiane et al. The utility of proadrenomedullin and procalcitonin in comparison to C-reactive protein as predictors of sepsis and bloodstream infections in critically ill patients with cancer. Crit Care Med. Dec. 2014 (pp. 1-9) DOI: 10.1097/CCM.0000000000000526. cited by applicant
Gordo-Remartinez.Usefulness of midregional proadrenomedullin to predict poor outcome in patients with community acquired pneumonia. PLOS ONE | DOI:10.1371/journal.pone.0125212 Jun. 1, 2015 (pp. 1-15). cited by applicant
Hoeboer SH et al. Old and new biomarkers for predicting high and low risk microbial infection in critically ill patients with new onset fever: a case for procalcitonin. Journal of Infection (2012) 64, 484e493. cited by applicant
Huang et al. Midregional proadrenomedullin as a prognostic tool in community-acquired pneumonia. CHEST /136 / 3 / Sep. 2009 p. 823. cited by applicant
Lundberg et al. Adrenomedullin and endothelin-1 are associated with myocardial injury and death in septic shock patients. Critical Care (2016) 20:178. cited by applicant
Renaud et al. Proadrenomedullin improves Risk of Early Admission to ICU score for predicting early severe community-acquired pneumonia. CHEST /142 / 6 / Dec. 2012 1447. cited by applicant
Schuetz P et al. Circulating precursor levels of endothelin-1 and adrenomedullin, two endothelium-derived, counteracting substances, in sepsis. Endothelium. Endothelium, 14:345-351, 2007. cited by applicant
Suberviola et al. Prognostic value of proadrenomedullin in severe sepsis and septic shock patients with community-acquired pneumonia. Swiss Med Wkly 2012;142:w13542. cited by applicant
Suberviola et al. Hospital mortality prognostication in sepsis using the new biomarkers suPAR and proADM in a single determination on ICU admission. Intensive Care Med 2013, pp. 1-12, DOI 10.1007/s00134-013-3056-z. cited by applicant
Travaglino F et al. Utility of Procalcitonin (PCT) and Mid regional pro-Adrenomedullin (MR-proADM) in risk stratification of critically ill febrile patients in Emergency Department (ED). A comparison with APACHE II score. BMC Infect Dis. Aug. 8, 2012 (pp. 1-8). cited by applicant

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