What is occlusion thrombosis

Deep vein thrombosis: diagnosis and therapy

MEDICINE: For further training

Deep vein thrombosis is the third most common acute cardiovascular disease after myocardial infarction and stroke. Only the rapid diagnosis and therapy of the thrombosis effectively prevents pulmonary embolism. In symptomatic patients, anticoagulation can be initiated on the basis of positive compression sonography. If the result is negative, a definitive diagnosis by means of duplex sonography or venography should be sought immediately.


Deep vein thrombosis (DVT) is a relatively common disease, with an annual incidence of about 3: 1,000. 93 percent of thromboses arise in the inferior vena cava and the pelvic leg veins, 1.5 percent in the veins of the upper extremities. The most important early complication is pulmonary embolism, more than 95 percent of which are caused by phlebothrombosis. The risk of pulmonary embolism increases with the expansion of the thrombosis. Half of the patients with a proximal leg vein thrombosis have a pulmonary embolism, which is usually oligo- or asymptomatic. In addition, a third of patients who escape the diagnosis of thrombosis and are not treated develop symptomatic pulmonary embolism. In arm vein thrombosis, pulmonary embolism occurs in less than two percent. A relevant late complication of leg vein thrombosis is the post-thrombotic syndrome, which can be observed after 10 to 15 years in 40 to 60 percent of conventionally treated patients. A leg ulcer develops in every tenth patient with leg vein thrombosis (20, 88).
The early registration of endangered patients and the rapid diagnosis of deep vein thrombosis continues to be a medical challenge, since 50 percent of the cases are symptom-free or with few complaints, especially in the early stages.


Diagnosis


Validity of the anamnesis and clinic
For the development of phlebothrombosis, the triad formulated by R. Virchow with changes in the vascular wall, the blood composition and the flow rate remains valid. With the help of a precise anamnesis, initial conclusions can be drawn about the pathogenesis of the thrombosis and essential predisposing factors can be recorded (Tables 1, 2).
The sensitivity of the clinical examination is good given typical symptoms and simultaneous evidence of thrombogenic risk factors (94). However, in less than a third of symptomatic patients, thrombosis presents itself as a classic syndrome with tension pain in the calf, edema, enlargement of epifascial veins ("Pratt's warning veins") and calf pain with dorsiflexion of the foot ("Homans sign"). Venous thromboses are usually clinically silent at the time they can be initially detected using apparatus-based methods (31). Clinically reliable early symptoms are not described. The sensitivity of the clinical examination is 50 to 90 percent for outpatients and between 0 and 40 percent for stationary patients. Conversely, the clinical suspicion of thrombosis can be confirmed with objective methods in less than 50 percent of patients (40, 44, 45). The vast majority of thromboses start in the muscle veins of the calf with temporary pain, then ascend and, when the strategic bottlenecks in the area of ​​the popliteal vein or proximal sections are affected, lead to sudden swelling. Due to anatomical peculiarities (crossing by the right common iliac artery and fibrous venous spur according to May), descending thromboses start twice as often from the left as compared to the right pelvic vein. Descending thromboses usually show sudden symptoms with acute swelling and livid discoloration of the entire leg.
The differential diagnosis includes all disorders of the knee and calf that lead to a painfully swollen leg (text box: differential diagnosis) (45). Because of the fluctuating predictive value of the clinical examination, the suspected clinical diagnosis must be corroborated quickly by an apparatus-based method with high sensitivity and specificity.


Venography
Ascending venography (first described by Rabinov and Paulin in 1972 and modified by Hach in 1977) has so far been regarded as the reference method by which other apparatus-based methods are measured (79). The strengths of venography lie in the ability to display thromboses of the lower leg venous veins up to the femoral vein and the clear documentation. A reliable phlebographic thrombosis criterion is a sharply delimited filling defect that can be visualized in two planes (Figure 1). Methodological weaknesses and invasiveness of venography limit its clinical use:
! if entire groups of veins are not shown (especially on the lower leg), it is not uncommon for a technically inadequate contrast medium filling to exist;
! important shunt veins (deep femoral vein and internal iliac vein) are not sufficiently contrasted;
! Thromboses with doubled veins often escape detection;
! Neighborhood relationships (Baker's cyst, lymph nodes, tumors) are not shown;
! an interobserver variance of 10 to 20 percent further limits the informative value;
! Even with the use of new isoosmolar, non-ionic contrast media, thromboses are induced in two to three percent of examinations, which usually remain asymptomatic (7, 8);
! Significant side effects (allergic reactions up to anaphylaxis, worsening of a pre-existing renal insufficiency, hyperthyroidism, local irritations and radiation exposure) require careful determination of the indication;
! Phlebography is contraindicated in phlegmasia coerulea dolens and during pregnancy.


