Review Laboratory Tests for Markers of Activation of Coagulation and Fibrinolysis Labortests für Marker der Gerinnungs- und Fibrinolyseaktivierung
F. Dati1·2, H. Pelzer1, Carola Wagner1
Summary: Molecular markers of activation of coagu- n the past two decades significant advances in the un- lation and fibrinolysis have become measurable by I derstanding of basic processes underlying hemostasis common laboratory techniques, e.g. solid phase enzy- and thrombosis have been'made [1,2]. me immunoassay. Thrombin-antithrombin III complex Especially the development of sensitive and specific (TAT), prothrombin fragment [+2 (Fl+2) and fibrin laboratory assays for measuring inhibitors and activa- monomer (FM) reflect thrombin generation or activity, tors of coagulation/fibrinolysis, their complexes as while D-Dimer and plasmin-a2-antiplasmin complex well as activation products has allowed to perform ex- (PAP) indicate secondary fibrinolysis and plasmin ge- tensive studies in various clinical conditions for better neration. Extensive clinical studies have shown the understanding the processes of thrombophilia and hy- specific usefulness of the different activation markers percoagulability, and the causes of thrombosis [3,4]. in thromboembolic diseases, inherited thrombophilia, disseminated intravascular coagulation as well as in anticoagulant or thrombolytic therapy. The review pre- Thrombophilia and hypercoagulability sented summarizes important actual developements in this field of laboratory diagnostics. Increased interest has been given in the last years par- ticularly to the markers of thrombophilia and activati- Keywords: Blood Coagulation Disorders; Dissemina- on of coagulation/fibrinolysis [5,6,7] (tab.l). ted Intravascular Coagulation; Fibrinolysis; Peptide Thrombophilia is characterized as a familial or ac- Fragments; Fibrin-Fibrinogen Degradation Products; quired abnormality of the hemostatic system likely to Thrombi n/metabolism; Plasm in/metabolism predispose to thrombosis such as deficiency of anti- thrombin , protein C or protein S or carrier state for Zusammenfassung: Die molekularen Marker der the FV Leiden mutation. Gerinnungs- und Fibrinolyseaktivierung sind heute mit On the other hand, hypercoagulability reflects a üblichen Labormethoden wie dem Festphasen-Enzym- shift in the hemostatic balance towards an increased immunoassay meßbar. Thrombin-Antithrombin - risk to develop thromboembolism. This is connected Komplex (TAT), Prothrombinfragment 1+2 (Fl+2) with an increased thrombin generation and/or decrea- und Fibrinmonomer (FM) repräsentieren die Bildung sed thrombin inhibition which in turn may promote in- bzw. Aktivität von Thrombin, während D-Dimer und appropriate or excessive fibrin formation and/or plate- Plasmin-a2-Antiplasmin-Komplex (PAP) sekundäre let aggregation. The measurement of the activation Fibinolyse und Plasminbildung anzeigen. Ausgedehnte markers thrombin-antithrombin III complex (TAT), klinische Studien haben den diagnostischen Nutzen prothrombin fragment 1+2 (Fl+2), fibrin monomer der verschiedenen Aktivierungsmarker bei throm- (FM), D-Dimer, and plasmin-a2-antiplasmin complex boembolischen Erkrankungen, angeborener Thrombo- (PAP) allows to determine the extent of hypercoagula- philie, disseminierter intravasaler Gerinnung sowie bei bility and prethrombotic states. Activation markers der antikoagulatorischen oder thrpmbolytischen Thera- provide new insights in the physiologic and pathophy- pie aufgezeigt. Die vorliegende Übersicht faßt wichti- siologic activation of the hemostatic system and are ge aktuelle Entwicklungen und Erkenntnisse auf die- useful for a more differentiated assessment of hemo- sem Gebiet der Laboratoriumsdiagnostik zusammen. static alterations in» an individual patient [8]. Schlüsselwörter: Blutgerinnungsstörungen; Disse- minierte intravasale Gerinnung; Fibrinolyse; Peptid- Formation of activation markers fragmente; Fibrin-Fibrinogenspaltprodukte; Throm- bin/Stoffwechsel; Plasmin/Stoffwechsel. From the scheme of the relevant part of the coagulati-
1 on and fibrinolysis cascade (fig. 1) it is evident that the Behring Diagnostics GmbH, Marburg, Germany key event in the activation of the plasmatic coagulation 2Author for correspondence: Dr. Francesco Dati, Behring Diagnostics GmbH, P.O. Box 1149, D-35001 Marburg, Germany. is the conversion of prothrombin to thrombin, since in Fax: +49-6421-39-3126 vivo only thrombin can convert fibrinogen into fibrin. Recieved: January 14, 1997 The enzyme complex prothrombinase splits prothrom-
