Timothy Browder

OBJECTIVE: The objective of this study was to analyze the preventable and potentially preventable deaths occurring at a mature Level I trauma center. METHODS: All trauma patients that died during their initial hospital admission during an 8-year period (January, 1998 to December, 2005) were analyzed. The deaths were initially reviewed at a weekly Morbidity and Mortality (M&M) conference followed by a multidisciplinary (Trauma Surgery, Critical Care, Emergency Medicine, Neurosurgery, Nursing, and Coroner) Combined Trauma Death Review Committee, and were classified into nonpreventable, potentially preventable, and preventable deaths. All preventable and potentially preventable deaths were identified for the purpose of the study. Quality improvement death forms included data on epidemiology, vital signs, injury severity, type of injury, probability of survival with Trauma and Injury Severity Score methodology, preventability (nonpreventable, potentially preventable, and preventable deaths), errors in the evaluation and management of the patient, and classification of errors (system, judgment, knowledge). Additional injury details, clinical course, circumstances leading to the death and autopsy findings were abstracted from the trauma registry and individual chart review. RESULTS: During the study period, 35,311 patients meeting trauma registry criteria were admitted and a total of 2,081 (5.9%) deaths occurred. Fifty-one deaths were classified as preventable or potentially preventable deaths (0.1% of admissions, 2.5% of deaths). Eleven of them (0.53% of deaths) were classified as preventable and 40 (1.92% of deaths) as potentially preventable deaths. Mean age was 40 years, 66.7% were men, mean Injury Severity Score was 27, 74.5% were blunt. The most common cause of death was bleeding (20, 39.2%) followed by multiple organ dysfunction syndrome (14, 27.5%) and cardiorespiratory arrest (8, 15.6%). This was caused by a delay in treatment (27, 52.9%), clinical judgment error (11, 21.6%), missed diagnosis (6, 11.8%), technical error (4, 7.8%), and other (3, 5.9%). The deaths peaked at two time periods: 26 (51.1%) during the first 24 hours and 16 (31.4%) after 7 days. Only one patient (2.0%) died in the first hour. The most common location of death was the intensive care unit (28, 54.9%), operating room (13, 25.5%), and emergency room (5, 9.8%). CONCLUSION: Preventable or potentially preventable deaths are rare but do occur at an academic Level I trauma center. Delay in treatment and error in judgment are the leading causes of preventable and potentially preventable deaths.

vascular endothelial growth factor basic fibroblast growth factor hepatocyte growth factor platelet factor 4 antithrombin III thrombospondin transforming growth factor-β1 plasminogen activator inhibitor type 1 urokinase-type plasminogen activator high molecular weight kininogen matrix metalloproteinase Angiogenesis is the process of sprouting and configuring new blood vessels from pre-existing blood vessels, whereas the hemostatic system maintains the liquid flow of blood by regulating platelet adherence and fibrin deposition. Both systems normally appear quiescent, yet both systems remain poised for repair of injury. With vessel injury, a rapid sequence of reactions must occur to occlude the vessel wall defect and prevent hemorrhage. Activated platelets link the margins of the defect and form a provisional barrier that is quickly enmeshed with polymerized fibrin. This clot structure initially requires immobilized vascular endothelial cells to anchor the clot and prevent further bleeding. Thereafter, endothelial cells at the clot margins become mobile, dismantling and invading the cross-linked fibrin structure to rebuild a new vessel wall. Although the positive and negative regulators that control the delicate balance of platelet reactivity and fibrin deposition have been elucidated over the past four decades, analogous proteins that control endothelial cell growth and inhibition have only been discovered within the past decade. Hemostasis and angiogenesis are becoming increasingly inter-related. Proteins generated by the hemostatic system coordinate the spatial localization and temporal sequence of clot/endothelial cell stabilization followed by