Gerinnungshemmende Therapie

2018 ◽  
Vol 47 (04) ◽  
pp. 164-170
Author(s):  
Carl-Erik Dempfle
Keyword(s):  
Vitamin K ◽  
Protein C ◽  
Protein S ◽  
Perioperatives Management ◽  
Niedermolekulares Heparin ◽  
Wird Eine ◽  
Operative Eingriffe

ZusammenfassungEine gerinnungshemmende Therapie mit Vitamin-K-Antagonisten erfordert eine individuelle Dosisfindung und eine ständige Therapiekontrolle.Die Wirkdauer insbesondere von Phenprocoumon ist mit bis zu 21 Tagen sehr lang und nicht vorhersehbar und verkürzt sich nach Vitamin-K-Gabe auf 2 Tage, es besteht ein erhebliches Blutungsrisiko und der Schweregrad der Blutungen ist in der Regel höher als bei vergleichbaren Blutungen unter direkten oralen Antikoagulanzien (DOAK). Für operative Eingriffe müssen Vitamin-K-Antagonisten meist abgesetzt werden, die Empfehlungen einer präoperativen 5-tägigen Therapiepause ohne Überbrückung durch ein niedermolekulares Heparin für Warfarin sind auf Phenprocoumon nicht übertragbar. Bei Absetzen von DOAK wird eine normale Hämostasefunktion hingegen in der Regel innerhalb von 24–48 Stunden erreicht. Längerfristige Behandlung mit Vitamin-K-Antagonisten führt häufig zu Osteoporose und vermehrter Atherosklerose, sowie zu zunehmender Beeinträchtigung der Nierenfunktion, Effekte, die unter DOAK nicht beobachtet werden.Spezielle Probleme für Vitamin K-Antagonisten ergeben sich bei Patienten mit Antiphospholipid-Syndrom, Protein C-Mangel, Protein S-Mangel oder Faktor VII-Mangel. Für eine bevorzugte Verwendung von DOAK sprechen rascher Wirkbeginn, kurze und vorhersehbare Wirkdauer bei standardisierter Dosierung, weniger und weniger schwere Blutungen, wesentlich einfacheres perioperatives Management und Vermeidung von Osteoporose und anderen Folgen der Vitamin-K-Antagonisten. Für die zugelassenen Indikationen haben DOAK daher etliche Vorteile im Vergleich zu den Vitamin-K-Antagonisten. Es ist aber zu berücksichtigen, dass auch bei Verwendung von DOAK eine gewissenhafte ärztliche Patientenführung nötig ist und die DOAK für einige Indikationen nicht zugelassen sind.

Protein S and C4b-Binding Protein: Components Involved in the Regulation of the Protein C Anticoagulant System

1991 ◽  
Vol 66 (01) ◽  
pp. 049-061 ◽  
Author(s):  
Björn Dahlbäck
Keyword(s):  
Vitamin K ◽  
Complement System ◽  
Protein C ◽  
Protein S ◽  
High Affinity ◽  
Anticoagulant System ◽  
Dependent Protein ◽  
The Complement System ◽  
Β Chain ◽  
Dependent Domain

