Search

Considering the increasing number of patients suffering from drug-induced coagulation disorders caused by antiplatelet or anticoagulant therapy, the right balance between minimizing the risk of bleeding and the risk of a venous thrombosis or embolism during otorhinolaryngologic (ORL) surgery is becoming increasingly important. According to a recent study, the highest risk of intraoperative bleeding in ORL surgery is associated with transoral tumor surgery, tonsillectomy, thyroidectomy, and glomus tumor surgery. The risk of venous thrombosis or embolism during ORL surgery is estimated to be 1%, and increases to 6% among tumor patients. Currently, there is no general recommendation for perioperative hemostatic management because of the limited available data. In the majority of patients who continue antiplatelet therapy with acetylsalicylic acid (ASS) to prevent thromboembolic events, the perioperative bleeding risk is considered to be acceptable. For patients with dual antiplatelet therapy, surgical procedures should be only performed after adaption of the medication., (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

In most patients, oral anticoagulation is performed with vitamin K antagonists (VKA) or non-vitamin K antagonist oral anticoagulants (NOAC). Because of a long half-life, VKA are dosed by measuring INR. In standard cases coagulation tests for NOAC are not necessary; application is performed in a fixed dose. Special coagulation tests like anti-Xa activity (for factor Xa inhibitors: apixaban, edoxaban, rivaroxaban) and diluted thrombin time (for dabigatran) are available. At this time, no cut-off values are validated which show a higher risk of intra- and postoperative bleeding. For elective surgery, VKA are bridged by parenteral anticoagulation (e.g. low molecular weight heparin), NOAC are discontinued perioperative. Also, neuraxial anesthesia techniques can be performed with a proper time interval between last intake of a NOAC and puncture. If required, a transition from NOAC to parenteral anticoagulation can be made. Severe bleeding complications can be treated for VKA and NOAC as well by application of prothrombin complex concentrate. A specific antidote to dabigatran is available., Competing Interests: Hartmuth Nowak erklärt, dass er innerhalb der letzten 3 Jahre Vortragshonorare von den folgenden Firmen erhalten hat: Bayer Vital GmbH, Bristol-Myers Squibb GmbH & Co. KGaA, Mitsubishi Tanabe Pharma GmbH.Matthias Unterberg erklärt, dass kein Interessenkonflikt vorliegt., (Georg Thieme Verlag KG Stuttgart · New York.)

Goal of this article is to select three molecules from all the candidates currently under clincial development and to present and comapre their characteristics. Dabigatran is a direct thrombin (FIIa) inhibitor, whereas Rivaroxaban and Apixaban are direct factor Xa (FXa) inhibitors. All three represent small molecules thatreversibly, rapidly and directly bind to their target, the active center of the respective activated coagulation factor. Phase III data have been published for venous thromboembolism prophylaxis for each of these three drugs. Interestingly, VTE prophylaxis is initiated postoperatively with these products. Rivaroxaban currently holds the only accepted indication in Switzerland. For the indications VTE, atrial fibrillation and acute coronary syndrome promising phase III data have been or are in the process of being published. Monitoring is not necessary for any of these three new anticoagulants.

An overview is given on the method and the applications of thrombin generation assays. Thrombin generation assays provide a tool which can be used to trace the entire thrombin formation and inactivation of a plasma sample. Therefore they are principally different from traditional global assays like PT and aPTT and promise new opportunities for the assessment of bleeding or thrombotic risks.

Comparative investigation concerning gelfiltration as well as haemostaseologic analysis of venoms and venom fractions of some snakes (elapidae and viperidae) have shown that in elapidae an inhibition of coagulation is dominant whilst in viperidae the stimulation of coagulation is of importance. Our investigations produce a basis to select substances for activation of coagulation and substances for inhibition of coagulation. Under pharmacological viewpoints the data may produce information to use snake fractions for anticoagulation or for procoagulant therapy in bleeding tendency.