Non-invasive diagnostics
¿Functional processes
Non-invasive methods such as vein occlusive plethysmography (VVP) and continuous-wave Doppler sonography (cw) are hemodynamic methods with a sensitivity of approximately 90 percent in detecting proximal thromboses. Vein occlusive plethysmography is used to assess the overall functional status proximal to the measurement site. Common to the various techniques is the short-term throttling of the venous outflow with a defined occlusion time. Cw Doppler sonography registers and assesses the flow signals in a side-by-side comparison (typical drainage points for the femoral vein, popliteal vein and posterior tibial vein). Disadvantages result from the low sensitivity of both procedures in asymptomatic patients, the lack of accuracy in the diagnosis of lower leg vein thrombosis and the low specificity in venous compressions in the pelvic area. Vein occlusive plethysmography and cw Doppler sonography therefore only play a subordinate role in modern thrombosis diagnostics (2).
À compression sonography
In symptomatic patients, real-time B-mode ultrasound can be used to detect proximal thrombosis with a sensitivity of almost 100 percent (62). The direct view of a thrombus is often possible, but not a prerequisite for a diagnosis. The best diagnostic criterion is the incompressibility of the affected veins with moderate external pressure (13). In outpatients with suspected leg vein thrombosis, compression sonography performed several times in a row has a positive prediction value of 94 percent (32). Like vein occlusive plethysmography, compression sonography is hardly suitable as a screening method for asymptomatic patients with a high risk of thrombosis.
Á duplex sonography
Duplex sonography combines the hemodynamic and visual information from Doppler and BMode sonography. With color-coded duplex technology, the Doppler signals are recoded into color signals. The direction of flow determines the color. The color Doppler indirectly improves the morphological and hemodynamic information (Figure 2), facilitates the search for vessels, enables the direction of flow to be determined and enables the semi-quantitative determination of the flow velocities (Table 3). A standardized examination procedure as well as minimum technical and personnel requirements are required for an optimized use of duplex sonography (text box: examination procedure of duplex sonography).
In 35 published studies with a total of 4,747 phlebographically controlled patients, the median sensitivity and specificity were 95 and 97 percent, respectively. Only 9 of the 35 studies mentioned also looked for lower leg vein thrombosis with a median sensitivity of 89 percent and median specificity of 92 percent. These figures show that the diagnostic gap in previous non-invasive procedures in the area of ​​the lower leg veins can be closed by duplex sonography (52).
Table 4 summarizes the advantages and disadvantages of duplex sonography compared to venography. In summary, definitive evidence of a clinical suspicion of thrombosis by means of venography, compression or duplex sonography should be sought. If there is an alternative available, venography as an invasive procedure can mostly be dispensed with. Primary venography can be indicated for:
! Unavailability of efficient ultrasound methods,
! unfavorable ultrasound conditions,
! expert questions and
! optional before thrombolytic and surgical therapy.


Special and experimental procedures
Computed tomography can reliably identify thrombosed abdominal and pelvic veins; it also has clear advantages over venography in the representation of large veins, the differentiation between fresh and old thrombi, and the delimitation of surrounding structures (73). Due to the high costs and very limited availability, the indication for magnetic resonance venography should currently only be made in exceptional cases, for example if differentiated anatomical relationships are required for a therapy decision. For proximal thromboses, the sensitivity is 100 and the specificity 98 percent (24, 93). The 125 iodine fibrinogen uptake test no longer plays a role in daily routine because of its low sensitivity in proximal thromboses, its low specificity and the risk of the transmission of infectious particles. The use of recombinant fibrinogen or pig-derived plasmin could be an alternative in the future. Other methods (radionuclide venography, thermographic methods, measurement of venous pressure, transcutaneous oxygen pressure measurement, and laser Doppler flowmetry) are in the experimental stage or do not contribute significantly to the diagnosis of deep vein thrombosis (63, 77, 93).


