PubMed · 13239608
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E HECHT. 1955. [Data on thrombokinase].. https://pubmed.ncbi.nlm.nih.gov/13239608/
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The development of drugs to neutralize the action of thrombin has to date focused on the alpha form of the protease. It is generally agreed that inactive prothrombin is proteolytically converted to active alpha-thrombin which may be further hydrolyzed to beta- and gamma-thrombin. While all three forms of the enzyme retain catalytic activities, only alpha-thrombin is presumed to be physiologically important. The beta- and gamma-thrombin are presumed to be degradation products of no physiological significance. Our demonstration that beta- and gamma-thrombin selectively activate PAR-4 in this and a previous report (J. Biol. Chem. 276, 21173-21183, 2001) necessitates a reevaluation of how we view their physiological roles and how we approach the pharmacological regulation of their actions. Beta-thrombin, like gamma-thrombin, at nM levels selectively activates PAR-4. This was demonstrated by full retention of aggregatory activity with platelets whose PAR-1 and GP Ib receptors were inactivated. Furthermore, the beta-thrombin response was abrogated by desensitizing platelets with suboptimal levels of the thrombin receptor activating peptide for PAR-4 (TRAP-4). For beta-thrombin and gamma-thrombin to have a physiological role, it is necessary to show they can be generated under physiological conditions. We demonstrate, for the first time, that alpha-thrombin is hydrolyzed in less than 1 min by activated factor X at physiological pH, in vitro. This implies that alpha-thrombin may be rapidly converted to beta-thrombin and/or gamma-thrombin in vivo in the proper microenvironment. The differential activation of the three platelet thrombin receptors by alpha-, beta- and gamma-thrombin implies selective structural variations between these thrombin species. Structural differences are likely to account for the marked differential responses observed with the antithrombotic, hirudin, which inhibits alpha-thrombin , is a slightly weaker inhibitor of beta-thrombin and a very weak inhibitor of gamma-thrombin -induced platelet aggregations. The converse order of inhibition is observed with the physiological protease inhibitor, alpha(1)-antitrypsin. Finally, a non-traditional inhibitor, histone-1, selectively inhibits only beta- and gamma-thrombin , primarily at the receptor level of PAR-4 rather than on the thrombin molecule. Trypsin, like beta- and gamma-thrombin , activates PAR-4 and is also inactive with TRAP-4 desensitized platelets. Therefore, it was reasoned that trypsin would be more structurally similar to gamma-thrombin than to alpha-thrombin. The analysis of the crystalline structures of alpha-, gamma-thrombin and trypsin from the databases confirm that this is the case. These findings should help to elucidate structure-function relationships of the different thrombins and may aid in the development of new anti-thrombotic drugs.
PURPOSE OF REVIEW: Low-molecular-weight heparins (LMWHs) have largely replaced unfractionated heparins for both prophylaxis and treatment of venous thromboembolism in nonpregnant patients. However, until recently, evidence in pregnant women was lacking, despite the increasing use of LMWHs during pregnancy in clinical practice. This review covers recent literature on the use of LMWHs in relation to pregnancy. RECENT FINDINGS: The main areas covered in this review are the use of LMWHs in both prophylaxis and treatment of venous thromboembolism in pregnancy. The review also considers issues relating to monitoring of LMWHs in pregnancy, and safety from both a maternal and a fetal perspective. SUMMARY: The available evidence demonstrates that LMWHs are of at least equivalent efficacy but have a better safety profile compared with unfractionated heparins in both prophylaxis and treatment of maternal venous thromboembolism, and are more convenient to administer. There is no consensus with respect to whether these agents require monitoring during pregnancy other than periodic checking of the platelet count. The clinical implication from the available evidence is that LMWHs should now be regarded as the anticoagulant agents of choice for both prophylaxis and treatment of maternal venous thromboembolism.
In the present study, the interaction between tissue factor pathway inhibitor (TFPI) and phospholipids has been characterized using a microtitre plate assay. TFPI was shown to bind calcium-independently to an acidic phospholipid surface composed of phosphatidylserine, but not a surface composed of the neutral phosphatidylcholine. The interaction was demonstrated to be dependent on the presence of the TFPI C-terminus. The presence of heparin (1 U/ml, unfractionated) was able to significantly reduce the binding of TFPI to phospholipid. The interaction of TFPI with phosphatidylserine was significantly decreased in the presence of calcium, but this was counteracted, and even enhanced, following complex formation of TFPI with factor Xa prior to incubation with the phospholipid surface. Moreover, a TFPI variant, not containing the third Kunitz domain and the C-terminus, was unable to bind to phospholipid. However, following the formation of a TFPI/factor Xa-complex this TFPI variant was capable of interacting with the phospholipid surface. This indicates that the role of factor Xa as a TFPI cofactor, at least in part, is to mediate the binding of TFPI to the phospholipid surface.