Are the Laboratory Results (Phenotype) Indicative of a True Genotype Abnormality?

Abstract

Thrombophilia is the imbalance between the procoagulant systems and the regulatory mechanisms leading to excessive fibrin production and resulting thrombus formation.1,2 These imbalances can be caused by genetic or acquired factors or by a combination of the two.1 However, the process leading to excessive fibrin formation is not as simple as a single factor being disproportionate to the other factors, but rather a multifactorial model, in which many factors interact, leading to the development of thrombosis.1 Therefore, to attempt to determine the correct cause, an assessment of established risk factors must be made.2 Currently, this is an incomplete process because we do not know all of the responsible factors. But we do know several of the major factors.2 One of the main factors analyzed in most assessments is protein S (PS).2 A deficiency of PS seems to be a major contributor to thrombophilia, yet its biochemistry, physiology, and pathobiology are complex.4,5 PS functions as an antithrombotic factor by an activated protein C (APC)-dependent mechanism and an APC-independent mechanism.2,4,6 Its ultimate antithrombotic role is to down-regulate thrombin formation. PS also seems to have a role in fibrinolysis, complement regulation, and other defense mechanisms.6 The importance of any of these mechanisms in vivo is unknown.6 PS is a nonenzymatic cofactor that binds in equilibrium to a large complement protein, C4b-binding protein.6 Only the unbound (or “free”) form of PS has APC cofactor activity on the phospholipid surface to inactivate factors Va and VIIIa.2,4 Thrombophilia is a defined as a “complex disease” in which multiple factors together have a major role in the disease process. Today we understand only the basics of causation of the disease process. There are many ways …