Diagnosis of the symptomatic patient
If, based on the anamnesis or clinic, there is a suspicion of a deep vein thrombosis, a step-by-step diagnosis of the imaging method is advisable, depending on the treatment options. In the case of pathological compression sonography, anticoagulation can be initiated immediately. If thrombosis and negative compression sonography are suspected, the diagnosis should be clarified quickly using color-coded duplex sonography. If duplex sonography is doubtful or not available, venography should be indicated. We do not recommend serial compression sonography with two checks within one week if the result is initially negative because of the dangers of undiagnosed and treated lower leg vein thrombosis.


Diagnosis of the asymptomatic patient
The screening of asymptomatic high-risk patients using non-invasive techniques is problematic because of the very fluctuating sensitivity (Table 5). The differences in sensitivity of the non-invasive methods in symptomatic and asymptomatic patients are probably explained by the different thrombus characteristics. Thrombi in symptomatic patients are usually large, occlusive and extend into proximal venous segments, whereas those in asymptomatic patients are small, non-occlusive and often limited to the calf (64, 65). Despite the relatively long examination time, non-invasive color-coded duplex sonography is the first choice examination method with high sensitivity and specificity. Indications for diagnosis in the absence of local symptoms are summarized in the text box: Indications for leg vein diagnosis.


Laboratory diagnostics: hemostaseological parameters
A promising diagnostic parameter is the determination of the D-dimers, a degradation product of fibrin. With the development of fast whole blood assays, D-dimer determination is likely to become an acute diagnostic tool. If the D-dimer level is low, proximal thrombosis can be ruled out with a negative predictive value of 98 percent. The sensitivity of increased concentrations is> 90 percent for proximal thrombosis and 70 percent for distal thrombosis (95).


Laboratory diagnostics: thrombophilia screening
In the case of aetiologically unclear thrombosis, clarification of procoagulant factors is necessary to assess the risk of recurrence and to plan therapy. The understanding of hereditary thrombophilia was significantly improved with the discovery of activated protein C (APC) resistance. The functional parameter "APC resistance" is explained in more than 80 percent of the cases by a single point mutation of the factor V gene (G 1691A), which leads to the destruction of the binding site for APC (factor V suffering) (5) . The result is a lack of inactivation of factor V by activated protein C with a predominance of procoagulatory factors. The mode of inheritance is presumably autosomal dominant. In heterozygous carriers of the mutation, the relative risk of "primary" thrombosis is seven-fold, in homozygous carriers 91-fold (81). Familial thrombophilia is almost 50 percent caused by APC resistance (16, 17). The likelihood of a thrombosis recurrence is four to five times higher if the Leiden mutation is present (82). Furthermore, the factor V mutation is found in 60 percent of pregnancy thromboses. Women who also take oral contraceptives and are carriers of the mutation have a 35-fold increased risk of thrombosis (90). On the basis of the current data situation, we recommend screening for APC resistance:
! Presence of familial thromboses,
! a first-time primary thrombosis, regardless of the age of the patient,
! recurrent thrombosis,
! Pregnancy and puerperium thrombosis,
! planned pregnancy and familial tendency to thrombosis and
! in the case of a planned oral contraception.
Hyperhomocysteinemia (inherited with defective cystathionine beta synthetase, acquired with vitamin B6, B12 and folic acid deficiency) is a new independent venous risk factor (18, 19). Further known procoagulant factors are hereditary antithrombin III, protein C and S deficits with a first thrombotic event between the ages of 20 and 40 and atypical thrombosis localization (sinus, liver and arm veins) and the acquired antiphospholipid antibodies (APL -Ak) associated with recurrent clinical events (venous and arterial thrombosis, multiple abortions, livedo) (28).


therapy
The highest priority in treatment is the inhibition of thrombosis growth, the elimination of the thrombosis with the aim of restitutio ad integrum and the prevention of pulmonary embolism and post-thrombotic syndrome. The treatment strategy is essentially based on:
! Basic measures,
! Immediate intravenous or subcutaneous anticoagulation with heparin, transitioning to oral anticoagulation, which is usually limited in time,
! Thrombolysis in individual cases
! and operative interventions for special indications.


