PubMed · 10543184
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K Okajima. 1999. [Antithrombin].. https://pubmed.ncbi.nlm.nih.gov/10543184/
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BACKGROUND: Impairment of the protein C anticoagulation pathway is critical to the thrombosis associated with sepsis and to the development of purpura fulminans in meningococcemia. We studied the expression of thrombomodulin and the endothelial protein C receptor in the dermal microvasculature of children with severe meningococcemia and purpuric or petechial lesions. METHODS: We assessed the integrity of the endothelium and the expression of thrombomodulin and the endothelial protein C receptor in biopsy specimens of purpuric lesions from 21 children with meningococcal sepsis (median age, 41 months), as compared with control skin-biopsy specimens. RESULTS: The expression of endothelial thrombomodulin and of the endothelial protein C receptor was lower in the patients with meningococcal sepsis than in the controls, both in vessels with thrombosis and in vessels without thrombosis. On electron microscopical examination, the endothelial cells were generally intact in both thrombosed and nonthrombosed vessels. Plasma thrombomodulin levels in the children with meningococcal sepsis (median, 6.4 ng per liter) were higher than those in the controls (median, 3.6 ng per liter; P=0.002). Plasma levels, protein C antigen, protein S antigen, and antithrombin antigen were lower than those in the controls. In two patients treated with unactivated protein C concentrate, activated protein C was undetectable at the time of admission, and plasma levels remained low. CONCLUSIONS: In severe meningococcal sepsis, protein C activation is impaired, a finding consistent with down-regulation of the endothelial thrombomodulin-endothelial protein C receptor pathway.
In the presence of glycosaminoglycans, thrombin is rapidly inactivated by two natural inhibitors secreted from liver: antithrombin (AT) is presumed to be the principal thrombin inhibitor in circulating blood, while for heparin cofactor II (HCII), a role outside circulation has been proposed. In this study, we show that HCII and AT differ with respect to their association with human tissues. Aside from brain, each of these inhibitors was found in sodium dodecyl sulphate (SDS) soluble extracts of various human organs, with a preponderance of HCII in placenta. AT levels, however, predominated in liver. Compared to plasma, the beta-variant of AT was found to be strongly enriched in human organs, while tissue-resident HCII did not differ in its electrophoretic mobility from the circulating form. In placenta, comparable amounts of HCII/thrombin and AT/thrombin complexes were detected, indicating that HCII may exert a thrombin regulating role in that organ under conditions of tissue or blood vessel damage. Transcripts coding for HCII and AT were detected in all tissues examined. The low levels of their mRNAs suggest that most of the tissue-associated thrombin inhibitor molecules originate from circulation and are retained in organs, possibly by specific receptors. The differential presence of HCII and AT in organs is in accordance with individual physiological roles of these inhibitors.
We defined the main cause for the increased immunogenicity of the commercial factor VIII (fVIII) plasma-derived concentrates reported to induce formation of inhibitory antibodies in haemophilia A patients in Germany and Belgium. Formation of these antibodies directed against the C2 domain of fVIII was previously attributed to the use of solvent/detergent (S/D) treatment and pasteurisation for virus inactivation of fVIII concentrate. Since fVIII concentrates associated with increased immunogenicity were prepared from plasma pools characterised by elevated levels of coagulation markers, we examined whether the plasma source or S/D treatment and pasteurisation are responsible for structural changes within the C2 domain causing its abnormal immunogenicity. We found that samples of fVIII concentrate that originated from the abnormal plasma pool had a reduced ability to bind to phospholipid and conformationally sensitive anti-C2 domain antibodies, this effect being mostly pronounced in the samples that underwent both S/D treatment and pasteurisation. Thus, our study suggests that insufficient quality of the starting plasma pools is the major factor determining the structural alterations in the C2 domain of fVIII, whereas combination of S/D treatment and pasteurisation aggravates these changes.