[Modern treatment of deep vein thrombosis and pulmonary embolism]. / Moderne Therapie tiefer Venenthrombosen und der Lungenarterienembolie.

Virchow's triad has been known for a 100 years. The development of therapeutic possibilities during this time was enormous. Today anticoagulant therapy is much more differentiated. Four new oral substances have replaced the traditional treatment with vitamin K antagonists in angiology. A standardized dosage is available. The monitoring of the coagulation parameters is no longer necessary, but it is important to monitor renal function. Direct oral anticoagulants are approved for the treatment of venous thrombosis and pulmonary embolism, but not during pregnancy or in children. Severe bleeding complications, especially intracerebral bleeding, are less common. The incidence of venous thromboembolism is still high. Obesity and cancer are of particular importance. The "therapeutic pact" with the patient requires that physicians master the art of "talking medicine".

Low incidence of heparin-induced skin lesions in orthopedic surgery patients with low-molecular-weight heparins.

BACKGROUND: Heparins are widely prescribed for prevention and therapy of arterial and venous thromboembolic diseases. Heparin-induced skin lesions are the most frequent adverse effect of subcutaneous heparin treatment in non-surgical patients (7.5%-39.8%); no data exist on surgical patients. Commonly, they are due to a delayed-type hypersensitivity reaction (DTH), but may also be a manifestation of life-threatening heparin-induced thrombocytopenia (HIT). Lesions of both entities resemble initially. The risk of HIT is highest among heparin-anticoagulated orthopedic surgery patients. OBJECTIVE: To determine incidence and causes of heparin-induced skin lesions in major orthopedic surgery patients. METHODS: In a prospective cohort study, consecutive patients with subcutaneous low-molecular-weight heparin (LMWH) treatment were examined for cutaneous adverse effects. Further diagnostics (skin biopsy, clinical/laboratory assessment for thrombosis, bleeding, HIT, cross-allergies) were performed. RESULTS: Six of 316 enrolled patients (1.9%; 95% CI: 0.4%-3.4%) developed heparin-induced skin lesions. All were caused by a DTH reaction, and none was due to HIT or other rare heparin-associated skin diseases. Therapeutic use (dosage) of LMWH was identified as only risk factor (odds ratio: 3.1, 95% CI: 1.4-4.9; P = .00141). In addition to DTH, 5 thromboembolic, 4 major bleeding complications but no cases of HIT or cross-allergies were observed. CONCLUSIONS AND CLINICAL RELEVANCE: Orthopedic surgery patients have-unlike non-surgical patients-a low risk for heparin-induced skin lesions during LMWH treatment; all lesions were due to a DTH reaction. The risk for DTH differs considerably between individual patient cohorts. No association with HIT was observed. These data help to tailor anticoagulatory treatment individually and to increase patient safety.

A multicenter study to assess the reproducibility of antiphospholipid antibody results produced by an automated system.

Essentials Inter-lab variation studies for antiphospholipid antibodies (aPL) with the same assay are lacking. We carried out an assessment of repeatability and reproducibility of an automated aPL assay. High intra-center repeatability for anticardiolipin and aß2 GPI makes duplicate testing unnecessary. Inter-lab reproducibility was high except for aß2GPI IgG. SUMMARY: Background Inter-assay variability is a well-known problem in antiphospholipid antibody testing, because of the lack of standardization. Inter-laboratory reproducibility for the same assay is similarly important. Objectives Testing repeatability and reproducibility of HemosIL® AcuStar for anticardiolipin (aCL) and antiß2-glycoprotein I antibodies (aß2GPI) IgG and IgM. Patients/Methods In this observational study, out of 420 samples from the thrombophilia centers of Ghent and Geneva, 100 samples were randomly selected and successively analyzed in three centers: Ghent (C1, in duplicate for repeatability evaluation), Geneva (C2) and Frankfurt (C3). Results Results from 99 samples were available, including 25 from patients with antiphospholipid syndrome (APS) and 74 from non-APS patients. The intra-center repeatability expressed as intra-class correlation coefficient (ICC) was higher than 0.99 for each parameter. Differences between two measurements rarely exceeded 1 U mL-1 for values below 100 U mL-1 , except for aß2GPI IgG, where differences varied from -4 to 4 U mL-1 . The inter-center ICCs were higher than 0.99, except for aCL IgM (ICC = 0.961). These ICCs remained high even when considering values below 100 U mL-1 (0.943, 0.964 and 0.977 for aCL IgG, aCL gM and aß2GPI IgM, respectively), except for aß2GPI IgG (ICC = 0.652). Qualitative comparison showed less than 5% discordant classification between centers, with somewhat more discordant results for aß2GPI IgG. Conclusions In terms of discriminating properties, the HemosIL® AcuStar has excellent intra-center repeatability and a good inter-center reproducibility for aCL IgG, aCL IgM and aß2GPI IgM. Some concern may arise for aß2GPI IgG.