endothelial cell growth and repair of a damaged blood vessel. We focus here on the regulation of angiogenesis during vessel repair mediated by proteins secreted by platelets and derived as cryptic fragments from the coagulation cascade and fibrinolytic system. At the site of vessel injury, adhered platelets secrete both positive and negative regulators of angiogenesis, mainly from internal α-granules. These positive regulators include: vascular endothelial growth factor-A (VEGF-A)1(1.Mohle R. Green D. Moore M.A.S. Nachman R.L. Rafii S. Constitutive production and thrombin-induced release of vascular endothelial growth factor by human megakaryocytes and platelets..Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 663-668Crossref PubMed Scopus (640) Google Scholar), VEGF-C (2.Wartiovaara U. Salven P. Mikkola H. Lassila R. Kaukonen J. Joukov V. Orpana A. Ristimaki A. Heikinheimo M. Joensuu H. Aitalo K. Palotie A. Peripheral blood platelets express VEGF-C and VEGF which are released during platelet activation..Thromb. Haemostasis. 1998; 80: 171-175Crossref PubMed Scopus (239) Google Scholar), basic fibroblast growth factor (bFGF) (3.Brunner G. Nguyen H. Gabrilove J. Rifkin D.B. Wilson E.L. Basic fibroblast growth factor expression in human bone marrow and peripheral blood cells..Blood. 1993; 81: 631-638Crossref PubMed Google Scholar), hepatocyte growth factor (HGF) (4.Nakamura T. Teramoto H. Ichihara A. Purification and characterization of a growth factor from rat platelets for mature parenchymal hepatocytes in primary culture..Proc. Natl. Acad. Sci. U. S. A. 1986; 83: 6489-6493Crossref PubMed Scopus (620) Google Scholar), angiopoietin-1, 2G. D. Yancopoulos, personal communication. insulin-like growth factor-1 and -2 (6.Karey K.P. Marquardt H. Sirbasku D.A. Human platelet-derived mitogens. I. Identification of insulin-like growth factors I and II by purification and N-terminal amino acid sequence analysis..Blood. 1989; 74: 1084-1092Crossref PubMed Google Scholar, 7.Karey K.P. Sirbasku D.A. Human platelet-derived mitogens. II. Subcellular localization of insulin-like growth factor I to the alpha granule and release in response to thrombin..Blood. 1989; 74: 1093-1100Crossref PubMed Google Scholar), epidermal growth factor (8.Ben-Ezra J. Sheibani K. Hwabg D.L. Lev-Ran A. Megakaryocyte synthesis is the source of epidermal growth factor in human platelets..Am. J. Pathol. 1990; 137: 755-759PubMed Google Scholar, 9.Hwang D.L. Lev-Ran A. Yen C.F. Sniecinski I. Release of different fractions of epidermal growth factor from human platelets in vitro: preferential release of 140 kDa fraction..Regul. Pept. 1992; 37: 95-100Crossref PubMed Scopus (17) Google Scholar), platelet-derived growth factor (10.Bar R.S. Boes M. Booth B.A. Dake B.L. Henley S. Hart M.N. The effects of platelet-derived growth factor in cultured microvessel endothelial cells..Endocrinology. 1989; 124: 1841-1848Crossref PubMed Scopus (111) Google Scholar, 11.Heldin C.-H. Westermark B. Wasteson A. Platelet-derived growth factor: isolation by a large-scale procedure and analysis of subunit composition..Biochem. J. 1981; 193: 907-913Crossref PubMed Scopus (147) Google Scholar), and sphingosine 1-phosphate (12.Lee O.-H. Kim Y.-M. Lee Y.M. Moon E.-J. Lee D.-J. Kim J.-H. Kim K.-W. Kwon Y.-G. Sphingosine 1-phosphate induces angiogenesis: its angiogenic action and signaling mechanism in human umbilical vein endothelial cells..Biochem. Biophys. Res. Commun. 1999; 264: 743-750Crossref PubMed Scopus (337) Google Scholar). Platelets also secrete negative regulators that suppress this inducement of angiogenesis and are discussed below. Moreover, one of the positive angiogenic regulators, hepatocyte growth factor, effects both stimulation and (via the generation of cryptic fragments) suppression of angiogenesis. In contrast to the multiple pro-angiogenic activities of HGF (13.Shima N. Itagaki Y. Nagao M. Yasuda H. Morinaga T. Higashio K. A fibroblast-derived tumor cytotoxic factor/F-TCF (hepatocyte growth factor/HGF) has multiple functions in vitro..Cell Biol. Int. Rep. 1991; 15: 397-408Crossref PubMed Scopus (56) Google Scholar, 14.Rosen E.M. Lamszus K. Laterra J. Polverini P.J. Rubin J.S. Goldberg I.D. Gherardi E. Plasminogen-related Growth Factors. John Wiley & Sons, Chichester, United