Pulmonary embolism: what have we learned since Virchow? Natural history, pathophysiology, and diagnosis.

R udolf Virchow, the brilliant 19th century pathologist, was the first to recognize that blood clots in the pulmonary artery originate as venous thrombi. He stated: “The detachment of larger or smaller fragments from the end of the softening thrombus which are carried along by the current of blood and driven into remote vessels. This gives rise to the very frequent process on which I have bestowed the name of Embolia.”1 All discussions of the pathogenesis of deep venous thrombosis (DVT) begin with Virchow’s triad as follows: hypercoagulability; stasis; and injury to the vessel wall.2 If one examines the commonly accepted risk factors for venous thromboembolism (VTE),3,4 nearly all fall into one or more of these categories, as shown in Table 1. The most important risk factor for VTE is inherited or acquired hypercoagulability. The first three inherited coagulopathies to be discovered (antithrombin III deficiency,5 protein C deficiency,6 and protein S deficiency5) are uncommon in the general population and are infrequent in patients with VTE (2 to 5%). However, as shown in Table 2, the five most recently discovered hypercoagulable states are far more frequent in the general population. Hypercoagulable states are now recognized in 25% of patients with VTE.7 The incidence of hypercoagulable states is even higher in patients with idiopathic VTE and in patients with recurrent VTE.8 With time, we will discover additional genetic defects that lead to hypercoagulability, such that the majority of patients with VTE will be found to have a hypercoagulable state. The commonly accepted risk factors for VTE (Table 1) act as precipitants of VTE in patients who have an underlying hypercoagulable state. For example, a 1995 study9 demonstrated that women with inherited clotting defects have a 9-fold to 19-fold increase in VTE if they use oral contraceptive agents. If these speculations are correct, the detection of a hypercoagulable state10–15 could lead to a more focused approach to VTE prophylaxis. Prophylaxis would be directed to those patients with hypercoagulability when they are exposed to one of the precipitants of (ie, risk factors for) VTE, such as surgery, trauma, cancer, and pregnancy. Even better, it might be possible to utilize gene therapy or other procedures to permanently eliminate the hypercoagulable state. If this were to be possible, the incidence of VTE could be decreased markedly, saving thousands of lives, and saving millions of dollars that currently are spent for the diagnosis and treatment of VTE. Further review articles on pulmonary embolism might not be needed.