George Broze

Washington University in St. Louis | WUSTL , Wash U · Department of Medicine

BACKGROUND. Tissue factor (TF) is critical for hemostasis. However, TF also plays a pathogenic role in a multitude of diseases, including: thrombosis, coagulation-associated inflammation, multi-organ failure associated with infections, tumor growth, angiogenesis and metastasis. Tissue Factor Pathway Inhibitor (TFPI), the regulator of TF actions, pr...

Background Hemostasis requires a balance between pro‐ and anti‐coagulant factors. Hemophiliacs bleed due to a procoagulant deficiency. The targeted reduction in the activity of endogenous anticoagulant pathways is currently being investigated as a means of improving hemostasis in hemophilia. Protein Z (PZ) is a co‐factor that serves as a catalyst f...

Background Mouse models can provide insight into the pathophysiology of human thrombosis and hemostasis. Tissue factor pathway inhibitor (TFPI) regulates coagulation through protein S (PS)‐enhanced factor (F)Xa inhibition and FXa‐dependent inhibition of FVIIa/tissue factor (TF) activity. TFPI is expressed as isoforms α and β in man, and α, β and γ...

Streptococcus (S.) pneumoniae is the most common causative pathogen in community-acquired pneumonia. Coagulation and inflammation interact in the host response to infection. Tissue factor pathway inhibitor (TFPI) is a natural anticoagulant protein that inhibits tissue factor (TF), the main activator of inflammation-induced coagulation. It was the o...

Coagulation factor IX (FIX) a plasma protein whose absence results in hemophilia B, a disease ameliorated by injection of FIX. The pharmacokinetics of infused FIX are complicated. Fifty-80% of injected FIX disappears within 5 minutes.[1-3] Furthermore, Briet has observed that FIX injected into hemophilia B patients lacking antigen disappears more r...

Acquired factor X (FX) deficiency unrelated to amyloidosis is a rare disorder in which an anti-FX antibody is infrequently detected. A patient with severe bleeding due to a calcium ion-dependent anti-FX IgG antibody is described. The FX affinity purified IgG bound the light chain of FX, but not FX lacking its γ-carboxyglutamic acid domain, and bind...

In a report reading like a fascinating detective story, Vincent and colleagues crack the mysterious case of east Texas bleeding disorder. They show that affected individuals have a mutation in exon 13 of the coagulation F5 gene that causes increased expression of an alternatively spliced transcript, which encodes a previously unrecognized factor V...

Sepsis, a leading cause of mortality in critically ill patients, is closely linked to the excessive activation of coagulation and inflammation. Protein Z, a cofactor for the protein Z-dependent protease inhibitor, enhances the inhibition of coagulation factor Xa, and protein Z-dependent protease inhibitor inhibits factor XIa in a protein Z-independ...

Protein Z (PZ), a vitamin K-dependent plasma protein, dramatically enhances inhibition of coagulation factor Xa by protein Z-dependent protease inhibitor (ZPI), serpinA10 [1]. ZPI also directly inhibits factor XIa [2]. That PZ and ZPI knockout mice show enhanced responses in models of induced thrombosis supports a physiological relevant role for th...

The anticoagulant serpin, protein Z-dependent protease inhibitor (ZPI), is catalytically activated by its cofactor, protein Z (PZ), to regulate the function of blood coagulation factor Xa on membrane surfaces. The X-ray structure of the ZPI-PZ complex has shown that PZ binds to a unique site on ZPI centered on helix G. In the present study, we show...

Tissue factor pathway inhibitor (TFPI) is a multivalent Kunitz-type protease inhibitor that regulates tissue factor (TF)-induced coagulation by inhibiting factor Xa (FXa) and the factor VIIa (FVIIa)/TF complex [1]. Full-length TFPIα (FL-TFPIα) is a 276-residue glycoprotein with an acidic amino-terminus followed by three tandem Kunitz-type domains a...

TFPI is a multivalent, Kunitz-type proteinase inhibitor, which, due to alternative mRNA splicing, is transcribed in three isoforms: TFPIalpha, TFPIdelta, and glycosyl phosphatidyl inositol (GPI)-anchored TFPIbeta. The microvascular endothelium is thought to be the principal source of TFPI and TFPIalpha is the predominant isoform expressed in humans...

