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A disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) belong to the zinc metalloproteinase. It was first detected in the liver by Northern blotting in 2001. The activity of ADAMTS13 in the plasma of healthy people is 50% to 78%. Extraterrestrial studies of ADAMTS13 in patients with thrombotic thrombocytopenic purpura, systemic lupus erythematosus, and cerebral infarction have shown that ADAMTS13 is significantly reduced in patients with a significant decrease in its secretion.
ADAMTS13 and Thrombotic Thrombocytopenic Purpura (TTP)
Thrombotic thrombocytopenic purpura (TTP) is defined by a severe deficiency in ADAMTS13 activity, and ADAMTS13 deficiency is a cause of clinical features of TTP. vWF is a multimeric glycoprotein that mediates platelet and subendothelial binding during vessel wall injury. ADAMTS13 is of great therapeutic interest because it is a target gene for thrombotic thrombocytopenic purpura (TTP). TTP is characterized by intravascular destruction of blood cells, such as platelets and red blood cells, which may cause major complications such as anemia, renal failure or neurological dysfunction. TTP is caused by a decrease in the function of ADAMTS13 due to mutation of the ADAMTS13 gene or autoantibody production of ADAMTS13. Studies by Ayanambakkam et al. have shown that reports of >10% activity in ADAMTS13 should not rule out the consideration of TTP diagnosis. The diagnosis of TTP requires measurement of ADAMTS13 activity and physician's clinical judgment.
ADAMTS13 and Angiogenesis
Farkas et al. studied 53 patients with thrombotic microangiopathy (TMA) and comorbid disease and 34 healthy controls. It was found that if the activity of ADAMTS13 is decreased, the level of VWF in patients with secondary TMA is elevated. Classical, lectin and alternative pathway activities, as well as levels of C3, C4, and factor H were significantly lower in secondary TMA patients with high levels of activation products (C3a and sC5b-9). Factor H concentration is associated with a relative lack of ADAMTS13. These data suggest that secondary TMA syndrome and its poor prognosis are characterized by relative ADAMTS13 deficiency, inflammation and complement activation, and consumption through classical and alternative pathways.
The vascular hemophilic factor is a relatively large molecular weight glycoprotein that promotes platelet aggregation and activation. ADAMTS13 is a lytic enzyme of the vascular hemophilic factor that inhibits platelet aggregation by selectively excising vascular hemophilic factors and promoting maturation of vascular hemophilic factor multimers. Clinical studies have shown that a decrease in the level of ADAMTS13 can increase the risk of thrombosis, which can activate platelets and cause the release of inflammatory mediators, eventually causing microvascular obstruction. Thrombin-sensitive protein-1 (TSP-1) is an adhesion protein that is a reductase of von Willebrand Factor (vWF) that inhibits the degradation of vWF by ADAMTS13 by competing with ADAMTS13.
Tang et al. successfully knocked out endogenous ADAMTS-13 in human umbilical vein endothelial cells (HUVEC) by siRNA and studied the effect of endogenous ADAMTS13 on angiogenesis in HUVEC. Studies have found that decreased protein levels of endogenous ADAMTS13 also affect angiogenesis. The length, size, and the number of connections of ADAMTS13 knockdown cells were significantly reduced by about 40% compared to control cells. The protein level of vascular endothelial growth factor (VEGF), a well-known angiogenesis regulator, was significantly reduced by 45% after knocking out ADAMTS13. These data indicate that one of the roles of endogenous ADAMTS13 is through the regulation of angiogenesis mediated by VEGF and AKT Signaling Pathways.
Desch et al. found that in the blood vessels of AdAMTS13-deficient mice, after the Shiga toxin challenge, the damaged endothelial cells attracted the aggregation of platelets and vWF. In the absence of sufficient ADAMTS13 activity, platelets and vWF accumulate and form embolic microthrombus. The blood vessels of wild-type mice show ADAMTS13 deficiency after injection of super-physiological vWF, which is caused by the anti-ADAMTS13 antibody. Here, any available ADAMTS13 is neutralized by the injected antibody neutralizing the vWF-rich embolus. The same prethrombotic appearance was shown in transgenic mice, indicating recombinant ADAMTS13 expressed in platelets. Despite two different challenges of pre-thrombotic treatment, transgenic mice were able to maintain anticoagulant ADAMTS13 activity and prevent the formation of vWF-rich microthrombus.
Figure 1. A simplified view of thrombotic challenges in the context of ADAMTS13 deficiency or platelet-expressed ADAMTS13. (Desch, 2015)
ADAMTS13 and Cancer
Liu et al. measured and compared the plasma levels of ADAMTS13 in 82 patients with acute myeloid leukemia (AML) and 34 healthy controls, and found that ADAMTS13 was lower in AML patients than in the control group. The level of ADAMTS13 in infected AML patients was lower than in non-infected patients. ADAMTS13 levels were negatively correlated with C-reactive protein (CRP), IL-6, TNFα, and IL-1β. In addition, ADAMTS13 in patients with high-risk AML is lower than in low-risk patients. ADAMTS13 levels are reduced in the plasma of AML patients, and levels of ADAMTS13 are associated with inflammation and infection in AML patients. In addition, low ADAMTS-13 levels are a potential risk factor for AML patients.
ADAMTS13 is a vWF lyase that cleaves a large vWF multimer in the circulation. The vWF accumulation in the circulation causes platelet aggregation and vascular occlusion, and the larger vWF also increases the adhesion of platelets to circulating cancer cells, thereby promoting tumor metastasis. Therefore, attenuation of ADAMTS13 activity increases the likelihood of tumor metastasis. Analysis of plasma in patients with localized solid tumors and disseminated tumors revealed an increase in the large fragment of vWF and a significant decrease in the activity of ADAMTS13 in disseminated tumor patients. This evidence suggests that ADAMTS13 plays an important role in the formation of emboli in platelets and tumor cells, which promote tumor metastasis. In colon cancer patients, patients with lower stage and stage II colon cancer had more ADAMTS13 expression than those with staged and stage IV colon cancer. These studies suggest that ADAMTS13 has a role in tumor development.