Therapeutic target
Prevention of pulmonary embolism (vascular occlusion of pulmonary arteries) and postthrombotic syndrome (chronic venous congestion affecting the lower extremity secondary to deep vein thrombosis)
Therapy recommendations
- Acute therapy according to guidelines: primary at least 5 d with low-molecular-weight heparin (NMH) or fondaparinux (heparin analog) recommended, supplemented by anticoagulation with vitamin K antagonists (VKA, coumarins) as early as possible, starting on day 2 of treatment.
In the EPCAT study, acetylsalicylic acid (ASA) was found to be noninferior to dalteparin in postdischarge thromboprophylaxis (thromboprophylaxis after orthopedic surgery; period within three months after surgery) Taking ASA around 10 pm results in more pronounced platelet inhibition in the cardiovascular critical morning hours.
- Thrombolysis only in:
- Deep leg or pelvic vein thrombosis and risk of impending gangrene.
- Acute arterial occlusion (thromboembolic) and impending limb loss.
- Secondary prophylaxis: coumarins (vitamin K antagonists, VKA); direct oral anticoagulants, DOAK for short.
- Therapy with consideration of secondary indications:
- Vascular recanalization measures: unfractionated heparin (UFH).
- HIT II (heparin-induced thrombocytopenia): argatroban, dabigatran, danaparoid, lepirudin.
- “Thromboprophylaxis in knee arthroscopy and plaster” (see below).
- “Thrombosis prophylaxis in tumor patients” (see below).
- See also under “Further therapy” due tocompression therapy, mobilization and stool regulation.
Note on early mobilization after NMH (low molecular weight heparin).
- Early mobilization of patients with deep vein thrombosis does not increase the risk of pulmonary embolism compared with bed rest!
- Outpatient initiated therapy with NHM reduces the incidence of thrombosis recurrence and pulmonary embolism compared with inpatient therapy.
Duration of oral anticoagulation
| Clinical constellation | Duration | |
| First thromboembolism | ||
| Reversible risk factors | 3 months | |
| Idiopathic or thrombophilia | 6-12 months | |
| Combined thrombophilia (e.g., factor V mutation + prothrombin mutation) or antiphospholid antibody syndrome | 12 months | |
| Chronic diseases leading to thrombophilia | indefinite time | |
| Recurrent thromboembolism | Continuous therapy | |
| Active malignancy | Continuous therapy | |
| Persistent risk factor | Persistent therapy |
“Pro/con” criteria for prolonged maintenance therapy with anticoagulants
| Criterion | Per | Contra |
| Recurrence (recurrence of thrombosis) | Yes | no |
| Bleeding risk | low | high |
| Anticoagulation quality, previous | good | bad |
| Gender | Man | Woman |
| D-dimers (after end of therapy) | ↑ | normal |
| Residual thrombus (residual thrombos) | Present | missing |
| Thrombus localization | proximal | distal |
| Thrombus extension | Long-stretch | short-range |
| Thrombophilia (increased tendency to thrombosis), severe | Yes | no |
| Patient request | For this | against |
Legend
- az. B. Antiphospholipid syndrome (APS; antiphospholipid antibody syndrome).
- bz.B. heterozygous factor V Leiden or heterozygous prothrombin mutation (factor II mutation).
Agents (main indication) for secondary prevention of thromboembolism/pulmonary embolism
Anticoagulation
| Agents | Special features |
| Phenprocoumon(coumarin derivative) | Target: INR 2.0-3.0KI in severe hepatic/renal insufficiency. |
| Apixaban |
Alternative in acute therapy and relapse prophylaxis.
KI creatinine clearance: < 15 ml/min; liver disease with coagulopathy. |
| Dabigatran | KI creatinine clearance: < 30 ml/min; hepatic insufficiency. |
| Edoxaban | KI creatinine clearance: < 30 ml/min; liver disease with coagulopathy (severe liver dysfunction). |
| Rivaroxaban | If appropriate, adjustment for renal insufficiencyKI if creatinine clearance: < 15 ml/min; relevant bleeding risk. |
Note: Patients with antiphospholipid syndrome should not be treated with direct oral anticoagulants (DOAKs). Pharmacologic properties NOAKs/direct oral anticoagulants (DOAKs).