Tissue factor pathway inhibitor (TFPI) produces factor Xa-dependent feedback inhibition of factor VIIa/tissue factor-induced coagulation. Messages for 2 isoforms of TFPI have been identified. TFPIα mRNA encodes a protein with an acidic N-terminus, 3 Kunitz-type protease inhibitor domains and a basic C-terminus that has been purified from plasma and...

Factor VII-activating protease (FSAP) activates both factor VII and pro-urokinase and inhibits platelet-derived growth factor-BB, thus regulating hemostasis- and remodeling-associated processes in the vasculature. A genetic variant of FSAP (Marburg I polymorphism) results in low enzymatic activity and is associated with an enhanced risk of carotid...

Histidine-rich protein II (HRPII) is an abundant protein released into the bloodstream by Plasmodium falciparum, the parasite that causes the most severe form of human malaria. Here, we report that HRPII binds tightly and selectively to coagulation-active glycosaminoglycans (dermatan sulfate, heparan sulfate, and heparin) and inhibits antithrombin...

Protein Z-dependent protease inhibitor (ZPI) is a recently identified member of the serpin superfamily that functions as a cofactor-dependent regulator of blood coagulation factors Xa and XIa. Here we provide evidence that, in addition to the established cofactors, protein Z, lipid, and calcium, heparin is an important cofactor of ZPI anticoagulant...

Protein S (PS) enhances the inhibition of factor Xa (FXa) by tissue factor pathway inhibitor-alpha (TFPI-alpha) in the presence of Ca(2+) and phospholipids. Altered forms of recombinant TFPI-alpha were used to determine the structures within TFPI-alpha that may be involved in this PS-dependent effect. Wild-type TFPI-alpha (TFPI(WT)), TFPI-alpha lac...

The relationship between protein Z levels and thrombosis is controversial. We performed a systematic review and meta-analysis of the available studies to assess the association between protein Z and vascular thrombotic diseases. We conducted an electronic literature search through MedLine, Embase, Google Scholar, Web of Science, The Cochrane Librar...

SUMMARY INTRODUCTION: Protein Z is a vitamin K-dependent protein that serves as a cofactor for the inhibition of activated factor X by the serpin protein Z-dependent protease inhibitor (ZPI). Protein Z plasma levels have been shown to be reduced in patients with peripheral arterial disease (PAD), but ZPI levels have not yet been reported. The aim o...

Protein Z-dependent protease inhibitor (ZPI) is a recently identified member of the serpin superfamily that functions as a cofactor-dependent regulator of blood coagulation factors Xa (FXa) and XIa. Here we show that ZPI and its cofactor, protein Z (PZ), inhibit procoagulant membrane-bound factor Xa by the branched pathway acyl-intermediate trappin...

The role of host-derived tissue factor (TF) in tumor growth, angiogenesis, and metastasis has hitherto been unclear and was investigated in this study. We compared tumor growth, vascularity, and responses to cyclophosphamide (CTX) of tumors in wild-type (wt) mice, or in animals with TF levels reduced by 99% (low-TF mice). Global growth rate of 3 di...

Protein Z (PZ) is a plasma vitamin K-dependent protein that functions as a cofactor to dramatically enhance the inhibition of coagulation factor Xa by the serpin, protein Z-dependent protease inhibitor (ZPI). In vitro, ZPI not only inhibits factor Xa in a calcium ion-, phospholipid-, and PZ-dependent fashion, but also directly inhibits coagulation...

Oncogenic events play an important role in cancer-related coagulopathy (Trousseau syndrome), angiogenesis and disease progression. This can, in part, be attributed to the up-regulation of tissue factor (TF) and release of TF-containing microvesicles into the pericellular milieu and the circulation. In addition, certain types of host cells (stromal...

We previously reported that the first epidermal growth factor-like (EGF1) domain in factor X (FX) or factor IX (FIX) plays an important role in the factor VIIa/tissue factor (FVIIa/TF)-induced coagulation. To assess the role of γ-carboxyglutamic acid (Gla) domains of FX and FIX in FVIIa/TF induced coagulation, we studied four new and two previously...

Decreased fibrinolytic function favors the development of pulmonary fibrosis. Thrombin-activatable fibrinolysis inhibitor (TAFI) is a strong suppressor of fibrinolysis, but its role in lung fibrosis is unknown. Therefore, we compared bleomycin-induced lung fibrosis in TAFI-deficient, heterozygous, and wild-type mice. The animals were sacrificed 21...