For decades, the options for therapeutic anticoagulation were limited to unfractionated heparin (UFH) and vitamin K antagonists (VKA), and their well-known limitations had to be accepted. With the introduction of the various LMWHs, the short- and medium-term anticoagulation could be much improved, but an alternative to VKA is still missing The heparins provided the proof of concept that FXa and thrombin represent suitable targets for therapeutic anticoagulation. Consequently, the search for new anticoagulants focuses on inhibitors of thrombin (DTI) or FXa (DXI). Apart from the VKA, the anticoagulants presently available or in an advanced stage of development can thus be divided in two classes: One are the glyco-anticoagulants with the natural sulfated glycosaminoglycans (GAGs) (UFH, LMWHs, and danaparoid) and the synthetic oligosaccharides (OS) (fondaparinux, idraparinux, and SR123781A). The other class are the xenobiotic anticoagulants, i.e. proteins and synthetic chemical entities. Die glyco-anticoagulants act partially (GAGs) or exclusively (oligosaccharides) by catalysing antithrombin, whereas the xenobiotic anticoagulants are direct inhibitors of either thrombin or FXa. At present, three parenteral DTI (lepirudin, argatroban, and bivalirudin) and since March 2008 one oral DTI (dabigatran etexilate) are clinically used for limited indications. In September 2008 rivaroxaban has been approved as the first oral DXI. This review describes the development of the anticoagualants as well as the pharmacological profile of the clinically used anticoagualants.

The options for drug-controlled anticoagulation are becoming noticeably more manifold. In the area of anaesthesiology and intensive care, there are furthermore special disease patterns, such as heparin-induced thrombocytopenia (HIT) to be known, diagnosed and treated. This article gives a review of the substance groups of the direct thrombin inhibitors (DTI) as alternative anticoagulants for HIT in combination with cardiovascular diseases. For the administration of DTIs, experience and the correct dose are the keys to success and are the deciding factors for the two sides of haemostasis: thrombosis and haemorrhage.

Heparin and Vitamin K antagonists have been the only available anticoagulants for several decades. Their use has lead to significant achievements in all fields of medicine despite various shortcomings and bleeding complications. With the objective of an improved benefit-/risk ratio selective inhibitors of factor Xa (Fondaparinux) and factor IIa (Ximelagatran) have been developed. Ximelagatran can also be orally administered. The results obtained from various clinical trials with these compounds are extremely encouraging. Thus, a significant improvement of antithrombotic treatment may be expected by their future use in the clinical and out-patient setting.

Two patients with severe bleeding complications under oral anticoagulant treatment are presented, in one case caused by pharmacokinetic drug interference (phenylbutazone), in the other by genetic predisposition to bleeding induced by coumarin anticoagulants. Another patient with decreasing INR due to drug interference (rifampicin) is presented as well. The possibility of drug interferences with coumarin anticoagulants has to be anticipated, whenever the medication of an orally anticoagulated patient is changed. A founder mutation of the factor IX propeptide constitutes a genetic predisposition to bleeding in patients put on coumarins. Its presence should be excluded in any patient suffering from hemorrhagic complications after starting anticoagulation when INR values are in the target range.

Argatroban is the smallest anticoagulant molecule of direct thrombin inhibitors. The main attributes of this synthetic drug are its rapid onset of anti-thrombin action, the rapid reversibility of its anticoagulant effect, potent inhibition of clot-bound thrombin, the absence of antibody formation and no need for dosage adjustment in patients with renal impairment. It is eliminated by hepatic metabolism. These properties make argatroban a predictable anticoagulant with intravenous use in a routine clinical setting. Argatroban is approved in the US and Canada for both prophylaxis and treatment of thrombosis in patients with heparin-induced throm-bocytopenia (HIT) and in the US as an antithrombotic agent during percutaneous coronary interventions in patients with HIT or a history of HIT. Preliminary reports document the feasibility of using argatroban for anticoagulation during hemodialysis and as adjunct to thrombolysis for treatment of myocardial infarction. Current recommendations for argatroban monitoring are to use the aPTT (activated partial thromboplastin time) for low doses and the ACT (activated clotting time) for high doses. The specific inhibition of thrombin can be measured with the ECT (ecarin clotting time).