314 J Lab Med 1997; 21 (6): 314-322 © 1997 Blackwell Wissenschafts-Verlag, Berlin F. Dati et al.: Activation markers of coagulation and fibrinolysis
Table 1 Markers of hemostasis activation Parameter It reflects
TAT [thrombin-antithrombin complex] The amount of the short-term generated thrombin F1+2 [prothrombin fragment 1+2] The amount of the long-term generated thrombin Fibrin monomer The in-vivo active thrombin -Thrombin activity -Fibrinogen consumption D-Dimer Secondary fibrinolysis Interaction between coagulation and fibrinolysis
PAP [plasmin-a2-antiplasmin complex] The amount of the generated plasmin FDP [fibrin(ogen) degradation products] The truly active plasmin
Intrinsic and extrinsic pathway I FXa 2+ (FVa, PL, Ca ) AT III
Plasminogen activator inhibitoinhibitor (PAI)
tissue-Plasminogen activator (t-PA)
Figure 1 Formation of activation Plasmin-
J Lab Med 1997; 21 (6): 314-322 315 F Dali et al.: Activation markers of coagulation and fibrinolysis
Methods for measurement of activation is AT III, especially when substitution therapy with AT Hi concentrate is performed). markers - monitoring of anticoagulant therapy with heparin/ The molecular markers of aciivalion of coagulation hirudin and vitamin K antagonists. and fibrinolysis are mainly measured by means of - monitoring of thrombolytic therapy in case of acute solid phase enzyme imimmoassays (ELISA), either myocardial infarction and thrombosis (especially with two different antibodies like in the case of TAT pulmonary embolism) (one directed to thrombin, the other to anlilhrombin III), or using a monoclonal antibody directed against Alterations connected with thrombo- the ncoanligen 13,4,9,10,111. embolic risk In the case of Fl+2 the use of monoclonal antibo- dies was nol satisfactory. The break-through was pro- There are various alterations in the coagulations sy- vided by Behring coworkers (Pelzer, Stueber) who stem which are characterized by an increased risk for synthesized a peptide from the C-terminal end of the thromboembolism. This predisposition to thrombosis fragment Fl+2 which is the cleavage site of prothrom- connected with an increased coagulation or decreased bin'by factor Xa [11,12]. Antibodies raised against this fibrinolysis has been termed hypercoagulability, i.e. it peptide and immunoadsorbed were then used to deve- is associated with hypercoagulable states [2,14,15]. lop an ELISA which is very specific for Fl+2 and hig- Alterations in the coagulation system in hypercoa- hly sensitive for detection of low amounts of Fl+2, al- gulable states are: lowing to monitor even a decreased thrombin formati- - reduced inhibitor capacity (FV Leiden mutation, de- on during anticoagulation treatment. fects/deficiency of AT III, protein C, protein S, he- parin cofactor Ð), presence of lupus anticoagulants and increased procoagulant activity (high prothrom- bin, F VIII, F VII, fibrinogen) [16,17]. Usefulness of activation markers Alterations in the fibrinolytic system in hypercoagu- lable states are: dysfibrinogenemia, deficiency of plas- The usefulness of laboratory tests for markers of hy- minogen, defects or diminished release of plasmino- percoagulability and thrombophilia can be seen espe- gen activators, increased inhibitors, F XII deficiency. cially in the following conditions (tab. 2) Other secondary causes of hypercoagulable states - diagnosis, evaluation and prevention of thrombotic are: clinical conditions associated with substantial diseases like in the case of venous or arterial throm- thromboembolic events like tissue injury, myeloproli- bosis. ferative disorders, pregnancy, estrogen therapy, cancer, - diagnosis and monitoring of inherited thrombophi- diabetes, nephrotic syndrome,'postoperative thrombo- lia, especially in congenital and familial abnormali- pathy, obesity, etc. ties of coagulation inhibitors. In these conditions the most important parameters are surely APC Re- sistance/FV Leiden, Protein C, Protein S, AT III and Pathophysiology of DIG antiphospholipid antibodies/lupus anticoagulants. - diagnosis and monitoring of disseminated intravas- DIG is not a specific disease entity, but a pathophysio- cular coagulation (DIG) (further important adjunct logic mechanism that' underlies many disorders ran-
