DÄ internationalArchive1-2/2008The Treatment of Deep Vein Thrombosis in the Pelvis and Leg

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The Treatment of Deep Vein Thrombosis in the Pelvis and Leg

Dtsch Arztebl Int 2008; 105(1-2): 25-34. DOI: 10.3238/arztebl.2008.0025

Hach-Wunderle, V; Düx, M; Hoffmann, A; Präve, F; Zegelman, M; Hach, W

Introduction: Deep vein thrombosis is associated with a risk of pulmonary embolism and post thrombotic syndrome (PTS).
Methods: Selective literature review with special reference to the American College of Chest Physicians' current guidelines and the German S2 interdisciplinary guideline.
Results and discussion: The most important therapeutic measure is prompt and adequate anticoagulation with heparin or fondaparinux. Thrombolysis or thrombectomy is only indicated in highly selected severe cases. The risk of PTS can be reduced by immediate ongoing treatment with compression stockings. Prevention of relapse is achieved using vitamin K antagonists with a target INR of 2.0 to 3.0. The duration of anticoagulation should be tailored to the localisation and etiology of the thrombosis, from at least 3 months to indefinite treatment. The ongoing risk of bleeding secondary to anticoagulation should be re-evaluated at regular intervals as a cost-benefit analysis. New anticoagulants for acute and long term treatment will soon be available for clinical use.
Dtsch Arztebl Int 2008; 105(1–2): 25–34
DOI: 10.3238/arztebl.2008.0025

Key words: venous thrombosis, anticoagulation, compression stockings, thrombophilia, prevention of recurrence
LNSLNS Deep vein thrombosis is one of the more common illnesses of modern times, with an incidence of 100 to 200 cases per 100 000 persons per year (1, 2). Its correlation with advanced age is particularly noteworthy in view of the aging of the population. The annual incidence of a first venous thromboembolic illness in children up to 15 years of age is low, at fewer than five cases per 100 000 persons per year, but the corresponding figure for persons over age 80 is 450 to 600 cases per 100 000 persons per year (3). The mortality within one month of diagnosis is about 6% for patients with deep vein thrombosis and 12% for patients with pulmonary embolism (3); thus, this disease is of major socioeconomic importance. The major tasks facing the medical profession include improvement in the prophylactic management of patients at risk and the immediate diagnosis and appropriate medical and physical treatment of the condition when it arises.

In this review article, the authors summarize the available study data on the subject and present them in a manner oriented toward everyday medical practice, while also taking the current national and international guidelines into consideration.

Immediate treatment: pharmacotherapy and physical measures
The most important therapeutic step when acute venous thromboembolism has been diagnosed is immediate and adequate anticoagulation (4, 5). In the only randomized study on the subject, published in 1960, it was found that, among a total of 73 patients with symptomatic pulmonary embolism, 53% of the non-anticoagulated patients had recurrent emboli, half of them with a fatal outcome, while there was not a single recurrent embolism among the patients treated with unfractionated heparin and a vitamin K antagonist (6). These findings yielded a "number needed to treat" (NNT) of 3.8 (95% confidence interval 2.2 to 15.3) for the prevention of fatal pulmonary embolism, 4.1 (2.2 to 23.0) for the prevention of non-fatal pulmonary embolism, and 2.0 (1.4 to 3.6) for the prevention of any pulmonary embolism, fatal or non-fatal. This was a breakthrough for the treatment of venous thromboembolic disease with heparin.

Alongside anticoagulation, compression therapy and the maintenance of mobility are also important (5). Today, these can be performed in the outpatient setting in most cases. These measures help prevent pulmonary embolism as well as progression of the thrombosis. Under certain conditions, thrombolysis or thrombectomy can be considered, with the goal of preventing a severe post-thrombotic syndrome by removing the thrombus as completely as possible.

Initial anticoagulation: heparin or fondaparinux
As long as there is no contraindication, anticoagulation should be begun as soon as deep vein thrombosis is suspected, in a therapeutic dose calculated according to the patient's weight. The available drugs include low-molecular-weight heparins (LWMH), unfractionated heparin (UFH), and the pentasaccharide fondaparinux (table 1 gif ppt).

