Abstract
The contact activation system (CAS) exerts effects on coagulation via multiple mechanisms, which modulate both the intrinsic and extrinsic coagulation cascades as well as fibrinolysis and platelet activation. While the effects of the CAS on blood coagulation measured as activated partial thromboplastin time shortening are well documented, genetic mutations that result in deficiencies in the expression of either plasma prekallikrein (PPK) or factor XII (FXII) are not associated with spontaneous bleeding or increased bleeding risk during surgery. Deficiencies in these proteins are often undiagnosed for decades and detected later in life during routine coagulation assays without an apparent clinical phenotype. Increased interest in the CAS as a potentially safe target for antithrombotic therapies has emerged, in large part, from studies on animal models with provoked thrombosis, which have shown that deficiencies in PPK or FXII can reduce thrombus formation without increasing bleeding. Gene targeting and pharmacological studies in healthy animals have confirmed that PPK and FXII blockade does not cause coagulopathies. These findings support the conclusion that CAS is not required for hemostasis. However, while deficiencies in FXII and PPK do not significantly affect bleeding associated with peripheral wounds, recent reports have demonstrated that these proteins can promote hemorrhage in the retina and brain. Intravitreal injection of plasma kallikrein (PKal) induces retinal hemorrhage and intracerebral injection of PKal increases intracranial bleeding. PPK deficiency and PKal inhibition ameliorates hematoma formation following cerebrovascular injury in diabetic animals. Moreover, both PPK and FXII deficiency are protective against intracerebral hemorrhage caused by tissue plasminogen activator-mediated thrombolytic therapy in mice with thrombotic middle cerebral artery occlusion. Thus, while the CAS is not required for hemostasis, its inhibition may provide an opportunity to reduce hemorrhage in the retina and brain. Characterization of the mechanisms and potential clinical implications associated with the effects of the CAS on hemorrhage requires further consideration of the effects of PPK and FXII on hemorrhage beyond their putative effects on coagulation cascades. Here, we review the experimental and clinical evidence on the effects of the CAS on bleeding and hemostatic mechanisms.
Highlights
The contact activation system (CAS) represents a group of plasma proteins, including factor XII (FXII), plasma prekallikrein (PPK), and high molecular weight kininogen (HK) that promotes inflammation and coagulation upon contact of blood with an activating surface or protease [1, 2]
These findings suggest that the CAS can exert both positive and negative effects on platelet activation during hemostasis, gene targeting and pharmacological studies indicated that blockade of CAS reduces cerebral hemorrhage, which is a primary area of concern regarding bleeding in patients on antithrombotic therapy
Girolami and colleagues [79] re-evaluated case reports on FXII deficiency and thrombosis. They showed that, in most cases, FXII deficiency was associated with other congenital or acquired prothrombotic risk factors. While these studies indicate that the CAS is not essential for either thrombosis or hemostasis, individuals with genetic deficiencies in the CAS are rare and it is not possible to ascertain from the anecdotal clinical information whether plasma kallikrein (PKal) and FXIIa could have significant roles in thrombosis or hemostasis associated with specific clinical indications
Summary
Specialty section: This article was submitted to Hematology, a section of the journal
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