Several lines of evidence from many studies11–20,33–36,38,44–45 suggest that there are at least four important components in the conceptual model relating thrombotic arteriopathy and PAH: (1) abnormal hematologic parameters; (2) presence of a prothrombotic state; (3) thrombotic arteriopathy; and (4) PAH (Fig 1
). In order for one to state that thrombotic arteriopathy is a cause of PAH, a number of scientific criteria must be fulfilled. The evidence must support biological plausibility, temporality, strength of association, and analogy.,49 The conceptual model in Figure 1 is a biologically plausible causal pathway relating the observed abnormal hematologic parameters, development of thrombotic arteriopathy, and culminating in PAH. However, the current evidence does not fully support temporality, strength of association, and analogy. Some evidence suggests that abnormalities of blood coagulation factors, antithrombotic factors, and the fibrinolytic system contribute to a prothrombotic state in patients with IPAH. However, other lines of evidence do not support this relationship. For example, given its allelic distribution is similar to reference control populations, factor V Leiden does not appear to contribute to the pathophysiology of IPAH in most patients. In addition, PAH is quite uncommon in the setting of inherited thrombophilias, like anti-phospholipid antibody syndrome. Furthermore, it remains uncertain whether the hematologic abnormalities observed in IPAH analogously contribute to a prothrombotic state in APAH, and requires further study.