Additional therapeutic options are needed for patients with bleeding disorders such as hemophilia A, hemophilia B, severe von Willebrand disease, and other rare factor deficiencies. A novel approach to improve coagulation in such clotting disorders has been identified that, parodoxically, involves heparinlike sulfated polysaccharides. Select molecu...

Tissue factor pathway inhibitor (TFPI) is mainly produced by endothelial cells and alternative mRNA splicing generates two forms, TFPIalpha and TFPIbeta. A portion of expressed TFPI remains associated with the cell surface through both direct (TFPIbeta) and indirect (TFPIalpha) glycosylphosphatidyl-inositol (GPT)-mediated anchorage. Compare the str...

The activity of the hemostatic system components facilitates tumor growth and dissemination. There exists a mechanism of direct inhibition of factor Xa that involves protein Z (PZ)/protein Z-dependent protease inhibitor (ZPI) system. ZPI also attenuates the activity of factor XIa. Data on the presence of PZ and ZPI in malignant tissue in situ are l...

Additional therapeutic options are needed for patients with bleeding disorders such as hemophilia A, hemophilia B, and severe von Willebrand disease. A novel treatment approach which may benefit such clotting disorders has been identified that, parodoxically, involves heparin-like sulfated polysaccharides. Select molecules of this broad class are l...

To assess the potential roles of protein Z (PZ) and protein Z-dependent protease inhibitor (ZPI) in venous thrombosis, their plasma levels were measured in 426 individuals with venous thrombosis and 471 control individuals participating in the Leiden Thrombophilia Study. A relationship between the level of PZ or ZPI and venous thrombosis was not de...

To assess the potential roles of protein Z (PZ) and protein Z-dependent protease inhibitor (ZPI) in venous thrombosis, their plasma levels were measured in 426 individuals with venous thrombosis and 471 control individuals participating in the Leiden Thrombophilia Study. A relationship between the level of PZ or ZPI and venous thrombosis was not de...

During tissue factor (TF)-induced coagulation, the factor (F)VIIa-TF complex activates factor (F)X and factor (F)IX. Through positive feedback, the generated FXa and FIXa activate FVII-TF. The first epidermal growth factor-like (EGF1) domains of FX and FIX serve as important TF-recognition motifs when FVIIa-TF activates FX or FIX. Here, we investig...

Tissue factor pathway inhibitor (TFPI)-alpha, a key regulator of tissue factor-induced coagulation, contains 3 tandem Kunitz-type inhibitory domains. Kunitz-1 binds and inhibits factor VIIa in the factor VIIa/tissue factor complex, and Kunitz-2 binds and inhibits factor Xa. The role of the Kunitz-3 domain of TFPI-alpha, however, has remained an eni...

TFPI is mainly produced by endothelial cells and alternative mRNA splicing generates two forms, TFPIα and TFPIβ. A small proportion of expressed TFPI remains associated with the cell surface through both direct (TFPIβ) and indirect (TFPIα) glycosylphosphatidylinositol (GPI)-mediated anchorage. TFPIβ lacks the C-terminus and Kunitz-3 (K3) domains of...

Cancer progression is often associated with thromboembolic complications. Coagulation factors and inhibitors influence various processes involved in malignant tumor growth and metastatic dissemination. Recently a new coagulation inhibitor - protein Z-dependent protease inhibitor (ZPI) has been characterized. ZPI is a plasma proteinase inhibitor in...

The activation of factor X by VIIa/TF and the Xa-dependent inhibition of the enzyme complex by tissue factor pathway inhibitor (TFPI) are considered primary steps in the initiation of coagulation. IX activation by VIIa/TF is considered to contribute catalyst necessary for further Xa production in the ensuing amplification phase. We have investigate...

The activation of factor X by VIIa/TF and the Xa-dependent inhibition of the enzyme complex by tissue factor pathway inhibitor (TFPI) are considered primary steps in the initiation of coagulation. IX activation by VIIa/TF is considered to contribute catalyst necessary for further Xa production in the ensuing amplification phase. We have investigate...

Earlier studies found strong support for a genetic basis for regulation of coagulation factor levels and measures of a prethrombotic state (d-dimer, prothrombin fragment 1.2). Estimation of how much of the variation in the levels of coagulation factors and measures of a prethrombotic state, including measures of protein C activation and inactivatio...

