[COVID-19-induced coagulopathy and thrombosis manifestations]. / COVID-19-induzierte Koagulopathien und thromboembolische Manifestationen.

CLINICAL ISSUE: Clinically, COVID-19 (coronavirus disease 2019) is increasingly seen as a systemic disease associated with multiorgan involvement through a hypercoagulatory condition in the sense of vasculopathy. STANDARD TREATMENT: Treatment with antiplatelet drugs or heparins appears to be indicated. The current evidence, at least for acetylsalicylic acid (ASA), is lacking. DIAGNOSTIC WORK-UP: Corresponding to the significant proportion of primarily microstructural vascular changes, the radiological diagnosis showed not only macrovascular pathologies, but also diffuse perfusion disorders. PERFORMANCE: Regional hypoperfusion in the lungs can be detected with and without pulmonary arterial embolism. Similar findings can be found in almost all organ systems. PRACTICAL RECOMMENDATIONS: A therapeutic intervention using low molecular weight heparins in hospitalized patients in situation-adapted dosage is indicated and is discussed in detail. In the detection of micro- and macrovascular thrombosis in the context of COVID-19, extended radiological diagnostics play a central role and are the basis of adapted therapy and secondary prevention.

[Prophylaxis of venous thromboembolic events in head and neck surgery]. / Die Prophylaxe venöser Thromboembolien bei Kopf­Hals­Operationen.

BACKGROUND: Application of perioperative thrombosis prophylaxis in head and neck surgery lacks consistent standards in Germany. Due to sparse data, the latest German S3 guideline concerning prophylaxis of thromboembolic events recommends a restrictive handling of anticoagulants in head and neck surgery, with few specific recommendations. OBJECTIVE: The aim of this paper is to provide concrete clinical recommendations based on a systematic literature review and the S3 guidelines. MATERIALS AND METHODS: A keyword-based literature search was performed and the German S3 guideline "Prophylaxis of Venous Thromboembolic Events" was used to state the current level of evidence and provide a clinical algorithm. RESULTS: Eight additional cohort studies dealing with the incidence of thromboembolic events in head and neck surgery were identified. There were no randomized controlled trials. In the proposed algorithm, a classification of dispositional (patient history) and expositional (operation time) risk into three groups enables preoperative risk evaluation indicating the individual demand for prophylaxis. In short operations without major tissue traumatization, routine drug-based thrombosis prophylaxis is not necessary, provided no third-grade risk factors (earlier thromboembolic event, coagulopathy, or malignant disease) are present. Low molecular weight heparins should be used as anticoagulants for drug-based prophylaxis. CONCLUSION: Prophylaxis of thromboembolic events in head and neck surgery is of high clinical relevance but there is currently limited evidence regarding its implementation. This paper is based on a systematic literature review and provides a clinical algorithm for head and neck surgeons.

Point-of-care PT and aPTT in patients with suspected deficiencies of coagulation factors.

INTRODUCTION: There are several clinical settings and patient conditions especially in intensive care units, emergency departments, and operating theaters, where the coagulation status of a patient must be known immediately and point-of-care (POC) systems are beneficial due to low time to result. METHODS: This noninterventional, single-blinded, multicenter study with prospectively collected whole blood samples was performed to evaluate the diagnostic accuracy of the CoaguChek PT Test (POC PT) and CoaguChek aPTT Test (POC aPTT) compared to standard laboratory testing in patients with suspected deficiencies of coagulation factors. RESULTS: In total, 390 subjects were included. Both POC PT and POC aPTT showed concordance with the laboratory PT and aPTT. Lot-to-lot variation was below 2% both for POC PT and for POC aPTT. The mean relative difference of capillary blood compared to venous blood was 0.2 % with POC PT and 8.4% with POC aPTT. The coefficients of variation for repeatability of POC PT using whole blood were found to be between 2% and 3.6%. CONCLUSION: Our findings suggest reliable quantitative results with this POC system to support on-site decision-making for patients with suspected deficiencies of coagulation factors in acute and intensive care.

