Ulrich K. Franzeck

Prospective 12-Year Follow-up Study of Clinical and Hemodynamic Sequelae After Deep Vein Thrombosis in Low-Risk Patients (Zürich Study)

BACKGROUND No prospective study of the long-term sequelae of more than 10 years after acute deep vein thrombosis exists so far. Therefore, 58 low-risk patients with DVT were included in a prospective study to evaluate the natural history of postthrombotic syndrome. METHODS AND RESULTS Clinical and hemodynamic examinations were performed at the time of admission; after 3, 6, and 12 months; after the 2nd, 3rd, 4th, 5th years; and finally after the 12th year. All patients received heparin initially and oral anticoagulants subsequently. After 12 years, 64% of the patients exhibited normal findings. Mild skin changes were found in 28%, marked trophic changes in 5%, and only one venous ulcer occurred. Regular use of compression stockings was reported by 54% of the patients with multilevel thrombosis. Although mean maximum venous outflow was significantly reduced from the acute event to 12 years later (P<.003) compared with the contralateral leg, a significant (P<.05) improvement was observed 6 months later. Recanalization of calf vein thrombosis was detected by Doppler sonography after 3 months. Sixty-four percent of the multilevel thromboses were recanalized completely or in part after 1 year; in 69%, valvular incompetence was found. CONCLUSIONS In contrast to earlier reports, this prospective study up to 12 years after deep vein thrombosis demonstrates a low incidence of postthrombotic syndrome by administration of oral anticoagulants and regular compression therapy. However, the adverse clinical event rate (mortality 14%) and a recurrence rate of 24% show that the prognosis after deep vein thrombosis does not appear favorable even in low-risk patients.

Evaluation of Flux Motion in Man by the Laser Doppler Technique

Analysis of flux motion by the laser Doppler technique in the forefoot of healthy controls and patients with peripheral arterial occlusive disease was performed by establishing computerized frequency histograms. It was found that the low frequency components (1-10 cycles/min) are caused by local vasomotion. The prevalence of high frequency flux waves (15-25 cycles/min) is significantly increased in peripheral ischemia compared to normal conditions. After successful reopening of large arteries by angioplasty the prevalence decreases (p less than 0.001). Preliminary results indicate that these high frequency rhythmic fluctuations might by induced by respiration.

Microcirculation abnormalities in patients with fibromyalgia – measured by capillary microscopy and laser fluxmetry

This unblinded preliminary case-control study was done to demonstrate functional and structural changes in the microcirculation of patients with primary fibromyalgia (FM). We studied 10 women (54.0 ± 3.7 years of age) with FM diagnosed in accordance with the classification criteria of the American College of Rheumatology, and controls in three groups (n = 10 in each group) – age-matched women who were healthy or who had rheumatoid arthritis or systemic scleroderma (SSc). All 40 subjects were tested within a 5-week period by the same investigators, using two noninvasive methods, laser fluxmetry and capillary microscopy. The FM patients were compared with the healthy controls (negative controls) and with rheumatoid arthritis patients and SSc patients (positive controls). FM patients had fewer capillaries in the nail fold (P < 0.001) and significantly more capillary dilatations (P < 0.05) and irregular formations (P < 0.01) than the healthy controls. Interestingly, the peripheral blood flow in FM patients was much less (P < 0.001) than in healthy controls but did not differ from that of SSc patients (P = 0.73). The data suggest that functional disturbances of microcirculation are present in FM patients and that morphological abnormalities may also influence their microcirculation.

The frequency histogram—A new method for the evaluation of laser doppler flux motion

A digital filter system (DFS) was implemented to describe the frequency components of laser Doppler signals. The DFS calculates a frequency histogram on the basis of the prevalence of a certain frequency band during the sample period. This approach seems to be more suitable for the detection of low-power small-amplitude flux motion components recorded by laser Doppler as compared to the commonly used fast Fourier algorithm. Fourier analysis provides an amplitude-relevant frequency spectrum which may overlook relevant frequency components with small amplitude due to low power or short duration. DFS allows better detection of such signals as demonstrated by the initial clinical results of this study evaluating flux motion on the feet of 4 healthy controls and 10 patients with peripheral arterial occlusive disease. Three frequency components are easily distinguished corresponding to low (3.6 +/- 1.5 cycles/minute) and high (18.6 +/- 4.5 cycles/min) frequency flux motion and the pulsatile waves due to cardiac action.

