The Vascular Endothelium and Coagulation: Homeostasis, Disease, and Treatment, with a Focus on the Von Willebrand Factor and Factors VIII and V

Abstract

The vascular endothelium has several important functions, including hemostasis. The homeostasis of hemostasis is based on a fine balance between procoagulant and anticoagulant proteins and between fibrinolytic and antifibrinolytic ones. Coagulopathies are characterized by a mutation-induced alteration of the function of certain coagulation factors or by a disturbed balance between the mechanisms responsible for regulating coagulation. Homeostatic therapies consist in replacement and nonreplacement treatments or in the administration of antifibrinolytic agents. Rebalancing products reestablish hemostasis by inhibiting natural anticoagulant pathways. These agents include monoclonal antibodies, such as concizumab and marstacimab, which target the tissue factor pathway inhibitor; interfering RNA therapies, such as fitusiran, which targets antithrombin III; and protease inhibitors, such as serpinPC, which targets active protein C. In cases of thrombophilia (deficiency of protein C, protein S, or factor V Leiden), treatment may consist in direct oral anticoagulants, replacement therapy (plasma or recombinant ADAMTS13) in cases of a congenital deficiency of ADAMTS13, or immunomodulators (prednisone) if the thrombophilia is autoimmune. Monoclonal-antibody-based anti-vWF immunotherapy (caplacizumab) is used in the context of severe thrombophilia, regardless of the cause of the disorder. In cases of disseminated intravascular coagulation, the treatment of choice consists in administration of antifibrinolytics, all-trans-retinoic acid, and recombinant soluble human thrombomodulin.

Keywords: coagulation; coagulopathies; embryo; factor V; factor VIII; homeostasis; treatment; vascular endothelium; von Willebrand factor.

Figure 1

Activation of the coagulation cascade following vascular damage. The initiation complex, formed by the interaction of FVIIa and TF with the membrane phospholipids of the cells in the vascular endothelium, collaborates with calcium to activate FIX and FX to give rise, respectively, to the corresponding tenase and prothrombinase complexes. F, coagulation factor; TF, tissue factor; (+), activation.

Figure 2

The fibrinolytic process. This pathway is modulated by proteases and clotting factors that stimulate the transformation of plasminogen into plasmin, which is in turn responsible for the subsequent degradation of fibrin. t-PA, tissue plasminogen activator; u-PA, urokinase; PAI-1, plasminogen activator inhibitor-1; A2AP, α2-antiplasmin; FXIa, activated factor XI; FXIIa, activated factor XII; KK, kallikrein; (+), activation; (–), inhibition.

Figure 3

Molecular characteristics of von Willebrand factor. (A) Domain-based structure of the protein, sites at which it interacts with other factors and cofactors, and activation and inactivation sites. (B) WPB-mediated activation and final interaction of vWF with platelets and FVIII. (C) Proteolytic inactivation resulting from interaction with ADAMTS13 and cleavage at the level of the A2 domain. vWF, von Willebrand factor; WPB, Weibel–Palade body; FVIII, factor VIII.

Figure 4

Molecular characteristics of factor VIII. (A) Domain-based structure of the protein, sites at which it interacts with other factors and cofactors, and activation and inactivation sites. (B) Thrombin-mediated activation and B domain deletion. (C) APC-mediated inactivation and A2 domain deletion. FVIII, factor VIII; APC, activated protein C; FIXa, activated factor IX; FX, factor X; vWF, von Willebrand factor.

Figure 5

Molecular characteristics of factor V. (A) Domain-based structure of the protein, sites at which it interacts with other factors and cofactors, and activation and inactivation sites. (B) Thrombin-mediated activation and B domain deletion. (C) Inactivation by APC and PS, in conjunction with phospholipids on the membrane of vascular endothelial cells or platelets; deletion of the A2 domain. FV, factor V; FX, factor X; APC, activated protein C; PS, protein S.

Figure 6

In vivo RNA expression for vWF, FVIII, and FV in different organs and tissues, according to the classification provided by the Human Protein Atlas. Tissues were grouped into organs, such as the bone marrow and lymphoid tissues (appendix, lymph node, spleen, thymus, tonsil), the brain (amygdala, basal ganglia, thalamus, midbrain, pons, medulla oblongata, hippocampal formation, spinal cord, white matter, cerebral cortex, cerebellum, choroid plexus, hypothalamus), connective and soft tissue (soft tissue, adipose tissue), the eye (retina), endocrine tissues (thyroid gland, parathyroid gland, adrenal gland, pituitary gland), female tissues (vagina, breast, cervix, endometrium, fallopian tube, ovary, placenta), the gastrointestinal tract (stomach, colon, duodenum, rectum, small intestine), kidneys and the urinary bladder, the liver and the gallbladder, male tissues (testis, epididymis, prostate, seminal vesicle), muscle tissues (heart muscle, skeletal muscle, smooth muscle), the pancreas, the proximal digestive tract (oral mucosa, salivary gland, esophagus, tongue), the respiratory system (nasopharynx, bronchus, lung), and the skin. nTPM, normalized protein-coding transcripts per million; vWF, von Willebrand factor; FVIII, factor VIII; FV, factor V. Created with GraphPad Prism 8 software (GraphPad Software, La Jolla, CA, USA).

Figure 7

Homeostasis-modifying treatments in hemostasis. Replacement therapies: recombinant factors, fresh frozen plasma, Octaplas^®, recombinant ADAMTS13, and adeno-associated viruses. Nonreplacement therapies: desmopressin; emicizumab; caplacizumab (anti-vWF); and immunomodulators, such as prednisone and rituximab. Rebalancing therapies: fitusiran, concizumab, marstacimab, and serpinPC. Anticoagulant therapies: DOACs. Antifibrinolytic therapies: tranexamic acid and β-aminocaproic acid. vWF, von Willebrand factor; FVIII, factor VIII; FV, factor V; FIX, factor IX; FX, factor X; TTP, thrombotic thrombocytopenic purpura; vWD, von Willebrand’s disease; FFP, fresh frozen plasma; AT-III, antithrombin III; TFPI, tissue factor pathway inhibitor; APC (PC), activated protein C; PS, protein S; DOACs, direct oral anticoagulants; rADAMTS13, recombinant ADAMTS13. (+), activation; (–), inhibition.