Screening for lupus anticoagulants in patients treated with vitamin K antagonists.

INTRODUCTION: The dRVVT test for detecting lupus anticoagulants (LA) is difficult to interpret when patients are treated with vitamin K antagonists (VKA). METHODS: We performed LA testing in 33 VKA-treated patients with definite antiphospholipid syndrome (APS) and compared the results with 100 controls subjects not receiving VKA and 110 APL-negative patients anticoagulated for reasons other than APS. RESULTS: Compared with the dRVVT ratio before the initiation of VKA therapy, a higher cutoff value, defined as the 99th percentile, was established for VKA-treated patients with INR values between 2.0 and 3.5. A dRVVT ratio of >1.7 yielded a sensitivity of 81.3%, specificity of 99.1%, and positive and negative predictive values of 98.7% and 85.8%, respectively, for detecting LA. Cohen's kappa coefficient indicated good agreement for the dRVVT ratio obtained from testing with and without VKA treatment (κ = 0.813; 95% CI: 0.773-0.853), which was higher (κ = 0.941; 95% CI: 0.917-0.965) when the LA diagnosis was based on the results of both the dRVVT and a second test system (i.e., Mixcon-LA assay). CONCLUSIONS: Lupus anticoagulants testing in VKA-treated patients with APS according to current guidelines appears to be possible for the majority of patients without discontinuing anticoagulant therapy.

Refinement of the cutoff values of the HemosIL AcuStar assay for the detection of anticardiolipin and anti-beta2 glycoprotein-1 antibodies.

BACKGROUND: The HemosIL AcuStar antiphospholipid assay (Instrumentation Laboratory, Bedford, MA, USA) is a fully automated assay using chemiluminescent technology for the detection of anticardiolipin and anti-beta2 glycoprotein-1 antibodies. This assay showed excellent agreement between results of different laboratories. The cutoff values to define positivity were calculated in 250 healthy blood bank donors but were associated with large confidence intervals (CIs). OBJECTIVE: The objective of this study was to more precisely determine the cutoff values of the HemosIL AcuStar antiphospholipid assay by increasing the number of healthy blood bank donors through a multicenter study and by applying a normalization procedure of the distribution of each antibody. METHODS: Five laboratories participated to this study, allowing the inclusion of 626 samples. We used a Box-Cox power transformation method to normalize the distribution and calculate the 99th percentile and the corresponding 95%CI for each antibody. RESULTS: The revised cutoff values were overall lower than those initially calculated with more stringent CIs and yielded a 4.2% increase in sensitivity with a 2.7% decrease in specificity regarding thrombotic events or obstetric complications. CONCLUSIONS: We provide refined cutoff values for the detection of anticardiolipin and anti-beta2 glycoprotein-1 antibodies with the HemosIL AcuStar Antiphospholipid assay that should be preferred for routine use.

[Incidental finding of pathological coagulation parameters]. / Zufallsbefund pathologischer Gerinnungsparameter.

Pathological coagulation parameters may reflect life-threatening hemorrhagic or thromboembolic diseases but may also be a laboratory result without any clinical significance, result from in vitro phenomena or preanalytical errors. This article gives an overview of potential pitfalls in coagulation diagnostics, lists the differential diagnoses of pathological coagulation parameters and describes further steps in the diagnostic approach to clarify pathological results. The focus lies on coagulation parameters that are frequently determined in routine clinical investigations, e.g. platelet count, prothrombin time, activated partial thromboplastin time (aPTT) and fibrinogen. Besides heparin, fondaparinux, danaparoid, and vitamin K antagonists, direct factor Xa inhibitors and direct thrombin inhibitors are nowadays available for therapeutic anticoagulation. This article gives an overview of the influence of anticoagulants on coagulation parameters which depends on the dose, the time of the last administration, as well as the method used for the determination of coagulation parameters. Moreover, common reasons for elevation of the fibrin degradation product D-dimer are presented. The clinical utility of D-dimer assays is limited by their poor specificity. Elevated D-dimer concentrations can be found in various diseases and also under normal physiological circumstances (e.g. in the elderly). Thus, the most useful clinical application of D-dimer is evidence of normal values to essentially rule out venous thromboembolism.

