[On the ancient and magical lesions in the sixteenth to eighteenth centuries]. / Über die alten und zauberischen Geschwäre im 16. bis 18. Jahrhundert.

At the beginning of the Renaissance magical, witchcraft and demonological medicine still played a large role in the poor healing ability of chronic leg ulcers. This included the general administration of magical potions and topical application. An example of the manipulation of the whole body by the devil was the Abracadabra text from Johann Christoph Bitterkraut in the year 1677. The use of bewitched ointments was particularly propagated by Paracelsus in 1622; however, even as early as the beginning of the seventeenth century, the invocation of supernatural powers was slowly diminishing until at the beginning of the nineteenth century the medical schools on chronic leg ulcers could be cultivated at the universities and by specialized wound healers.

[Dabigatran therapy--perioperative management and interpretation of coagulation tests]. / Therapie mit Dabigatran. Periinterventionelles Management und Interpretation von Gerinnungstests.

UNLABELLED: Dabigatran, an oral, reversible direct factor IIa inhibitor, is approved in Europe for stroke prevention in atrial fibrillation and for the prevention of venous thromboembolism after elective hip and knee replacement. In contrast to vitamin K antagonists, a routine coagulation monitoring during the treatment with dabigatran etexilate is not necessary. However, in specific clinical situations such as invasive emergency procedures or serious haemorrhage, the actual anticoagulant status of dabigatran may be of importance for the treating clinician and can be assessed by clotting tests (aPTT, TT, ECT). The diluted thrombin time test (Hemoclot®), which is specifically calibrated for dabigatran, is useful for quantitative determination of the dabigatran serum concentration. In general, discontinuation of dabigatran etexilate 24 hours before standard elective surgery is sufficient to normalise the bleeding risk in patients with normal renal function. In patients with renal impairment and/or in the case of a high bleeding risk procedure the recommended duration of discontinuation is prolonged. If a bleeding episode occurs in a patient on dabigatran, further treatment should be based on the severity and localisation of the bleeding. A distinct feature of dabigatran is the possibility of effectively removing dabigatran from the circulation by haemodialysis. RECOMMENDATION: In the case of clinically minor bleedings, a delay in the administration of the next dabigatran etexilate dose is recommended. The length of the delay is based on the patient's individual thromboembolic risk. In minor bleedings the use of prothrombin complex concentrates is not indicated. In the case of moderate or major bleedings the main focus should be on stabilising the circulation by using fluids and blood products and, if a lesion can be identified, the local treatment thereof. If time and infrastructure is available, dialysis offers an effective and fast option to remove dabigatran out of the circulation. In the incidence of severe and life threatening bleedings, an additional, more complex haemostasis management is required. Besides haemodynamic stabilisation of the circulation, administration of prothrombin complex concentrates should not be delayed. It has to be kept in mind that standard laboratory coagulation parameters may not accurately reflect the effect of prothrombin complex concentrates in patients on dabigatran. Hence the effect of the prothrombin complex concentrate should be monitored clinically and adjusted by means of onset of coagulation in vivo.

[New oral anticoagulants. Significance for dermatology and phlebology]. / Neue orale Antikoagulanzien. Bedeutung für die Dermatologie und Phlebologie.

Venous thromboembolism and atrial fibrillation are common and are treated with vitamin K antagonists in 1.7% of the total population in the western world. The limitations of the vitamin K antagonists and of heparin have led to the development of new oral drugs. These drugs inhibit thrombin or factor Xa and can be given in a fixed dosage; they have a broad therapeutic margin and relatively few drug interactions. Specific risks and problems also are associated with the new drugs such as interference with common coagulation tests without being able to draw any conclusion as to the actual bleeding risk and the lack of specific antidotes. No established coagulation monitoring is available. The article gives reviews the current knowledge and provides practical advice on how to use the new drugs for the approved indications such as knee and hip replacement, therapy of deep venous thrombosis and of atrial fibrillation. Beyond that, recommendations are given for perioperative management and for change of treatment.

[Diagnosis and treatment of venous thrombosis]. / Diagnostik und Therapie der venösen Thrombose.

