Andreas Stümpflen

Clinical Studies and Thrombin Generation in Patients Homozygous or Heterozygous for the G20210A Mutation in the Prothrombin Gene

A genetic variation in the prothrombin gene, the G-->A transition at nucleotide 20210, is a risk factor for venous thrombosis in heterozygotes and is associated with increased prothrombin activity. The homozygous phenotype and the extent of thrombin generation in heterozygous and homozygous subjects are unknown. We investigated a family that included 2 homozygous and 5 heterozygous carriers of the 20210 A allele. The homozygous propositus and his presumably heterozygous father suffered from deep-vein thrombosis. His presumably heterozygous mother and his homozygous sister had recurrent phlebitis at a young age. The remaining 5 affected family members are still asymptomatic. We studied thrombin generation in the family and in 22 unrelated carriers of the 20210 A allele by measuring (1) prothrombin fragment F1+2 (F1+2) as an index of ongoing thrombin generation and (2) the endogenous thrombin potential (ETP) as an index of the possible thrombin-forming capacity. Their F1+2 levels were not different from those of age-matched controls, and thus, ongoing hemostatic system activation was not detectable. A significantly increased ETP was found in the heterozygous carriers of the 20210A allele compared with the controls (527.8+/-114.9 versus 387+/-50.1 nmol/L x min, P<0.0001). In the 2 homozygotes, the ETP was almost twice (639 and 751 nmol/L x min, respectively) as high as in the controls. We conclude that homozygosity for the G20210A mutation in the prothrombin gene is associated with a severe, albeit more benign, thrombotic diathesis compared with homozygosity for deficiencies of antithrombin, protein C, or protein S. In carriers of the 20210 A allele, the pathomechanisms leading to thrombosis should be sought in the higher amounts of thrombin that may be formed once thrombin generation is triggered, rather than in ongoing thrombin generation in vivo.

Value of color duplex sonography for evaluation of tibioperoneal arteries in patients with femoropopliteal obstruction: A prospective comparison with anterograde intraarterial digital subtraction angiography

PURPOSE This study investigated the accuracy of color duplex sonography (CDS) compared with anterograde intraarterial digital subtraction angiography in the evaluation of the tibioperoneal arteries in patients with peripheral arterial occlusive disease. METHODS Fifty consecutive patients with femoropopliteal obstruction were examined immediately before planned percutaneous transluminal angioplasty. All CDS examinations were performed by one observer; the angiograms were interpreted independently by two readers (A1, A2). We compared agreement concerning judgement of the dominant crural artery (suitable for an eventual femorocrural bypass operation) and judgement of the severity of arterial lesions. RESULTS Concerning judgement of the dominant artery, the interobserver agreement between the two readers of the angiograms was better (kappa value, 0.76) than the agreement between CDS versus A1 (0.61) and CDS versus A2 (0.56). However, the differences were not statistically significant. The results were independent (no significant differences in the kappa values) of the following criteria: presence of diabetes; clinical stage of peripheral arterial occlusive disease; kind of femoropopliteal obstruction; and status of the popliteal artery. Concerning the evaluation of the severity of arterial lesions, the kappa values were significantly higher (p < 0.05) for A1 versus A2 (posterior tibial, 0.87; anterior tibial, 0.79; peroneal, 0.52) than for CDS versus A1 (0.51; 0.46; 0.07) and CDS versus A2 (0.35; 0.38; -0.05). The sensitivity of CDS (vs A1 as reference) for detecting a hemodynamically relevant arterial lesion (stenosis or occlusion) was 100% in the posterior tibial artery, 78% in the anterior tibial artery, and 92% in the peroneal artery. CONCLUSION Compared with intraarterial anterograde digital subtraction angiography, the value of CDS-with its currently used technology-for evaluation of the dominant lower leg artery suitable for an eventual femorocrural bypass operation in patients who have femoropopliteal obstruction is limited. It cannot replace an accurate preoperative angiogram for the routine clinical practice, and its use should be restricted to special cases (such as patients with a history of severe allergic reaction to contrast media or of severely impaired kidney function). CDS is also limited in the accurate judgement of the morphologic features of the runoff arteries in their full length in patients with peripheral arterial occlusive disease.

Comparison of transesophageal and transthoracic contrast echocardiography for detection of a patent foramen ovale

Abstract Presence of a patent foramen ovale may indicate paradoxic embolism in patients with otherwise unexplained embolie disease.1–3 Transthoracic contrast echocardiography has been used as a simple technique for detecting patent foramen ovale.4–6 However, particularly in patients with poor transthoracic image quality, presence of a patent foramen ovale might be missed. Transesophageal contrast echocardiography provides superior visualization of the atrial septum and therefore is believed to improve diagnostic accuracy. The present study investigates the influence of image quality on the detection of a patent foramen ovale by both transthoracic and transesophageal contrast echocardiography.

