Fibrinogen adsorption--a new treatment option for venous leg ulcers?

The initial element in the causation of venous ulceration is a disturbance of venous blood flow that leads to an increase in venous pressure. Eventually, however, it is the microcirculatory consequences of venous hypertension that lead to trophic skin changes and finally to ulceration. A reduction in blood viscosity results in an improvement at the microcirculatory level. The elimination of fibrinogen from plasma improves blood viscosity. This case report concerns a 75-year-old woman with venous ulcers of both legs (left lower leg: deep ulceration with a surface area of 3 x 5 cm; right lower leg: superficial, confluent ulceration with a total surface area of 5 x 10 cm). The patient underwent 20 sessions of fibrinogen adsorption, while simultaneously continuing with a regimen of conservative measures (activated charcoal cloth dressing with silver, calcium alginate dressings and short-stretch compression bandages). Following binding to a peptide (Gly-Pro-Arg-Pro-Lys), fibrinogen and fibrin were specifically removed from the patient's plasma: her fibrinogen concentration was lowered from an original mean level of 310 mg/dl (SD +/- 104 mg/dl) to 136 mg/dl (SD +/- 54 mg/dl), and there was no return to the baseline concentration by the time of the next fibrinogen adsorption session. In response to this treatment the patient's ulcers healed rapidly within 9 weeks. Dizziness and hematomas at the vascular access sites in both antecubital fossae were reported as adverse effects. A fall in hematocrit was also noted (before treatment 37% +/- 1%; after treatment 35% +/- 2%). This may have been caused by hemodilution due to the procedure and to cell losses during blood-plasma separation, a phenomenon that is known to occur during apheresis. This case report suggests that fibrinogen adsorption is low in adverse effects and is a useful addition to the range of treatments available for ulcers of venous etiology.

The efficacy and safety of a coumarin-/troxerutin-combination (SB-LOT) in patients with chronic venous insufficiency: a double blind placebo-controlled randomised study.

BACKGROUND: The objective was to evaluate the oedema-protective effect of a vasoactive drug (coumarin/troxerutin [SB-LOT]) plus compression stockings in patients suffering from chronic venous insufficiency after decongestion of the legs as recommended by the new guidelines. PATIENTS AND METHODS: 231 patients were randomly assigned medical compression stockings plus SB-LOT (90 mg coumarin and 540 mg troxerutin per day) or medical compression stockings plus placebo for the first 4 weeks and SB-LOT or placebo for the second 12 weeks of the study. The primary efficacy endpoint was the lower leg volume measured by well-established water plethysmometry. RESULTS: 226 patients were evaluated. After ceasing compression stockings, an edema protective effect was detected in the SB-LOT-group but not in the controls. Recurrence of leg volume increase was by 6.5 +/- 12.1 ml and by 36.7 +/- 12.1 ml in the SB-LOT and placebo group, respectively (p = 0.0402). The local complaint score and general aspects of quality of life were also superior for the SB-LOT-group (p = 0.0041). Significant differences were also observed with regard to clinical global impression and therapeutic effect. No serious adverse drug reaction or clinically relevant impairment of laboratory parameters occur. CONCLUSION: This study confirms the oedema-protective effect of SB-LOT in chronic venous insufficiency and provides a treatment option for patients who discontinue compression after a short time.

Tight junction proteins: a novel class of integral membrane proteins. Expression in human epidermis and in HaCaT keratinocytes.

Tight junction proteins comprise a novel group of integral membrane proteins necessary for cell-to-cell contacts and responsible for the barrier function in epithelial and endothelial cells in various tissues. The tight junction membrane domain contains at least three distinct proteins, named occludin, claudin and junctional adhesion molecule. Claudins are products of a gene family consisting of more than 20 members. We investigated mRNA expression of occludin and 13 different claudins in neonatal foreskin, adult skin and cultivated HaCaT keratinocytes by the Northern blot technique, and performed immunohistochemical staining of adult skin for occludin, claudin 1 and claudin 2. Occludin, claudin 1 and claudin 3 mRNAs were expressed in human neonatal and adult keratinocytes as well as in HaCaT keratinocytes. All other tested claudins were negative. Immunohistochemical staining of adult skin was positive for occludin in the intercellular space of the granular layer, and for claudin 1 in the inter-cellular space of the spinosum layer and basal layer, but negative for claudin 2 in all skin layers. Claudin 1 was also positive in the outer root sheath of hair follicles. Our results indicate that occludin, claudin 1 and claudin 3 are involved in cell-to-cell contacts between keratinocytes in human epidermis, although their functional importance remains unknown.

