Search for Coagulopathy Does Not Obviate Search for Venous Thrombosis in Suspected Paradoxical Embolism

Search for Venous Thrombosis in Suspected Paradoxical Embolism To the Editor: Paradoxical embolism via a patent foramen ovale (PFO) has been suggested as a mechanism of otherwise unexplained, cryptogenic stroke.1 Paradoxical embolism, however, can be diagnosed only if there is evidence of a venous thrombosis coexisting with arterial embolism and right-to-left shunting via a PFO. When looking for venous thrombosis in suspected paradoxical embolism, the diagnostic yield depends on the interval between the event and the investigation and the used diagnostic methods.2 Diagnosing venous thrombosis in patients with suspected paradoxical embolism is sometimes difficult since the thrombosis (1) may be confined to the calf veins and thus only detectable by venography; (2) may be localized in places other than in the leg veins and thus not detectable by leg venography; (3) may be not the cause but the consequence of arterial embolism; or (4) may spontaneously dissolve, re-embolize, or recanalize.3 Due to these problems, a timely search for venous thrombosis is only rarely performed in patients with suspected paradoxical embolism, especially if they have no clinical symptoms of thrombosis. Several strategies are possible to overcome these obstacles. The first strategy is by improving noninvasive methods to visualize venous thrombosis in different locations, like magnetic resonance venography.4 Another strategy is by search for a clotting diathesis in patients with suspected paradoxical embolism. This indirect strategy is based on the assumption that hypercoagulability leads to a higher incidence of venous thrombosis and thus, in the presence of a PFO, might increase the possibility of paradoxical embolism. Hypercoagulability can be assessed by genetic testing for factor VG1691A mutation, prothrombinG20210A variant, and TT677 genotype of methylenetrahydrofolate reductase. The risk for venous thrombosis is increased 3to 8-fold in heterozygous carriers of the factor VG1691A mutation, 3-fold in heterozygous carriers of the prothrombinG20210A variant, and only 0.16-fold in homozygous carriers of the TT677 genotype of methylenetrahydrofolate reductase.5,6 Addressing the issue of understanding the pathophysiology of PFO-related strokes, the study of Pezzini et al looked for the prevalences of factor VG1691A mutation, prothrombinG20210A variant, and TT677 genotype of methylenetrahydrofolate reductase in patients with ischemic strokes occurring at 45 years of age.7 In patients with PFO-related strokes they found a higher prevalence of the prothrombinG20210A variant and, to a lesser extent, factor VG1691A mutation than in the remaining patients and in the controls after adjusting for age, sex, smoking, hypertension, and hypercholesterinemia. They conclude that these thrombophilic mutations may represent risk factors for PFO-related strokes. Although their findings are interesting and plausible, several issues have to be raised: 1. The creation of the PFO and PFO group seems arbitrary, since 6 patients with PFO were included in the PFO group. In these patients, priority was given to the other mechanism of stroke. Since several potential stroke mechanisms may coexist in an individual patient, why were the authors sure that it was not due to paradoxical embolism in these patients? If these 6 patients had been included in the PFO group, how would the results have changed? 2. The onset of stroke in close temporal relationship with a Valsalva maneuver renders paradoxical embolism into a more probable cause of stroke.2 How many of the patients had a Valsalva maneuver in their history? Did this event influence the decision to include them in the PFO group? 3. Transthoracic and/or transesophageal echocardiography had been performed in all included patients. Did the authors also look for PFO by echocardiography and, if yes, were there any false-positive or false-negative cases when compared with transcranial Doppler? 4. Coagulation testing (prothrombin, activated partial thromboplastin times, antiphospholipid antibodies, fibrinogen, protein C, protein S, activated protein C resistance, and antithrombin) had been performed in all included patients. How were the relations between coagulation test abnormalities and thrombophilic mutations in the PFO and PFO groups? 5. In how many patients were investigations of the lower limbs performed and how were the results related with the prevalence of thrombophilic mutations in the PFO and PFO groups? 6. Three of the patients in the PFO group had deep-vein thrombosis at the time of stroke. Did these 3 patients have thrombophilic mutations? 7. Risk factors for vascular events such as hypertension, diabetes mellitus, smoking, and hypercholesterinemia were assessed. These are well-known risk factors for arterial atherosclerosis. Risk factors for the development of venous thrombosis, however, comprise previous thrombosis/pulmonary embolism, immobilization, previous surgery, malignancy, oral contraceptives, and hormonal replacement therapy. It has been shown that the clinical penetrance of the thrombotic tendency associated with the prothrombinG20210A variant is more expressed in the presence of circumstantial risk factors.6 How was the prevalence of these risk factors in the different groups? 8. Is there any other explanation, besides paradoxical embolism, for the higher prevalence of thrombophilic mutations in the PFO than in the PFO group? In summary, the presented data are not convincing enough to recommend laboratory testing for coagulopathies in patients with PFO-related strokes. Neither will this way of testing clarify the question of whether the stroke is due to paradoxical embolism in a patient with PFO. Screening for mutations does not obviate the search for venous thrombosis when looking for paradoxical embolism. In contrast with the authors, we do not believe that “deep-vein thrombosis in stroke patients with PFO is usually undetectable.” If paradoxical embolism really exists, venous thrombosis has to be diagnosed at the right time by using the appropriate diagnostic methods.