bin and its cofactor thrombin-thrombomodulin (Rezaie, 2010). Activated protein C functions as an anticoagulant by proteolytically degrading procoagulant cofactors essential for the generation of thrombin (Rezaie, 2010). The cofactor protein S enchances effects of activated protein C (Anderson and Weitz, 2010). In addition, the serine protease inhibitor antithrombin regulates the coagulation cascade by inactivating thrombin as well as other enzymes in the cascade (Rodgers, 2009).

In individuals with inherited (e.g., antithrombin deficiency, Factor V Leiden) or acquired (e.g., obesity, pregnancy) hypercoagulable states, the function of the enzymes involved in the aforementioned coagulation cascade and its regulation are altered or deficient, leading to excessive coagulability (Anderson and Weitz, 2010). Excessive coagulation can contribute to the development of thrombosis, myocardial infarction, and stroke (Anderson and Weitz, 2010).

INCREASED SUSCEPTIBILITY

Both epidemiologic and mechanistic research suggest that most individuals who experience an adverse reaction to vaccines have a preexisting susceptibility. These predispositions can exist for a number of reasons— genetic variants (in human or microbiome DNA), environmental exposures, behaviors, intervening illness, or developmental stage, to name just a few— all of which can interact as suggested graphically in Figure 3-1.

Some of these adverse reactions are specific to the particular vaccine, while others may not be. Some of these predispositions may be detectable prior to the administration of vaccine; others, at least with current technology and practice, are not. Moreover, the occurrence of the adverse event is often the first sign of the underlying condition that confers susceptibility.

The best-understood vaccine-associated adverse effect is the occurrence of invasive disease (such as meningoencephalitis and arthritis) caused by the vaccine virus itself in individuals with an acquired or genetic immunodeficiency who receive live vaccines such as VZV, MMR, and oral polio vaccine. Although the incidence of such infections may decrease with the introduction of newborn screening for severe combined immunodeficiency, the occurrence of vaccine-related disease can be the trigger that leads to the recognition of immunodeficiency (Galea et al., 2008; Ghaffar et al., 2000; Kramer et al., 2001; Levy et al., 2003). Invasive disease may also occur by viral reactivation in individuals who previously received these vaccines while healthy, but who subsequently become immunocompromised, for example, as a result of chemotherapy should they later develop cancer or leukemia (Chan et al., 2007; Levin et al., 2003). Not all individuals who suffer invasive disease have demonstrated recognized immune deficien-cies, even when vaccine virus is recovered from the patient (Iyer et al.,



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