Res Pract Thromb Haemost
January 2025
Background: The development of acquired factor (F)V with inhibitor (AFVwI) is rare, resulting mainly in bleeding complications, although sporadic cases of thrombosis in adults have been reported.
Key Clinical Question: How do you diagnose and manage a pediatric case of acute deep venous thrombosis associated with the concurrent finding of AFVwI?
Clinical Approach: A 13-year-old female with Crohn's Disease and May-Thurner anatomy developed extensive deep venous thrombosis of the left lower extremity, complicated by the finding of AFVwI, discovered during the evaluation of a prolonged prothrombin time and a low FV activity. Anticoagulation was initiated with low-molecular-weight heparin followed by a direct oral anticoagulant, rivaroxaban, without any complications.
Background: Factor V (FV) B-domain contains an acidic region (FV-AR2) and a basic region (FV-BR), which interact with each other and maintain FV in a procofactor form; removal of either region via deletion/proteolysis results in an active FVa molecule. Tissue factor pathway inhibitor type-1 (TFPI) and type-2 (TFPI2) each contain a C-terminus basic segment homologous to FV-BR; this region in TFPI (and predicted in TFPI2) binds to FV-AR2 in platelet FVa (that lacks FV-BR) with high affinity and inhibits FVa function.
Objectives: To understand molecular interactions between FV-AR2 with FV-BR, TFPI-BR and TFPI2-BR.
Tissue factor pathway inhibitor-2 (TFPI-2) is a homologue of TFPI-1 and contains three Kunitz-type domains and a basic C terminus region. The N-terminal domain of TFPI-2 is the only inhibitory domain, and it inhibits plasma kallikrein, factor XIa, and plasmin. However, plasma TFPI-2 levels are negligible (≤20 pM) in the context of influencing clotting or fibrinolysis.
View Article and Find Full Text PDFCoagulation factor V (FV) circulates as an inactive procofactor and is activated to FVa by proteolytic removal of a large inhibitory B-domain. Conserved basic and acidic sequences within the B-domain appear to play an important role in keeping FV as an inactive procofactor. Here, we utilized recombinant B-domain fragments to elucidate the mechanism of this FV autoinhibition.
View Article and Find Full Text PDFBackground: Generation of active procoagulant cofactor factor Va (FVa) and its subsequent association with the enzyme activated factor X (FXa) to form the prothrombinase complex is a pivotal initial event in blood coagulation and has been the subject of investigative effort, speculation, and controversy. The current paradigm assumes that FV activation is initiated by limited proteolysis by traces of (meizo) thrombin.
Methods And Results: Recombinant tick salivary protein TIX-5 was produced and anticoagulant properties were studied with the use of plasma, whole blood, and purified systems.
Inhibitory antibodies to factors VIII or IX represent a serious complication for hemophilia patients. Treatment involves products that bypass the intrinsic pathway and promote thrombin generation. Direct infusion of factor Xa should also restore hemostasis; however, it has a short half-life in plasma and could activate systemic coagulation in an uncontrolled fashion.
View Article and Find Full Text PDFPhosphoinositide signaling pathways regulate numerous processes in eukaryotic cells, including migration, proliferation, and survival. The regulatory lipid phosphatidylinositol 4,5-bisphosphate is synthesized by two distinct classes of phosphatidylinositol phosphate kinases (PIPKs), the type I and II PIPKs. Although numerous physiological functions have been identified for type I PIPKs, little is known about the functions and regulation of type II PIPK.
View Article and Find Full Text PDFPhosphoinositides regulate numerous cellular processes required for growth, proliferation, and motility. Whereas phosphoinositide signal transduction pathways within the cytosol have been well characterized, nuclear signaling pathways remain poorly understood. Accumulating experimental data have now started to uncover critical functions for nuclear phosphoinositides.
View Article and Find Full Text PDFOver the last decades, evidence has accumulated suggesting that there is a distinct nuclear phosphatidylinositol pathway. One of the best examined nuclear lipid pathways is the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PI4,5P(2)) by PLC resulting in activation of nuclear PKC and production of inositol polyphosphates. However, there is a growing number of data that phosphoinositides are not only precursor for soluble inositol phosphates and diacylglycerol, instead they can act as second messengers themselves.
View Article and Find Full Text PDFMembrane ruffle formation requires remodeling of cortical actin filaments, a process dependent upon the small G-protein Rac. Growth factors stimulate actin remodeling and membrane ruffling by integration of signaling pathways that regulate actin-binding proteins. Phosphatidylinositol 4,5-bisphosphate (PIP2) regulates the activity of many actin-binding proteins and is produced by the type I phosphatidylinositol phosphate kinases (PIPKIs).
View Article and Find Full Text PDFThe ability of cells to form cell contacts, adhere to the extracellular matrix, change morphology, and migrate is essential for development, wound healing, metastasis, cell survival and the immune response. These events depend on the binding of integrin to the extracellular matrix, and assembly of focal adhesions, which are complexes comprising scaffolding and signalling proteins organized by adhesion to the extracellular matrix. Phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P(2)) regulates interactions between these proteins, including the interaction of vinculin with actin and talin.
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