Value of quantitative photoplethysmography for functional vascular diagnostics. Current status and prospects.

The paper presents recent advances in photoplethysmography (PPG) and the role played by PPG in the noninvasive diagnostics of venous and arterial disease. The technical principles of the new self-calibrating photoplethysmographs are explained. These units allow a quantitative evaluation of all measurement data (e.g. time values, amplitudes, flow rates, blood volume kinetics) and hence a precise analysis of both venous and arterial hemodynamics. In combination with appropriate tests (muscle pump test, vein occlusion test, noninvasive venous pressure test, arterial pulse and pressure test), they are suitable for diagnosing and assessing the severity of vascular disease and monitoring its course and the efficacy of therapy. Now that PPG has gained worldwide acceptance as a routine diagnostic technique for venous disease, its spectrum should be expanded to the arterial side as well.

[Malignant atrophic papulosis (Köhlmeier-Degos): diagnosis, therapy and course]. / Papulosis maligna atrophicans (Köhlmeier-Degos). Diagnose, Therapie, Verlauf.

A 71-year-old male patient presented with malignant atrophic papulosis (Köhlmeier-Degos disease). He developed multiple distinctive cutaneous lesions. The histopathological findings showed an obliterated arteriole with a wedge-shaped area of ulcerated and necrobiotic dermis. Laboratory tests were within normal limits or not specific. Although the involvement of the gastrointestinal tract and other organs has been noted in approximately 60% of the reported cases, in this patient so far the skin seems to be the only involved site. There is no proven effective therapy for Köhlmeier-Degos disease. In our case treatment with pentoxifylline and aspirin led to healing of all skin lesions within 3 months. One year after beginning treatment, the patient showed neither new cutaneous lesions, nor any signs of systemic involvement. The combination of pentoxifylline and aspirin should be considered when planning treatment strategies for malignant atrophic papulosis.

The histomorphologic changes at the saphenofemoral junction in varicosis of the greater saphenous vein.

BACKGROUND: Insufficiency of the greater saphenous vein starts at its junction with the femoral vein, so that the histomorphologic changes at the saphenofemoral junction are of special interest. METHOD: In this study we examined which histologic changes occur in the vein walls 5 cm distal to the junction of the greater saphenous vein into the femoral vein and whether these changes correlate to the clinical severity of venous disease. For this the morphologic changes of 28 venous specimens were described qualitatively and the two layers of the media were measured at their thickest and thinnest points. RESULTS: The three-layered structure of the vessel wall with intima, media and adventitia was destroyed in 21% of the cases, the intima and media were fused into one another due to loss of the membrana elastica interna. In 93% the intima was thickened at circumscribed areas. Sprouting of capillaries into the intima was found only if varicosis lasted for longer than 15 years. Aneurysms were found in 29% of the specimen. In part of severe aneurysms the media was completely missing. The thickness of the circular muscle layer of the media varied more than that of the longitudinal muscle layer (difference between minimal and maximal thickness 400 +/- 130 microM compared to 190 +/- 90 microM). With increasing clinical severity of the chronic venous insufficiency the difference between minimal and maximal thickness of the circular muscle layer increased (330 +/- 90 microM at stage I according to Widmer, 490 +/- 130 at stage III). CONCLUSION: The coexistence of muscular hypertrophy and atrophy in varicose veins is regarded by us as a reaction to altered perfusion and pressure in the veins. Considering the frequently severe damage to the veins, indication for a vein sparing therapy has to be viewed with care.

[Disseminated ischemic necrosis and livedo racemosa in a chronic dialysis patient with calciphylaxis]. / Disseminierte ischämische Nekrosen und Livedo racemosa bei einer Patientin mit Kalziphylaxie nach Langzeitdialyse.