Basic treatment
Although there are no controlled studies on the necessity of immobilization, it is common doctrine to prescribe seven to ten days of bed rest for all patients with multiple or isolated proximal thrombosis (23). Elevating the legs is recommended as this improves the venous return flow significantly. In the case of isolated lower leg vein thrombosis, immobilization is not necessary, provided that compression and anticoagulation are guaranteed, especially for outpatients. According to more recent data, immediate mobilization does not seem to lead to any disadvantage with regard to the recurrence of pulmonary embolisms, even in the case of proximal thrombosis (9, 72, 77). However, no generally binding recommendations should be derived from this until larger controlled studies are available.
Compression therapy is of great importance in the acute treatment of thrombosis. For optimal pressure development, the compression bandages (wraps with short-stretch bandages) must be renewed daily. The mechanisms of action of compression therapy are the avoidance of further thrombus apposition, the fixation of floating thrombus parts, and the acceleration of the venous and lymphatic return flow (15). Contraindications to proper compression treatment are peripheral arterial occlusive disease with ankle artery pressures < 70="" mm="" hg="" und="" die="" seltene="" phlegmasia="" coerulea="" dolens.="" auch="" die="" intermittierende="" pneumatische="" kompressionstherapie="" ist="" im="" stadium="" der="" akuten="" thrombose="" kontraindiziert.="" kompressionsstrümpfe="" sind="" wegen="" des="" initial="" rasch="" abnehmenden="" beinödems="" in="" der="" akutbehandlung="" ungeeignet="" und="" allenfalls="" prophylaktisch="" am="" nichtbetroffenen="" bein="">