In the diagnosis of deep vein thrombosis in ambulatory patients, the recommended initial steps are assessment of clinical probability (CP) and a sensitive D-dimer test. With a low CP and negative D-dimer, thrombosis can be ruled out. All other constellations require further investigation with imaging techniques. Compression ultrasonography is the first-line investigation. Low-molecular weight heparin or fondaparinux is the treatment of choice for uncomplicated venous thrombosis. Secondary prophylaxis with a vitamin K antagonist is introduced in parallel as quickly as possible. The duration of treatment depends on the exposure and predisposing factors, weighing carefully the risk of recurrence on the one hand against the risk of bleeding on the other. The danger of a post thrombotic syndrome is reduced by the immediate begin of a long lasting compression therapy.

Invasive therapeutic options in truncal varicosity of the great saphenous vein.

It is known from current pathophysiology that disease stages I and II of truncal varicosity of the great saphenous vein do not cause changes in venous pressure on dynamic phlebodynamometry. This is possibly also the case for mild cases of the disease in stage III. In pronounced cases of stage III and all cases of stage IV, however, venous hypertension occurs which triggers the symptoms of secondary deep venous insufficiency and all the complications of chronic venous insufficiency. From these facts the therapeutic consequence is inferred that in stages I and II and perhaps also in very mild cases of stage III disease, it is enough "merely" to remove varicose veins without expecting there to be any other serious complications in the patient's further life caused by the varicosity. Recurrence rates are not included in this analysis. In marked cases of disease stages III and IV of the great saphenous vein, however, secondary deep venous insufficiency is to be expected sooner or later. The classical operation with saphenofemoral high ligation ("crossectomy") and stripping strictly adheres to the recognized pathophysiologic principles. It also takes into account in the greatest detail aspects of minimally invasive surgery and esthetics. In the past few years, developments have been advanced to further minimize surgical trauma and to replace the stripping maneuver using occlusion of the trunk vein which is left in place. Obliteration of the vessel is subsequently performed via transmission of energy through an inserted catheter. This includes the techniques of radiofrequency ablation and endovenous laser treatment. High ligation is not performed as a matter of principle. In a similar way, sclerotherapy using microfoam is minimally invasive in character. All these procedures may be indicated for disease stages I and II, and with reservations also in mild forms of stage III disease. Perhaps high ligation previously constituted overtreatment in some cases. Targeted studies are still needed to prove whether secondary deep venous insufficiency can be avoided in advanced stages of varicose vein disease without high ligation and thus without exclusion of the whole recirculation circuit.

[Diagnosis and treatment of venous thrombosis]. / Diagnostik und Therapie der venösen Thrombose.

In the diagnosis of deep vein thrombosis in ambulatory patients, the recommended initial steps are assessment of clinical probability (CP) and a sensitive D-dimer test. With a low CP and negative D-dimer, thrombosis can be ruled out. All other constellations require further investigation with imaging techniques. Compression ultrasonography is the first-line investigation. Low-molecular weight heparin is the treatment of choice for uncomplicated venous thrombosis. Secondary prophylaxis with a vitamin K antagonist is introduced in parallel as quickly as possible. The duration of treatment depends on the exposure and predisposing factors, weighing carefully the risk of recurrence on the one hand against the risk of bleeding on the other. If there are contraindications to anticoagulation with heparins or coumarins, various other anticoagulant drugs are available.

[Venous thrombosis in pregnancy]. / Die Venenthrombose in der Schwangerschaft.

Lung embolism is one of the most common causes of death during pregnancy and the puerperium. It is usually due to thrombosis of the deep leg and pelvic veins. As a result of modern imaging methods, it can be reliably diagnosed at an early stage. In some cases, special haemostaseological tests can identify congenital or acquired defects. This allows an initial assessment of the individual risk of thrombosis to be made. Body weight-dependent anticoagulation therapy with heparin is the major medication-based treatment. Compression treatment can be administered if accepted by the patient.

[Vascular manifestation of von Recklinghausen neurofibromatosis: case report of venous dysplasia]. / Vaskuläre Manifestation bei Neurofibromatose von Recklinghausen: Kasuistik einer venösen Dysmorphie.