Unlabelled: The administration of GP IIb/IIIa antagonists has been shown to be effective in reducing myocardial infarction and cardial death when given before PTCA. This prospective study was performed to determine the efficacy of abciximab in a bail-out situation to manage threatened or acute vessel closure., Methods: Acute or threatened vessel closure was observed in 104 (5.5%) out of 1903 consecutive patients treated with PTCA in our institution. Of the 104 patients 46 (44%) were treated for unstable angina (CCS IV). Abciximab was administered in bail-out situations in a dosage of 0.25 mg/kg given as a bolus, which was followed by an intravenous infusion of 10 micrograms/min over 12 hours. Repeat PTCA was performed shortly after the administration of the abciximab bolus. After the procedure, the sheath was left in place and control angiography was carried out 24 h later., Results: In 100 of the 104 patients TIMI flow III could be restored by abciximab therapy and RePTCA. In 4 patients an additional stent implantation was necessary due to persistent flow limitation. One day post PTCA, early follow-up angiography demonstrated patency of all vessels except two. In-hospital events occurred in 4 patients. Three of these patients underwent emergency CABG due to subacute vessel closure a few hours after PTCA and died during or directly after surgery. Follow-up after one year included clinical status and control angiography of the target vessel. During long-term follow-up, MACE occurred in 15 patients (2 MI, 8 CABG and 5 RePTCA)., Conclusion: The results of this prospective trial demonstrate the efficacy of abciximab therapy in bail-out situations occurring during or early after PTCA. The use of abciximab in bail-out situations appears clinically beneficial. Further studies have to compare the efficacy of this approach with prophylactic abciximab treatment.

Diagnosing pulmonary embolism (PE) remains a challenge due to the often confusing clinical presentation of the disease. Plasma D-dimer testing with ELISA is increasingly becoming part of the initial diagnostic work up. Due to the high specificity of the assay, a negative test can reliably exclude PE. Importantly, massive PE can be promptly diagnosed or excluded by echocardiography which is a particularly valuable noninvasive method for detection of right ventricular dysfunction at the bedside. High-risk patients can thus be identified and treated immediately without further time-consuming examinations. Confirmation of PE in patients with inconclusive or normal echocardiograms is often based on lung scans, but diagnostic uncertainty is common with this procedure. The popularity of pulmonary angiography is decreasing due to its invasiveness, whereas spiral CT appears to be a promising alternative. Search for (residual) deep vein thrombosis is useful for guiding therapy in stable patients with small pulmonary emboli, since their risk is determined by the potential for PE recurrence. Recent evidence confirmed that right ventricular dysfunction predicts an unfavorable prognosis and might therefore justify thrombolytic treatment of massive PE regardless of systemic hemodynamics. On the other hand, simplified anticoagulation regimens with low-molecular weight heparins have yielded very promising results in stable patients. These diagnostic and therapeutic principles based on cardiovascular risk stratification will hopefully result in a more effective approach to patients with venous thromboembolism in the future.

In the medical unit of our regional hospital we observed eight cases of anticoagulant-related pseudothrombocytopenia within two years. Attention is drawn to this often misdiagnosed laboratory artefact. In every unexpected thrombocytopenia found by automatic cell-counting a simple blood smear should be studied especially for thrombocyte-aggregates and the automatic platelet-count should be repeated using another anticoagulant, before other investigations are undertaken.

The surgical management of patients on anticoagulant treatment is a controversial issue. The attending surgeon must consider the risk of embolism and hemorrhage to prevent possible complications. With the aid of the local haemostatic technique described in this article minor dental surgery can be safely carried out in patients with a prothrombin time corresponding to the International Normalized Ratio (INR) 2.0.

The impairment of the functions of red blood cells or their destruction during storage can be delayed or even inhibited by oligoamines especially RE 1492 (N,N',N''-Tris-(4-phenylbutyl)benzene-1,3,5-trimethanamine). When citrated whole blood (WB) is stored at 4 degrees C for 7 d half of the red blood cells (RBC) have lost their ability to form rouleaux. Addition of 100 mumols/L RE 1492 maintains 50% reaggregability up to day 28th of storage. When citrated WB is stored at 37 degrees C the reaggregability has declined to 40 percent after 10 h. With 100 mumols/L RE 1492 no reduction of this property is observed up to 48 h. These results are correlated with the maintainance of the discocyte form of RBC and a persistent filtrability of RBC suspensions through a 5 microns microporous membrane. With 100 mumols/L RE 1492 only one fifth of the haemolysis of untreated WB occurs. The efflux of potassium ions from RBC into the blood plasma during a 72 h storage is bisected by RE 1492. The binding of oxygen to RBC remains unchanged.