SummaryThe protein C anticoagulant system provides important control of the blood coagulation cascade. The key protein is protein C, a vitamin K-dependent zymogen which is activated to a serine protease by the thrombin-thrombomodulin complex on endothelial cells. Activated protein C functions by degrading the phospholipid-bound coagulation factors Va and VIIIa. Protein S is a cofactor in these reactions. It is a vitamin K-dependent protein with multiple domains. From the N-terminal it contains a vitamin K-dependent domain, a thrombin-sensitive region, four EGF)epidermal growth factor (EGF)-like domains and a C-terminal region homologous to the androgen binding proteins. Three different types of post-translationally modified amino acid residues are found in protein S, 11 γ-carboxy glutamic acid residues in the vitamin K-dependent domain, a β-hydroxylated aspartic acid in the first EGF-like domain and a β-hydroxylated asparagine in each of the other three EGF-like domains. The EGF-like domains contain very high affinity calcium binding sites, and calcium plays a structural and stabilising role. The importance of the anticoagulant properties of protein S is illustrated by the high incidence of thrombo-embolic events in individuals with heterozygous deficiency. Anticoagulation may not be the sole function of protein S, since both in vivo and in vitro, it forms a high affinity non-covalent complex with one of the regulatory proteins in the complement system, the C4b-binding protein (C4BP). The complexed form of protein S has no APC cofactor function. C4BP is a high molecular weight multimeric protein with a unique octopus-like structure. It is composed of seven identical α-chains and one β-chain. The α-and β-chains are linked by disulphide bridges. The cDNA cloning of the β-chain showed the α- and β-chains to be homologous and of common evolutionary origin. Both subunits are composed of multiple 60 amino acid long repeats (short complement or consensus repeats, SCR) and their genes are located in close proximity on chromosome 1, band 1q32. Available experimental data suggest the β-chain to contain the single protein S binding site on C4BP, whereas each of the α-chains contains a binding site for the complement protein, C4b. As C4BP lacking the β-chain is unable to bind protein S, the β-chain is required for protein S binding, but not for the assembly of the α-chains during biosynthesis. Protein S has a high affinity for negatively charged phospholipid membranes, and is instrumental in binding C4BP to negatively charged phospholipid. This constitutes a novel mechanism for control of the complement system on phospholipid surfaces. Recent findings have shown circulating C4BP to be involved in yet another calcium-dependent protein-protein interaction with a protein known as the serum amyloid P-component (SAP). The binding sites on C4BP for protein S and SAP are independent. SAP, which is a normal constituent in plasma and in tissue, is a so-called pentraxin being composed of 5 non-covalently bound 25 kDa subunits. It is homologous to C reactive protein (CRP) but its function is not yet known. The specific high affinity interactions between protein S, C4BP and SAP suggest the regulation of blood coagulation and that of the complement system to be closely linked.

scholarly journals The gene encoding vitamin K-dependent anticoagulant protein C is expressed in human male reproductive tissues.

1995 ◽  
Vol 43 (6) ◽  
pp. 563-570 ◽  
Author(s):  
X He ◽  
L Shen ◽  
A Bjartell ◽  
J Malm ◽  
H Lilja ◽  
...  
Keyword(s):  
Vitamin K ◽  
Leydig Cells ◽  
Protein C ◽  
Protein S ◽  
Northern Blotting ◽  
Human Testis ◽  
Post Translational Modification ◽  
Reproductive Tissues ◽  
Human Male ◽  
Dependent Protein

Protein C is a vitamin K-dependent protein circulating in plasma as a zymogen to an anticoagulant serine protease. After its activation, protein C cleaves and inactivates coagulation factors Va and VIIIa. Human protein C is synthesized in liver and undergoes extensive post-translational modification during its synthesis. Recently, the protein C inhibitor was demonstrated to be synthesized in several organs of the human male reproductive tract. Moreover, vitamin K-dependent protein S, which functions as a co-factor to activated protein C, was found to be synthesized in the Leydig cells of human testis. The aim of this study was to elucidate whether the protein C gene is also expressed in the male reproductive system. Specific immunostaining of protein C was found in Leydig cells of human testis, in the excretory epithelium of epididymis, and in some epithelial glands of the prostate, whereas no immunostaining was detected in seminal vesicles. Northern blotting and non-radioactive in situ hybridization demonstrated protein C mRNA in Leydig cells, in the excretory epithelium of epididymis, and in some of the epithelial glands of the prostate. The mRNA was distributed perinuclearly and the localization was in accordance with the specific immunostaining for protein C. The epithelium of epididymis was also found to contain both protein S mRNA and immunoreactivity. The demonstration of both protein C and protein S immunoreactivities, as well as their mRNAs, in male reproductive tissues suggests as yet unknown local functions for these proteins.

scholarly journals Vitamin K-Dependent Coagulation Factors That May be Responsible for Both Bleeding and Thrombosis (FII, FVII, and FIX)

2018 ◽  
Vol 24 (9_suppl) ◽  
pp. 42S-47S ◽  
Author(s):  
Antonio Girolami ◽  
Silvia Ferrari ◽  
Elisabetta Cosi ◽  
Claudia Santarossa ◽  
Maria Luigia Randi
Keyword(s):  
Venous Thrombosis ◽  
Vitamin K ◽  
Protein C ◽  
Protein S ◽  
Coagulation Factors ◽  
Bleeding Tendency ◽  
Clotting Factors ◽  
Protein Z ◽  
Clinical Observations

