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1.  Structure-function and regulation of ADAMTS13 protease 
ADAMTS13, a plasma reprolysin-like metalloprotease, cleaves von Willebrand factor (VWF). Severe deficiency of plasma ADAMTS13 activity results in thrombotic thrombocytopenic purpura (TTP), while mild to moderate deficiencies of plasma ADAMTS13 activity are emerging risk factors for developing myocardial and cerebral infarction, preeclampsia, and malignant malaria. Moreover, Adamts13−/− mice develop more severe inflammatory responses, leading to increased ischaemia/perfusion injury and formation of atherosclerosis. Structure-function studies demonstrate that the N-terminal portion of ADAMTS13 (MDTCS) is necessary and sufficient for proteolytic cleavage of VWF under various conditions and attenuation of arterial/venous thrombosis after oxidative injury. The more distal portion of ADAMTS13 (TSP1 2–8 repeats and CUB domains) may function as a disulphide bond reductase to prevent an elongation of ultra large VWF strings on activated endothelial cells and inhibit platelet adhesion/aggregation on collagen surface under flow. Remarkably, the proteolytic cleavage of VWF by ADAMTS13 is accelerated by FVIII and platelets under fluid shear stress. A disruption of the interactions between FVIII (or platelet glycoprotein 1bα) and VWF dramatically impairs ADAMTS13-dependent proteolysis of VWF in vitro and in vivo. These results suggest that FVIII and platelets may be physiological cofactors regulating VWF proteolysis. Finally, the structure-function and autoantibody mapping studies allow us to identify an ADAMTS13 variant with increased specific activity but reduced inhibition by autoantibodies in patients with acquired TTP. Together, these findings provide novel insight into the mechanism of VWF proteolysis and tools for the therapy of acquired TTP and perhaps other arterial thrombotic disorders.
PMCID: PMC3713533  PMID: 23809107
2.  ADAMTS13, TTP and Beyond 
PMCID: PMC4001087  PMID: 24790789
Von willebrand factor cleaving protease; ADAMTS; Thrombotic thrombocytopenic purpura; Inflammation; Thrombosis; Atherosclerosis
3.  Current status in diagnosis and treatment of hereditary thrombotic thrombocytopenic purpura 
PMCID: PMC4204482  PMID: 25343060
Thrombotic thrombocytopenic purpura; ADAMTS13; von Willebrand factor; diagnosis; therapy; inherited or hereditary; arterial thrombosis
4.  Biochemistry and physiological functions of ADAMTS7 metalloprotease 
Advances in biochemistry  2013;1(3):10.11648/j.ab.20130103.11.
Here, we provide a comprehensive review of current findings concerning the biochemistry and physiological functions of ADAMTS7, a metalloprotease that is known to interact with cartilage oligomeric matrix protein, progranulin, and alpha2-macroglobulin. Such broad substrate specificity and potentially diverse physiological functions make ADAMTS7 an interesting enzyme to study. ADAMTS7 has been shown to play a role in the pathogenesis of arthritis and disc disorders. More recently, the ADAMTS7 locus is identified to have a strong association with coronary atherosclerotic disease. However, the role of ADAMTS7 in the development of atherosclerosis is yet to be determined. The development of an easy and high throughput assay for ADAMTS7 activity and appropriate animal models will allow us to uncover the novel mechanisms of coronary arterial disease.
PMCID: PMC3821704  PMID: 24222922
ADAMTS7; Substrate Specificity; Structure-Function; Cardiovascular Disease; Smooth Muscle Cell
6.  Genetic ablation of Adamts13 gene dramatically accelerates the formation of early atherosclerosis in a murine model 
ADAMTS13 cleaves von Willebrand factor (VWF), thereby modulating thrombosis and inflammation. Low plasma ADAMTS13 activity is associated with cardiovascular events including myocardial and cerebral infarction. Here, we investigated the role of ADAMTS13 in the development of early atherosclerosis in a murine model.