Table 2 Usefulness of Laboratory Tests for Markers of Thrombophilia and Hypercoagulability
- Diagnosis, evaluation and prevention of thrombotic diseases (venous thrombosis / thromboembolism) (arterial thrombosis) {risk pregnancy) - Diagnosis and monitoring of inherited thrombophilia (congenital and familial abnormalities of coagulation inhibitors) - Diagnosis and mqnitoring of DIG (e.g. in sepsis, trauma, malignancy) - Monitoring of anticoagulation (heparin / hirudin) (vitamin K antagonists) - Monitoring of thrombolytic therapy (acute myocardial infarction) (thrombosis)
316 J Lab Med 1997; 21 (6): 314-322 Ihr gerinnungsanalytischer Weg Sichere Frühzeitiger Ausschlußdiagnose Nachweis und bei Lungenembolien präzise und bei Verlaufskontrolle tiefer einer Gerinnungs- Venenthrombose aktivierung
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Preisstand: 1 April 1997 Blackwell Wissenschafts-Verlag Berlin · Wien Kurfürstendamm 57 · D-10707 Berlin · Tel.: +30/32 79 06-27/28 Fax: +30/32 79 06-44 e-mail: [email protected] · Internet: http://www.blackwis.com F. Dati et al.: Activation markers of coagulation and fibrinolysis
Table 3 Trigger mechanisms precipitating intravascular coagulation (DIG) and diseases which are frequently asso- ciated with DIG Mechanism Syndroms Endothelial damage: Septicemia with gram-negative bacteria endotoxins, Jmmune complexes Hepatic insufficiency Malaria Reduced clearance and impaired degradation of coagu- Shock, giant hemangioma lation factors Aortic aneurysm Liver damage Portal hypertension (Tissue-) thromboplastin and thromboplastin-like' sub- Tumors stances; colloidal substances Acute leukemia Hepatic cell necrosis Multiple trauma Viral infections Septic abortion, retained abortion Amniotic fluid embolism Hemolysis (hemolytic-uremic syndrome, thrombotic- thrombocytopenic purpura) Proteolytic enzymes Leukemia Snake bite Foreign surfaces Extracorporeal circulation Antigen/antibody complexes Multiple transfusions Graft rejection Inborn defects Protein C deficiency (Purpura fulminans) Hereditary fructose intolerance adapted from Matthias [39] ging from sepsis to malignancy. In DIG there is simul- TAT, Fl+2, FPA, fibrin monomer and with consumpti- taneous activation of the coagulation, fibrinolytic, and on / decrease of AT III, fibrinogen, platelets and va- platelet systems with resultant systemic hemorrhage rious1 coagulation factors. and microvascular thrombosis [18] (fig. 2). Fibrinolytic activation with degradation of fibrin Stimuli that act as triggering events for DIG include and plasmin-induced changes is connected with eleva- endotoxins, immune complexes, thromboplastin, tion of D-Dimer and PAP and with decrease of fibri- thromboplastin-like and colloidal substances, proteoly- nogen, plasminogen and ci2-antiplasmin. tic enzymes, foreign surfaces, antigen/antibody com- plexes (tab. 3). Application of activation markers in various clinical conditions
Lupus anticoagulants (LA) and increased thrombin Laboratory testing in DIG generation in patients with systemic lupus erythemato- sus (SLE) [21] In disseminated intravascular coagulation (DIG) there In patients with lupus anticoagulants as defined by the are several laboratory parameters which make possible prolongation of at least two different, lipid-depending its detection and the therapy monitoring [5,9,19,20] coagulation tests and positivity of a confirmatory test (tab. 4). increased Fl+2 levels were found. The presence of LA Abnormal values of laboratory tests in DIG are both in SLE patients seems to be strictly related to an on- numerous and variable owing to the wide spectrum of going prothrombotic state. underlying diseases. Presentation of common abnor- malities include elevation of prothrombin time (PT) Activation markers and hypercoagulability [22,23] and activated partial thromboplastin time (APTT). Per- Patients with perioperative hypercoagulability, as de- sistent thrombin formation -leads to continued fibrino- tected by increased levels of Fl+2 and TAT, treated by gen to fibrin conversion with formation/elevation of high dose heparin show improving health conditions
J Lab Med 1997; 21 (6): 314-322 319 F. Dali et al.. Activation markers of coagulation and fibrinolysis
PJathophysiology of Dlc Inflammatory Stimulus !