Kingdom1997: 215-226Google Scholar), alternative processing of the HGF α-chain mRNA generates anti-angiogenic HGF fragments consisting of either the first kringle domain (NK1) or the first two kringle domains (NK2) (14.Rosen E.M. Lamszus K. Laterra J. Polverini P.J. Rubin J.S. Goldberg I.D. Gherardi E. Plasminogen-related Growth Factors. John Wiley & Sons, Chichester, United Kingdom1997: 215-226Google Scholar). These first two kringles contain the HGF binding site for its receptor, c-Met (14.Rosen E.M. Lamszus K. Laterra J. Polverini P.J. Rubin J.S. Goldberg I.D. Gherardi E. Plasminogen-related Growth Factors. John Wiley & Sons, Chichester, United Kingdom1997: 215-226Google Scholar). NK1 and NK2 suppress HGF-induced endothelial cell migration and abrogate HGF-induced angiogenesis in the rat cornea (14.Rosen E.M. Lamszus K. Laterra J. Polverini P.J. Rubin J.S. Goldberg I.D. Gherardi E. Plasminogen-related Growth Factors. John Wiley & Sons, Chichester, United Kingdom1997: 215-226Google Scholar). These observations led to recombinant construction of NK4, which contains all four kringle domains of HGF (15.Date K. Matsumoto K. Kubs K. Shimura H. Tanaka M. Nakamura T. Inhibition of tumor growth and invasion by a four-kringle antagonist (HGF/NK4) for hepatocyte growth factor..Oncogene. 1998; 17: 3045-3054Crossref PubMed Scopus (180) Google Scholar). HGF/NK4 is a more potent antagonist of c-Met activation by HGF (15.Date K. Matsumoto K. Kubs K. Shimura H. Tanaka M. Nakamura T. Inhibition of tumor growth and invasion by a four-kringle antagonist (HGF/NK4) for hepatocyte growth factor..Oncogene. 1998; 17: 3045-3054Crossref PubMed Scopus (180) Google Scholar). HGF/NK4 potently inhibits tumor growthin vivo by increasing tumor cell apoptosis without affecting the proliferation rate of tumor cells (15.Date K. Matsumoto K. Kubs K. Shimura H. Tanaka M. Nakamura T. Inhibition of tumor growth and invasion by a four-kringle antagonist (HGF/NK4) for hepatocyte growth factor..Oncogene. 1998; 17: 3045-3054Crossref PubMed Scopus (180) Google Scholar). A similar pattern of tumor inhibition occurs through angiogenesis inhibition (16.Holmgren L. O'Reilly M.S. Folkman J. Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression..Nat. Med. 1995; 1: 149-153Crossref PubMed Scopus (1706) Google Scholar). Taken together, the anti-tumor activity of HGF/NK4 in vivo is at least partly mediated through an anti-angiogenic activity (15.Date K. Matsumoto K. Kubs K. Shimura H. Tanaka M. Nakamura T. Inhibition of tumor growth and invasion by a four-kringle antagonist (HGF/NK4) for hepatocyte growth factor..Oncogene. 1998; 17: 3045-3054Crossref PubMed Scopus (180) Google Scholar). Thus, expression of NK1 or NK2 or cryptic cleavage of HGF into NK1, NK2, or NK4 could counterbalance HGF-induced angiogenesis in vivo. Unique to platelets, PF4 binds surface heparin-like glycosaminoglycans on endothelial cells, thereby quenching the anti-thrombotic activity of antithrombin III (AT-III) and allowing a clot to form. Nearly two decades ago, PF4 was the first hemostatic protein demonstrated to be an inhibitor of angiogenesisin vivo (17.Taylor S. Folkman J. Protamine is an inhibitor of angiogenesis..Nature. 1982; 297: 307-312Crossref PubMed Scopus (521) Google Scholar, 18.Maione T.E. Gray G.S. Petro J. Hunt A.J. Donner A.L. Bauer S.I. Carson H.F. Sharpe R.J. Inhibition of angiogenesis by recombinant human platelets factor-4 and related peptides..Science. 1990; 247: 77-79Crossref PubMed Scopus (631) Google Scholar). One mechanism for the initial endothelial cell inhibition following platelet secretion is that PF4 blocks heparin-like glycosaminoglycans that function as critical, low affinity receptors for heparin-binding endothelial growth factors on the surface of endothelial cells (18.Maione T.E. Gray G.S. Petro J. Hunt A.J. Donner A.L. Bauer S.I. Carson H.F. Sharpe R.J. Inhibition of angiogenesis by recombinant human platelets factor-4 and related peptides..Science. 1990; 247: 77-79Crossref PubMed Scopus (631) Google Scholar). PF4 also directly neutralizes the heparin-binding region of growth factors (19.Perollet C. Han Z.C. Savona C. Caen J.P. Bikfalvi A. Platelet factor 4 modulates fibroblast growth factor 2 (FGF-2) activity and inhibits FGF-2 dimerization..Blood. 