Guidance for diagnosis and treatment of DIC from harmonization of the recommendations from three guidelines.

Three guidelines have recently been published for the diagnosis and treatment of disseminated intravascular coagulation (DIC) in adults. This communication seeks to harmonize the recommendations in these guidelines using a modified GRADE system. The scoring system for diagnosis of DIC using global coagulation tests is known to correlate with key clinical observations and outcomes (Moderate quality). The cornerstone of DIC treatment is the treatment of the underlying condition (Moderate quality). In general, transfusion of platelets or plasma (components) in patients with DIC should be reserved for patients who are bleeding (Low quality). Therapeutic doses of heparin should be considered in cases of DIC where clinical features of thrombosis predominate. Heparin is not recommended in those patients with a high risk of bleeding, (Moderate quality). However, prophylactic doses of unfractionated heparin or low molecular we ight heparin is recommended in critically ill and non-bleeding patients with DIC for prevention of venous thromboembolism (Moderate to High quality). Although further prospective evidence from randomized controlled trials is required, administration of antithrombin or recombinant thrombomodulin may be considered in certain patients with DIC. In general, patients with DIC should not be treated with antifibrinolytic agents (Low quality). However those who present with severe bleeding, that is characterized by a markedly hyperfibrinolytic state such as leukemia (Low quality) and trauma (Moderate quality), may be treated with antifibrinolytic agents. © 2013 International Society on Thrombosis and Haemostasis.

[Pharmacology of the new oral anticoagulants]. / Pharmakologie der neuen oralen Antikoagulanzien.

New oral anticoagulants, such as dabigatran, rivaroxaban, apixaban, and edoxaban display pharmacologic and pharmacodynamic data similar to low molecular weight heparins. Peak levels are found 2-4 h after oral ingestion and elimination half-lives are in the range of 7-14 h. The drugs differ primarily concerning renal elimination. Dose adjustment is only performed in patients with impaired renal function, high risk of bleeding and patients with co-medications which influence the metabolism or anticoagulant effect of the drugs. Due to the short half-life, perioperative bridging is not necessary. Currently, no specific antidotes are available: however, assay systems are available for measuring the plasma concentration of dabigatran and rivaroxaban. In emergency cases a normal thrombin time excludes relevant levels of dabigatran, whereas a normal anti-factor Xa assay result excludes relevant levels of factor Xa inhibitors.The new anticoagulants are being used for prophylaxis of venous thrombosis in elective hip and knee surgery, as well as for treatment of venous thrombosis and for prevention of stroke and systemic embolism in patients with atrial fibrillation. Additional indications are to follow. Dabigatran is given at a dose of 110 mg initially 1-4 h after surgery followed by 220 mg once daily for prophylaxis of thrombosis and at doses of 110 mg or 150 mg twice daily for therapeutic anticoagulation. The prophylactic and therapeutic doses of rivaroxaban are 10 and 20 mg and, of apixaban 2.5 mg and 5 mg twice daily, respectively.

Anticoagulation in neurointerventions: basic pharmacology and pathophysiology, current status, practical advice.

This article gives an overview of anticoagulative medication accompanying neurointerventional procedures. The basic pharmacology of prevalent medication is outlined and the thrombogenicity of standard procedures is described. A brief overview of the literature on risks and benefits of standard medications and their monitoring is provided. A customized regime of care is presented.

Prevention, diagnosis, therapy and follow-up care of sepsis: 1st revision of S-2k guidelines of the German Sepsis Society (Deutsche Sepsis-Gesellschaft e.V. (DSG)) and the German Interdisciplinary Association of Intensive Care and Emergency Medicine (Deutsche Interdisziplinäre Vereinigung für Intensiv- und Notfallmedizin (DIVI)).