Methods and Results
ApoE−/− and Adamts13−/−ApoE−/− mice were fed with a high fat Western diet for 12 weeks. Atherosclerotic lesions in the aorta and aortic roots were quantified after staining. Leukocyte rolling and adhesion onto cremaster venules after oxidative injury were determined by intravital microscopy. While plasma cholesterol levels were largely similar in both groups, the extent of atherosclerotic lesions in the aorta en face and in the aortic roots in the Adamts13−/−ApoE−/− mice increased ~5.5 fold (p=0.0017) and ~6.1 fold (p=0.0037), respectively. Also, the ratio of plasma high to low molecular weight VWF multimers increased ~3 fold. The leukocyte rolling velocities were significantly reduced (p<0.001) with an increased number of leukocyte rolling (p=0.0026) and macrophage infiltration into the atherosclerotic lesions in the Adamts13−/−ApoE−/− mice.
Our results suggest that ADAMTS13 plays a critical role in modulating the development of early atherosclerosis, likely through proteolytic cleavage of ultra large VWF multimers, thereby inhibiting platelet deposition and inflammation.
PMCID: PMC3422623  PMID: 22652598
von Willebrand factor cleaving protease; inflammation; and animal model
7.  Novel Recombinant Glycosylphosphatidylinositol (GPI)-Anchored ADAMTS13 and Variants for Assessment of Anti-ADAMTS13 Autoantibodies in Patients with Thrombotic Thrombocytopenic Purpura 
Thrombosis and haemostasis  2011;106(5):947-958.
Immunoglobulin Gs (IgGs) against ADAMTS13 are major causes of acquired (idiopathic) thrombotic thrombocytopenic purpura (TTP). We report here a novel cell-based assay using glycosylphosphatidylinositol (GPI)-anchored ADAMTS13 or variants expressed on cell membrane for assessment of autoantibodies in patients with TTP. We showed that IgGs from all 26 patients with acquired TTP bound to cells expressing a GPI anchored full-length ADAMTS13 (gFL) and a variant truncated after the spacer domain (gS). Also, IgGs from 25/26 (96.7%) of these TTP patients bound to cells expressing a GPI-anchored C-terminal fragment, TSP1 2-8 plus CUB (gT2C). In contrast, none of the 20 healthy blood donors showed detectable binding of their IgGs to the cells expressing gFL, gS, and gT2C. A moderate, but statistically significant correlation was observed between plasma concentrations of anti-ADAMTS13 IgG and positive cells expressing gFL (r=0.65), gS (r=0.67), and gT2C (r=0.42). These results suggest that the microtiter-plate assay and the cell-based assay may detect differential antigenic epitopes. Moreover, antigens clustered on cell membrane may enhance antibody binding affinity, thereby increasing analytical sensitivity. Finally, our assay was able to determine kinetic changes of plasma levels of anti-ADAMTS13 IgGs in TTP patients during plasma therapy. Together, our findings suggest that the novel cell-based assay may be applicable for rapid identification and mapping of anti-ADAMTS13 autoantibodies in patients with acquired TTP.
PMCID: PMC3208768  PMID: 21901237
von Willebrand factor cleaving protease; thrombotic microangiopathies; diagnostic test; autoantibody
8.  Essential Domains of ADAMTS13 Metalloprotease Required for Modulation of Arterial Thrombosis 
ADAMTS13 inhibits platelet aggregation and arterial thrombosis by cleavage of von Willebrand factor (VWF). However, the structural components of ADAMTS13 required for inhibition of arterial thrombosis are not fully defined.
Methods and Results
Using recombinant proteins and a murine model, we demonstrate that ADAMTS13 variant either truncated after the 8th TSP1 repeat or spacer domain inhibits ferric chloride-induced arterial thrombosis in Adamts13−/− mice with similar efficacy to full-length ADAMTS13. The results obtained from monitoring thrombus formation in carotid and mesenteric arteries are highly concordant. Further analyses by site-directed mutagenesis and human monoclonal antibody inhibition assay reveal that the Cys-rich and spacer domains of ADAMTS13, particularly the amino acid residues between Arg559 and Glu664 in the spacer domain, may be critical for modulation of arterial thrombosis in vivo. Finally, the thrombosis-modulating function of ADAMTS13 and variants/mutants is highly correlated with the VWF-cleavage activity under fluid shear stress.
Our results suggest that the amino-terminus of ADAMTS13, specifically the variable region of the spacer domain, is crucial for modulation of arterial thromboses under (patho) physiological conditions. These findings shed more light on the structure-function relationship of ADAMTS13 in vivo and may be applicable for rational design of protein or gene-based therapy of arterial thromboses.