1998; 91: 3289-3299Crossref PubMed Google Scholar). Further, a heparin-independent pathway of PF4 inhibition of endothelial cell growth exists. The endothelial cell stimulatory activity of epidermal growth factor and VEGF-A121, endothelial mitogens that lack heparin affinity, is susceptible to PF4 inhibition (20.Gengrinovitch S. Greenberg S.M. Cohen T. Gitay-Goren H. Rockwell P. Maione T.E. Levi B.-Z. Neufeld G. Platelet factor-4 inhibits the mitogenic activity of VEGF-121 and VEGF-165 using several concurrent mechanisms..J. Biol. Chem. 1995; 270: 15059-15065Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar). Moreover, an analogue of PF4 that lacks heparin affinity (rPF4-241) inhibits angiogenesis (21.Maione T.E. Gray G.S. Hunt A.J. Sharpe R.J. Inhibition of tumor growth in mice by an analogue of platelet factor 4 that lacks affinity for heparin and retains potent angiostatic activity..Cancer Res. 1991; 51: 2077-2083PubMed Google Scholar). TSP-1 is the most abundant constituent of platelet α-granules and participates in efficient platelet aggregation (22.Jaffe E. Leung L.L.K. Nachman R.L. Levin R.L. Mosher D.F. Thrombospondin is the endogenous lectin of human platelets..Nature. 1982; 295: 246-248Crossref PubMed Scopus (106) Google Scholar, 23.Rabbi-Sabile S. Thibert V. Legrand C. Thrombospondin peptides inhibit the secretion-dependent phase of platelet aggregation..Blood Coagul. Fibrinolysis. 1996; 7: 237-240Crossref PubMed Scopus (10) Google Scholar). TSP-1 is a large (450 kDa), modular glycoprotein complexed with active transforming growth factor-β1 (TGF-β1) in α-granules and, upon release, can activate latent TGF-β1 secreted by endothelial cells (24.Schultz-Cherry S. Ribeiro S. Gentry L. Murphy-Ullrich J.E. Thrombospondin binds and activates the small and large forms of latent transforming growth factor-beta in a chemically defined system..J. Biol. Chem. 1994; 269: 26775-26782Abstract Full Text PDF PubMed Google Scholar). TSP-1 binds fibrin (25.Panetti T.S. Kudryk B.J. Mosher D.F. Interaction of recombinant procollagen and properdin modules of thrombospondin-1 with heparin and fibrinogen/fibrin..J. Biol. Chem. 1999; 274: 430-437Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar), fibronectin (26.Iruela-Arispe M.L. Liska D.J. Sage E.H. Bornstein P. Differential expression of thrombospondin 1, 2, and 3 during murine development..Dev. Dyn. 1993; 197: 40-56Crossref PubMed Scopus (197) Google Scholar), plasminogen (27.Adams J.C. Thrombospondin-1..Int. J. Biochem. Cell Biol. 1997; 29: 861-865Crossref PubMed Scopus (101) Google Scholar), surface heparin-like glycosaminoglycans (26.Iruela-Arispe M.L. Liska D.J. Sage E.H. Bornstein P. Differential expression of thrombospondin 1, 2, and 3 during murine development..Dev. Dyn. 1993; 197: 40-56Crossref PubMed Scopus (197) Google Scholar), CD36 and αvβ3 integrins on activated endothelial cells (27.Adams J.C. Thrombospondin-1..Int. J. Biochem. Cell Biol. 1997; 29: 861-865Crossref PubMed Scopus (101) Google Scholar), and αIIbβ3 integrins on activated platelets (27.Adams J.C. Thrombospondin-1..Int. J. Biochem. Cell Biol. 1997; 29: 861-865Crossref PubMed Scopus (101) Google Scholar). TSP-1 may re-adjust growth factor and integrin signaling pathways between endothelial cells and the fibrin clot (27.Adams J.C. Thrombospondin-1..Int. J. Biochem. Cell Biol. 1997; 29: 861-865Crossref PubMed Scopus (101) Google Scholar) and prevent endothelial cell motility induced by fibrin. TSP-1 stimulates endothelial cell adhesion and spreading but blocks the chemokinetic response of endothelial cells to bFGF (28.Good D.J. Polverini P.J. Rastinejad F. Beau M.M.L. Lemons R.S. Frazier W.A. Bouck N.P. A tumor suppressor-dependent inhibitor of angiogenesis is immunologically and functionally indistinguishable from a fragment of thrombospondin..Proc. Natl. Acad. Sci. U. S. A. 1990; 87: 6624-6628Crossref PubMed Scopus (908) Google Scholar). Platelet α-granules are a rich source for active TGF-β1 (29.Assoain R.K. Komoriya A. Meyers C.A. Miller D.M. Sporn M.B. Transforming growth factor-beta in human platelets..J. Biol. Chem. 1983; 258: 7155-7160Abstract Full Text PDF PubMed Google Scholar). TGF-β1 promotes the formation of quiescent capillary tubules in vitro and mediates potent inhibition of endothelial cell proliferation