[Management of catheter-related upper extremity deep vein thrombosis]. / Management bei katheterassoziierter Armvenenthrombose.

Central venous catheters (CVCs) are important tools in the care of patients with acute or chronic diseases, but catheter-related thrombosis and thrombotic occlusions are frequent complications, especially if CVCs are implanted for long-term use. In this review we focus on the management of these complications. Risk factors for catheter-related thrombosis include dislocation of the catheter tip, the presence of malignant disease and hypercoagulability. Catheter-related thrombosis is associated with catheter infection, pulmonary embolism and post-thrombotic syndrome. Catheter-related thromboses which most frequently involve the subclavian vein are usually diagnosed by duplex ultrasound examination and treated with anticoagulation therapy for a minimum of three months or longer if the catheter is left in place. Prevention of catheter-related thrombotic complications includes proper positioning of the CVC with the catheter tip lying in the proximal superior vena cava and regular flushing of the catheter with saline solution or unfractionated heparin. The use of anticoagulants for primary prevention is currently not recommended.

[Risk of bleeding and haemorrhagic complication with rivaroxaban--periprocedural management of haemostasis]. / Blutungsrisiko und Blutungsnotfälle unter Rivaroxaban. Periinterventionelles Hämostasemanagement.

UNLABELLED: Rivaroxaban, the first direct factor-Xa inhibitor anticoagulant, has been approved for the prevention of venous thromboembolism in adult patients undergoing elective hip or knee replacement surgery, for stroke prophylaxis in patients with non-valvular atrial fibrillation and for the treatment of deep vein thrombosis. There is no requirement for coagulation monitoring with rivaroxaban in routine clinical practice. However, in certain clinical circumstances such as life-threatening bleeding or an emergency operation the measurement of the thromboplastin time with a sensitive reagent will deliver first information. A quantitative determination of rivaroxaban plasma concentration is possible using an anti-factor Xa assay. In the case of a patient under long-term anticoagulation with rivaroxaban requiring an elective surgery, a discontinuation of rivaroxaban 20 to 30 hours before the operation is sufficient to normalize the associated bleeding risk, as long as the renal and liver function is normal. A longer interval should be taken into consideration, when the patient presents a renal and liver impairment or is of a higher age. In the event of an emergency operation effective rivaroxaban concentrations might be present. Nevertheless, we advise against using a prophylactic dose of factor concentrates. RECOMMENDATIONS: From a clinical perspective, in the event of a minor bleeding we recommend a temporary discontinuation of rivaroxaban, whereas for clinically relevant major or severe bleeding events a mechanical compression or a limited surgical i.e. interventional treatment is required. Supportive measures such as the administration of blood products or tranexamic acid might be beneficial. In addition to haemodynamic supportive measures life threatening bleeding events demand a comprehensive haemostasis management, as well as the application of PCC.

[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 aspects of paradoxical embolism.

Paradoxical emboli have their origin in the low-pressure venous system and can cause ischemic stroke or peripheral arterial embolism through a cardiac or pulmonary shunt. In most cases, a patent foramen ovale (PFO) is found. About 20 % of the population has a patent foramen ovale. This review gives insight into publications concerning the association between the presence of a patent foramen ovale and cryptogenic stroke; the association of PFO, coagulation disorders and stroke; and recurrence rates of stroke in patients with PFO. Diagnostic features are discussed, as are the different therapy modalities, taking existing national and international guidelines into account. Also, our own recommendations are given. In addition some new information on the potential improvement of migraine after PFO closure is discussed. It is widely accepted that the optimal therapy for the prevention of recurrent stroke in patients with PFO and cryptogenic stroke has not yet been found. Randomized, controlled clinical studies are ongoing in the United States and will give even more insight and answer open questions in the future.