Vitamin K-dependent clotting factors are commonly divided into prohemorrhagic (FII, FVII, FIX, and FX) and antithrombotic (protein C and protein S). Furthermore, another protein (protein Z) does not seem strictly correlated with blood clotting. As a consequence of this assumption, vitamin K-dependent defects were considered as hemorrhagic or thrombotic disorders. Recent clinical observations, and especially, recent advances in molecular biology investigations, have demonstrated that this was incorrect. In 2009, it was demonstrated that the mutation Arg338Leu in exon 8 of FIX was associated with the appearance of a thrombophilic state and venous thrombosis. The defect was characterized by a 10-fold increased activity in FIX activity, while FIX antigen was only slightly increased (FIX Padua). On the other hand, it was noted on clinical grounds that the thrombosis, mainly venous, was present in about 2% to 3% of patients with FVII deficiency. It was subsequently demonstrated that 2 mutations in FVII, namely, Arg304Gln and Ala294Val, were particularly affected. Both these mutations are type 2 defects, namely, they show low activity but normal or near-normal FVII antigen. More recently, in 2011-2012, it was noted that prothrombin defects due to mutations of Arg596 to Leu, Gln, or Trp in exon 15 cause the appearance of a dysprothrombinemia that shows no bleeding tendency but instead a prothrombotic state with venous thrombosis. On the contrary, no abnormality of protein C or protein S has been shown to be associated with bleeding rather than with thrombosis. These studies have considerably widened the spectrum and significance of blood coagulation studies.

scholarly journals Thrombophilia And Arterial Ischemic Stroke

2017 ◽  
pp. 45
Author(s):  
A.A. Abrishamizadeh
Keyword(s):  
Ischemic Stroke ◽  
Vitamin K ◽  
Arterial Thrombosis ◽  
Protein C ◽  
Antithrombin Iii ◽  
Factor V Leiden ◽  
Protein S ◽  
Factor V ◽  
Factor V Leiden Mutation ◽  
C Protein

Ischemic stroke (IS) is a common cause of morbidity and mortality with significant socioeconomic impact especially when it affects young patients. Compared to the older adults, the incidence, risk factors, and etiology are distinctly different in younger IS. Hypercoagulable states are relatively more commonly detected in younger IS patients.Thrombophilic states are disorders of hemostatic mechanisms that result in a predisposition to thrombosis .Thrombophilia is an established cause of venous thrombosis. Therefore, it is tempting to assume that these disorders might have a similar relationship with arterial thrombosis. Despite this fact that 1-4 % of ischemic strokes are attributed to Thrombophillia, this   alone rarely causes arterial occlusions .Even in individuals with a positive thrombophilia screen and arterial thrombosis, the former might not be the primary etiological factor.Thrombophilic   disorders can be broadly divided into inherited or acquired conditions. Inherited thrombophilic states include deficiencies of natural anticoagulants such as protein C, protein S, and antithrombin III (AT III) deficiency, polymorphisms causing resistance to activated protein C(Factor V Leiden mutation), and disturbance in the clotting balance (prothrombin gene 20210G/A variant). Of all the inherited  thrombophilic disorders, Factor V Leiden mutation is perhaps the commonest cause. On the contrary, acquired thrombophilic disorders are more common and include conditions such as the antiphospholipid syndrome, associated with lupus anticoagulant and anticardiolipin antibodies.The more useful and practical approach of ordering various diagnostic tests for the uncommon thrombophilic states tests should be determined by a detailed clinical history, physical examination, imaging studies and evaluating whether an underlying hypercoagulable state appears more likely.The laboratory thrombophilia   screening should be comprehensive and avoid missing the coexisting defect and It is important that a diagnostic search protocol includes tests for both inherited and acquired thrombophilic disorders.Since the therapeutic approach (anticoagulation and thrombolytic therapy) determines the clinical outcomes, early diagnosis of the thrombophilic  disorders plays an important role. Furthermore, the timing of test performance of some of the  thrombophilic  defects (like protein C, protein S, antithrombin III and fibrinogen levels) is often critical since these proteins can behave as acute phase reactants and erroneously elevated levels of these factors may be observed in patients with acute thrombotic events. On the other hand, the plasma levels of vitamin K-dependent proteins (protein C, protein S and APC resistance) may not be reliable in patients taking vitamin K antagonists. Therefore, it is suggested that plasma-based assays for these disorders should be repeated3 to 6 months after the initial thrombotic episode to avoid false-positive results and avoid unnecessary prolonged   anticoagulation therapy. The assays for these disorders are recommended after discontinuation of oral anticoagulant treatment or heparin for at least 2 weeks.    