Significance of left-sided heart disease for the detection of patent foramen ovale by transesophageal contrast echocardiography

Detection of patent foramen ovale by contrast echocardiography is based on transient inversion (right atrial pressure higher than left atrial pressure) of the interatrial pressure gradient. Therefore, the presence of left-sided heart disease with potential elevation of left atrial pressure might obscure the diagnosis of patent foramen ovale. Accordingly, 150 patients (88 men, 62 women; mean age 51.7 +/- 15.2 years) were evaluated for a patent foramen ovale by transesophageal contrast echocardiography. Additionally, atrial septal motion during normal respiration and during the Valsalva maneuver was analyzed. Patency of the foramen ovale was observed in 20 (27%) of 74 patients without left-sided heart disease and with previous arterial embolism, in none (0%) of 25 patients with left-sided heart disease and embolism, in 7 (39%) of 18 patients without left-sided heart disease and without embolism and in 3 (9%) of 33 patients with left-sided heart disease and without embolism. The detection rate of patent foramen ovale was lower in patients with than without left-sided heart disease (5% vs. 29%, p = 0.0007) but was similar in patients with and without embolism (20% vs. 19.5%, p = NS). Abnormal atrial septal motion was more frequently observed in patients with left-sided heart disease (p = 0.0003) and was inversely correlated to detection of patent foramen ovale (p = 0.0003). Multivariate analysis revealed an independent association between the absence of left-sided heart disease and the detection of patent foramen ovale (p = 0.0003). These data suggest that in patients with left-sided heart disease, patency of the foramen ovale may be missed even by transesophageal contrast echocardiography.

Hemodynamic and hemorheologic determinants of left atrial spontaneous echo contrast and thrombus formation in patients with idiopathic dilated cardiomyopathy

The purpose of the present study was to evaluate the specific role of hemorheologic and hemodynamic parameters for spontaneous echo contrast and thrombus formation in vivo. We therefore investigated the association between the presence of left atrial spontaneous echo contrast and thrombus formation by transesophageal echocardiography and multiple clinical, hemodynamic, and hemorheologic parameters in 70 patients with idiopathic dilated cardiomyopathy. Transesophageal echocardiography showed left atrial spontaneous echo contrast and left atrial thrombi in 33% and 19% of patients, respectively. Patients with left atrial spontaneous echo contrast had a lower cardiac index (2.1 +/- 0.9 versus 2.6 +/- 0.9 L/min/m2; p < 0.02), a lower left atrial (21 +/- 8 versus 38 +/- 10 cm/sec; p < 0.001) and left atrial appendage flow velocity (17 +/- 14 versus 39 +/- 13 cm/sec; p < 0.001), a larger left atrial diameter (53 +/- 6 versus 46 +/- 10 mm; p < 0.002), and more often presented with atrial fibrillation (62% versus 32%; p < 0.02). Plasma fibrinogen concentration (4.0 +/- 1.1 versus 3.5 +/- 0.7 gm/L; p < 0.02) and plasma viscosity (1.83 +/- 0.10 versus 1.76 +/- 0.15 mPa.sec; p < 0.05) were higher in patients with spontaneous echo contrast. Multivariate analysis revealed an association between the presence of spontaneous echo contrast and left atrial flow velocity p < 0.0001) and plasma viscosity (p < 0.01). In patients with left atrial (appendage) thrombus or a history of embolism, left atrial appendage flow velocity was lower (15.0 +/- 8.2 versus 29.6 +/- 14.5 cm/sec; p < 0.005) and spontaneous echo contrast was more frequently observed (52% versus 23%; p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Noninvasive estimation of coronary flow reserve by transesophageal Doppler measurement of coronary sinus flow

Abstract Currently available methods for the measurement of coronary flow reserve (CFR) are invasive and time-consuming, and need adequate laboratory equipment and staff. 1–4 Furthermore, most of these methods are limited by various methodologic problems. 5,6 Transesophageal echocardiography enables visualization of the distal coronary sinus in most patients. Accordingly, we investigated the ability of transesophageal echocardiography to calculate CFR by Doppler measurement of coronary sinus flow (CSF) at rest and after dipyridamole administration.

Effects of transvenous regional guanethidine block in the treatment of critical finger ischemia.

The objective of this study was to determine the effects of transvenous regional guanethi dine block in the treatment of patients with critical finger ischemia. Twenty-seven patients (17 collagen vascular disease, four thromboangiitis obliterans, three embolism, three atherothrombosis) presenting with ischemic rest pain and/or ulcerations of the fingers received a single block with 5 mg guanethidine injected in 60 mL into the clini cally more affected hand under 30 minutes of arterial arrest. Marked hyperemia was induced in the treated upper limb, increases (p < 0.01) in finger blood flow, finger skin temperature, and laser Doppler flux were higher and longer lasting than in forearm blood flow, persisting for a whole month. Effects in patients with ischemic finger ulcers were less pronounced than in those without, yet statistically significant increases of all evaluated parameters were observed in these patients too. No effects were seen in the contralateral untreated upper limb or in systemic blood pressure. Subjective symptoms (reduction of rest pain, numbness, vasospastic attacks) were improved in 25/27 (92.6%) patients, ischemic rest pain disappeared in 20/27 (74.1%), and complete healing of finger tip ulcerations within 1 month was achieved in 10/12 (83.3%) affected patients. No side effects were observed. This described method combines good clinical efficacy with lack of undesirable side effects and can be repeated easily. Therefore, this technique is recom mended for broader clinical use.

Abnormal blood rheology in idiopathic dilated cardiomyopathy

Abstract Thromboembolic events represent a frequent complication in dilated cardiomyopathy. 1 Intracardiac thrombi occur in a high proportion of patients 2,3 and are primarily ascribed to a reduction in cardiac output with low intracardiac blood flow velocity. 4 Hemorrheologic factors are known to play an important role in the coagulation process, particularly in presence of low flow states. 5 Hemorrheologic abnormalities in patients with dilated cardiomyopathy may therefore favor the generation of intracardiac thrombi. Such abnormalities in patients with low cardiac output might even further compromise peripheral blood flow and thus reduce tissue oxygen supply. Therefore, rheologic parameters were studied in patients with idiopathic dilated cardiomyopathy and compared with a healthty control group.