Calciphylaxis occurred in a 40-year old female patient with end-stage renal failure. The patient developed livedo racemosa ("livedo reticularis") with painful skin necrosis and ulcers involving multiple areas of the hip and legs after 22 years of hemodialysis. X-ray-examinations revealed calcinosis of peripheral arteries, especially of the pelvis, thigh and hands, while histological examinations showed a fibrosis and calcinosis of small subcutaneous arteries. A generalized cutaneous microangiopathy could be demonstrated by transcutaneous oxygen pressure measurements. Laboratory data showed a moderate secondary hyperparathyroidism with mild elevation of calcium-phosphate product. In addition to the hemodialysis an attempt was made to improve the microcirculation by vasoactive drugs. The clinical course was characterized by slow healing of the ulcers and occurrence of new areas of cutaneous necrosis. Calciphylaxis is a rare late complication in patients with advanced, often end-stage renal failure. It has characteristic histopathological features and is frequently, but not always, associated with a disturbed calcium and phosphorus metabolism and mildly elevated levels of parathyroid hormone. Calciphylaxis is classified as a special type of metastatic calcinosis.

Cutaneous microcirculation in skin lesions associated with chronic venous insufficiency.

BACKGROUND: There are various types of skin lesions in chronic venous insufficiency. OBJECTIVE: To determine an association between different skin lesions and different changes in the cutaneous vascular bed. METHODS: Twenty-eight patients with chronic venous insufficiency (CVI) without and with various types of skin lesions (ie, hyperpigmentation, lipodermatosclerosis, white atrophy, and venous ulcer) and 12 healthy control subjects were examined by video-capillaroscopy, transcutaneous oxygen tension measurement, photoplethysmography, and Doppler ultrasonography to detect disturbances of cutaneous microcirculation and venous macrocirculation. RESULTS: There were no significant differences between the different CVI groups with respect to their venous function disorder. However, important variations were noted in the cutaneous microcirculation. In all the patient groups, an increase in the mean halo diameter could be demonstrated even in clinically healthy skin. In all types of skin lesions, the mean capillary diameter was significantly enlarged. Severe morphological capillary changes and a significant reduction of the mean transcutaneous oxygen tension values were found in conjunction with lipodermatosclerosis and white atrophy and in the areas surrounding venous ulcers. CONCLUSION: The results of this study point to the conclusion that, once they have become established, microvascular disturbances play an independent role in the development of the skin lesions associated with CVI.

Capillary microscopic findings in patients with CVI under different hydrostatic conditions.

Capillary microscopy in patients with CVI can show many morphological abnormalities like tortuous and elongated capillaries, heterogenous distribution of capillary tufts or microvascular thrombosis. Microcirculatory changes also become evident when examination is done under different hydrostatic conditions. For this purpose a new fiberoptic microscope was used, with an optical surface probe including a CCD camera. Fifteen patients with CVI stages I and II and 10 healthy volunteers were examined at the medial ankle area in supine, sitting and standing position. Patients with CVI showed larger vessel diameters in comparison to controls, the differences increasing with rising hydrostatic pressure. The perfusion type changed in both groups with venules becoming more evident especially in standing position.

[Microwave volumetry of the extremities: a technical measuring alternative to the noninvasive venous occlusion test]. / Mikrowellen-Volumetrie der Extremitäten: eine messtechnische Alternative für den rückwirkungs-freien Venenverschlusstest.

Venous occlusion plethysmography is a well-established noninvasive procedure for the investigation of venous outflow disorders. Various different sensor systems are available for the purpose, e.g. photoplethysmography, strain-gauge plethysmography and impedance plethysmography. The technique of microwave volumetry described in this paper is based on the interaction of the electromagnetic fields within the loss medium, tissue, and uses an air-filled resonant cavity as a sensor. As in the case of a microwave oven, this is excited by a high-frequency generator, but involves the use of far less power. As the volume of the measured objects (foot, arm) increases, the losses in the resonator also increase and can be analysed in a computer. The results can be represented in the form of a classical venous occlusion curve.

[A case of giant condyloma acuminatum. On differential diagnosis of giant condylomas from Buschke-Löwenstein tumors and verrucous carcinoma]. / Ein Fall von Condyloma acuminatum giganteum. Zur Differentialdiagnose der Riesenkondylome von den Buschke-Löwenstein-Tumoren und dem verrukösen Karzinom.