and migration (30.Roberts A.B. Sporn M.B. Regulation of endothelial cell growth, architecture, and matrix synthesis by TGF-beta..Am. Rev. Respir. Dis. 1989; 140: 1126-1128Crossref PubMed Scopus (105) Google Scholar). TGF-β1 blocks the proliferation of endothelial cells to even supramaximal concentrations of bFGF (30.Roberts A.B. Sporn M.B. Regulation of endothelial cell growth, architecture, and matrix synthesis by TGF-beta..Am. Rev. Respir. Dis. 1989; 140: 1126-1128Crossref PubMed Scopus (105) Google Scholar). In vivo, however, TGF-β1 induces angiogenesis (30.Roberts A.B. Sporn M.B. Regulation of endothelial cell growth, architecture, and matrix synthesis by TGF-beta..Am. Rev. Respir. Dis. 1989; 140: 1126-1128Crossref PubMed Scopus (105) Google Scholar, 65.Ucki N. Nakazato M. Ohkawa T. Ikeda T. Amuro Y. Hada T. Higashino K. Excessive production of transforming growth factor beta-1 can play an important role in the development of tumorigenesis by its action for angiogenesis: validity of neutralizing antibodies to block tumor growth..Biochim. Biophys. Acta. 1992; 1137: 189-196Crossref PubMed Scopus (129) Google Scholar) that is thought to reflect recruitment of macrophages, which secrete endothelial cell growth factors (30.Roberts A.B. Sporn M.B. Regulation of endothelial cell growth, architecture, and matrix synthesis by TGF-beta..Am. Rev. Respir. Dis. 1989; 140: 1126-1128Crossref PubMed Scopus (105) Google Scholar). Regulation of plasminogen activation is critical to the sequence of stable fibrin clot formation followed by controlled fibrin digestion. PAI-1 is maintained in an active conformation in complexes with vitronectin within platelet α-granules (31.Hill S.A. Shaughnessy S.G. Joshua P. Ribau J. Austin R.C. Podor T.J. Differential mechanisms targeting type I plasminogen activator inhibitor and vitronectin into the storage granules of a human megakaryocytic cell line..Blood. 1996; 87: 5061-5073Crossref PubMed Google Scholar). Platelet-derived PAI-1 prevents initial fibrinolysis of platelet-rich thrombi (31.Hill S.A. Shaughnessy S.G. Joshua P. Ribau J. Austin R.C. Podor T.J. Differential mechanisms targeting type I plasminogen activator inhibitor and vitronectin into the storage granules of a human megakaryocytic cell line..Blood. 1996; 87: 5061-5073Crossref PubMed Google Scholar) but is less effective in the inhibition of the endothelial cell membrane-associated plasminogen activator (uPA) activity (37.Fukao H. Ueshima S. Okada K. Matsuo O. The role of the pericellular fibrinolytic system in angiogenesis..Jpn. J. Physiol. 1997; 47: 161-171Crossref PubMed Scopus (21) Google Scholar) that is generated by endothelial sprouts (33.Collen A. Koolwijk P. Kroon M. von Hinsbergh V.W.M. Influence of fibrin structure on the formation and maintenance of capillary-like tubules by human microvascular endothelial cells..Angiogenesis. 1998; 2: 153-165Crossref PubMed Google Scholar, 34.Kroon M.E. Koolwijk P. van Goor H. Weidle U.H. Collen A. van der Pluijm G. von Hinsbergh V.W.M. Role and localization of urokinase receptor in the formation of new microvascular structures in fibrin matrices..Am. J. Pathol. 1999; 154: 1731-1742Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar) (Fig.1). By limiting plasmin generation within the clot structure, PAI-1 can suppress angiogenesis F. Wilson E.L. P. Rifkin D.B. of action of angiostatic suppression of plasminogen activator activity stimulation of plasminogen activator inhibitor Physiol. 1993; PubMed Scopus Google Scholar, E. A. E. In vivo of expression of urokinase and its inhibitor PAI-1 a role in regulating Natl. Acad. Sci. U. S. A. 1992; PubMed Scopus Google Scholar) By platelet-derived and Collen D. The presence and release of from human 1981; PubMed Google Scholar) and R.L. Platelet and Biol. Chem. Full Text PDF PubMed Google Scholar) may also angiogenesis (37.Fukao H. Ueshima S. Okada K. Matsuo O. The role of the pericellular fibrinolytic system in angiogenesis..Jpn. J. Physiol. 