We present the case report of a patient with neurofibromatosis and regional dysmorphism in the superficial femoral vein. Colour coded duplex sonography revealed an incidental finding: thickening of a short portion of the vein wall with calcification. This unusual finding strongly suggests a causal relationship. Pathological processes in the arteries have often been described in patients with von Recklinghausen's disease (neurofibromatosis). Dysplastic and hyperplastic reactions of the intramural nerve tissues and the smooth muscle elements in the vascular wall have been observed. This leads to the formation of aneurysms and arteriovenous fistulas and to stenosing processes in the peripheral, visceral and cerebral arteries. However, involvement of the veins in type 1 von Recklinghausen's neurofibromatosis has only been reported in old histopathological studies of medium-sized and small vessels.

Combined occurrence of a heterozygous missense mutation in the protein C gene and allelic exclusion of one protein S allele leading to severe venous thrombosis.

Individuals with more than one defect in the natural anticoagulant system exhibit an increased risk for thrombosis. We report on a family with two cases of combined protein C (PROC) and protein S (PROS) deficiency, five cases of isolated PROC deficiency Type I, and two cases of isolated PROS deficiency Type I. PROC and PROS deficiency were documented by functional and immunologic tests. The sequencing of all exons and splice junctions of the PROC gene led to the identification of a new, unpublished G-->A transition at nt 8490, leading to an exchange of alanine 259 by threonine. The mutation was present in all family members with PROC deficiency. The carriers of the isolated PROC mutation were asymptomatic at ages of 4, 7, 10, 11, and 80 years. The combination of the PROC mutation with a PROS deficiency in two family members triggered venous thromboembolism at age 31 and 6 years, respectively. The PROS deficiency was associated with complete exclusion of one PROS allele. Two family members with isolated PROS deficiency are still asymptomatic at age 21 and 9 years, respectively. Our findings in this family suggest that the heterozygous mutation at codon 259 of the PROC gene represents a mild thrombotic risk factor and only confers a high thrombotic risk in combination with a second defect, such as the complete exclusion of one PROS allele.

Effects of a low-molecular-weight heparin on thrombus regression and recurrent thromboembolism in patients with deep-vein thrombosis.

BACKGROUND: Low-molecular-weight heparins are frequently used to treat venous thromboembolism, but optimal dosing regimens and clinical outcomes need further definition. METHODS: In this multicenter, open-label study with blinded adjudication of end points, we randomly assigned patients with acute deep-vein thrombosis to one of three treatment regimens: intravenous administration of unfractionated heparin; subcutaneous administration of a low-molecular-weight heparin, reviparin, twice a day for one week; or subcutaneous administration of reviparin once a day for four weeks. The primary end point was evidence of regression of the thrombus on venography on day 21; secondary end points were recurrent venous thromboembolism, major bleeding within 90 days after enrollment, and death. RESULTS: Of the patients receiving unfractionated heparin, 40.2 percent (129 of 321) had thrombus regression, as compared with 53.4 percent (175 of 328) of patients receiving reviparin twice daily and 53.5 percent (167 of 312) of the patients receiving reviparin once daily. With regard to thrombus regression, reviparin administered twice daily was significantly more effective than unfractionated heparin (relative likelihood of thrombus regression, 1.28; 97.5 percent confidence interval, 1.08 to 1.52), as was reviparin administered once daily (relative likelihood, 1.29; 97.5 percent confidence interval, 1.08 to 1.53). Mortality and the frequency of episodes of major bleeding were similar in the three groups. CONCLUSIONS: In acute deep-vein thrombosis, reviparin regimens are more effective than unfractionated heparin in reducing the size of the thrombus. Reviparin is also more effective than unfractionated heparin for the prevention of recurrent thromboembolism and equally safe.

The chronic venous compartment syndrome.