[Risk assessment of recurrence of venous thromboembolism]. / Bewertung des Rezidivthromboserisikos venöser Thromboembolien.

Recurrent venous thromboembolism is associated with increased mortality in 5-9% of the patients. On the other hand prolonged anticoagulation can increase the bleeding risk which can also be responsible for an increased mortality. Therefore, it is necessary to validate the recurrence risk of venous thromboembolism on an individual basis. In this review the most relevant risk factors for recurrent venous thromboembolism are analyzed. Spontaneous thrombosis is associated with significantly increased recurrence rates in comparison to risk associated venous thrombosis. In addition, a positive D-dimer result after stop of anticoagulation, an increased amount of residual thrombus in proximal veins analyzed by compression sonography, a proximal localization of thrombosis, symptomatic pulmonary embolism and male sex are clinically relevant risk factors for increased recurrence rates. While mild thrombophilic defects like heterozygous factor V Leiden mutation are not associated with a clinically relevant recurrence risk, inherited inhibitor deficiencies and the antiphospholipid-syndrome are known to be responsible for an increased recurrence rate of venous thromboembolism. A new recurrence risk-score (RR-Score) for individual judgement of patients with a first spontaneous venous thrombosis is introduced.

[Progress in diagnostic evaluation of platelet function disorders]. / Fortschritte in der Thrombozytenfunktionsdiagnostik.

Both for diagnosis of congenital and acquired platelet dysfunction as well as for therapy monitoring after application of platelet function inhibitors various methods have been established for evaluation of platelet function. In contrast to the gold standard of platelet function testing, the light transmission aggregometry in platelet rich plasma the Point-of-care (POC) analyzers allow fast analysis of platelet function without extensive laboratory work up. The conditions of the pre-analytical phase, however, are still of enormous importance in the prevention of medical errors. There is increasing clinical data in monitoring the effect of platelet aggregation inhibitors, showing that quantitative determination of the platelet function degree correlates with risk of increased bleeding or stent thrombosis. However, it is still unclear, which is the optimal test system, to predict the clinical outcome of these patients.

Comparison of the fibrinogen Clauss assay and the fibrinogen PT derived method in patients with dysfibrinogenemia.

UNLABELLED: Fibrinogen assays are an important screening tool for blood coagulation disorders. Although different methods are available, no consensus has been reached as to which method is preferable. In 27 patients with dysfibrinogenemia, plasma fibrinogen concentration was measured by Clauss and PT-derived methods on two fully automated coagulation analyzers utilizing different reagents. In addition, immunological and heat fibrinogen concentrations as well as global coagulation tests were measured. RESULTS: The median fibrinogen determined by the Clauss assay was 0.40 g/l, with a range of 0.30-2.07 g/l (normal range: 2.67-4.37 g/l) and 0.60 g/l, with a range of 0.60-2.20 g/l (normal range: 1.5-4.5 g/l) using two different reagents. The median fibrinogen determined by the PT-derived method was 2.41 g/l, with a range of 0.97-4.87 g/l (normal range: 1.84-4.8 g/l) and 2.64 g/l, ranging from 1.38 to 4.39 g/l (normal range: 2.0-4.0 g/l) by the use of two different reagents. No correlation was found when comparing both methods using two reagents from different manufacturers. The PT-derived method "overestimated" the fibrinogen by approximately five times the value measured by the Clauss assay. While fibrinogen measured by the PT-derived method correlated with fibrinogen antigen concentrations measured by the immunological fibrinogen (p<0.002) or heat fibrinogen method (p<0.002), fibrinogen measured by the Clauss method correlated with functional coagulation parameters, such as Reptilase Time (p<0.002), Thrombin Time (p<0.002) or Prothrombin Time (p<0.02). CONCLUSION: Although many patients with dysfibinogenemia are asymptomatic, in case of bleeding, immediately diagnosis and treatment is warranted. The Clauss assay is the diagnostic tool of choice when diagnosing or treating patients with low fibrinogen levels. The use of the PT-derived method may potentially pose a greater risk to patients, as the plasma concentration may be erroneously reported as normal.

[Significance of platelet function tests]. / Stellenwert der Thrombozytenfunktionsdiagnostik.