PMCID: PMC3174348  PMID: 21799176
9.  A shear-based assay for assessing plasma ADAMTS13 activity and inhibitor in patients with thrombotic thrombocytopenic purpura 
Transfusion  2011;51(7):1580-1591.
Severe deficiency of plasma ADAMTS13 activity is a frequent finding in patients with hereditary and acquired thrombotic thrombocytopenic purpura (TTP). To date, plasma ADAMTS13 activity is determined by cleavage of either pre-denatured von Willebrand factor (VWF) or small peptides derived from the VWF-A2 domain. The physiological relevance of the assay results is uncertain.
We sought to develop a novel shear-based assay to assess plasma ADAMTS13 activity and inhibitor. We also compared this assay with a fluorogenic peptide assay.
We found that an incubation of purified plasma VWF with 0.5-1.0 μl of citrated plasma under constant vortexing at 2,500 rpm for 60 minutes in the presence of 5 mM CaCl2, 1.7 μM ZnCl2 and low concentration of NaCl resulted in the maximal cleavage of VWF. The cleavage product could be separated by a 2.5% agarose gel and detected by Western blotting. The assay revealed that plasma and recombinant ADAMTS13 are highly sensitive to inhibition by zinc and chloride ions. Under the optimal conditions, the shear-based assay appeared to be more sensitive than the guanidine-denaturization assay for determining plasma ADAMTS13 activity.
Our fluid shear-based assay may be useful for investigating basic biological function and regulation of ADAMTS13 metalloprotease. It may also be applicable for assessing plasma ADAMTS13 activity and inhibitors in TTP patients.
PMCID: PMC3168518  PMID: 21251003
10.  Toward a definition of “fresh” whole blood: an in vitro characterization of coagulation properties in refrigerated whole blood for transfusion 
Transfusion  2011;51(1):10.1111/j.1537-2995.2010.02772.x.
The hemostatic property of “fresh” whole blood (WB) has been observed in military application and cardiac surgery and is associated with reduced blood loss, transfusion requirements, and donor exposures. The time from donation to transfusion defining “fresh” has not been systematically studied. We undertook an in vitro study of coagulation properties of refrigerated WB stored for 31 days.
Study design and methods
Twenty-one WB units were obtained from healthy volunteer donors and stored under standard AABB refrigerated conditions. Samples were obtained on the day after donation and again on Days 2, 4, 7, 11, 14, 17, 21, 24, and 31. Tests included complete blood count, pH, pO2, pCO2, glucose, lactate, thromboelastography (TEG), and platelet function by light transmission aggregometry (LTA).
There was progressive decline in pH, pO2, glucose, and sodium, but progressive increase in potassium, pCO2, and lactate. TEG variables in all units were normal through Day 11; abnormal values in some variables in some units began on Day 14. Final aggregation levels exhibited no change from Day 1 to Day 21 with adenosine diphosphate and epinephrine, but a decline with collagen (Day 7) and ristocetin (Day 17).
This in vitro study of coagulation properties demonstrates preservation of normal integrated coagulation function to a minimum of 11 days under standard conditions of refrigerated storage of WB for transfusion. These observations strongly suggest that the hemostatic quality of WB may extend beyond current transfusion practices. If confirmed clinically, this would increase availability and extend benefits of reduced donor exposure and transfusion requirements.
PMCID: PMC3821701  PMID: 20663116
11.  Ticlopidine-, Clopidogrel-, and Prasugrel-Associated Thrombotic Thrombocytopenic Purpura: A 20-Year Review from the Southern Network on Adverse Reactions (SONAR) 
Thienopyridine-derivatives (ticlopidine, clopidogrel, and prasugrel) are the primary antiplatelet agents. Thrombotic thrombocytopenic purpura (TTP) is a rare drug-associated syndrome, with the thienopyridines being the most common drugs implicated in this syndrome. We reviewed 20 years of information on clinical, epidemiologic, and laboratory findings for thienopyridine-associated TTP. Four, 11, and 11 cases of thienopyridine-associated TTP were reported in the first year of marketing of ticlopidine (1989), clopidogrel (1998), and prasugrel (2010), respectively. As of 2011, the FDA received reports of 97 ticlopidine-, 197 clopidogrel-, and 14 prasugrel-associated TTP cases. Severe deficiency of ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) was present in 80% and antibodies to 100% of these TTP patients on ticlopidine, 0% of the patients with clopidogrel-associated TTP (p < 0.05), and an unknown percentage of patients with prasugrel-associated TTP. TTP is associated with use of each of the three thienopyridines, although the mechanistic pathways may differ.
