Normal hemostasis

2020 ◽  
pp. 626-649
Author(s):  
Jeanine M. Walenga
Keyword(s):  
2015 ◽  
Vol 35 (04) ◽  
pp. 338-350 ◽  
Author(s):  
L. Labberton ◽  
E. Kenne ◽  
T. Renné

SummaryBlood coagulation is essential for hemostasis, however excessive coagulation can lead to thrombosis. Factor XII starts the intrinsic coagulation pathway and contact-induced factor XII activation provides the mechanistic basis for the diagnostic aPTT clotting assay. Despite its function for fibrin formation in test tubes, patients and animals lacking factor XII have a completely normal hemostasis. The lack of a bleeding tendency observed in factor XII deficiency states is in sharp contrast to deficiencies of other components of the coagulation cascade and factor XII has been considered to have no function for coagulation in vivo. Recently, experimental animal models showed that factor XII is activated by an inorganic polymer, polyphosphate, which is released from procoagulant platelets and that polyphosphate-driven factor XII activation has an essential role in pathologic thrombus formation. Cumulatively, the data suggest to target polyphosphate, factor XII, or its activated form factor XIIa for anticoagulation. As the factor XII pathway specifically contributes to thrombosis but not to hemostasis, interference with this pathway provides a unique opportunity for safe anticoagulation that is not associated with excess bleeding.The review summarizes current knowledge on factor XII functions, activators and inhibitors.


Blood ◽  
1984 ◽  
Vol 64 (3) ◽  
pp. 707-714 ◽  
Author(s):  
RL Edwards ◽  
D Perla

Abstract Human monocytes generate the procoagulant tissue factor (MTF) following exposure to a variety of immune stimuli in vitro. The generation of MTF is modified by T cells, lymphokines, and immunoregulatory lipoproteins, and recent studies have shown that MTF can be activated in an immune- specific manner following exposure to antigen. We have examined the role of serum factors in the regulation of MTF generation. Low concentrations (less than 1%) of heat-inactivated normal human serum greatly enhanced MTF generation in cultures of normal peripheral blood mononuclear cells. The stimulatory effect was observed in cultures of both unstimulated cells and cells exposed to bacterial lipopolysaccharide. Stimulation was not observed at high serum concentrations (greater than 10%) and could not be explained by endotoxin contamination or activation of the assay system. Stimulatory activity was present in plasma and BaSO4-adsorbed plasma as well as autologous and allogeneic serum, was not abolished by removal of serum lipoproteins, and did not require the presence of T cells for its expression. Sera from 28 different normal volunteers were screened for stimulatory activity and demonstrated a wide variation in potency. These results suggest that a potent factor is present in sera that enhances the expression of MTF activity in vitro. This factor is distinct from previously described lipoprotein regulators and may play a role in the initiation of coagulation in both normal hemostasis and pathologic states.


1998 ◽  
Vol 45 (2) ◽  
pp. 417-428 ◽  
Author(s):  
E Zdebska ◽  
J Woźniak ◽  
A Dzieciatkowska ◽  
J Kościelak

Activated blood platelets shed microparticles with procoagulant activity that probably participate in normal hemostasis. We have isolated spontaneously formed microparticles from human blood and analysed them for ultrastructure, antigenic profile, and biochemical composition. In transmission electron microscopy microparticles appeared as regular vesicles with a mean diameter of 300 nm (50-600 nm). In flow cytometry almost all microparticles reacted with fluorescein isothiocyanate (FITC) labeled antibody to platelet glycoprotein complex IIb-IIIa (GpIIb-IIIa) and with FITC-annexin V but only 40-50% of microparticles reacted with FITC-antibody to platelet glycoprotein Ib (GpIb). The latter result was confirmed by double labeling of microparticles with FITC-antibody to GpIIb-IIIa and phycoerythrin (PE) labeled antibody to GpIb. Large microparticles reacted better with anti-GpIb than the small ones. A decreased level of GpIb was also demonstrated by SDS/polyacrylamide gel electrophoresis of microparticles. Compositional studies indicated, that in terms of cholesterol and protein contents, microparticles resembled platelets rather than platelet membranes as previously thought. They are, however, deficient in certain components. Thus, in comparison to platelets, microparticles had reduced contents of sialic acid (by 56.4%), galactosamine (by 48.2%), glucosamine (by 22.4%), galactose by (11.8%) and fucose (by 21.6%). Mannose content was increased by 11.8%. Total phospholipids in microplatelets were lower by 17.8%. Glycerophospholipids only were affected with phosphatidylserine being decreased as much as by 43.2%. Neutral glycosphingolipids, gangliosides and ceramides in microparticles were reduced by half.