BACKGROUND: A chronic exertional compartment syndrome has only been observed in athletes and soldiers. In the vast majority, the disease affects the anterior compartment and the fibular muscle group, and only rarely the lateral and dorsal muscle compartments. Muscle tissue necrosis does not occur. In the course of venous diseases with a severe chronic venous stasis syndrome, a chronic venous compartment syndrome develops that differs considerably from the familiar functional syndrome. The predominant symptom is an uncurable cuff ulceration on the lower leg. PATIENTS AND METHODS: From 1993 to 1996 a total of 16 patients with a chronic fascial compression syndrome underwent surgery on 18 extremities. The crural fascia was resected and a mesh graft was applied. RESULTS: In the group of ten controls with healthy veins the average pressure in the deep compartment was 13.6 mmHg (range 9-17 mmHg) lying down and 29.9 mmHg (range 15-42 mmHg) standing up. In 14 patients with chronic fascial compression syndrome, the average pressure was higher, measuring 21.1 mmHg (range 8-47 mmHg) lying down and 62.5 mmHg (range 33-87) standing up. After surgery, the pressure dropped to 15.5 mmHg (range 5-24 mmHg) lying down and 34.5 mmHg (range 10-58 mmHg) standing up, but did not fall as low as the average values recorded in the control group or in the patient's healthy leg. The results from the standing up position were statistically significant (p = 0.003). Computed tomography showed major changes in the muscles indicating muscle atrophy and fatty degeneration. The crural fascia seemed to be incorporated in the scars of the subcutaneous tissue in large areas. After crural fasciectomy and healing of the ulceration, the tissue structure of the muscles recovered. CONCLUSIONS: In chronic fascial compression syndrome, the trellis arrangement of the collagen fibres becomes disordered. This results in a loss of flexibility during muscle contraction. Every step causes an increase of intracompartmental pressure and microstructural injury. The consequence is resection of the crural fascia.

Postmenopausal hormone replacement therapy and the vascular wall: epidemiology and clinical studies.

The clinical relevance of estrogen's multiple acute and more delayed effects on vascular wall structure and function is incompletely understood. This review attempts to reevaluate epidemiological findings and clinical studies concerning the vascular actions of estrogens and gives implications for strategies in postmenopausal hormone replacement therapy (HRT). There is large evidence from observational studies that HRT reduces the risk of cardiovascular mortality and morbidity in postmenopausal women. However, according to the only large randomized, placebo-controlled, secondary prevention Heart and Estrogen/progestin Replacement Study (HERS), women with prevalent cardiovascular disease (CVD) have increased CVD events within the first year after onset of HRT. The net effects of HRT on atherosclerosis, coagulation, fibrinolysis or the inflammatory response are unproven. Randomized trials of intermediate outcomes reveal that HRT has favorable effects on isolated cardiovascular risk factors, e.g. lipoproteins, carbohydrate metabolism and vasodilatation, but the impact of this effects on clinical endpoints is still not clear. The basis of "evidenced based medicine" is currently not sufficient to provide exact recommendation who will benefit from HRT and who might not. Therefore, the decision about hormone use should consider individual benefit-risk profiles.

Postmenopausal hormone replacement therapy and the vascular wall: mechanisms of 17 beta-estradiol's effects on vascular biology.

17 beta-estradiol (E2) protects against atherosclerosis independent of changes in plasma lipoproteins in a variety of animal models, which is explained by direct effects of E2 on the vascular wall. E2 improves vasomotion by modulation of vasoconstrictor and vasodilator systems through endothelium-dependent and endothelium-independent mechanisms. E2 affects the remodeling of the vascular wall by inhibiting smooth muscle cell proliferation and accelerating reendothelialization of injured blood vessels. E2 modulates the vascular inflammatory response by inhibiting cytokine production, cytokine-induced expression of cell adhesion molecules and platelet aggregation/adhesion. This review focuses on the cellular and molecular mechanisms underlying these vasculoprotective actions of E2. E2 can act through nongenomic stimulation of membrane/intracellular mediators and/or the classical genomic pathway of steroid actions, which is dependent on transcription and protein synthesis. The existence of at least two nuclear estrogen receptor (ER) subtypes alpha and beta and a putative membrane ER present the potential of tissue-specific as well as biologically different E2 actions. Nuclear ERs act as ligand-activated transcription factors and can affect gene regulation by interaction with the classical estrogen response element or other nonreceptor transcription factors. The molecular basis of genomic E2 actions by identifying transcription factors and regulatory elements involved in the induction and inhibition of E2 regulated gene expression is only at the beginning of being understood. The impact of E2-mediated increased NO availability on the hemodynamic and antiatherosclerotic actions of E2 is still a debate of controversy.