Effect of postural changes on human lymphatic capillary pressure of the skin.

1. The influence of postural changes on cutaneous lymphatic capillary pressure and venous pressure was measured at the dorsum of the foot in twelve healthy volunteers. Measurements were performed in the supine and sitting positions. 2. Lymphatic skin capillaries were visualized by fluorescence microlymphography with fluorescein isothiocyanate (FITC)‐Dextran 150000. Subsequently a lymphatic capillary was punctured with a glass micropipette and pressure was measured using the servo‐nulling technique. Lymphatic capillary pressure, venous pressure, heart and respiration rates were recorded simultaneously. 3. Mean lymphatic capillary pressure was significantly higher (P = 0.0096) in the sitting (9.9 +/‐ 3.0 mmHg) than in the supine (3.9 +/‐ 4.2 mmHg) position. There was no significant difference (P = 0.09) between lymphatic capillary pressure and venous pressure (6.8 +/‐ 3.4 mmHg) in the supine position. During sitting mean lymphatic capillary pressure was significantly lower (P = 0.0022) than mean venous pressure (53.3 +/‐ 4.1 mmHg). The smaller increase in lymphatic capillary pressure may be caused by the discontinuous fluid column in the lymphatic system and enhanced orthostatic contractile activity of lymphatic collectors and precollectors. Spontaneous low frequency pressure fluctuations occurred in 89% of recordings during sitting, which was significantly (P = 0.02) higher than in the supine position (54%). 4. The present results support the suggestion of enhanced intrinsic contractile activity of lymph precollectors and collectors in the dependent position. This mechanism is primarily responsible for the propulsion of lymph from the periphery to the thoracic duct during quiet sitting, when extrinsic pumping by the calf muscles is not active.

Intravital detection of skin capillary aneurysms by videomicroscopy with indocyanine green in patients with progressive systemic sclerosis and related disorders.

Conventional capillaroscopy and infrared fluorescence videomicroscopy with indocyanine green were performed at the nailfold in 12 healthy controls and 38 patients with microangiopathy due to systemic sclerosis or related disorders. Saccular aneurysms featuring head and neck (type 1) and aneurysmatic enlargements (type 2) were defined. Microaneurysms were located at the apex or near the apex of capillary loops and were significantly more common in patients than in controls (p less than 0.02 for type 1 and p less than 0.001 for type 2). Combination of the two lesions was found only in patients and appears to be a valuable new diagnostic sign for the presence of microangiopathy. In comparison with conventional capillaroscopy, about twice as many microaneurysms were detected by videomicroscopy with indocyanine green coupling almost completely to plasma proteins. The new technique allows visualization of capillary aneurysms even when filled only by plasma.

Microvascular Changes in Arterial Occlusive Disease: Target for Pharmacotherapy

The main techniques which have been used to study skin microcirculation in patients with peripheral arterial occlusive disease include intravital microscopy with and without the use of fluorescent dyes, laser Doppler fluxmetry and transcutaneous oximetry. In patients with severe ischaemia (rest pain or incipient gangrene) the number of perfused skin capillaries is reduced. Parallel to the decreased number of microvessels containing blood, transcutaneous oxygen tension is low or even approaches the zero level. The tendency to oedema formation is documented by increased leakage of intravenously injected sodium fluorescein at the capillary apex of foot skin (‘candlelight phenomenon’). Laser Doppler flux at rest may still be within the normal range even in advanced disease, since the sample volume of these instruments also contains non-nutritive shunt vessels. However, reactive hyperaemia after arterial occlusion is decreased and delayed in peripheral ischaemia. Whereas rhythmic low-frequency vasomotion is significantly enhanced in patients with intermittent claudication, vasoparalysis with no flux fluctuations prevails in patients with critical ischaemia.