Acute deep vein thrombosis is usually treated with heparin. Unfractionated heparin with a molecular weight from 3000 to 30 000 daltons (average value, 15 000 daltons) and low-molecular-weight heparins with molecular weights ranging from 3000 to 7000 daltons have been approved for this purpose. Heparins form a complex with antithrombin that inhibits coagulation factor Xa and thrombin; the degree of inhibition depends on the molecular weight of the drug and corresponds to a 1:1 ratio with UFH and a 1.5:1 to 4.5:1 ratio with LMWH (diagram 1 gif ppt).

Low-molecular-weight heparins are now the agents of first choice because of their ease of use, high bioavailability, and low complication rate. Many randomized, controlled studies have shown them to be at least as safe, and at least as effective, as unfractionated heparin (7). They are injected subcutaneously in pre-packaged individual doses, adapted according to body weight, either once or twice daily depending on the drug (table 1). No routine checking of their anticoagulant effect is required in most cases, but special attention should be paid to this in patients with an abnormal body weight, pregnant women, or patients with renal insufficiency. In these special situations, the anticoagulant effect is usually monitored with an anti-factor Xa test, which should be performed 3 to 4 hours after subcutaneous injection. If low-molecular-weight heparin is given once daily, the target range for this test is 0.6 to 1.3 IU/mL; if it is given twice daily, the target range is 0.4 to 0.8 IU/mL. As a further safety precaution, the manufacturer's instructions for the use of the drug should be followed. The accumulation of different LMWH preparations in patients with renal insufficiency varies as a function of the preparations' molecular weight (diagram 2 gif ppt).

Unfractionated heparin is given first by bolus injection and then by subcutaneous injection or intravenous infusion in a dose adapted to the patient's weight (table 1). Laboratory testing of the anticoagulant effect, as measured by the activated partial thromboplastin time (APTT), is obligatory; prolongation of the initial value by a factor of 1.5 to 2.5 is the target. Unfractionated heparin does not accumulate to the same extent as low-molecular-weight heparins in patients with renal insufficiency and is therefore preferred for use in such patients.

The pentasaccharide fondaparinux is a good alternative to heparins for the treatment of acute leg vein thrombosis. This substance effects a selective antithrombin-mediated inhibition of factor Xa. In a randomized, controlled trial involving more than 2000 patients with acute deep vein thrombosis, fondaparinux was found to be just as safe and just as effective as the low-molecular-weight heparin enoxaparin (8). The drug is injected subcutaneously once daily in a constant dose adapted to the patient's body weight (table 1). Routine laboratory testing of the anticoagulant effect is not required; an anti-factor Xa test can be used for monitoring in the exceptional situations mentioned above in the paragraph on low-molecular-weight heparins. Fondaparinux should be used with caution in patients with renal insufficiency, because it is eliminated via the kidneys and because its half-life is considerably longer than those of the low-molecular-weight heparins. As fondaparinux is a synthetic product, the danger of a complication resembling type II heparin-induced thrombocytopenia (HIT) is considered to be minimal, but not entirely excluded (9).

The platelet count should be measured before or at the start of anticoagulation (baseline value) and again at some point from day 5 to day 7. If heparin is to be given for a long time, the platelet count should continue to be checked regularly (e.g. twice a week) until the end of the third week of treatment. If the platelet count should drop to half its baseline value or less, the patient may be suffering from type II HIT, with potentially lethal thrombotic complications.

As soon as type II HIT is suspected, heparin should be discontinued immediately and replaced with another anticoagulant (e.g. lepirudin [a type of hirudin], argatroban, danaparoid) (10). Type II HIT has been
found to be associated with the molecular weight of the heparin preparation used: it occurs much less often with low-molecular-weight heparin than with unfractionated heparin (11).