| Apixaban | Dabigatran | Edoxaban | Rivaroxaban | |
| Target | Xa | thrombin IIa | Xa | Xa |
| Application | 2 TD | (1-) 2 TD | 1 TD | 1 (-2) TD |
| Bioavailability [%] | 66 | 7 | 50 | 80 |
| Time to peak level [h] | 3-3,5 | 1,5-3 | 1-3 | 2-4 |
| Half-life [h] | 8-14 | 14-17 | 9-11 | 7-11 |
| Elimination |
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| For renal insufficiency | contraind. Creatinine clearance: < 15 ml/min | contraind. Creatinine clearance: < 30 ml/min | contraind. Creatinine clearance: < 30 ml/min | contraind. Creatinine clearance: < 15 ml/min |
| Interaction | CYP3A4 | strong P-GP inhibitorRifampicin, amiodarone, PP! | CYP3A4 | CYP3A4 inhibitor |
Further notes
- If anticoagulant therapy is discontinued after a thromboembolic first venous event, there is an increased risk of recurrence.
- The WARFASA study and another study demonstrate that acetylsalicylic acid (ASA) also has a relevant effect in preventing venous thromboembolism recurrence (risk reduction in event rate of approximately 33% versus 90% with vitamin K antagonist administration); administration of ASA after discontinuation of oral anticoagulation is an option in the presence of cardiovascular risk factors.
- Therapy recommendations for DOAK in obesity:
- Body weight ≤ 120 kg or a BMI ≤ 40 kg /m2 no dose adjustments.
- BMI > 40 kg /m2 or body weight > 120 kg, VKA (see above) should be used or trough and peak level measurements of DOAK should be taken
- If level measurements fall within the expected ranges, the respective dosage can be left in place.
- If the level measurements are below the expected ranges, a VKA should rather be used.
Active substances (taking into account secondary indications)
Vascular recanalization measures
| Agents | Special features |
| Unfractionated heparin (UFH) | KI in severe renal/liver failure. |
- Mode of action: Inactivation of thrombin, IXa, Xa, XIa, XIIa → antithrombin III (AT-III) must be present.
- Side effects: Bleeding, thrombocytopenia, transaminases ↑, allergic reactions, hair loss, osteoporosis.
HIT II (heparin-induced thrombocytopenia)
| Active ingredient group | Active ingredients | Special features |
| Direct thrombin inhibitor (DTI) | Argatroban | Dose adjustment in renal insufficiencyKI in severe renal insufficiency. |
| Thrombin inhibitor | Dabigatran | Antidote: Idarucizumab can completely abolish the effect of the oral anticoagulant dabigatran within four hours (as measured by diluted thrombin time (dTT) and ecarinic clotting time (ECT)) |
| Thrombin inhibitor | Lepirudin | Dose adjustment in renal/hepatic insufficiency. |
| Heparinoids | Danaparoid | Ant-Xa level controlKI in severe renal/liver failure if alternative therapy available. |
- Renal insufficiencyUnfractionated heparin (UHF; therapy control by PTT! ): see above.
Mode of action
- Heparins
- Heparin-ATIII complex inactivates thrombin, factors Xa, XIIa, XIa, IXa.
- Heparin inhibits platelet function.
- Low molecular weight heparins: selective inhibition of factor Xa.
- Mode of action Argatroban: Direct reversible inhibition of soluble as well as clot-bound thrombin (used in HIT II).
- Mode of action Dabigatran: selective thrombin inhibitor.
- Mode of action Lepirudin: direct thrombin inhibition (used in HIT II).
Thromboprophylaxis in knee arthroscopy and plaster cast
In the POT-KAST and POT-CAST studies, anticoagulation did not result in a decrease in symptomatic venous thromboembolism (VTE).CONCLUSION: “Routine thromboprophylaxis with a standard regimen after knee arthroscopy or plaster immobilization of the lower leg is not effective”.Too low a dose or too short a duration of anticoagulation is discussed for the failure.
Thromboprophylaxis in tumor patients
- Low-molecular-weight heparins should be preferred; new oral anticoagulants should not be used
- Depending on individual risk, outpatients also require thromboprophylaxis
- The risk assessment should be done according to the Khorana score
Khorana score
| Characteristics | Points |
| Tumor localization brain tumor (primary), stomach, pancreas. | 2 |
| Tumor location bladder, testis, lung, kidney, gynecologic tumors, lymphoma | 1 |
| Platelets (before chemotherapy) ≥ 350,000/μl | 1 |
| Hb < 10 g/dL or administration of erythropoiesis-stimulating agents. | 1 |
| BMI ≥ 35 kg/m² | 1 |
Interpretation
- ≥ 3 points – high risk of thromboembolism.
- 1-2 points – medium risk of thromboembolism
- 0 points – low risk of thromboembolism