Tissue factor pathway inhibitor (TFPI) is a multivalent Kunitz-type proteinase inhibitor that produces factor (F)Xa-dependent feedback inhibition of the factor VIIa/tissue factor (FVIIa/TF) catalytic complex that is responsible for the initiation of coagulation. Since 1985, when Rapaport and colleagues reported that the lipoprotein fraction of plas...

The endothelium is a major source of tissue factor pathway inhibitor (TFPI), the endogenous regulator of TF-induced coagulation, and a significant proportion of the expressed TFPI remains associated with the endothelial surface. Phosphatidylinositol-specific phospholipase C (PI-PLC) treatment reduced TFPI at the surface of cultured endothelial cell...

The hemostatic process is tightly regulated by several antithrombotic mechanisms. Among them, protein Z (PZ)-dependent protease inhibitor (ZPI) potently inhibits factor (F)Xa in a manner dependent on calcium ions, phospholipids and PZ. Autoimmune antiphospholipid antibodies (aPL) are mainly directed against phospholipid-binding plasma proteins such...

As the activity of the tissue factor pathway inhibitor (TFPI) may be impaired in patients with antiphospholipid antibodies (aPL), 162 aPL patients were evaluated for autoantibodies to recombinant TFPI (anti-TFPI) using an optimized ELISA. Anti-TFPI (>18 U mL(-1) for IgG and/or > 15 U mL-1 for IgM) were detected in 54 patients with aPL (33.3%) and i...

Factor V Leiden (FVL) is a common genetic risk factor for thrombosis in humans. The incomplete penetrance of FVL suggests important contributions from other genetic or environmental modifying factors. Variation in the expression of tissue factor pathway inhibitor (TFPI) has also been proposed as a risk factor for venous thrombosis and has been show...

In order to examine the physiological role of thrombin-activatable fibrinolysis inhibitor (TAFI), we generated homozygous TAFI deficient mice by targeted gene disruption. Intercrossing of heterozygous TAFI mice showed that TAFI mice were born in the expected Mendelian ratio, indicating that transmission of the mutant TAFI allele did not lead to emb...

To investigate the consequence of deficiency in thrombin-activatable fibrinolysis inhibitor (TAFI), we generated homozygous TAFI-deficient mice by targeted gene disruption. Intercrossing of heterozygous TAFI mice produced offspring in the expected Mendelian ratio, indicating that transmission of the mutant TAFI allele did not lead to embryonic leth...

Lipoprotein (a) [Lp(a)] has been associated with both anti-fibrinolytic and atherogenic effects. However, no direct link currently exists between this atherogenic lipoprotein and intravascular coagulation. The current study examined the binding and functional effects of Lp(a), its lipoprotein constituents, apoliprotein (a) [apo(a)] and low-density...

Protein Z (PZ) is a 62 kDa vitamin K-dependent plasma protein that serves as a cofactor for the inhibition of factor Xa by protein Z-dependent protease inhibitor (ZPI). ZPI is a recently identified 72 kDa member of the serpin superfamily of proteinase inhibitors that contains a tyrosine at its reactive center. PZ circulates in plasma in a complex w...

Tissue factor initiates blood coagulation after atherosclerotic plaque disruption. Tissue factor pathway inhibitor (TFPI) inhibits tissue factor activity and may reduce thrombus formation in this setting. We evaluated the effect of heterozygous TFPI deficiency on the development of atherosclerosis and thrombosis in atherosclerosis-prone mice. Mice...

Protein Z-dependent protease inhibitor (ZPI) is plasma proteinase inhibitor in the serpin superfamily that produces rapid inhibition of factor Xa in the presence of phospholipids, Ca++ and protein Z (PZ). Mouse ZPI cDNA was isolated and cloned from mouse liver RNA using RT-PCR. The cDNA contains 100 nucleotides 5' of a translation initiation codon...

Protein Z (PZ) is a vitamin K-dependent plasma protein that forms a Ca++-dependent complex with factor Xa at phospholipid surfaces. This interaction between PZ and factor Xa enhances by >1,000-fold the inhibition of factor Xa by the serpin called protein Z-dependent protease inhibitor (ZPI). These experiments show that PZ also binds ZPI in a proces...

