(A) Reactive center amino acid sequence of α₁AT and its biologically active mutants. Three letter abbreviations are used for amino acids (aa). (B) Agents and targets to rebalance hemostasis. The schematic is a drawing of tissue factor and factor VIIa–induced hemostasis (TF-VIIa) with FIX (IX) and FX (X) activation leading to FXa (Xa) (tenase) with subsequent thrombin formation (prothrombinase). Overlying this hemostatic pathway are the 3 major anticoagulant systems in vivo: antithrombin, activated protein C being formed by thrombin when both are bound to thrombomodulin, and tissue factor pathway inhibitor (TFPI). A listing of hemostatic rebalancing agents that are approved for clinical use or are in clinical development and their hemostatic targets are shown. A zymogen-like FXa containing an I16L polymorphism is more resistant to constitutive levels of antithrombin and may overcome a hemostatic block of tenase. Emicizumab is a monoclonal antibody that binds factors X/Xa and IX/IXa to overcome a factor VIII deficiency or inhibitor. Fitusiran is a small interfering RNA (siRNA) that lowers levels to antithrombin to rebalance hemostasis in patients with factor VIII or factor IX deficiency. Concizumab, PF-06741086, and Bayer 1093884 are monoclonal antibodies that block TFPI and increase thrombin generation due to more direct FVIIa-TF activation of FX. Protease nexin I is a serpin thrombin inhibitor. Its inhibition increases thrombin generation in hemophilic plasma (see text). Activated protein C–specific serpin (α₁AT [SerpinPC]) made from strategic amino acid replacement in α₁-antitrypsin (see text) leads to increased thrombin formation that may rebalance hemostasis in patients with hemophilias. (C) Targets of C1 inhibitor and α₁AT-SLLR/V in contact activation and hereditary angioedema (HAE). This figure shows the contact activation and kallikrein/kinin systems. The contact activation system consists of zymogen FXII (XII) autoactivating on an artificial or biologic negatively charged surface to FXIIa. This pathway is accelerated by the presence of H-kininogen (HK). Formed FXIIa activates zymogen prekallikrein (PK) to PKa. PKa activates more FXII to FXIIa, leading to reciprocal activation and amplification of activation of the system. Formed FXIIa activates plasminogen to plasmin, the classic complement pathway, and factor XI to FXIa to initiate blood coagulation. PKa also cleaves HK to liberate bradykinin (BK) from HK that activates its vascular receptors, the bradykinin B2 (B2R) and B1 (B1R). cHK is cleaved BK-free HK that is a marker for contact and kallikrein/kinin system activation. Formed BK is thought to be the major agent inducing angioedema in the majority of patients with HAE. Importantly, C1 inhibitor or the iterated forms of α₁AT (eg, α₁AT-SLLR/V) (see text) block all forms of FXIIa, PKa, and FXIa to inhibit all their activities.