2006 ◽  
Vol 203 (3) ◽  
pp. 513-518 ◽  
Author(s):  
Christoph Kleinschnitz ◽  
Guido Stoll ◽  
Martin Bendszus ◽  
Kai Schuh ◽  
Hans-Ulrich Pauer ◽  
...  

Formation of fibrin is critical for limiting blood loss at a site of blood vessel injury (hemostasis), but may also contribute to vascular thrombosis. Hereditary deficiency of factor XII (FXII), the protease that triggers the intrinsic pathway of coagulation in vitro, is not associated with spontaneous or excessive injury-related bleeding, indicating FXII is not required for hemostasis. We demonstrate that deficiency or inhibition of FXII protects mice from ischemic brain injury. After transient middle cerebral artery occlusion, the volume of infarcted brain in FXII-deficient and FXII inhibitor–treated mice was substantially less than in wild-type controls, without an increase in infarct-associated hemorrhage. Targeting FXII reduced fibrin formation in ischemic vessels, and reconstitution of FXII-deficient mice with human FXII restored fibrin deposition. Mice deficient in the FXII substrate factor XI were similarly protected from vessel-occluding fibrin formation, suggesting that FXII contributes to pathologic clotting through the intrinsic pathway. These data demonstrate that some processes involved in pathologic thrombus formation are distinct from those required for normal hemostasis. As FXII appears to be instrumental in pathologic fibrin formation but dispensable for hemostasis, FXII inhibition may offer a selective and safe strategy for preventing stroke and other thromboembolic diseases.


2019 ◽  
Vol 45 (07) ◽  
pp. 720-729 ◽  
Author(s):  
Philip Crispin ◽  
Ray Mun Koo

AbstractThe understanding of molecular mechanisms brought about by the rapid expansion of gene sequencing has helped to characterize molecular interactions underpinning normal hemostasis and identify inherited and acquired risks for thrombosis and hemorrhage. The widespread availability of molecular testing may serve to replace some currently available investigations with more precise diagnostic tools and add to phenotypic tests. Molecular studies will increasingly enable prenatal diagnosis, confirm difficult diagnostic challenges, early intervention, and assist in prognostication. This approach facilitates specific individualization of treatment options, with personally targeted therapy expected to increase. There remain many challenges, however, in the clinic. Prior to any test there should be consideration of how the results may influence treatment, and also how they may affect the patient within their familial and social environments. Massive parallel sequencing has the capacity to produce results that create uncertainty that needs to be considered prior to testing. In this context, the potential benefits of adding phenotypic and genotypic personal data to large databases should be discussed with patients. There is a paradox in that personalized medicine is dependent on large datasets to interpret the significance of genetic variation. This review will provide an outline of specific current and emerging roles for molecular testing for the personalization of care in the practice of thrombosis and hemostasis and highlight principles that can be implemented as new opportunities inevitably arise with the rapid expansion of knowledge from genomics.


Blood ◽  
1960 ◽  
Vol 16 (4) ◽  
pp. 1433-1438 ◽  
Author(s):  
W. O. CRUZ ◽  
J. R. MAGALHAES ◽  
L. MEIS

Abstract Dog arterial and venous plasma and lymph were fractionated by Cohn method 10 and the fractions tested for inhibitory activity when added to normal arterial blood in the dog hind leg preparation adapted for studies on hemostasis. Cohn fraction IV from arterial or venous plasma and from lymph was the only fraction, at low concentrations, able to inhibit the hemostatic ability of normal arterial plasma. Some facts suggest that alpha-lipoproteins are the plasma constituent of fraction IV with inhibitory effect on normal arterial blood. Biochemical changes in blood plasma seem more important or more directly connected with the mechanism of normal hemostasis control than the participation of blood cellular elements.