Invasive treatments: thrombolysis and thrombectomy
Thrombus-eliminating measures, i.e., thrombolysis and thrombectomy, are performed with the goal of preventing severe post-thrombotic damage of the venous system. No randomized, controlled studies are yet available on the possible additional benefit of these methods over anticoagulation alone; therefore, the indication for either of them is to be viewed critically (5). Catheter-guided thrombolysis may soon bring about a shift in the therapeutic paradigm. At present, there are established dosage schemes for systemic thrombolysis with streptokinase and urokinase in both conventional and ultra-high doses. The drug is administered by intravenous infusion over one or more days, with daily monitoring of coagulation status and ultrasonographic imaging of the thrombosis. The treatment-related morbidity and mortality are considerably higher than those of anticoagulation alone, mainly because of the increased risk of hemorrhage: the risk of major hemorrhage is up to 15%, with an intracranial hemorrhage risk of 1.5% and a fatal hemorrhage risk of 1% (12). Furthermore, the treatment is performed successfully in a relatively small number of cases, as only about one third of patients have a totally recanalized venous system afterward. Systemic thrombolysis, therefore, is considered only in exceptional cases, e.g., young patients (<50 years old) with a fresh (< 7 days) and extensive thrombosis (involving, e.g, the calf, thigh, and pelvic veins). Recent study results are encouraging for the use of catheter-guided thrombolysis: in a small, randomized study with streptokinase, as well as in a number of observational studies with various different thrombolytic agents (13), the technique was found to be markedly superior to anticoagulation alone, with respect to both the acute success of treatment and the long-term recanalization rate 6 or 12 months afterward. The current data suggest that the patients who stand to benefit the most from this procedure are those with an acute thrombosis of the iliofemoral veins, rather than those with an occlusion of the femoro-popliteal circulation. The rate of major hemorrhage varies widely from study to study, ranging from 0% to 13%. Larger, randomized, controlled studies are needed to determine the place of this technique in the overall therapeutic strategy for acute deep vein thrombosis.

In the past, thrombectomy was often performed in cases of acute pelvic vein thrombosis. It was found, however, that this approach provided no clear advantage over anticoagulation alone with respect to the prevention of a post-thrombotic syndrome. In any case, there are still no randomized, controlled studies directly comparing the two treatment measures. The current state of knowledge implies that thrombectomy should only be considered in special situations, such as the following:

- in descending thrombosis, with simultaneous surgical elimination of the source of external venous compression preventing flow,
- in phlebitis of the great or small saphenous vein with a thrombus protruding into the deep vein, or
- in the rare entity of phlegmasia cerulea dolens, with impending gangrene of the leg (14).

A floating thrombus is not an indication for surgery.

Compression and active ambulatory exercise therapy
Position-dependent pain and swelling are among the typical manifestations of severe deep vein thrombosis in the leg. These problems regress within a few days after the application of compression dressings with short- or middle-stretch bandages. A compression stocking is used if the thrombosis does not cause severe pain (or no longer causes severe pain) and is not associated with marked swelling. As a rule, a class II stocking with 23 to 32 mmHg of pressure at the heel is used. The length of the stocking is usually initially determined by the site of the thrombosis: a stocking up to the groin (length A–G) is used in cases of thigh or pelvic vein thrombosis, a stocking up to the knee (length A–D) in cases of calf vein thrombosis. A calf compression stocking (A–D) usually suffices for long-term treatment in most cases regardless of the original site of the thrombosis.

A post-thrombotic syndrome (PTS) of greater or lesser severity develops after 20% to 50% of cases of deep vein thrombosis of the leg. PTS can be treated or prevented with appropriate compression therapy. In two randomized trials, the immediate and consistent wearing of a calf-compression stocking in acute deep vein thrombosis of the leg (independently of the site of thrombosis) was found to yield significantly better results after two years of follow-up than treatment without compression. The incidence of severe post-thrombotic changes was reduced to 11% at five years, compared to 23% without compression, in the trial by Brandjes et al. (15) and to 3% at two years, compared to 11% without compression, in the trial by Prandoni et al. (16). If compression therapy is not begun until one year after the acute thrombosis, it has no advantage over treatment without compression with regard to the prevention of post-thrombotic syndrome (17). The duration of compression is based on the findings of phlebological follow-up examinations. If venous dysfunction persists, with a tendency toward edema, then continuing compression is recommended; otherwise, the current data suggest that compression can be discontinued after a maximum of two years.

Active exercise therapy in patients with acute venous thrombosis, performed simultaneously with compression therapy and adequate anticoagulation, has a beneficial effect on pain and swelling in the affected limb. The patient is instructed to perform walking exercises several times a day, until the point that these become painful. Conversely, strict bed rest is a major risk factor for the development and progression of thrombosis. Among 357 patients who were put to bed rest for five days while being anticoagulated with heparin, 26% developed phlebographically confirmed progression of their deep vein thrombosis, compared to only 1% of patients put to bed rest for one to two days (18). Immobilization should accordingly be limited to cases where it is absolutely necessary, e.g., certain traumatic injuries and postoperative situations, and severe systemic illnesses. Early mobilization in bed, e.g., with breathing exercises, active physical therapy, and a "bed bicycle," would seem to be advisable in parallel with anticoagulation.