1997; 47: 161-171Crossref PubMed Scopus (21) Google Scholar). in to activation of this can the coagulation and vitronectin for binding to the endothelial cell urokinase receptor S. J. A. of high molecular weight kininogen to human endothelial cells is mediated a site within domains 2 and 3 of the urokinase 1997; PubMed Scopus Google Scholar). generation of from inhibits the migration of endothelial cells to vitronectin and both of the fibrin of also inhibits endothelial cell proliferation and is anti-angiogenic on the Y. D. S.A. Inhibition of angiogenesis by peptides derived from 1998; Scholar). Activated coagulation factor factor II to and a domain Kim E. Kim Human fragment 1 and 2 inhibit cell Biophys. Res. Commun. 1998; PubMed Scopus Google Scholar). fragment of into and induces angiogenesis in vivo cleavage of the of the receptor on endothelial cells without the for fibrin formation E. M.E. promotes angiogenesis by a mechanism of fibrin J. Physiol. 1993; 264: PubMed Google Scholar). two kringle domains of are and of inhibit the proliferation of endothelial cells in vitro and angiogenesisin vivo Kim E. Kim Human fragment 1 and 2 inhibit cell Biophys. Res. Commun. 1998; PubMed Scopus Google Scholar). Thus, the stimulatory effects of on endothelial cells be by kringle released upon activation of In the presence of inhibits the activated form of factors II and in This is coagulation factors are to the surface of activated platelets and endothelial an important role in limiting the of an clot to the of vascular injury. and can the site of M.S. S. Folkman J. activity of the conformation of the 1999; PubMed Scopus Google Scholar). a potent inhibitor of endothelial cell proliferation in angiogenesis in vivo M.S. S. Folkman J. activity of the conformation of the 1999; PubMed Scopus Google Scholar). Thus, the angiogenic activity of generated at the site of may be balanced only by and -2 of but also through production of anti-angiogenic small peptides from the of the and of to form fibrin at the site of vessel and the adhered platelets, endothelial cells, and the with binding of latent regulators of plasminogen fibrin also high affinity binding for bFGF A. T. of basic fibroblast growth factor to and Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar), by This fibrin is cross-linked over the several by In fibrin as a factor on endothelial cells Folkman J. The of fibrin on cultured vascular endothelial PubMed Scopus Google Scholar), an that be during and must be initially mediates endothelial cell adhesion and spreading endothelial cell αvβ3 integrin binding to the at and of its α-chain P. A.J. adhesion in human for vascular endothelial 1996; PubMed Scopus Google Scholar). into fibrin requires growth endothelial cell receptor, and plasminogen activation (33.Collen A. Koolwijk P. Kroon M. von Hinsbergh V.W.M. Influence of fibrin structure on the formation and maintenance of capillary-like tubules by human microvascular endothelial cells..Angiogenesis. 1998; 2: 153-165Crossref PubMed Google Scholar, 34.Kroon M.E. Koolwijk P. van Goor H. Weidle U.H. Collen A. van der Pluijm G. von Hinsbergh V.W.M. Role and localization of urokinase receptor in the formation of new microvascular structures in fibrin matrices..Am. J. Pathol. 1999; 154: 1731-1742Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar). production of plasmin at the endothelial invasion the of the fibrin matrix for capillary formation B. P. Y. L. In vitro angiogenesis is by the of fibrin and is related to integrin Biol. 1997; Scopus Google Scholar). endothelial cells into and within the more and fibrin on the of fibrin with vascular endothelial on endothelial cells and capillary C. D. J. mediates endothelial cell capillary formation in fibrin and Cell Res. 1998; PubMed Scopus (184) Google Scholar). Thus, fibrin a role in the of vascular fibrin the platelet over immobilized endothelial cells to prevent hemorrhage. fibrin as a release for endothelial growth factors A. T. of basic fibroblast growth factor to and Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar) and fibrinolytic P. E.M. Platelet Rev. 1993; 7: PubMed Scopus Google Scholar). as the clot is fibrin of endothelial cell migration P. A.J. adhesion in human for vascular endothelial 1996; PubMed Scopus Google Scholar, C.A. U. D.J. a cell surface receptor with tumor cell mediates endothelial cell migration on and invasion into a fibrin 1996; PubMed Scopus Google Scholar) and capillary formation C. D. J. mediates endothelial cell capillary formation in fibrin and Cell Res. 1998; PubMed Scopus (184) Google Scholar). is to the clot structure and is initially from activation (31.Hill S.A. Shaughnessy S.G. Joshua P. Ribau J. Austin R.C. Podor T.J. Differential mechanisms targeting type I plasminogen activator inhibitor and vitronectin into the storage granules of a human megakaryocytic cell line..Blood. 