Is plasminogen activator inhibitor type 2 really a plasminogen activator inhibitor after all?

Gardiner, Elizabeth E.; Medcalf, Robert L.

doi:10.1111/jth.12704

Cited by 17 publications

(15 citation statements)

References 24 publications

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“…S4. The presence of SerpinB2 in blood clots ( Figure 2B) might support the view that SerpinB2 also has a role in inhibiting fibrinolysis, at least in mice [15,16].…”

Section: Discussionsupporting

confidence: 75%

“…PAI-1 also inhibits fibrinolysis by inhibiting plasmin generation by tPA and uPA, with PAI-1 −/− mice showing enhanced fibrinolysis and thrombolysis [13][14][15]. Some in vivo evidence for SerpinB2-mediated inhibition of fibrinolysis was only recently reported, with SerpinB2 −/− mice showing increased venous thrombus resolution [15], although the observation was complicated by increased uPA and decreased plasminogen activator inhibitor type 1 (PAI-1) expression [16].…”

Section: Introductionmentioning

confidence: 99%

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SerpinB2 deficiency in mice reduces bleeding times via dysregulated platelet activation

Schroder

Gardner

et al. 2018

Platelets

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SerpinB2, also known as plasminogen activation inhibitor type 2 (PAI-2), is classically viewed as an inhibitor of fibrinolysis. However, we show herein a distinct, hitherto unrecognized role for SerpinB2 in hemostasis. Mice deficient in SerpinB2 expression and mice with an active site mutation in SerpinB2, both showed significant reductions in tail bleeding times. This hemostatic phenotype was associated with platelets, with SerpinB2 and SerpinB2-urokinase complexes clearly present in platelet fractions, and immunohistochemistry of blood clots suggesting SerpinB2 is associated with platelet aggregates. Thromboelastography illustrated faster onset of clot formation in blood from SerpinB2 deficient mice, whereas clotting of platelet-free plasma was unaffected. The results appear consistent with the low circulating SerpinB2 levels and hypercoagulation seen during pre-eclampsia; however, SerpinB2 was not detected in human platelets.

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“…S4. The presence of SerpinB2 in blood clots ( Figure 2B) might support the view that SerpinB2 also has a role in inhibiting fibrinolysis, at least in mice [15,16].…”

Section: Discussionsupporting

confidence: 75%

Section: Introductionmentioning

confidence: 99%

SerpinB2 deficiency in mice reduces bleeding times via dysregulated platelet activation

Schroder

Gardner

et al. 2018

Platelets

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“…These symptoms are not observed in PAI‐1 gene inactivated mice , which indicates the limitation of animal models of these maladies . PAI‐2 was first identified in placenta as a member of the SERPIN family and was shown to inhibit both uPA and tPA . Its plasma levels are barely detectable, however, except during late pregnancy , its efficacy in inhibiting tPA is weaker than that of PAI‐1 , and its role in hemostasis is questionable .…”

Section: Plg Activation Potential In Plasma and On The Surface Of Vecsmentioning

confidence: 99%

“…PAI‐2 was first identified in placenta as a member of the SERPIN family and was shown to inhibit both uPA and tPA . Its plasma levels are barely detectable, however, except during late pregnancy , its efficacy in inhibiting tPA is weaker than that of PAI‐1 , and its role in hemostasis is questionable . Other biological roles in inflammation, immunity and tumor growth have been suggested .…”

Section: Plg Activation Potential In Plasma and On The Surface Of Vecsmentioning

confidence: 99%

Regulation of plasminogen activation on cell surfaces and fibrin

Urano

Castellino

Suzuki

2018

Journal of Thrombosis and Haemostasis

103

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SummaryThe fibrinolytic system dissolves fibrin and maintains vascular patency. Recent advances in imaging analyses allowed visualization of the spatiotemporal regulatory mechanism of fibrinolysis, as well as its regulation by other plasma hemostasis cofactors. Vascular endothelial cells (VECs) retain tissue‐type plasminogen activator (tPA) after secretion and maintain high plasminogen (plg) activation potential on their surfaces. As in plasma, the serpin, plasminogen activator inhibitor type 1 (PAI‐1), regulates fibrinolytic potential via inhibition of the VEC surface‐bound plg activator, tPA. Once fibrin is formed, plg activation by tPA is initiated and effectively amplified on the surface of fibrin, and fibrin is rapidly degraded. The specific binding of plg and tPA to lytic edges of partly degraded fibrin via newly generated C‐terminal lysine residues, which amplifies fibrin digestion, is a central aspect of this pathophysiological mechanism. Thrombomodulin (TM) plays a role in the attenuation of plg binding on fibrin and the associated fibrinolysis, which is reversed by a carboxypeptidase B inhibitor. This suggests that the plasma procarboxypeptidase B, thrombin‐activatable fibrinolysis inhibitor (TAFI), which is activated by thrombin bound to TM on VECs, is a critical aspect of the regulation of plg activation on VECs and subsequent fibrinolysis. Platelets also contain PAI‐1, TAFI, TM, and the fibrin cross‐linking enzyme, factor (F) XIIIa, and either secrete or expose these agents upon activation in order to regulate fibrinolysis. In this review, the native machinery of plg activation and fibrinolysis, as well as their spatiotemporal regulatory mechanisms, as revealed by imaging analyses, are discussed.

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“…This has yet to be studied. Likewise, the same questions apply to the other major inhibitors of fibrinolysis, such as α-2 antiplasmin, PAI-2, 44,45 and TAFI.…”

Section: Inhibitors Of Fibrinolysis In Traumamentioning

confidence: 99%

The Central Role of Fibrinolytic Response in Trauma-Induced Coagulopathy: A Hematologist's Perspective

Kwaan

2019

Semin Thromb Hemost

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Severe trauma is the leading cause of death globally. Though improved resuscitation, particularly early initiation, has reduced the 24-hour mortality rate, the overall morbidity and 30-day mortality remain high mostly due to massive hemorrhage and head injury in the early stages and sepsis and multiorgan failure later on. With recent clinical trials of antifibrinolytic treatment with tranexamic acid, and with the observations that fibrinolytic activity varies widely among the injured patients, the role of the fibrinolytic system in trauma has become a major focus of investigations in trauma-induced coagulopathy. Most of the body's response to trauma involves the endothelium, tissue factor release, and platelet activation. In addition, there are inflammatory and immune responses. All these events directly or indirectly affect the fibrinolytic system. A full understanding of these mechanisms has translational implications on the management of these patients. In this article, the multifaceted responses of fibrinolysis following injury are reviewed.

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Is plasminogen activator inhibitor type 2 really a plasminogen activator inhibitor after all?

Cited by 17 publications

References 24 publications

SerpinB2 deficiency in mice reduces bleeding times via dysregulated platelet activation

SerpinB2 deficiency in mice reduces bleeding times via dysregulated platelet activation

Regulation of plasminogen activation on cell surfaces and fibrin

The Central Role of Fibrinolytic Response in Trauma-Induced Coagulopathy: A Hematologist's Perspective

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