PMCID: PMC3804561  PMID: 23111862
thrombotic thrombocytopenic purpura; ticlopidine; clopidogrel; prasugrel; adverse event
13.  Ticlopidine- and clopidogrel-associated thrombotic thrombocytopenic purpura (TTP): review of clinical, laboratory, epidemiological, and pharmacovigilance findings (1989–2008) 
Thrombotic thrombocytopenic purpura (TTP) is a fulminant disease characterized by platelet aggregates, thrombocytopenia, renal insufficiency, neurologic changes, and mechanical injury to erythrocytes. Most idiopathic cases of TTP are characterized by a deficiency of ADAMTS13 (a disintegrin and metalloprotease, with thrombospondin-1-like domains) metalloprotease activity. Ironically, use of anti-platelet agents, the thienopyridine derivates clopidogrel and ticlopidine, is associated with drug induced TTP. Data were abstracted from a systematic review of English-language literature for thienopyridine-associated TTP identified in MEDLINE, EMBASE, the public website of the Food and Drug Administration, and abstracts from national scientific conferences from 1991 to April 2008. Ticlopidine and clopidogrel are the two most common drugs associated with TTP in FDA safety databases. Epidemiological studies identify recent initiation of anti-platelet agents as the most common risk factor associated with risks of developing TTP. Laboratory studies indicate that most cases of thienopyridine-associated TTP involve an antibody to ADAMTS13 metalloprotease, present with severe thrombocytopenia, and respond to therapeutic plasma exchange (TPE); a minority of thienopyridine-associated TTP presents with severe renal insufficiency, involves direct endothelial cell damage, and is less responsive to TPE. The evaluation of this potentially fatal drug toxicity can serve as a template for future efforts to comprehensively characterize other severe adverse drug reactions.
PMCID: PMC3500614  PMID: 19180126
drug-associated TTP; epidemiology; ADAMTS13
16.  Molecular Biology of ADAMTS13 and Diagnostic Utility of ADAMTS13 Proteolytic Activity and Inhibitor Assays 
ADAMTS13, a reprolysin-like metalloprotease, limits platelet-rich thrombus formation in the small arteries by cleaving von Willebrand factor (vWF) at the Tyr1605-Met1606 peptide bond. Deficiency of plasma ADAMTS13 activity, due to either an inherited or an acquired etiology, may lead to a potentially lethal syndrome, thrombotic thrombocytopenic purpura (TTP). Molecular cloning and characterization of the ADAMTS13 gene have provided further insight into the structure-function relationships, biosynthesis, and regulation of the ADAMTS13 protease, in addition to understanding the pathogenesis of TTP and perhaps other thrombotic disorders. ADAMTS13 consists of a short propeptide, a typical reprolysin-like metalloprotease domain, followed by a disinte-grin-like domain, first thrombospondin type 1 (TSP1) repeat, Cys-rich domain, and spacer domain. The carboxyl terminus of ADAMTS13 has seven more TSP1 repeats and two CUB domains. ADAMTS13 is synthesized mainly in hepatic stellate cells, but also in vascular endothelial cells. Recognition and cleavage of vWF require the proximal carboxyl terminal domains, but not the middle and distal carboxyl terminal domains. Cleavage of vWF appears to be modulated by shear force, binding to platelet or platelet glycoprotein-1bα, heparin, inflammatory cytokine (interleukin-6), and chloride ion. At the site of thrombus formation, the ADAMTS13 may be inactivated by thrombin, plasmin, and factor Xa. Having a sensitive and specific assay for ADAMTS13 activity is not only critical to understand the basic biology of ADAMTS13 protease, but also to facilitate a more timely and accurate clinical diagnosis of TTP, and to initiate potentially life-saving plasma exchange therapy. Although many assays have been developed and tested for clinical applications, the fluorescent resonance energy transfer-vWF73 assay appears to be the simplest and most promising assay to date.