1996; 87: 5061-5073Crossref PubMed Google Scholar, D. M. E. I. and of J. B. Scholar). kringles of is a inhibitor of angiogenesis discovered by its to prevent the growth of M.S. L. Y. C. M. Y. Sage E.H. Folkman J. a angiogenesis inhibitor that mediates the suppression of by a 1994; Full Text PDF PubMed Scopus Google Scholar). potently and inhibits endothelial cell proliferation in vitro and angiogenesis in M.S. L. Y. C. M. Y. Sage E.H. Folkman J. a angiogenesis inhibitor that mediates the suppression of by a 1994; Full Text PDF PubMed Scopus Google Scholar, M.S. L. C. Folkman J. induces and of human primary in Med. 1996; 2: PubMed Scopus Google Scholar). Further, of all kringle domains of anti-angiogenic activity Y. D. J. D. S. S.G. O'Reilly M.S. M. Folkman J. domains of characterization of the activity on endothelial Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, Y. A. D. M. of plasminogen is a inhibitor of endothelial cell Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). binds to the of on the surface of endothelial cells, into endothelial cells and M.S. J. P. L. S. binds on the surface of human endothelial Natl. Acad. Sci. U. S. A. 1999; PubMed Scopus Google Scholar). mechanisms have been demonstrated to active These include: cleavage by active matrix metalloproteinase -2 M.S. D. Folkman J. Regulation of production by matrix in a of Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus (239) Google Scholar), F. A. Collen D. of fragment from plasminogen by 1998; 37: PubMed Scopus Google Scholar), activities of human and Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar), and activities of human and Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google cleavage by a tumor plasmin P. M. P.J. of by and of by a plasmin secreted by cultured Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google P. A.J. M. C. P.J. formation and in kringle of Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google and cleavage of plasminogen on the surface of by K. is for the generation of in 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). also the rate of plasminogen activation through inhibition of plasminogen activator M.S. S. inhibits endothelial and invasion by plasminogen J. 1999; PubMed Scopus Google Scholar). Thus, generation of may the of endothelial cell migration and proliferation into the clot both directly and through inhibition of plasminogen the first as the clot and the vessel of angiogenesis by platelet-derived positive regulators, and fibrin must be clot angiogenesis must be to This regulation is through proteins secreted by platelets and cryptic fragments generated from hemostatic proteins in coagulation and Although the of release of cryptic fragments is can that may activities N. E. by as pericellular Full Text Full Text PDF Scopus Google Scholar, 34.Kroon M.E. Koolwijk P. van Goor H. Weidle U.H. Collen A. van der Pluijm G. von Hinsbergh V.W.M. Role and localization of urokinase receptor in the formation of new microvascular structures in fibrin matrices..Am. J. Pathol. 1999; 154: 1731-1742Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar, H. Ueshima S. Okada K. Matsuo O. The role of the pericellular fibrinolytic system in angiogenesis..Jpn. J. Physiol. 1997; 47: 161-171Crossref PubMed Scopus (21) Google Scholar, E. I. and of J. B. Scholar). Platelet secretion is within the first of and in deposition of both positive and negative regulators of angiogenesis. Platelet-derived and TGF-β1 may endothelial cell migration and proliferation from platelet-derived positive regulators of angiogenesis and fibrin. In this positive regulators of angiogenesis derived from platelets may function as factors Lee Kim I. is an apoptosis factor for endothelial 1999; PubMed Scopus Google Scholar, A. G. T.J. of on human for cell and with angiogenic growth 1999; Google Scholar). of to and fragments 1 and 2 occurs with platelet Further, of the that is generated may Thus, fragments 1 and 2 of and anti-angiogenic could also the initial pro-angiogenic from platelets, and fibrin. and initially prevent plasmin Thereafter, pericellular fibrinolysis and angiogenesis are by endothelial cell expression of the receptor M.E. Koolwijk P. van Goor H. Weidle U.H. Collen A. van der Pluijm G. von Hinsbergh V.W.M. Role and localization of urokinase receptor in the formation of new microvascular structures in fibrin matrices..Am. J. Pathol. 