Intravital Capillaroscopy in Patients with Chronic Venous Insufficiency and Lymphoedema: Relevance to Daflon 500 mg

Microangiopathy of chronic venous insufficiency is characterized by elongated, dilated and coiled skin capillaries, which are surrounded by an enlarged pericapillary space (halo). Reduction of capillary number and even areas devoid of microvessels (atrophie blanche) are common in severe chronic venous insufficiency associated with focal microvascular ischaemia (decreased transcutaneous oxygen tension). The superficial network of skin lymphatic capillaries is obliterated in part. Oedema formation results from increased permeability of blood capillaries (enhanced transcapillary diffusion of sodium fluorescein) and deficient lymphatic drainage of interstitial fluid.

Effect of Venous and Lymphatic Congestion on Lymph Capillary Pressure of the Skin in Healthy Volunteers and Patients with Lymph Edema

The aim of the present study was to assess the influence of venous and lymphatic congestion on lymph capillary pressure (LCP) in the skin of the foot dorsum of healthy volunteers and of patients with lymph edema. LCP was measured at the foot dorsum of 12 patients with lymph edema and 18 healthy volunteers using the servo-nulling technique. Glass micropipettes (7–9 μm) were inserted under microscopic control into lymphatic microvessels visualized by fluorescence microlymphography before and during venous congestion. Venous and lymphatic congestion was attained by cuff compression (50 mm Hg) at the thigh level. Simultaneously, the capillary filtration rate was measured using strain gauge plethysmography. The mean LCP in patients with lymph edema increased significantly (p < 0.05) during congestion (15.7 ± 8.8 mm Hg) compared to the control value (12.2 ± 8.9 mm Hg). The corresponding values of LCP in healthy volunteers were 4.3 ± 2.6 mm Hg during congestion and 2.6 ± 2.8 mm Hg during control conditions (p < 0.01). The mean increase in LCP in patients with lymph edema was 3.4 ± 4.1 mm Hg, and 1.7 ± 2.0 mm Hg in healthy volunteers (NS). The maximum spread of the lymph capillary network in patients increased from 13.9 ± 6.8 mm before congestion to 18.8 ± 8.2 mm during thigh compression (p < 0.05). No increase could be observed in healthy subjects. In summary, venous and lymphatic congestion by cuff compression at the thigh level results in a significant increase in LCP in healthy volunteers as well as in patients with lymph edema. The increased spread of the contrast medium in the superficial microlymphatics in lymph edema patients indicates a compensatory mechanism for lymphatic drainage during congestion of the veins and lymph collectors of the leg.

Flow Velocity of Cutaneous Lymphatic Capillaries in Patients with Primary Lymphedema

For the first time measurements of lymph flow velocities in cutaneous microlymphatics of patients with lymphedema were performed and compared with healthy subjects. Flow velocity in single lymphatic skin capillaries was measured using fluorescence video microscopy after subepidermal microinjection of FITC-dextran 150,000 in 15 healthy volunteers and 16 patients with primary lymphedema. Initial filling of the lymphatic capillary network was fast with significantly higher mean velocities in patients with primary lymphedema than in healthy controls (890 +/- 43 vs. 550 +/- 390 microns/s, p < 0.05). The resting velocities were not significantly different between controls and patients (10.3 +/- 4.1 vs. 16.6 +/- 13.9 microns). In 12 out of the 16 lymphedema patients cutaneous backflow of the fluorescent contrast medium from deeper invisible lymphatics was observed. In 4 of these patients rhythmic reflux with a mean frequency of 1.4 +/- 0.5 cycles/min was measured by video densitometry in microlymphatics with a significantly (p < 0.01) enhanced diameter. Mean flow velocity (Vp) in these precollectors was significantly increased compared to the resting velocities (p < 0.01). On the basis of these results the hypothesis is advanced that rhythmic cutaneous backflow originates from intrinsic contractions of deeper lymph collector segments and is transmitted to the superficial microlymphatics through incompetent connecting channels. This newly recognized mechanism appears to be an important factor for the pathophysiology of lymphedema.