Over the past decade, ambulatory treatment for deep vein thrombosis has become increasingly popular. This was possible only after clinical trials revealed that anticoagulation by the subcutaneous injection of low-molecular-weight heparin at home is just as safe and just as effective as the intravenous infusion of unfractionated heparin in the hospital (19, 20).
Later randomized, controlled studies showed that bed rest does not prevent symptomatic pulmonary embolism (21, 22). A further study documented the benefit of immediate compression treatment with respect to regression of symptoms (23) and thereby provided the breakthrough for ambulatory treatment of deep vein thrombosis of the leg and pelvis. Today, 80% to 90% of all patients with acute deep vein thrombosis qualify for ambulatory treatment.

The prerequisites for ambulatory treatment are the following:

- After a thorough explanation of this form of treatment, the patient must give informed consent and be compliant with the proposed treatment.
- The patient should have neither a bleeding tendency nor any serious accompanying illnesses.
- The treatment center should have a large experience in treating this condition and a physician must be available around the clock.
- The type of thrombosis (e.g. floating thrombus) and its localization (e.g. pelvic vein thrombosis) are of secondary importance for the decision to treat in the outpatient setting.

A brief period of inpatient observation may, however, be justified if there is a fear that complications might develop that would be difficult to control out of the hospital, e.g., fulminant pulmonary embolism.

Inferior vena cava filters
Interruption of blood flow in the inferior vena cava with various filter systems has been used for more than 30 years to reduce the risk of pulmonary embolism in patients with proximal deep vein thrombosis of the leg. In a randomized, controlled trial, the insertion of an inferior vena cava filter in addition to standard anticoagulation was found to reduce the frequency of both early and late pulmonary emboli (< 12 days and within 8 years, respectively) to a significant extent, but not to reduce mortality, and the number of subsequent leg vein thromboses was significantly higher after filter implantation (24). Therefore, the current indication for the implantation of an inferior vena cava filter is a high risk of pulmonary embolism in a patient for whom anticoagulation is contraindicated, or else recurrent pulmonary embolism despite adequate anticoagulation.

Transient inferior vena cava filters can be used instead of permanent ones, but there are still no studies that clearly demonstrate their benefit.

Long-term therapeutic anticoagulation
The necessity of pharmacological long-term anticoagulation after acute deep vein thrombosis is evident from the results of randomized clinical trials. These trials have revealed the following:

- In patients with distal deep vein thrombosis, the therapeutic administration of unfractionated heparin for only a few days was associated with progression or recurrence of the thrombosis in 20% of cases (25).
- Long-term prophylactic administration of unfractionated heparin instead of anticoagulation led to a 47% recurrence rate (e1).
- Oral anticoagulation for a short time (six weeks) was associated with significantly more symptomatic recurrences than an oral anticoagulation for a long time (six months): the recurrence rates were 9.5% and 0.4%, respectively (e2).

Vitamin K antagonists (VKA) are the drugs of choice for the prevention of recurrent thromboses. In selected patients, low-molecular-weight heparins can also be used, primarily in patients with cancer or in those for whom vitamin K antagonists are contraindicated.

Standard medication: vitamin K antagonists
As long as no invasive diagnostic or therapeutic measures are planned and there are no other contraindications, secondary prophylaxis with a vitamin K antagonist is begun immediately after the diagnosis of deep vein thrombosis between day 1 and day 3. Heparin or fondaparinux is given simultaneously in a dose adapted to the patient's body weight and discontinued only when the effectiveness of anticoagulation with the vitamin K antagonist is stable within the desired target range. Usually, an International Normalized Ratio (INR) above 2.0 for two to three days is desired before heparin or fondaparinux is discontinued. The phase of parallel anticoagulation with two anticoagulant substances usually lasts five to seven days. Anticoagulation with a vitamin K antagonist alone without accompanying heparinization is dangerous and contraindicated, because it takes hours or days for the antithrombotic protective action to set in as the levels of the vitamin-K-dependent coagulation factors slowly drop.