Medical therapy
¿Anticoagulation with standard heparin
The anticoagulant of first choice in acute thrombosis therapy is still unfractionated standard heparin (UFH). Adequate anticoagulation within the first 24 hours is of particular importance, since thrombosis recurrences occur in up to 50 percent of patients if the intensity is insufficient (50). This makes it necessary to monitor the anticoagulant effect of the unfractionated heparins and to adjust the heparin dose individually (39). Treatment can be initiated as either continuous intravenous infusion or intermittent subcutaneous injection therapy (46). As long as the partial thromboplastin time (PTT) is in the targeted therapy range (extension of the PTT to 1.5-2.5 times the control value), the effectiveness of both heparin applications is comparable (84). Each treatment with unfractionated heparin is started with an intravenous bolus of 5,000 IU (international unit) (53). It is advisable to initiate therapy as soon as a thrombosis is suspected, but no later than after the diagnosis has been confirmed by an objective procedure, provided there are no manifest contraindications. Symptomatic pulmonary embolisms occur in 0.5 to 1 percent of patients with continuous intravenous heparin infusion, the mortality rate is below 0.5 percent (47). We also see an indication for anticoagulation in the case of lower leg vein thrombosis, which can ascend proximally in 20 percent without therapy (78, 87).
After the bolus administration, continuous intravenous heparin therapy is continued with a maintenance dose of 30,000 to 40,000 IU heparin daily (Table 6) (50). Dose modifications are made with activated partial thromboplastin time (APTT) values
required outside the target area and must be carried out schematically (Table 7) (48). The duration of intravenous anticoagulation can be shortened to five days without loss of safety or effectiveness, provided that oral anticoagulation is initiated within the first 48 hours (47). The advantages are the cost savings through shorter hospital stays and the rarer occurrence of heparin-associated thrombocytopenia type II (3, 56). In patients with a high risk of bleeding (post-traumatic or perioperative), it is advisable to delay the start of oral anticoagulation (47).
According to the publication of several controlled studies, the subcutaneous, weight-adjusted administration of unfractionated heparin is of equal importance to continuous intravenous heparin infusion in acute therapy (Table 6) (43, 46). The advantages of subcutaneous therapy compared to intravenous therapy lie in the simpler application, cost savings, lower rate of bleeding complications and in the outpatient treatment.
À low molecular weight heparins
The excellent bioavailability of the various low molecular weight heparins (LMWH) with a longer half-life allows weight-adjusted dosing with a small number of injections required (1, 35, 49, 75). More recent pharmacodynamic data show that certain LMWH show a sustained, 24-hour anticoagulant effect after one or two injections and that laboratory monitoring can be dispensed with (86). A meta-analysis of 16 randomized studies with various low-molecular-weight heparins such as tinzaparin, enoxaparin, nadroparin and dalteparin shows that it is at least as effective in thrombosis therapy as compared to unfractionated heparin (61).
However, there are clear differences in the frequency of thromboembolic complications and bleeding for the LMWH investigated, so the results of one substance cannot be transferred to other preparations. Important advantages result from the significantly lower incidence of undesirable side effects (Table 8). The imminent approval of certain low molecular weight heparins in Germany opens up the attractive prospect of considerably simplifying acute thrombosis therapy with one or two injections without laboratory controls. Current studies also show that thrombosis therapy at home with LMWH can be just as effective and safe as inpatient therapy with unfractionated heparin (58, 69). It is very likely that selected low molecular weight heparins will replace traditional heparin therapy in the future.
Á Anticoagulation with Markumar
The switch from antithrombotic therapy to coumarins must be carried out overlapping with heparin for at least four to five days. Although the Quick value can already be in a therapeutic range after two to three days, oral vitamin K antagonists only develop their full anticoagulant effect after three to four days, because at the beginning of coumarin treatment, protein C, which is also vitamin K-dependent, is shorter Half-life decreases faster than the coagulation factors. Therefore, the thrombogenic potential initially predominates. 20 percent of patients treated with coumarins alone without accompanying heparinization develop symptomatic thrombosis (10). In addition, the risk of coumarin necrosis increases with the dose at the start of anticoagulation. It is therefore recommended today to slowly creep in the coumarin therapy and to choose an initial dose of phenprocoumon, which is predominantly used in Germany, of 6 to a maximum of 9 milligrams daily. A practical scheme for oral anticoagulation is to start with 2-2-2-2 or 3-3-2 tablets of phenprocoumon for the first four or three days, respectively.
The "international normalized ratio" (INR) is the result of international efforts to determine the degree of anticoagulation independently of the test system used (71). Until the INR system is widely established, the quick and INR values ​​must be specified in parallel for the purposes of medical communication. Anticoagulation of medium intensity with an INR value between 2 and 3 is recommended for the treatment of primary and secondary venous thrombosis for the first time (51), although a much lower intensity seems to be sufficiently effective (4). In the case of recurrent thromboembolism of unknown origin or as a result of a thrombophilia that cannot be influenced (hereditary or acquired), intensified anticoagulation with an INR value between 3 and 4.5 (Quick 20 to 15 percent) is required (70, 78). Although the risk of bleeding increases exponentially with increasing intensity of the anticoagulation, on the other hand the risk of severe bleeding correlates inversely with the duration of the anticoagulation and falls after the first year of anticoagulation from 3 percent per month to 0.3 percent (59).
While significant progress has been made in the question of the optimal intensity, the optimal duration of oral anticoagulation is still the subject of current studies (68, 85). Although controlled studies of sufficient size are lacking, anticoagulation is widespread for three to six months in deep vein thrombosis. The problem of the optimal duration lies in the heterogeneity of the thrombosis in terms of etiology, course, and risk of recurrence (38). Prospective studies show fewer recurrences of thrombosis with reversible and temporary risk factors (perioperative and post-traumatic) compared with idiopathic thrombosis or with permanent risk factors that cannot be influenced (carcinoma, hereditary and acquired thrombophilia) (68, 80, 85). The data from the DURAC study (duration of anticoagulation trial study group) published in 1995 confirm the superiority of six-month therapy compared to six-week coumarin therapy for first-time idiopathic or first-time secondary thrombosis with a permanent risk factor, with a reduction in thrombosis recurrences by almost 50 percent (85). Based on the current data, the previous recommendations on the duration of coumarin therapy should be revised and further differentiated (Table 9) (38, 68, 85).
 Thrombolysis
Only the drug-based thrombolysis leads to a high reperfusion rate, whereby the complete recanalization with preservation of the valve function is presumably decisive for the prevention of the post-thrombotic syndrome. The success rates of fibrinolysis depend to a large extent on the age of the thrombosis and decrease significantly in the case of thromboses more than a week old (34, 83). The course of the post-thrombotic syndrome over a period of ten or more years has only been described in a few prospective studies, with leg ulcers still breaking up in seven percent of successfully fibrinolyzed patients (20, 25). In addition, pulmonary embolism is by no means less common with thrombolysis than with conventional anticoagulation (74). In addition, there is a two to four-fold increased risk of intracranial bleeding during fibrinolytic therapy (67). The lethality of acute phlebothrombosis is given as 0.4 to 1.6 percent under adequate heparin therapy and 1 to 2.4 percent under fibrinolysis (15).
The indication for fibrinolytic therapy can be made elective in:
! Multi-stage thrombosis,
! a presumed age of thrombosis of less than seven to ten days,
! safe exclusion of diseases that make the experience of the post-thrombotic syndrome unlikely and
! Review of all contraindications (Table 10).
It is estimated that if the precautions are strictly observed, at most 10 to 20 percent of patients with proximal thrombosis can be considered for lysis therapy. After extensive consultation, more than 50 percent of patients decide against thrombolysis (12). Whether modifications of the thrombolysis with regard to the duration and dose (ultra-high-dose short-term lysis with streptokinase) (Table 11), the substance used (urokinase, rt-PA, APSAC), the application (locoregional lysis, catheter lysis) and the accompanying measures (temporary cava filter) Improving the benefit / risk ratio is being examined in current studies.