The influence of non-steroidal antiphlogistics (NSA, fluor derivatives of phenylanthranilic acid) on fibrinolysis, platelet function, prostaglandin metabolism and pharmacokinetics of indirect anticoagulants was studied in rats and rabbits in vitro and in vivo. NSA were found to shorten the euglobulin lysis time and to enlarge the lysis zones on fibrin plates. They potentiated the fibrinolytic activity of streptokinase and trypsin. Furthermore, they inhibited platelet aggregation induced by arachidonic acid in rabbits. NSA in combination with inhibitors of thromboxane synthetase potentiated inhibition of aggregation. After oral administration, NSA inhibited formation of thromboxane A2 and prostacyclin in rabbits in a dose-dependent manner. At comparatively low doses, thromboxane A2 synthesis was more effectively inhibited than prostacyclin formation. Due to pharmacokinetic interactions NSA enhanced the anticoagulant effect of indirect anticoagulants and accelerated their distribution and elimination.

Experimental investigations have shown that antiaggregants affect the size rather than the rate of venous thrombosis, while clinical trials with prophylactic acetylsalicylic acid have indicated primarily a reduced incidence of pulmonary embolism. Current experiences with acetylsalicylic acid in combination with dipyridamole or low-dose heparin suggest that the incidence of pathology diagnosed by 125I-fibrinogen and of deep vein thrombosis is equally reduced.

Automated counting resulted in erroneously low numbers of platelets (pseudothrombocytopenia) in three patients. The machine-derived values (ELT-8) were initially 30 000, 8000 and 8000/microliter, respectively. Numerous agglutinates could be demonstrated in the counting chamber. Whereas counting in the first patient showed a real value with an average of 252 000/microliter both the other preparations could not be counted due to numerous agglutinates. The artificially low number of platelets in the counter can thus be explained by lack of recognition as platelets due to the size of the in vitro formation of agglutinates. Should these be of the size of white cells leukocytosis may be suggested. Formation of agglutinates was not limited to use of EDTA as anticoagulant but could also be observed with other anticoagulants such as heparin and citrate. For prevention of superfluous and potentially dangerous therapeutic steps the diagnosis of platelet deficiency should be ascertained in any case by additional determination of the platelet count in the counting chamber.

Due to an advanced prostatic carcinoma 166 patients were given a massive dose of oestrogen over a period of 10 days (6 g Honvan i.v.). A retrospective comparison of a control group of 94 patients without prophylaxis against thrombosis and a control group of 36 patients having received Heparin-Dihydergot did not show a significant difference of cardiovascular complications. Therefore, further 36 patients received a thrombocyte aggregation inhibitor (Godamed) as prophylaxis against embolic thrombosis. At the same time lung perfusion scintigraphy (99m Tc-Microspheres) was made directly before and after oestrogen therapy. Clinically and lung scintigraphically there was no different thromboembolic incidence compared to the patients given a Heparin-Dihydergot prophylaxis.

As long-term anticoagulant therapy with coumarin derivates like Sintrom becomes more and more important the question arises whether there is an interaction with a new drug like Ludiomil. An open, noncomparative trial was carried out with 20 patients receiving Sintrom (overall mean :3.0 mg/d, range :0 to 10 mg/d) for a period of 4 weeks, and in addition, during the second and third week Ludiomil (50 mg t. i. d.) orally. As a measurement of the efficacy of the antiocoagulant therapy, the correlation coefficients between the doses of Sintrom and the prothrombin value of the nex day were calculated for each patient and each week separately. An analysis of variance did not show any statistically significant difference between the correlation coefficients of the weeks with and without Ludiomil therapy, i.e. there is no change in the efficacy of the anticoagulant therapy. During the Ludiomil therapy the control of the anticoagulant therapy was slightly better, i.e. the fluctuations of the prothrombin values less, but statistically these differences were not significant. The plasma levels of Ludiomil in these patients were similar to thse found previously in both depressed and healthy volunteers.