We report on a 67-year-old man with a large papillomatous tumour of the penis clinically resembling verrucous carcinoma. HPV 6 and HPV 11 DNA could be isolated by hybridization techniques. The tumour showed exclusively exophytic growth with anastomosing acanthosis and papillomatosis. Groups of vacuolated cells were present in the spinous and granular layers. Endophytic and destructive proliferations and cytologic criteria of malignancy were absent. This tumor was a giant condyloma acuminatum and not either a Buschke-Löwenstein tumour or a verrucous carcinoma. There was no recurrence 2 years after local excision. The differential diagnosis of giant condylomas and Buschke-Löwenstein tumours is discussed.

Stasis papillomatosis. Clinical features, etiopathogenesis and radiological findings.

Stasis papillomatosis can be divided into localized and widespread forms. Ten patients with this disease are discussed with emphasis on their clinical and lymphoradiological findings. Using isotope lymphography we were able to find an overall lymphostasis in only four patients. In all patients, local lymphatic disturbances were detected by means of indirect lymphography with intradermal lymph cysts as the most specific sign. Local dermal lymphostasis seems to be the common final pathogenesis in spite of different etiologies (ie, primary lymphedema, chronic venous insufficiency, trauma recurrent erysipelas, and local lymphangiodysplasia of unknown origin). A maximum variant was seen, following en-bloc resection of subcutaneous tissue in a patient suffering from congenital lymphedema.

[An epidemiologic study of the pathogenesis of varices. The Bochum study I-III]. / Etude épidémiologique sur la pathogénèse des varices. Etude de Bochum I-III.

A longitudinal study was carried out at 11 secondary schools (Gymnasium) of the city of Bochum to investigate the early and preclinical stages of developing varicose veins. The same pupils were examined when being in the 5th, 9th, and 13th classes (Bochum Study I, II and III). A significant correlation between familial predisposition and the occurrence of varicose veins could not be found until the Bochum Study III. The girls dominated with respect to reticular varices and telangiectasias, the boys with respect to trunk varices, branch varices and incompetent perforators. Photoplethysmography showed shorter refilling times for children and adolescents than for adults, but was not suitable to distinguish between pathological and normal findings. Large varices appeared later than small varices and were preceded by refluxes of the long and short saphenous veins. We thus have for the first time a preclinical sign, which clearly identifies individuals at risk.

[Perforating cutaneous amyloidosis]. / Perforierende kutane Amyloidose.

Two patients, a 79-year-old man suffering from familial lichen amyloidosus and a 44-year-old women with biphasic cutaneous amyloidosis, developed small, centrally ulcerated papules. Histological and ultrastructural examination confirmed transepidermal elimination of amyloid. In contrast to other transepidermal elimination diseases, the material eliminated in perforating cutaneous amyloidosis is of epidermal origin.

[Tumor form of lymphostatic papillomatosis of the skin]. / Tumorform einer Papillomatosis cutis lymphostatica.

The case of a patient with two plantar papillomatous tumours that had had a relapsing course over 10 years is presented. The tumours were located on the right forefoot and the left great toe. Several operations were performed for different diagnoses, i.e. plantar verrucae, verrucous carcinoma and pyoderma vegetans. Histologically, the papillomas proved to be pseudocarcinomatous hyperplasias with multiple ectatic dermal lymph plexuses. Indirect lymphography revealed a circumscribed lymphatic dysplasia with cystic-ectatic cutaneous vessels within the tumour area. Draining lymphatic collectors were conspicuously reduced in number. Isotope lymphography showed a normal lymph transport rate from the foot to the groin. It is concluded that the circumscribed disturbance of lymphatic drainage is the decisive cause of the reactive papillomatous hyperplasia. Thus, these papillomas clinically resembling verrucous carcinoma represent the tumour variant of a papillomatosis cutis lymphostatica.

[D-SGP Duo--a new plethysmography for acral, arterial and venous blood pressure measurement]. / D-SGP Duo--ein neuer Plethysmograph zur akralen, arteriellen und venösen Blutdruckmessung.

This is to present a new portable plethysmograph using modern microprocessor technology, a two-channel digital strain gauge plethysmograph (D-SGP Duo). This system contains two strain gauges and a pressure gauge and has measuring programmes for thrombosis screening (venous occlusion test) and for the acral blood pressure measurement. For the first time it is possible to determine not only the acral systolic arterial pressure but also the acral venous blood pressure. Examples of application are given.