Structure and function of thrombomodulin: a natural anticoagulant

Dittman, William A.; Majerus, PW

doi:10.1182/blood.v75.2.329.329

Cited by 299 publications

(28 citation statements)

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“…Cytokines, such as IL-1 and TNF-a, cause endothelial and monocyte activation resulting in a switch from an anticoagulant to a prothrombotic phenotype by (for example) downregulation of thrombomodulin (Dittman & Majerus, 1990) and upregulation of TF (Khan et al, 2010). IL-1b and TNF-a are produced by APML cells (Griffin et al, 1987).…”

Section: The Contribution Of Inflammatory Cytokinesmentioning

confidence: 99%

The pathogenesis and management of the coagulopathy of acute promyelocytic leukaemia

2011

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Summary Coagulopathy occurs in most patients with (APML) and is life‐threatening; therefore prompt diagnosis and recognition of any coagulation defect is imperative. Unfortunately haemorrhage remains a major cause of early death, preventing some from reaching treatment. The coagulopathy is caused directly or indirectly by the leukaemic cells through expression of activators of coagulation and fibrinolysis, proteases and cytokine generation, compounded by failure of platelet production due to marrow invasion. At presentation the predominant feature is usually hyperfibrinolysis. Since the introduction of all‐trans retinoic acid (ATRA), patient outcome has dramatically improved; yet, haemorrhagic complications remain the most frequent cause of mortality. Thrombotic complications occur but are less well recognized and potentially underreported. Supportive measures and prompt initiation of ATRA currently represent the mainstay of treatment of the coagulopathy in patients with suspected APML, but unanswered questions remain as to the optimal approach to further decrease the associated haemorrhagic and thrombotic risks. In particular, it is unclear how to best predict and monitor the coagulopathy; whether there is a role for the early use of antifibrinolytics; the most appropriate trigger for giving fibrinogen replacement and the value of low‐dose anticoagulation to suppress coagulation activation once fibrinolysis has been suppressed.

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Section: The Contribution Of Inflammatory Cytokinesmentioning

confidence: 99%

The pathogenesis and management of the coagulopathy of acute promyelocytic leukaemia

2011

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“…Therefore, it is a striking observation that IE CSA are only present at high levels during pregnancy and that anti-IE CSA antibodies are largely restricted to pregnant women. Indeed, CSA is expressed throughout the surface of endothelial cells in the microvasculature of other target organs, such as the brain and the lung (Dittman and Majerus, 1990; Wong et al 1991). Furthermore, it has been demonstrated that IE CSA cytoadhere to monkey brain microvascular endothelial cells and human lung epithelial cells, apparently expressing chondroitin sulfate (Robert et al 1995; Traore et al 2000).…”

Section: Selection Mechanismmentioning

confidence: 99%

Plasmodium falciparumduring pregnancy: a puzzling parasite tissue adhesion tropism

Nunes

Scherf

2007

Parasitology

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P. falciparum malaria severely affects pregnant women and children. Despite immunity through lifelong exposure to malaria, pregnant women become susceptible to infections causing anaemia, abortions and low birth weight. They experience massive accumulation of infected erythrocytes (IEs) in the placenta. Adhesion of IEs to host endothelial receptors is mediated by members of a large diverse protein family called P. falciparum erythrocyte membrane protein 1 (PfEMP1). Pregnancy malaria is generally associated with the emergence of a distinct subset of parasites expressing a unique PfEMP1 that binds to the host-receptor chondroitin sulfate A (CSA). Resistance to pregnancy malaria is associated with the acquisition of antibodies that block IEs binding to placental CSA. The absence (or rare occurrence) of CSA-binding parasites in malaria patients (children, men and non-pregnant women) suggests that these parasites become virulent only during pregnancy. The molecular mechanisms used by P. falciparum to achieve the timely expression of the Pf-CSA ligand in pregnant women remain puzzling. In this review we will discuss two hypothetical mechanisms by which CSA-binding parasites may arise during pregnancy. The first, a selection process by the placenta of a distinct sub-population of P. falciparum expressing a particular PfEMP1. The second, an induction mechanism that facilitates the expression of a particular PfEMP1 protein by specific host factor(s) present only during pregnancy.

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“…Free a-thrombin triggers platelet clotting, generates fibrin and active factor XIII to stabilize the clot and activates clotting factors V, VIII and XI, which in turn generate more o~-thrombin (Fenton, 1986;Davie et al, 1991, and references therein). In contrast, a-thrombin bound to thrombomodulin decelerates clotting by preferentially activating protein C, which then proteolytically inactivates factors Va and Villa in the clotting cascade leading to thrombin (Esmon, 1987;Dittman & Majerus, 1990). Thrombin also triggers the inflammation response to vascular damage by activating neutrophils and monocytes (reviewed by Coughlin, 1994).…”

Section: Introductionmentioning

confidence: 99%

Structure of a Bovine Thrombin–Hirudin₅₁₋₆₅Complex Determined by a Combination of Molecular Replacement and Graphics. Incorporation of Known Structural Information in Molecular Replacement

et al. 1996

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Crystals of the bovine thrombin-hirudinsl_65 complex have space group P6122 with cell constants a = 116.4, and c = 200.6A and two thrombin molecules in the asymmetric unit. Only one thrombin molecule could be located by generalized molecular replacement; the second was fit visually as a rigid body to an improved electron-density difference map. The structure was refined to R = 0.192 with two B values per residue (main chain and side chain) at 3.2A. The polar interactions of the peptides with the exosite of thrombin show differences consistent with the known flexibility in the interactions of the C-terminal peptide of hirudin with thrombin. The hirudin peptide in complex 2 has a higher temperature factor as compared with peptide 1 which may be correlated partly with a larger number of short-range electrostatic interactions between peptide 1 and thrombin and partly with the fact that thrombin 2 is E-thrombin which is cleaved at Thr149A near the peptide binding site. Later, using this structure as a test case, it was shown that the position for the second thrombin could also be determined by a novel modification of the molecular-replacement method in which the contribution of the known molecule is subtracted from the structure factors. This approach is facile and applicable to any crystal containing two or more macromolecules in the asymmetric unit in which some but not all of the molecules can be determined by molecular replacement.

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Structure and function of thrombomodulin: a natural anticoagulant

Cited by 299 publications

References 0 publications

The pathogenesis and management of the coagulopathy of acute promyelocytic leukaemia

The pathogenesis and management of the coagulopathy of acute promyelocytic leukaemia

Plasmodium falciparumduring pregnancy: a puzzling parasite tissue adhesion tropism

Structure of a Bovine Thrombin–Hirudin₅₁₋₆₅Complex Determined by a Combination of Molecular Replacement and Graphics. Incorporation of Known Structural Information in Molecular Replacement

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Structure and function of thrombomodulin: a natural anticoagulant

Cited by 299 publications

References 0 publications

The pathogenesis and management of the coagulopathy of acute promyelocytic leukaemia

The pathogenesis and management of the coagulopathy of acute promyelocytic leukaemia

Plasmodium falciparumduring pregnancy: a puzzling parasite tissue adhesion tropism

Structure of a Bovine Thrombin–Hirudin51−65Complex Determined by a Combination of Molecular Replacement and Graphics. Incorporation of Known Structural Information in Molecular Replacement

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Structure of a Bovine Thrombin–Hirudin₅₁₋₆₅Complex Determined by a Combination of Molecular Replacement and Graphics. Incorporation of Known Structural Information in Molecular Replacement