1999; 154: 1731-1742Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar) and M.E. Koolwijk P. van Goor H. Weidle U.H. Collen A. van der Pluijm G. von Hinsbergh V.W.M. Role and localization of urokinase receptor in the formation of new microvascular structures in fibrin matrices..Am. J. Pathol. 1999; 154: 1731-1742Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar) and also N. E. by as pericellular Full Text Full Text PDF Scopus Google Scholar). generation of could occur the mechanisms discussed and both the of endothelial repair and rate of plasmin fragments of and HGF may also be generated during Thus, domain and NK2, or NK4 may angiogenesis induced by the activity of platelet-derived angiogenic growth factors and fibrin during Platelet proteins and cryptic fragments generated during and fibrinolysis may endothelial cell during and control the rate of angiogenesis during vessel The of the hemostatic system to proteins that angiogenesis a new to angiogenesis is by and with during vessel

Angiogenesis research is being translated to the clinic. Certain guidelines may facilitate this effort. Recruitment of endothelial cells by a tumor is an early event in angiogenesis, a process regulated at genetic and epigenetic levels. The microvascular endothelial cell has become an important second target in cancer therapy. Angiogenesis inhibitors are either "direct" or "indirect" and their optimal dosing depends on a different logic than conventional chemotherapy. Conversely, antiangiogenic scheduling of chemotherapy can by-pass drug resistance. Like all solid tumors, hematologic malignancies are angiogenesis-dependent. Further, angiogenesis is modulated by proteins and cells from the hematopoietic and hemostatic systems. Clinical testing of angiogenesis inhibitors has accentuated the need for surrogate markers of tumor angiogenesis activity. Microvessel density, so valuable as a prognostic indicator of metastatic risk, cannot determine efficacy of an angiogenesis inhibitor. In the future, angiogenesis inhibitors may be added to chemotherapy or to radiotherapy, or to other modalities. Also, combinations of angiogenesis inhibitors may be administered together.

OBJECTIVE: The objective of this study was to determine the optimal use of fresh-frozen plasma (FFP) in trauma. Our hypothesis was that a higher FFP: packed red blood cells (PRBC) ratio is associated with improved survival. METHODS: This is a 6-year retrospective trauma registry and blood bank database study in a level I trauma center. All massively transfused patients (> or =10 PRBC during 24 hours) were analyzed. Patients with severe head trauma (head Abbreviated Injury Severity score > or =3) were excluded from the analysis. Patients were classified into four groups according to the FFP:PRBC ratio received: low ratio (< or =1:8), medium ratio (>1:8 and < or =1:3), high ratio (>1:3 and < or =1:2), and highest ratio (>1:2). RESULTS: Of 25,599 trauma patients, 4,241 (16.6%) received blood transfusion. Massive transfusion occurred in 484 (11.4%) of the transfused. After exclusion of 101 patients with severe head injury 383 patients were available for analysis. The mortality rate decreased significantly with increased FFP transfusion. However, there does not seem to be a survival advantage after a 1:3 FFP:PRBC ratio has been reached. Using the highest ratio group as a reference, the relative risk of death was 0.97 (p = 0.97) for the high ratio group, 1.90 (p < 0.01) for the medium ratio group, and 3.46 (p < 0.01) for the low ratio group. There was an increasing trend toward more FFP use during time with the mean units per patient increasing 83% from 6.3 +/- 4.6 in 2000 to 11.5 +/- 9.7 in 2005. CONCLUSION: Higher FFP:PRBC ratio is an independent predictor of survival in massively transfused patients. Aggressive early use of FFP may improve outcome in massively transfused trauma patients.