Numerous laboratory tests are in use to detect congenital or acquired platelet function disorders. Platelet aggregometry, using ADP, collagen, arachidonic acid or ristocetin as inductor is the standard test system for diagnosis. It is also used to detect platelet non-response to antiplatelet therapy. Studies have demonstrated that laboratory assessment of platelet non response to aspirin or clopidogrel is associated with adverse outcomes, and they indicate the importance of adjusting antiplatelet therapy in patients with a low degree of platelet inhibition. Nevertheless, a standardized method for identifying these patients is still missing.

Heparin-induced non-necrotizing skin lesions: rarely associated with heparin-induced thrombocytopenia.

SUMMARY BACKGROUND: Recently, there has been an increasing number of reports regarding adverse skin reactions to subcutaneous heparin administration. Case series have implied that heparin-induced skin lesions are predominantly associated with life-threatening heparin-induced thrombocytopenia (HIT) in at least 22% of patients. Skin lesions, therefore, have been included in clinical scores for HIT. OBJECTIVES: To determine the association of heparin-induced skin lesions with HIT. This would have a pivotal impact on further anticoagulatory management in patients with heparin-induced skin lesions. PATIENTS/METHODS: In our observational cohort study, 87 consecutive patients with heparin-induced skin lesions (85 occurring during low-molecular-weight heparin administration) were evaluated using a standardized internal protocol, including HIT diagnostics (heparin-platelet factor 4-ELISA, heparin-induced platelet activation assay), platelet count monitoring, clinical/sonographical screening for thrombosis, skin allergy testing and, if necessary, histology. RESULTS: None of the observed heparin-induced skin lesions was due to HIT; all lesions were caused by delayed-type IV-hypersensitivity reactions (DTH) instead. Even the cutaneous reaction in one patient with concomitant HIT could be classified histologically as DTH reaction, amounting to an association of heparin-induced skin lesions and HIT in 1.2% (1/87; 95% confidence interval, 0.00-0.06). CONCLUSION: Heparin-induced skin lesions associated with use of low-molecular-weight heparins do not seem to be strongly associated with a systemic immunologic reaction in terms of HIT and might rather be due to DTH reactions than due to microvascular thrombosis. Hence, we propose refining existing pretest probability scores for HIT, unless underlying causes have been clarified.

Alteration of pharmacokinetics of lepirudin caused by anti-lepirudin antibodies occurring after long-term subcutaneous treatment in a patient with recurrent VTE due to Behcets disease.

The direct thrombin inhibitor lepirudin is mainly applied in heparin-induced thrombocytopenia. We report here the case of a 37-year-old kurdish woman in whom Behcets disease was diagnosed in 1998 when she presented with a Budd Chiari syndrome (BCS) complicated by pulmonary embolism. Recurrent venous thromboembolism (VTE) occurred despite anticoagulant therapy with UFH, LMWH or phenprocoumon and various immunosuppressive therapy regimens. In 2001, when BCS recurred ultimately i.v. lepirudin was administered. When the patient improved and remained clinically stable lepirudin was applied subcutaneously. During long-term treatment with twice-daily 50 mg no further VTE was observed over the following years. Additionally, no bleeding complications occurred. In May 2005 anticoagulant therapy was switched to phenprocoumon. BCS reoccurred when INR values were suboptimal in February 2007, and lepirudin treatment was immediately restarted. After admission the patient received 50 mg b.i.d. lepirudin s.c. with plasma levels in the therapeutic range (0.5-1.0 mg / l). Over the following months, lepirudin levels repeatedly exceeded the upper limit of this range and the dosage was stepwise reduced. Finally, 20 mg b.i.d. were sufficient to obtain therapeutic levels. Renal function was normal, but lepirudin antibodies were present in high titer, as assessed by ELISA. We suppose that these antibodies reduce renal filtration of lepirudin thus leading to increased plasma levels. This case is an example for successful long-term therapeutic-dose anticoagulation with s.c. lepirudin in a patient with Behcets disease and recurrent VTE despite therapeutic anticoagulant therapy with LMWH or vitamin K antagonists. However, frequent measurement of lepirudin plasma levels is needed. If stepwise dose lowering is required over time, the presence of lepirudin antibodies should be considered.