Practice guidelines are systematically developed statements and recommendations that assist the physicians and patients in making decisions about appropriate health care measures for specific clinical circumstances taking into account specific national health care structures. The 1(st) revision of the S-2k guideline of the German Sepsis Society in collaboration with 17 German medical scientific societies and one self-help group provides state-of-the-art information (results of controlled clinical trials and expert knowledge) on the effective and appropriate medical care (prevention, diagnosis, therapy and follow-up care) of critically ill patients with severe sepsis or septic shock. The guideline had been developed according to the "German Instrument for Methodological Guideline Appraisal" of the Association of the Scientific Medical Societies (AWMF). In view of the inevitable advancements in scientific knowledge and technical expertise, revisions, updates and amendments must be periodically initiated. The guideline recommendations may not be applied under all circumstances. It rests with the clinician to decide whether a certain recommendation should be adopted or not, taking into consideration the unique set of clinical facts presented in connection with each individual patient as well as the available resources.

[The TAFI system. The new role of fibrinolysis]. / Das TAFI-System. Die neue Rolle der Fibrinolyse.

The primary focus of the blood coagulation system is the prevention of blood loss. The system is regulated by various inhibitors, and by the fibrinolytic system, which removes the final product of the blood coagulation system, the fibrin clot. The fibrinolytic system is activated in the course of coagulation activation. The thrombin-activated fibrinolysis inhibitor (TAFI) is an important regulator of fibrinolysis. TAFI is activated by thrombin, and activation is enhanced in the presence of thrombomodulin. TAFIa, the product of TAFI activation, removes lysine residues from fibrin, which are essential for the binding of t-PA, plasminogen, and plasmin to fibrin. The fibrin loses its cofactor activity in t-PA-induced plasminogen activation, resulting in less plasmin, and the remaining plasmin finds less binding sites on fibrin, resulting in an increased resistance of the clot towards plasmin proteolysis. High concentrations of thrombin result in high TAFIa-activity and consequently in highly resistant fibrin clots. Patients with hyperprothrombinaemia consequently display elevated TAFIa-levels, which may contribute to the risk for thrombosis. Treatment with recombinant factor VIIa also leads to high concentrations of thrombin, resulting in fibrin clots with enhanced resistance towards fibrinolysis. At low thrombin concentration, as observed in patients with bleeding disorders or patients treated with anticoagulant drugs, less TAFIa is produced in the course of coagulation activation, and the clots are less resistant towards fibrinolysis. TAFIa-inhibitors are currently being developed for the treatment of throboembolic disorders or hypofibrinolytic DIC. Enhancement of TAFIa-activity may be helpful in patients with bleeding.

Changes in fibrinogen and fibrin induced by a peptide analog of fibrinogen gamma365-380.

BACKGROUND: The effects of synthetic peptides with sequences derived from the gamma-chain of fibrinogen on the functional properties of fibrinogen and fibrin were investigated. METHODS: Methods included thrombelastography, clot turbidity measurement, clot elasticity measurement, platelet aggregation, and scanning transmission electron microscopy (STEM). RESULTS: Peptide gamma369-380 (NH(2)-WATWKTRWYSMK-COOH) showed the greatest impact on fibrin structure, compared with the 76 other overlapping dodecapeptides. Addition of this peptide, or peptide gamma365-380 (NH(2)-NGIIWATKTREWYSMK-COOH) to a mixture of fibrinogen and thrombin resulted a shorter clotting time, higher clot turbidity, lower clot elastic modulus, a higher degree of D-trimer and D-tetramer formation, and impaired plasmin proteolysis of the clot. In STEM, fibrin formed in the presence of peptide gamma369-380 consisted of a more extensive array of linear fibrils typically consisting of 20 or more molecules. Fibrils were better organized than those from non-peptide containing mixtures. CONCLUSIONS: Replacement of the tryptophan residue gamma376 massively reduced the effect of the peptide on fibrin structure. Binding of the peptide to fibrinogen induces conformational changes, which result in accelerated clotting and increased lateral association of fibrin protofibrils. The results imply a relevant functional role of sites interacting with peptide gamma369-380 region in the fibrinogen molecule.