PMCID: PMC2577222  PMID: 16388417
Thrombotic thrombocytopenic purpura (TTP); von Willebrand factor; microvascular thrombosis; ADAMTS13; metalloprotease; assays; clinical application
17.  A novel association of acquired ADAMTS13 inhibitor and acute dengue virus infection 
Transfusion  2009;50(1):208-212.
Dengue is a mosquito-borne viral disease with an increasing incidence worldwide. Thrombocytopenia is a common finding in dengue virus (DV) infection; however, the underlying mechanisms remain unknown.
Here we provide the first evidence of a case of antibody formation against ADAMTS13 (ADAMTS13 inhibitor) in the course of a severe acute DV infection resulting in thrombotic microangiopathy (TMA). The patient presented with classical dengue symptoms (positive epidemiology, high fever, myalgia, predominantly in the lower limbs and lumbar region for 1 week) and, after 11 days of initial symptoms, developed TMA. Clinical and laboratorial investigation of dengue and TMA was performed.
The patient presented with ADAMTS13 inhibitor (IgG) during the acute phase of the disease, without anti-platelet antibodies detectable. Dengue infection had laboratorial confirmation. There were excellent clinical and laboratory responses to 11 serial plasma exchanges. Anti-ADAMTS13 inhibitor disappeared after remission of TMA and dengue resolution. No recurrence of TMA symptoms was observed after 2-year follow-up.
Although the real incidence of dengue-related TMA is unknown, this case provides the basis for future epidemiologic studies on acquired ADAMTS13 deficiency in DV infection. The prompt clinical recognition of this complication and early installment of specific therapy with plasma exchange are likely to improve the outcome of severe cases of dengue.
PMCID: PMC3169087  PMID: 19788513
18.  Two Mechanistic Pathways for Thienopyridine-Associated Thrombotic Thrombocytopenic Purpura 
We sought to describe clinical and laboratory findings for a large cohort of patients with thienopyridine-associated thrombotic thrombocytopenic purpura (TTP).
The thienopyridine derivatives, ticlopidine and clopidogrel, are the 2 most common drugs associated with TTP in databases maintained by the U.S. Food and Drug Administration (FDA).
Clinical reports of TTP associated with clopidogrel and ticlopidine were identified from medical records, published case reports, and FDA case reports (n = 128). Duration of thienopyridine exposure, clinical and laboratory findings, and survival were recorded. ADAMTS13 activity (n = 39) and inhibitor (n = 30) were measured for a subset of individuals.
Compared with clopidogrel-associated TTP cases (n = 35), ticlopidine-associated TTP cases (n = 93) were more likely to have received more than 2 weeks of drug (90% vs. 26%), to be severely thrombocytopenic (84% vs. 60%), and to have normal renal function (72% vs. 45%) (p < 0.01 for each). Compared with TTP patients with ADAMTS13 activity >15% (n = 13), TTP patients with severely deficient ADAMTS13 activity (n = 26) were more likely to have received ticlopidine (92.3% vs. 46.2%, p < 0.003). Among patients who developed TTP >2 weeks after thienopyridine, therapeutic plasma exchange (TPE) increased likelihood of survival (84% vs. 38%, p < 0.05). Among patients who developed TTP within 2 weeks of starting thienopyridines, survival was 77% with TPE and 78% without.
Thrombotic thrombocytopenic purpura is a rare complication of thienopyridine treatment. This drug toxicity appears to occur by 2 different mechanistic pathways, characterized primarily by time of onset before versus after 2 weeks of thienopyridine administration. If TTP occurs after 2 weeks of ticlopidine or clopidogrel therapy, therapeutic plasma exchange must be promptly instituted to enhance likelihood of survival.