Operative interventions
Despite the favorable early results (62 percent complete, 38 percent partial thrombus removal), the importance of thrombectomy is discussed restrictively, since the surgical venous endothelial injury and incomplete thrombus removal lead in most cases to rethrombosis during the inpatient stay (60, 91). In addition, the incidence of post-thrombotic syndrome does not appear to be lower postoperatively (42). The only accepted indication for surgery is the very rare phlegmasia coerulea dolens. Thrombectomy can be discussed in individual cases in the case of isolated pelvic vein thrombosis that descends to the krosse confluence and in the case of thrombosis of the great saphenous vein ("collar button thrombosis") (Figure 3), but does not constitute a routine treatment (Table 12).
If pulmonary embolism occurs despite adequate or contraindicated anticoagulation, the indication for implantation of a cava umbrella that can be inserted transjugularly is given (29). Alternatively, surgical ligation, plication, or compartmentalization of the inferior vena cava can be used (6).


Therapy of axillary subclavian venous thrombosis
The thrombosis of the axillary vein (Paget-von-Schroetter syndrome) is clinically evident in the triad of forearm, upper arm and shoulder pain, swelling and cyanosis. The causes are often bilateral shoulder girdle compression syndrome, central venous catheters, intravenous infusion of drugs (cytostatics, hypertonic solutions), malignancies, thrombophilic conditions and physical exertion ("par effort"). Complications such as phlegmasia coerulea dolens and ulcers as a result of arm vein thrombosis hardly play a role. The diagnosis is carried out according to the strategies that are also valid for leg vein thrombosis. The therapeutic measures to be applied are based on both the occupation and the age of the respective patient. Symptoms usually resolve within a few days under conservative therapy (short-term immobilization, elevation, compression, and therapeutic heparinization). It is recommended that subsequent coumarin therapy be used for a period of three months. Thrombolysis should only be discussed in exceptional cases (for example in younger athletes with significant stasis). A thrombectomy should not be performed, as in 0.6 percent of the treated cases a possible loss of extremities must be expected (41).


Therapy during pregnancy and the puerperium
Standard heparin is the anticoagulant of choice because it does not cross the placenta and has no harmful effects on the fetus or newborn. The aim is therapeutic heparinization. First, heparin is administered intravenously over five to ten days, later subcutaneously (89). The disadvantage of heparin therapy is the dramatic increase in osteoporosis when more than 20,000 IU of heparin is administered daily for more than five months (36). Since the low molecular weight heparins also do not cross the placenta and are likely to induce significantly less osteoporosis, pregnancy thrombosis will be treated with LMWH in the near future (53). Coumarin derivatives are generally contraindicated in pregnancy because they are teratogenic and, especially when taken in the third to ninth week of pregnancy, can lead to a constellation of symptoms with nasal hypoplasia, microcephaly and calcifications of the epiphyses ("fetal warfarin syndrome") (57). It is controversial whether coumarin therapy should be started postpartum during lactation, since coumarins can be found in breast milk in small amounts. Pregnancy thrombosis should be anticoagulated for at least 6 weeks after the birth or for a total of three months. The puerperium thrombosis is anticoagulated for at least three months (89).


How this article is cited:
Dt Ärztebl 1997; 94: A-301-311
[Issue 6]
The numbers in brackets refer to the bibliography in the special print, to be requested from the author.


Address for the authors:
Prof. Dr. med. Curt Diehm
Dr. med. Frank Stammler
Department of Internal Medicine / Angiology
Karlsbad-Langensteinbach Clinic
Guttmannstrasse 1
76307 Karlsbad

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