Protein Z-dependent protease inhibitor (ZPI) is a 72-kd member of the serpin superfamily of proteinase inhibitors that produces rapid inhibition of factor Xa in the presence of protein Z (PZ), procoagulant phospholipids, and Ca(++) (t(1/2) less than 10 seconds). The rate of factor Xa inhibition by ZPI is reduced more than 1000-fold in the absence o...

Protein Z-dependent protease inhibitor (ZPI) is a 72-kd member of the serpin superfamily of proteinase inhibitors that produces rapid inhibition of factor Xa in the presence of protein Z (PZ), procoagulant phospholipids, and Ca++ (t1/2 less than 10 seconds). The rate of factor Xa inhibition by ZPI is reduced more than 1000-fold in the absence of PZ...

Protein Z (PZ) is a vitamin K-dependent plasma protein whose function has been uncertain. The structure of PZ is very similar to that of the coagulation-related factors VII, IX, and X and PC, but PZ differs from these other proteins in that it is not the zymogen of a serine protease. We have shown recently that PZ forms a calcium ion-dependent comp...

Tissue factor pathway inhibitor (TFPI) plays a key role in the regulation of tissue factor-initiated blood coagulation secondary to loss of the integrity of the blood vessel wall. TFPI is a naturally occurring Kunitz-type protease inhibitor that inhibits coagulation factor Xa and, in a factor Xa-dependent manner, mediates feedback inhibition of the...

The intimal thickening that follows vascular injury is inhibited by periprocedural tissue factor pathway inhibitor (TFPI) treatment in animal models. TFPI is a multivalent Kunitz-type protease inhibitor that inhibits factor Xa via its second Kunitz domain and the factor VIIa/tissue factor (TF) complex via its first Kunitz domain. The basic C-termin...

In the presence of phospholipid vesicles and calcium ions, protein Z (PZ) serves as a cofactor for the inhibition of coagulation factor Xa by a plasma protein called PZ-dependent protease inhibitor (ZPI). To further characterize ZPI, its cDNA has been isolated and cloned from a human liver cDNA library. The ZPI cDNA is 2.44 kb in length and has a r...

Mice doubly heterozygous for a modified tissue factor pathway inhibitor (TFPI) allele (tfpi delta) lacking its Kunitz-type domain-1 (TFPI+/delta) and for a deficiency of the factor VII gene (FVII+/-) were mated to generate 309 postnatal and 205 embryonic day 17.5 (E17. 5) offspring having all the predicted genotypic combinations. Progeny singly hom...

Tissue factor pathway inhibitor (TFPI) in vivo is thought to be synthesized mainly by endothelial cells. To date, no significant regulator of TFPI synthesis has been described. Vascular smooth muscle cells (VSMC) express tissue factor in vitro and in vivo, which may contribute to vascular thrombosis. We hypothesized that VSMC might also express TFP...

Human protein Z (PZ) is a 62,000-Mr, vitamin K-dependent plasma protein whose structure is similar to coagulation factors VII, IX, X, protein C, and protein S, but whose function is not known. The procoagulant activity of factor Xa in a one-stage plasma coagulation assay is reduced when factor Xa is first incubated with PZ. This apparent inhibitory...

Tissue factor pathway inhibitor (TFPI) is a trivalent Kunitz-type plasma proteinase inhibitor that regulates the initiation of coagulation by producing activated factor X (FXa)-dependent feedback inhibition of the catalytic complex of FVIIa and tissue factor (TF). The second Kunitz domain of TFPI binds and inhibits FXa, whereas the first Kunitz dom...

Tissue factor (TF) pathway inhibitor (TFPI) regulates factor X activation through the sequential inhibition of factor Xa and the VIIa.TF complex. Factor Xa formation was studied in a purified, reconstituted system, at plasma concentrations of factor X and TFPI, saturating concentrations of factor VIIa, and increasing concentrations of TF reconstitu...

Tissue factor pathway inhibitor (TFPI) is a primary regulator of the initiation of blood coagulation. TFPI is internalized and degraded by HepG2 cells through the low-density-lipoprotein receptor-related protein (LRP) but also binds another molecule present on the cell surface at approx. 10-fold the abundance of LRP [Warshawsky, Broze and Schwartz...