PMCID: PMC3167088  PMID: 17868804
19.  Correction of ADAMTS13 Deficiency by In Utero Gene Transfer of Lentiviral Vector encoding ADAMTS13 Genes* 
Deficiency of ADAMTS13 results in thrombotic thrombocytopenic purpura (TTP). Plasma infusion or exchange is the only effective treatment to date. We show in the present study that an administration of a self-inactivating lentiviral vector encoding human full-length ADAMTS13 and a variant truncated after the spacer domain (MDTCS) in mice by in utero injection at embryonic days 8 and 14 resulted in detectable plasma proteolytic activity (~5–70%), which persisted for the length of the study (up to 24 weeks). Intravascular injection via a vitelline vein at E14 was associated with significantly lower rate of fetal loss than intra-amniotic injection, suggesting that the administration of vector at E14 may be a preferred gestational age for vector delivery. The mice expressing ADAMTS13 and MDTCS exhibited reduced sizes of von Willebrand factor compared to the Adamts13−/− mice expressing eGFP. Moreover, the mice expressing both ADAMTS13 and MDTCS showed a significant prolongation of ferric chloride-induced carotid arterial occlusion time as compared to the Adamts13−/− expressing eGFP. The data demonstrate the successful correction of the prothrombotic phenotypes in Adamts13−/− mice by a single in utero injection of lentiviral vectors encoding human ADAMTS13 genes, providing the basis for developing a gene therapy for hereditary TTP in humans.
PMCID: PMC2613173  PMID: 18957966
20.  Pathogenesis of Thrombotic Microangiopathies 
Annual review of pathology  2008;3:249-277.
Profound thrombocytopenia and microangiopathic hemolytic anemia characterize thrombotic microangiopathy, which includes two major disorders: thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). TTP has at least three types: congenital or familial, idiopathic, and nonidiopathic. The congenital and idiopathic TTP syndromes are caused primarily by deficiency of ADAMTS13, owing to mutations in the ADAMTS13 gene or autoantibodies that inhibit ADAMTS13 activity. HUS is similar to TTP, but is associated with acute renal failure. Diarrhea-associated HUS accounts for more than 90% of cases and is usually caused by infection with Shiga-toxin-producing Escherichia coli (O157:H7). Diarrhea-negative HUS is associated with complement dysregulation in up to 50% of cases, caused by mutations in complement factor H, membrane cofactor protein, factor I or factor B, or by autoanti-bodies against factor H. The incomplete penetrance of mutations in either ADAMTS13 or complement regulatory genes suggests that precipitating events or triggers may be required to cause thrombotic microangiopathy in many patients.
PMCID: PMC2582586  PMID: 18215115
thrombotic thrombocytopenic purpura; hemolytic uremic syndrome; von Willebrand factor-cleaving metalloprotease; ADAMTS13; complement dysregulation
21.  The Proximal Carboxyl-terminal Domains of ADAMTS13 Determine Substrate Specificity and Are All Required for Cleavage of von Willebrand Factor* 
The Journal of biological chemistry  2005;280(33):29428-29434.
ADAMTS13 limits platelet-rich thrombosis by cleaving von Willebrand factor at the Tyr1605–Met1606 bond. Previous studies showed that ADAMTS13 truncated after spacer domain remains proteolytically active or hyper-active. However, the relative contribution of each domain within the proximal carboxyl terminus of AD-AMTS13 in substrate recognition and specificity is not known. We showed that a metalloprotease domain alone was unable to cleave the Tyr–Met bond of glutathione S-transferase (GST)-VWF73-H substrate in 3 h, but it did cleave the substrate at a site other than the Tyr–Met bond after 16–24 h of incubation. Remarkably, the addition of even one or several proximal carboxyl-terminal domains of ADAMTS13 restored substrate specificity. Full proteolytic activity, however, was not achieved until all of the proximal carboxyl-terminal domains were added. The addition of TSP1 2–8 repeats and two CUB domains did not further increase proteolytic activity. Furthermore, ADAMTS13 truncated after the spacer domain with or without metalloprotease domain bound GST-VWF73-H with a Kd of ≈7.0 or 13 nM, comparable with full-length ADAMTS13 (Kd = 4.6 nM). Metalloprotease domain did not bind GST-VWF73-H detectably, but the disintegrin domain, first TSP1 repeat, Cys-rich domain, and spacer domain bound GST-VWF73-H with Kd values of 489, 136, 121, and 108 nM, respectively. These proximal carboxyl-terminal domains dose-dependently inhibited cleavage of fluorescent resonance energy transfer (FRETS)-VWF73 by full-length ADAMTS13 and ADAMTS13 truncated after the spacer domain. These data demonstrated that the proximal carboxyl-terminal domains of ADAMTS13 determine substrate specificity and are all required for recognition and cleavage of von Willebrand factor between amino acid residues Asp1595 and Arg1668.
PMCID: PMC2577221  PMID: 15975930

Results 1-21 (21)