[Avoiding emergency situations under anticoagulant therapy with vitamin K antagonists]. / Vermeidung von Notfallsituationen bei gerinnungshemmender Therapie mit Vitamin-K-Antagonisten Ein praktischer Leitfaden zu Einstellung, Umstellung und Uberbrückung von Therapiepausen.

Despite 50 years of clinical experience with vitamin K antagonists such as phenprocoumon or warfarin, many clinicians are uncertain how to start treatment, deal with overdose or bleeding complications, and how to bridge anticoagulation when treatment with vitamin K antagonists is interrupted. Patients with overdose of vitamin K antagonists or bleeding complications are treated with vitamin K, prothrombin complex concentrates (PCC), or recombinant factor VIIa. Rapid reversal of anticoagulation is only achieved by using PCC or recombinant factor VIIa. Both should be combined with vitamin K for a sustained effect. For elective surgery, treatment with vitamin K antagonists is paused and vitamin K given either orally or intravenously. Unfractionated or low molecular weight heparin is given when INR levels are below therapeutic range. Patients with contraindications to heparin may be treated with alternative anticoagulants such as danaparoid, lepirudin or fondaparinux.

[Sepsis-associated coagulation disorders]. / Gerinnungsstörungen bei Sepsis.

Coagulation activation with intravascular fibrin formation is a general finding in patients with sepsis. Low coagulation factors may be caused by disseminated intravascular coagulation, as well as by loss of plasma and impaired hepatic synthesis in the course of sepsis. The leading clinical symptom in consumption coagulopathy is bleeding. Therefore, treatment mainly consists of substitution of coagulation factors and platelets. Meningococcal and pneumococcal, as well as some other infections may lead to sepsis-induced purpura fulminans, a condition associated with microvascular thrombosis, necrosis, and haemorrhage. A typical laboratory sign is a very low plasma protein C level. Treatment with protein C concentrate or recombinant activated protein C (Drotrecogin alfa, activated) has been shown to be beneficial in sepsis-induced purpura fulminans. Unfractionated heparin or low molecular weight heparin has been recommended for prophylaxis of venous thrombosis, but there are no clinical studies specifically on patients with sepsis. Antithrombin concentrate is used in patients with antithrombin deficiency treated with heparin for acute venous thrombosis or embolism, extracorporeal circulation procedures or other invasive procedures. There is no indication for general use of antithrombin concentrate in patients with sepsis even in patients with low plasma antithrombin levels. Drotrecogin alfa, activated, is used for treatment of patients with severe sepsis. Its use is not limited to patients with sepsis-induced disseminated intravascular coagulation, although these patients appear to benefit especially from this therapy.

[Perioperative coagulation diagnostics]. / Perioperative Gerinnungsdiagnostik.

The main diagnostic tool for the preoperative identification of patients with an increased risk of bleeding or thrombosis is the patient history. Laboratory diagnostics should only be performed if a bleeding diathesis is suspected from patient history or clinical symptoms of bleeding, or if an adequate patient history cannot be performed. Measurement of prothrombin time, aPTT, or bleeding time as a general preoperative screening procedure is neither cost-effective nor efficient for the identification of patients with increased bleeding risk. Normal values of prothrombin time and aPTT do not exclude the most prevalent bleeding disorder, von Willebrand's disease. A normal platelet count does not exclude a severe platelet function defect. Selection of specific laboratory assays is performed on the basis of the individual patient history and clinical picture; laboratory 'profiles' can be defined for some specific clinical conditions. In some cases, patients should be referred to a specialized coagulation clinic for further diagnostics and treatment planning. Preoperative laboratory diagnostics for thrombophilia are not necessary in most cases. The decision for intensified antithrombotic measures is made according to patient history and the postoperative clinical course.

Fibrinogen Mannheim II: a novel gamma307 His-->Tyr substitution in the gammaD domain causes hypofibrinogenemia.