Malignom und Thrombose: eine wechselseitige klinische Beziehung

VASA ◽  
2005 ◽  
Vol 34 (4) ◽  
pp. 225-234 ◽  
Author(s):  
Luxembourg ◽  
Bauersachs
Keyword(s):  
Vitamin K ◽  
Venöse Thromboembolie ◽  
Niedermolekulares Heparin ◽  
Operative Eingriffe

Die venöse Thromboembolie (VTE) ist die zweithäufigste Todesursache bei Tumorpatienten und ist Zeichen einer verschlechterten Prognose. Insbesondere bei Patienten mit idiopathischer VTE findet sich in etwa 10% eine zugrunde liegende Tumorerkrankung. Dennoch ist derzeit die Effektivität einer extensiven Tumorsuche bei diesen Patienten nicht belegt. Zahlreiche plasmatische und zelluläre Faktoren sind an der Genese der Hyperkoagulabilität bei Malignomen beteiligt, z.B. Cancer-Prokoagulant und eine Gerinnungsaktivierung im Sinne einer akuten Phase-Reaktion. Operative Eingriffe bei Tumorpatienten gehen mit einem erhöhten Thromboembolierisiko einher, so dass eine intensivere und längere Thromboseprophylaxe nötig werden kann. Auch bei konservativ behandelten Patienten ist ein aktives Malignom mit einem erhöhten Thromboserisiko assoziiert. Tumorpatienten haben unter einer Standard-Thrombosebehandlung mit Vitamin K-Antagonisten (VKA) eine signifikant höhere Versagerrate und vermehrt Rezidiv-VTE. Niedermolekulares Heparin ist in der längerfristigen Sekundärprophylaxe der VTE signifikant wirksamer als VKA. Daher gibt es die Empfehlung niedermolekulares Heparin bei Tumorpatienten für die ersten 3–6 Monate der Sekundärprophylaxe zu verwenden. Erste Hinweise, dass niedermolekulares Heparin bei Tumorpatienten in nicht metastasiertem Stadium zu einer verbesserten Gesamtprognose führen kann, müssen durch weitere Studien belegt werden.

Thromboembolic Disease – Critical Evaluation of Laboratory Investigation

1992 ◽  
Vol 68 (01) ◽  
pp. 007-013 ◽  
Author(s):  
Johan Malm ◽  
Martin Laurell ◽  
Inga Marie Nilsson ◽  
Björn Dahlbäck
Keyword(s):  
Plasminogen Activator ◽  
Laboratory Investigation ◽  
Patient Group ◽  
Vitamin K ◽  
Protein C ◽  
Protein S ◽  
Venous Occlusion ◽  
Thromboembolic Disease ◽  
Fibrinolytic System ◽  
Laboratory Evaluation

SummaryPrevious studies of patients with thromboembolic disease have revealed an association either with hereditary anticoagulant protein deficiencies or with defects in the fibrinolytic system. To obtain a more comprehensive picture and to investigate which analyses are useful in the evaluation of such patients, we have performed an extensive laboratory investigation in 439 individuals with thromboembolic disease. Anticoagulant protein deficiencies were found in 24 patients. Deficiencies of protein C (n = 10) and protein S (n = 9) were most common followed by deficiencies of antithrombin III (n = 3) and plasminogen (n = 2). Six of the nine protein S deficient patients demonstrated a selective deficiency of free protein S with normal total protein S concentrations. To diagnose protein C and S deficiencies among the 201 patients receiving oral vitamin K antagonists, the concentrations of protein C and S were compared with the mean concentration of several other vitamin K-dependent proteins. One protein C and three protein S deficiencies were identified among the treated patients. The number of protein C deficiencies found in this group was significantly lower than the number found among untreated patients. Although fewer protein S deficiencies were also identified among the treated patients, than in the untreated group, the difference was not statistically significant. The results suggest that protein C deficiencies went undetected in the treated group and that oral anticoagulant therapy should be discontinued before efforts to diagnose protein C deficiency are made. We found no cases with heparin cofactor II deficiency. Lupus anticoagulant was present in 10 patients. Evaluation of the fibrinolytic system revealed that the patient group had slightly lower mean euglobulin fibrinolytic activity (EFA) after venous occlusion than controls and a subgroup (approximately 15%) of patients with EFA below the level of the 5th percentile of controls, could be distinguished. Repeated analysis demonstrated a substantial individual day-to-day variation in both patients and controls and the combined EFA results did not clearly distinguish patients from controls. There was a significant negative correlation between EFA and plasminogen activator inhibitor (PAI) levels in both patients and controls and the patient group had significantly higher levels of PAI than the control group. In contrast, there was no difference between controls and patients in tissue plasminogen activator (tPA) release after venous occlusion and no correlation between EFA and tPA was observed. These results suggest that although a statistically significant difference between patients and controls in values of fibrinolytic parameters was found, an extensive laboratory evaluation of the fibrinolytic system in individual patients may not be warranted. The association between patients with thrombosis and deficiencies of anticoagulant proteins suggests that the investigation of individual patients should focus on these components.

