Inactivation factors

Table 20.1 Inactivation factors (IF) for selected sterilization protocols and their corresponding biological indicator (Bl) organisms... 

Type 1 patients unresponsive to desmopressin, patients with types 2 and 3 von Willebrand s disease, and major surgery patients require replacement therapy with plasma-derived intermediate- and high-purity factor VIII virus-inactivated factor VIII concentrates containing von Willebrand factor. 

Fig. 7. Our current understanding of the protein C pathway. V, and VIII, represent inactivated factors V and VIII, respectively. For an explanation of other abbreviations see text.

Thrombomodulin is a protein on the endothelium that (1) binds with thrombin, reducing its availability for the clotting process and (2) activates protein C, which acts as an anticoagulant by inactivating factors V and VIII. 

Protein C A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and Villa at the rate-limiting steps of thrombin formation. [NIH]... 

Partially responsible for inhibition of the extrinsic pathway. Inactivates factors V and VIII and promotes fibrinolysis. Activity declines following warfarin administration. cofactor to accelerate the anticoagulant activity of protein C. Decreased levels occur following warfarin administration. ... 

Activated Protein C (CJ [42617-41 -4] (19—21) is a naturally occurring serine protease that, in combination with free Protein S, degrades and inactivates Factors V, Va, VIII, and Villa. By degradation of these factors the blood becomes anticoagulated and thus Ca may be a useful therapeutic agent. 

Heparin acts indirectly at multiple points within the coagulation cascade, Its major anticoagulant effect is via interaction with its requisite co-factor, antithrombin III (AT). The heparin-AT complex inactivates factors IXa, Xa, and XIla, and binds thrombin at its active site to prevent the conversion of fibrinogen to fibrin (3). Heparin also prevents fibrin stabilization through the inhibition of fibrin stabilization factor. Heparin has no fibrinolytic activity and therefore is ineffective as a thrombolytic (4,5). 

Heparin binds to antithrombin (a protease inhibitor that inactivates factors Ha, IXa, Xa and XIa) and markedly accelerates its inhibitory effect on coagulation. In addition, heparin inhibits platelet function, The newer low-molecular-weight heparins augment antithrombin activity preferentially against factor Xa and do not prolong the APTT like standard (unfractionated) heparin does. 

Arrighi, S. Rossi, R. Borri, M.G. Lesnikov, V. Lesnikova, M. Franco, E. Divizia, M. De Santis, M.E. Bucci, E. In vitro and in animal studies on a double virus-inactivated factor VIII concentrate. Thromb. Hemost. 1995, 74,... 

Thus, for an initial burden of 102 spores an inactivation factor of 108 will be needed to give the required sterility assurance of 10-S (Fig. 20.3). The sterilization process will therefore need to produce sufficient lethality to achieve an 8 log cycle reduction in viable organisms this will require exposure of the product to eight times the D-value of the reference organism (8D). In practice, it is generally... 

Temperature (°C) Holding time (minutes) (kPa) (psi) Inactivation factor (decimalreductions)... 

The coagulation proteins that are synthesized in the liver are listed in Table 47-1. These proteins interact to produce a fibrin clot. Inhibitors of the coagulation system, including antithrombin, protein C, and protein S, are also synthesized in the fiver. Some of the coagulation factors (II, VII, IX, and X) require vitamin K for posttranslational carboxylation within the hepatocyte. Protein C and S are also carboxylated by a vitamin K-dependent enzyme. Activated protein C in plasma inhibits coagulation by inactivating factors V and... 

Proteinase inactivation occurs by a stoichiometric reaction between proteinase and inhibitor that results in the formation of a covalent ester bond between the reactive site residue of the inhibitor (Arg in antithrombin) and the active site residue (Ser in the proteinase). The proteinases thrombin, factor Xa, factor IXa, and, less effectively, factor Vila and factor XIa are all inactivated by antithrombin (Figure 36-16). Other SERPINS can inactivate procoagulant proteinases, heparin cofactor II can inactivate thrombin, and O I-proteinase inhibitor can inactivate factor Xa. An altered a i -proteinase inhibitor (a i -proteinase inhibitor... 

Determination of the amount of Protein S antigen Determination of the ability of activated Protein C to inactivate Factor Va in patients in which the Protein C activity is normal... 

Unfractionated heparin (UFH) inhibits platelet aggregation and fibrin formation by accelerating the action of antithrombin, which in turn inactivates factors Ha, IXa, and Xa. The benefit of heparin in UA has been well defined in early trials (48,49). In the RISC trial, a combination of aspirin and heparin reduced the incidence of MI and death during the first five days by 75% when compared with placebo. This result was successfully replicated in several small trials examining the role of heparin in UA. A meta-analysis of these trials revealed a 33% reduction in the combined risk of death or MI in patients treated with aspirin plus heparin compared with those treated with aspirin alone (66). With benefit of heparin clearly established in UA patients, later trials attempted to expand the role of heparin in NSTEMI. 

In summary, there is always a finite probability of a survivor occurring, no matter the strength or duration of a sterilization process. In other words, absolute sterility, in the sense of total freedom from all viable life forms, can never be achieved in practice. The acceptance of exponential inactivation lunetics has led to two different approaches to the establishment of standards of satisfactory sterilization treatment, the inactivation factor approach and the sterility assurance level (SAL) approach. 

There are both practical and academic problems associated with setting standards for sterility on the basis of inactivation factors. 

By 1965, 25 kGy was quoted [8] as being the accepted dose of radiation for sterilizing disposable medical equipment in most countries except Denmark, where 45 kGy was being claimed to be necessary. As a consequence there was a flurry of scientific activity to validate the choice of 25 kGy retrospectively. Much of this work was done in laboratory studies with the most radiation-resistant microorganism then known, the spore of Bacillus pumilus E601 and centered on the determination of inactivation factors. An inactivation factor is the number of decimal reduction values (Dig-values) delivered by a particular dose. For these spores irradiated in air the 0 q was consistently found to be 1.7 kGy, hence the inactivation factor was 15. This implies that an SAL of belter than 10 can be achieved for items contaminated with up to 10 spores of these microorganisms per item, and by inference for higher bioburdens of less radia-... 

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