In Germany, the most commonly used vitamin K antagonist is phenprocoumone (half-life 105 to 144 hours), while warfarin (half-life 36 to 42 hours) is most commonly used in the English-speaking countries. If the patient is to undergo invasive procedures in the foreseeable future that will require a switch to intravenous anticoagulation, warfarin should be used in preference to phenprocoumone because of its shorter half-life. The therapeutic range of the INR for both drugs is 2.0 to 3.0.

The duration of anticoagulation with vitamin K
antagonists should be chosen in consideration of the patient's individual risk of recurrent thrombosis on the one hand and of hemorrhage on the other. After a first thrombosis, anticoagulation is maintained for 3 to 12 months at a conventional dose (INR 2.0 to 3.0) (table 2 gif ppt [4]). Any continuation of anticoagulation beyond this time is done on an individual basis.

High risk of recurrence
Potential indications for indefinitely continued anticoagulation include active malignant disease, recurrent thromboembolism, and certain thrombophilic diatheses in the presence of a thromboembolic event that has already occurred (4). After a first idiopathic thrombosis, anticoagulation is usually given for at least 6 to 12 months, and indefinitely in some cases. Long-term anticoagulation should always be considered when one or more permanent risk factors are present, such as certain thrombophilic coagulation disorders, post-thrombotic residual changes in the veins, and persistent elevation of the D-dimer concentration in the blood. In terms of a risk/benefit analysis, it can be assumed that patients with an idiopathic thrombosis and a permanent risk factor stand to benefit more from permanent anticoagulation than those with a secondary ("triggered") thrombosis.

Permanent risk factors
There are hardly any validated methods in the literature for determining the degree of severity of a clotting diathesis. The authors consider the following situations to pose a high risk of thrombosis: congenital antithrombin or protein C deficiency, a homozygous factor V mutation, persistent antiphospholipid syndrome, and certain combined defects, e.g., a heterozygous factor V mutation together with a heterozygous prothrombin mutation. Patients with post-thrombotic residual changes in the venous circulation are presumed to have a two- to three-fold elevation of the risk of recurrence compared to patients with a normal venous status, regardless of whether the initial thrombosis was idiopathic or triggered (e3). Persistent elevation of the D-dimer concentration in the blood after at least three months of oral anticoagulation for a first thrombosis is also associated with an elevated risk of recurrent thrombosis (e4, e5).

Low risk of recurrence
The risk of recurrence is considered to be low in cases of secondary thrombosis triggered by a transient risk factor such as surgery or trauma. Anticoagulation is usually given only for three months in such cases.

Heterozygous mutations of factor V and prothrombin are among the more common thrombophilic coagulopathies. In the authors' view, and according to the relevant literature, the presence of one of these defects does not affect the decision to provide anticoagulation for a longer period after an initial thrombosis (4, 5, e6) (table 2 gif ppt).

The risk of hemorrhage
If anticoagulation is to be given for an indefinite period of time, then the risk of recurrent thrombosis should be weighed against the risk of hemorrhage in yearly intervals. The risk of hemorrhage under treatment with vitamin K antagonists is affected by individual factors including comorbidity and medications as well as by the age of the patient. It is also a function of the duration and intensity of anticoagulation. In randomized trials, the incidence of severe hemorrhage under conventionally dosed oral anticoagulation (INR 2.0 to 3.0) was significantly lower in the first three months of treatment (0.4 events per 100 patient-years) than after treatment for 12 months or more (1.5 events per 100 patient-years) (13).

In view of these findings, one should consider lowering the intensity of anticoagulation (to a target INR of 1.5 to 2.0) in certain patients for whom long-term anticoagulation is indicated but who also have an elevated risk of hemorrhage (e7). If this is done, the risk of hemorrhage will be lowered, but at the cost of a higher risk of recurrent thrombosis (13).

Alternative medical treatment: low-molecular-weight heparins instead of vitamin K antagonists
If oral anticoagulation is contraindicated or inadequate, low-molecular-weight heparins are the next alternative to be considered. Patients for whom this is a relevant consideration include those with a high risk of hemorrhage (such as patients with gastrointestinal ulcers) or those who have already sustained a severe hemorrhage (e.g. retroperitoneal or intracranial), as well as those who are especially at risk for recurrent thrombosis, such as cancer patients. Moreover, patients for whom oral anticoagulation is difficult to monitor, or whose compliance with oral anticoagulation is inadequate, may benefit from a switch to a low-molecular-weight heparin. Treatment with low-molecular-weight heparins can be given from the start even if it can be foreseen that the anticoagulation will have to be interrupted multiple times for planned invasive procedures (for more information on the bridging of anticoagulation for invasive procedures, see reference [e8]).