Tissue factor pathway inhibitor (TFPI), a 42 kD protein, provides the physiological inhibition of tissue factor initiated coagulation by inhibition of both factor Xa and factor VIIa/tissue factor. In plasma, most TFPI is lipoprotein bound with an additional “releasable” pool bound to the endothelial cell surface. TFPI clearance is via receptor medi...

Tissue factor pathway inhibitor (TFPI) is a multivalent Kunitz-type proteinase inhibitor that directly inhibits factor Xa and, in a factor Xa-dependent fashion, produces feedback inhibition of the factor VIIa/TF catalytic complex responsible for the initiation of coagulation. To further define the physiologic role of TFPI, gene-targeting techniques...

Tissue factor pathway inhibitor (TFPI) is a potent inhibitor of blood coagulation factor Xa (fXa) and factor VIIa. We have recently shown that fXa binding stimulates the uptake and degradation of cell surface-bound 125I-TFPI (Ho, G., Toomey, J. R., Broze, G. J., Jr., and Schwartz, A. L. (1996) J. Biol. Chem. 271, 9497-9502). In the present study we...

Tissue factor pathway inhibitor (TFPI) is a multivalent Kunitz-type proteinase inhibitor that directly inhibits factor Xa and, in a factor Xa–dependent fashion, produces feedback inhibition of the factor VIIa/TF catalytic complex responsible for the initiation of coagulation. To further define the physiologic role of TFPI, gene-targeting techniques...

Previous reports suggest that tissue factor (TF) may play an essential role in embryonic vascular development and tumor angiogenesis. To further examine this relationship, the morphology of fully developed TF-deficient embryos and the growth of TF-deficient teratomas and teratocarcinomas were analyzed. In a 129/Sv genetic background, TF null embryo...

To facilitate investigations into the physiologic and pathologic roles of factor XI, we have developed a murine model of severe factor XI deficiency using the technique of homologous recombination in embryonic stem cells. The factor XI gene was disrupted by introducing a neomycin phosphotransferase gene into the fifth exon. The activated partial th...

Coagulation is initiated by the binding of factor VIIa to tissue factor, with resultant limited factor IX and X activation and thrombin production. Owing to the feedback inhibition of the factor VIIa/tissue factor complex by tissue factor pathway inhibitor (TFPI), additional factor X activation and thrombin generation must proceed through a pathway...

Tissue factor pathway inhibitor (TFPI) is a plasma serine protease inhibitor that directly inhibits coagulation factor Xa and regulates blood coagulation via inhibition of factor VIIa-tissue factor enzymatic activity. We previously demonstrated that >90% of TFPI bound to a single population of low affinity binding sites on hepatoma cells (2 x 10(6)...

Thrombin generation during coagulation affects the fibrinolysis resistance of clots. This phenomenon is mediated at least in part by a plasma carboxypeptidase that has been called carboxypeptidase-U, carboxypeptidase-R, pro-carboxypeptidase-B, and thrombin-activatable fibrinolysis inhibitor. Carboxypeptidase-U circulates as an inactive proenzyme an...

Tissue factor (TF) is an integral membrane glycoprotein that is believed to be the physiologic initiator of the blood coagulation cascade. Disruption of the mouse tissue factor gene leads to embryonic lethality between days E9.5-E11.5 of gestation. On E9.5, TF(-/-) embryos appear indistinguishable from their TF(+/+) and TF(+/-) littermates. By E10....

Coagulation factor Xa is a plasma serine protease that catalyzes prothrombin to thrombin conversion, which, in turn, leads to the generation of the fibrin clot. Of the several parameters that govern the plasma level of factor Xa, control of its catabolism is of crucial importance. However, little is known regarding the mechanisms by which factor Xa...

Tissue factor pathway inhibitor (TFPI) is a Kunitz-type serine proteinase inhibitor that directly inhibits factor Xa and, in a factor Xa dependent manner, inhibits the factor VIIa/tissue factor catalytic complex. The inhibitory effect of TFPI in prothrombin activation assays using purified components of the prothrombinase complex was examined. When...

Tissue factor pathway inhibitor (TFPI) is a potent inhibitor of the blood coagulation factor VIIa-tissue factor complex, as well as a direct inhibitor of factor Xa. Intravenously administered TFPI is rapidly cleared from circulation predominantly via liver. We previously reported that the low density lipoprotein receptor-related protein (LRP), a mu...