BACKGROUND: In recent years it has become clear that the molecular investigation of hypofibrinogenemia provides unique insight into regions of the fibrinogen molecule that are important in molecular assembly, secretion and stability. OBJECTIVES: To investigate a case of hypofibrinogenemia at the molecular level. PATIENTS AND METHODS: The study was conducted on a 37-year-old woman from Mannheim, Germany, who had an antigenic plasma fibrinogen concentration of 0.86 g L(-1). Mutation screening was performed by DNA sequencing and the effect of the identified mutation was investigated at the protein level. RESULTS: Analysis of exon 8 of the fibrinogen gamma gene identified a heterozygous CAT-->TAT transition at codon 307. This novel His-->Tyr substitution was not detected when plasma fibrinogen was analyzed by electrospray ionization mass spectrometry. The mutation predicts a mass increase of 26 Da in the gamma chain, but purified gamma chains had a normal mass, indicating non-expression of the gamma(Tyr307) chain in plasma fibrinogen. CONCLUSIONS: This work reports a novel gamma307 His-->Tyr mutation (fibrinogen Mannheim II) that causes hypofibrinogenemia. Crystal structures show that His307 is located immediately adjacent to three residues that have been implicated in fibrin polymerization at the D:D interface. However, the histidine residue appears critical in maintaining structure of the fibrinogen gammaD domain, rather than in determining function.

Expression and activity of matrix metalloproteinase-2 in calcific aortic stenosis.

Calcific aortic stenosis is the main heart valve disease in the elderly, leading to massive focal calcification and thickening of the valve cusps. Matrix metalloproteinases (MMPs) are thought to contribute to this process. Therefore, the study assessed the expression of the gelatinases MMP-2 and MMP-9 and the endogenous tissue inhibitor of metalloproteinase (TIMP)-2 as well as the gelatinolytic activity in normal and stenotic valves. Human tricuspid aortic valves with and without calcific aortic stenosis were studied by immunohistochemistry for MMP-2, MMP-9 and TIMP-2. The gelatinolytic activity in native valve sections was assessed by gelatin in situ zymography with or without addition of the MMP activator p-aminophenymercuric acetate (APMA). Staining intensities for MMP-2 and TIMP-2 were elevated in stenotic valves as compared to controls. Minor staining of MMP-9 was present exclusively in stenotic valves. The morphologic distribution of gelatinolytic activity was comparable to the staining pattern of MMP-2, and since MMP-9 immunostaining demonstrated only a low number of positive cells, the observed gelatinolytic activity is likely due to MMP-2. Gelatinolytic activity was low in normal valves but significantly increased by the MMP activator APMA. In contrast, stenotic valves showed a strong basal gelatinolytic activity that could not be significantly enhanced by APMA suggesting that MMP-2 is present as a latent pro-enzyme in normal valves and activated in stenotic valves. Thus, MMP-2 might be involved in the matrix remodeling during calcific aortic stenosis.

Valproate induces reversible factor XIII deficiency with risk of perioperative bleeding.

The antiepileptic drug valproic acid (VPA) induces subclinical changes in both the intrinsic and extrinsic coagulation system. However, fatal bleeding is very rare. This study reports a 39-year-old patient who underwent selective amygdalohippocampectomy because of drug-resistant temporal lobe epilepsy. Preoperatively, the patient was on a combined therapy with VPA and topiramate, and routine coagulation laboratory parameters were entirely normal. Epilepsy surgery was immediately followed by severe intracranial bleeding events which promped repeated craniectomy. Extensive laboratory analyses revealed a factor XIII activity level of 17%, indicating factor XIII deficiency confirmed by a reduced XIIIA-antigen. After termination of treatment with VPA, factor XIII levels returned to normal. Control examinations after 9 and 24 months showed normal range values for all coagulation parameters, including factor XIII, platelet function, and von Willebrand factor. To our knowledge, this case is the first description of a well-documented, clinically relevant transient factor XIII-deficiency syndrome related to VPA treatment.