[Predisposition and initiation of venous thrombosis]. / Prädisposition und Auslöser der venösen Thrombose.

The causes of thromboembolic disease are complex. In addition to acquired risks, thrombophilic diatheses in particular now play an important role. The combination of predisposing factors increases the risk of thrombosis. However, a precise prognosis cannot yet be made for an individual patient.

Recombinant hirudin (lepirudin) provides safe and effective anticoagulation in patients with heparin-induced thrombocytopenia: a prospective study.

BACKGROUND: The immunological type of heparin-induced thrombocytopenia (HIT) is the most frequent drug-induced thrombocytopenia. This study evaluated the efficacy of recombinant hirudin (r-hirudin or lepirudin), a potent thrombin inhibitor, for anticoagulation in patients with confirmed HIT. METHODS AND RESULTS: Eighty-two patients in this prospective, multicenter study received 1 of 4 intravenous r-hirudin regimens: A1, HIT patients with thrombosis (n=51), 0.4-mg/kg bolus and then 0.15 mg. kg-1. h-1; A2, HIT patients with thrombosis receiving thrombolysis (n=5), 0. 2-mg/kg bolus and then 0.1 mg. kg-1. h-1; B, HIT patients without thrombosis (n=18), 0.1 mg. kg-1. h-1; and C, during cardiopulmonary bypass surgery (n=8), 0.25-mg/kg bolus and then 5-mg boluses as needed. Response criteria were increase in platelet count by >/=30% to >10(9)/L and activated partial thromboplastin time (aPTT) values 1.5 to 3.0 times baseline values achieved with a maximum of 2 dose increases. No placebo control was used for ethical reasons. Outcomes of a subset of r-hirudin-treated patients who met predefined inclusion criteria (n=71) were compared with those of a historical control group (n=120) for combined and individual incidences of death, amputations, new thromboembolic complications, and incidences of bleeding. Platelet counts increased rapidly in 88.7% of r-hirudin-treated patients with acute HIT. In regimens A1 and A2, the 25% and 75% quartiles of the aPTT were within the target range at all but 1 time point. The incidence of the combined end point (death, amputation, new thromboembolic complications) was significantly reduced in r-hirudin patients compared with historical control patients (P=0.014). During first selected treatment, the adjusted hazard ratio for r-hirudin patients versus historical control was 0.279 (95% CI, 0.112 to 0.699; P=0.003). Bleeding rates were similar in both groups. CONCLUSIONS: r-Hirudin treatment is associated with a rapid and sustained recovery of platelet counts, sufficient aPTT prolongations, and true clinical benefits for patients with HIT.

Heparin-related thrombosis despite normal platelet counts in vascular surgery.

BACKGROUND: Acute graft thrombosis is a severe complication in vascular surgery that may require limb amputation or even cause death. Because nearly all patients undergoing vascular surgery have had previous exposure to heparin, the presence of heparin-related anti-platelet antibodies typical for heparin-associated thrombocytopenia (HAT) is one underlying possible mechanism of acute graft thrombosis. Although thrombocytopenia is a typical finding of HAT, it is not clear whether the occurrence of clinically important HAT is necessarily associated with thrombocytopenia. PATIENTS AND METHODS: Ten out of 246 patients undergoing vascular surgery were diagnosed with HAT because of otherwise unexplained acute graft thrombosis that required recurrent surgical interventions. RESULTS: In all of the 10 patients, heparin-related anti-platelet antibodies were detected although the platelet counts were within the normal range. When HAT was diagnosed, heparin administration was stopped and, after autoantibody cross-reactivity with the heparinoid Danaparoid had been excluded, anticoagulation was continued using this anticoagulant. After heparin therapy was discontinued none of the 10 patients developed further thrombotic complications. CONCLUSION: The data presented demonstrate clearly that a normal platelet count does not exclude the possibility of HAT. As a consequence of this, HAT should be suspected in patients who develop thrombotic complications during heparin treatment, regardless of the actual platelet counts.