1979 ◽  
Author(s):  
R. Canfield ◽  
B. Lahiri ◽  
R. D’Alisa ◽  
V. Butler ◽  
H. Nossel ◽  
...  

Factor XIIIa introduces up to six crossllnklng bonds per molecule of fibrin; the bonds between the γ chains on adjacent fibrin molecules form most rapidly. Since cross linking is essential for normal hemostasis and is likely to be important in tests to detect thrombosis, we have attempted to develop a radioimmunoassay that exhibits specificity for the γ chain crosslinks. The immunogen consisted of a 54 amino acid, crosslinked peptide, isolated from purified human γ-γ chains following CNBr cleavage, gel filtration on Sephadex G-50 and ion-exchange chromatography on SP-Sephadex. Amino acid analysis and Edman degradation through step 24 confirmed the sequence of Chen and Doolittle (Biochemistry 10: i486, 1971), and the two degradation steps that failed to liberate the expected PTH-amino acids matched the reported location of the Gin-Lys crosslinks. Antisera were obtained against this immunogen coupled either to bovine thyroglobulin or bovine serum albumin. All antisera elicited bound immunogen that was covalently coupled to ribonuclease radiolabeled with 125I as a tracer. The unlabeled γ-γ, crosslinked peptide effectively inhibited binding (0.03-0.08 picomoles for 50% inhibition), while with some antisera up to 500 times more of the 27 amino acid γ monomer peptide was required for the same degree of inhibition. Fibrinogen and fragment D also were poor Inhibitors. The results Indicate that it is possible by radioimmunoassay to distinguish the COOH-termlnal region of the γ-γ dlmer from that of uncrosslinked molecules.


2001 ◽  
Vol 86 (07) ◽  
pp. 75-82 ◽  
Author(s):  
Peter Walsh

SummaryTo account for the variable hemostatic defect in patients with factor XI (FXI) deficiency, with normal hemostasis in contact factor deficiencies, a coagulation paradigm is presented whereby trace quantities of thrombin, generated transiently by exposure of tissue factor at sites of vascular injury, activates FXI bound to the platelet surface in the presence of prothrombin or high Mr kininogen (HK). Tissue factor pathway inhibitor (TFPI) limits the flux of thrombin generated by the tissue factor pathway, and protease nexin II (PNII), released from activated platelets, inhibits solution phase FXIa and localizes FIX activation to the platelet surface where FXIa is protected from inactivation by PNII. Either prothrombin or HK binds to the Apple 1 (A1) domain of FXI, thereby exposing a platelet-binding site in the FXI A3 domain. Dimeric FXI binds to activated platelets directly through the A3 domain of one monomer. After proteolytic activation of platelet-bound FXI by thrombin (or FXIIa), a substrate binding site for FIX is exposed in the opposite monomer that promotes FIX activation on the platelet surface resulting in the local explosive generation of thrombin and the formation of hemostatic thrombi at sites of vascular injury.


Hematology ◽  
2010 ◽  
Vol 2010 (1) ◽  
pp. 387-396 ◽  
Author(s):  
Lawrence Brass

Abstract The contribution of platelets to normal hemostasis and vascular disease is well described. However, recent studies make it clear that much remains to be learned about platelet activation at the single cell and the molecular level, and about the contribution of platelets to inflammation, tumor angiogenesis, and embryonic development. This article is divided into two themes. The first is an overview of current knowledge of the mechanisms that drive platelet function in vivo and a brief summary of some of the emerging ideas that are modifying older views. The second theme is a consideration of the strengths and weaknesses of the tools we have as hematologists to assess platelet function in the clinical setting, identify mechanisms, and evaluate the impact of antiplatelet agents.


2001 ◽  
Vol 86 (07) ◽  
pp. 66-74 ◽  
Author(s):  
James Morrissey

SummaryTissue factor is considered to be the physiologic trigger of the blood clotting system in normal hemostasis and in many – perhaps most – thrombotic diseases. A wealth of new knowledge is available regarding the structure and assembly of the TF:VIIa complex and the role of factor VIIa and tissue factor in hypercoagulable states. The exciting recent finding that tissue factor can function as a signaling receptor, and suggestions that tissue factor may have important, non-hemostatic roles, will be the subject of much additional study in the near future.


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