Various types of low-molecular-weight heparin
have been found to be just as effective as vitamin K antagonists with respect to the prevention of recurrent thrombosis, while having a comparable or lower rate of hemorrhagic complications (4, 13). This is particularly true when a full therapeutic dose of low-molecular-weight heparin is used, but also when half of the therapeutic dose is given. A prophylactic dose can be considered for patients with an elevated risk of hemorrhage.

Cancer patients with thromboembolic disease, in particular, stand to benefit from treatment with low-molecular-weight heparins rather than vitamin K antagonists. The trial of Lee et al., which involved the largest number of patients, revealed that treatment with the low-molecular-weight heparin dalteparin for one month at the full therapeutic dose, and then for five months at three-quarters of the therapeutic dose, was superior with respect to the rate of recurrent thromboses and did not elevate the risk of hemorrhage or death (e9). The demonstration that anticoagulation with various low-molecular-weight heparins is more effective than anticoagulation with vitamin K antagonists in cancer patients led to a recommendation that low-molecular-weight heparins should be given for at least three to six months in acute deep vein thrombosis (4).

Future medications: new substances
New anticoagulant substances are currently being evaluated for use in acute and long-term therapy for deep vein thrombosis (diagram 1). New types of factor Xa inhibitor include idraparinux (given subcutaneously once per week), rivaroxaban (p.o.), and apixaban (p.o.). Thrombin inhibition is the mechanism of action of dabigatran (p.o.). These substances are under study in large-scale clinical trials (e10).

Conclusion
The treatment of deep vein thrombosis in the leg and pelvis has undergone a radical transformation in the past decade, mainly because of the development of new anticoagulant drugs. Continuing research in the field will probably soon yield new knowledge with immediate therapeutic implications.


Conflict of interest statement
Professor Hach-Wunderle received lecture honoraria and consulting fees from Sanofi-Aventis and GlaxoSmithKline as well as financial support from Medi Bayreuth, Juzo, and Sanofi-Aventis. Dr. Präve received lecture honoraria from Sanofi-Aventis and GlaxoSmithKline. The remaining authors state that they have no conflict of interest as defined by the guidelines of the International Committee of Medical Journal Editors.

Manuscript received on 31 August 2007; revised version accepted on
5 November 2007.

Translated from the original German by Ethan Taub, M.D.


Corresponding author
Prof. Dr. med. Viola Hach-Wunderle
Krankenhaus Nordwest
Gefäßzentrum – Sektion Angiologie
Steinbacher Hohl 2–26
60488 Frankfurt am Main, Germany
Hach-Wunderle@t-online.de



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Kreis M: The Differential Diagnosis of Right Lower Quadrant Pain: 1/d, 2/d, 3/c, 4/a, 5/c, 6/c, 7/d, 8/e, 9/c, 10/c
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Haas S, Schellong S: New anticoagulants. From bench to bedside. Hämostaseologie 2007; 1: 41–7. MEDLINE
Gefäßzentrum am Krankenhaus Nordwest, Frankfurt a. M.:
Prof. Dr. med. Hach-Wunderle, Prof. Dr. med. Düx, Prof. Dr. med. Zegelman
Praxis für Innere Medizin und Gefäßkrankheiten, Frankfurt a. M.:
Prof. Dr. med. Hach-Wunderle, Anja Hoffmann, Dr. med. Präve,
Prof. Dr. med. Hach
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e8. Bauersachs RM, Schellong S, Haas S et al.: Überbrückung der oralen Antikoagulation bei interventionellen Eingriffen. Dtsch Arztebl 2007; 104(18): A1237–44. VOLLTEXT
e9. Lee AYY, Levine MN, Baker RI et al.: Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003; 349: 146–53. MEDLINE
e10. Haas S, Schellong S: New anticoagulants. From bench to bedside. Hämostaseologie 2007; 1: 41–7. MEDLINE