ANTICOAGULANT AND ANTIGENIC LEVELS OF PROTEIN C AND PROTEIN S IN PATIENTS ON STABILIZED ORAL ANTICOAGULANT TREATMENT

1987 ◽  
Author(s):  
A D'Angelo ◽  
F Gilardoni ◽  
M P Seveso ◽  
P Poli ◽  
R Quintavalle ◽  
...  
Keyword(s):  
Vitamin K ◽  
Oral Anticoagulant ◽  
Protein C ◽  
Protein S ◽  
Reference Interval ◽  
Factor Ix ◽  
Activity Levels ◽  
Anticoagulant Treatment ◽  
Oral Anticoagulant Treatment ◽  
Congenital Deficiency

Isolated deficiencies of protein C and protein S, two vitamin K-dependent plasma proteins, constitute about 70% of the congenital abnormalities of blood coagulation observed in patients with recurrent venous thrombosis beLow the age of 40. The laboratory diagnosis of congenital deficiency of these proteins represents a major problem since a large proportion of patients are on oral anticoagulation (OA) at the time the deficiencies are suspected.Under these circumstances the availability of a reference interval obtained in patients on stabilized OA has proven useful.Functional (C) and antigenic levels (Ag) of protein C, protein S, factor IX and II were estimated in 136 patients on stabilized OA, subdivided according to the degree of anticoagulation (Internatio nal Normalized Ratio, INR).The results indicate that with increasing anticoagulation the activity levels of all the vitamin K-dependent factors decrease to a greater extent than the corresponding antigenic levels. At variance with the other factors, total protein S antigen levels are only moderately reduced by OA with protein S anticoagulant activi ty comparing well to factor IX clotting activity. These data suggest the possibility of identifying both quantitative and qualita tive deficiencies of protein C and protein S in patients on oral anticoagulant treatment.

Vitamin K–Dependent Protein S: Beyond the Protein C Pathway

2017 ◽  
Vol 44 (02) ◽  
pp. 176-184 ◽  
Author(s):  
Björn Dahlbäck
Keyword(s):  
Vitamin K ◽  
Protein C ◽  
Vascular System ◽  
System Development ◽  
Regulatory Protein ◽  
Protein S ◽  
Receptor Interaction ◽  
Fetal Life ◽  
High Molecular Weight Complex ◽  
Increased Risk

AbstractProtein S is a vitamin K–dependent plasma glycoprotein circulating in plasma at a concentration of around 350 nM. Approximately 60% of protein S in human plasma is bound to the complement regulatory protein C4b-binding protein (C4BP) in a high-affinity, high-molecular-weight complex. Protein S in plasma has multiple anticoagulant properties and heterozygous protein S deficiency is associated with increased risk of venous thrombosis. Homozygous deficiency in man and mice is associated with severe thrombosis in fetal life, defects in the vascular system development, and not compatible with life. Protein S has additional functions beyond being an anticoagulant. It affects the complement regulatory properties of C4BP, and moreover, protein S interacts with tyrosine kinase receptors of the TAM family, which comprises Tyro3, Axl, and Mer. The TAM receptor interaction is important for the ability of protein S to stimulate phagocytosis of apoptotic cells. This review will discuss the multiple functions of protein S, describing its role as cofactor to activated protein C with a subsequent focus on the other functions of protein S.

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