Thrombin Activation of Coagulation — >· Plasmin fleneration Platelet lactivation Fibrin clot |— ^ | p". 1 r f T \ t Degradation Fibrinolysis Intravascu!ar Fibrinolysis Thrombo- of coagulation inhibition thrombosis activation cytopenia factors I Microcirculatory Degradation disturbance of fibrin r t I \ j Organ Hemorrhage I failure — M Figure 2 Pathophysiology of DIG indicated by normalization of Fl+2 and especially of (in fact TAT/PAP ratio is higher in patients with sepsis TAT concentrations. The measurement of heparin con- or cancer than in those with hematologic malignan- centrations is often not relevant for the monitoring of cies) but also the severity of DIC affects the imbalan- therapy success. ce between thrombin and plasmin activity. Such results may contribute to the decision on the proper therapy, Monitoring of DIC [24] possibly using a combination of anticoagulants and an- DIG patients show often an excessive activation of co- tifibrinoiytic agents. agulation as demonstrated by elevated concentrations of TAT and Fl+2. The TAT / Fl+2 ratio is variable in DIC. The TAT / Conclusions Fl+2 ratio seems to be relatively high when TAT is elevated to a greater extent. Generally, a lower ratio of TAT and Fl+2 are markers of activation of coagulation TAT /Fl+2 could be used to demonstrate the rate of - TAT is a useful tool for the diagnosis of hypercoa- thrombin inactivation by antithrombin III/heparin. gulable states and for monitoring of therapy in DIC, tumors and risk pregnancy [14, 28]. Hypercoagulability in cancer [25,26] Markers of coagulation and fibrinolysis activation (TAT, D-Dimer and PAP) are often elevated in lung cancer patients and are even more markedly increased Table 4 Changes of laboratory tests results in disse- in patients with metastases. These results confirm the minated intravascular coagulation (DIC) presence of a subclinical chronic activation of the co- agulation and fibrinolysis in cancer patients, detectable by the activation markers which may be useful as po- Thrombin-induced changes in DIC tential markers of the clinical progression and progno- Thrombin-antithrombin III complex (TAT) T sis of lung cancer. Fibrin monomer (FM) (soluble fibrin/SF) T Imbalance between thrombin and plasmin activity in Fibrinopeptide A (FPA) T DIC [27] Antithrombin III (ATI4I) 4, The measurement of TAT and PAP in DIC allows to Fibrinogen i obtain information on the degree of thrombin and,plas- Coagulation factors i min activity. In mild DIC both thrombin and plasmin activity were increased, while thrombin activity was predomi- PlasmMnduced changes In DIC nant in moderate DIC, and plasmin activity became D-Dimer excessive when DIC was severe. The differences in the Plasmin-aa-Antiplasmin 'Complex (PAP) elevation of TAT and PAP levels may be partly due to Fibrinogen the delay of subsequent plasmin formation after cxa-Antiplasmin thrombin generation. Not only the underlying disease
320 J Lab Med 1997; 21 (6): 314-322 F. Dati et al.: Activation markers of coagulation and fibrinolysis
- TAT is a marker of still-present thrombin generati- 4. Bauer KA, Rosenberg RD, Activation markers of coagulation on/inhibition after thrombolysis in AMI [29,30,31] Baillieres Clin Haematol 1994;7:523-40. 5. Farced J, Bick RL, Hoppensteadt DA, Bermes EW. Molecular and a prognostic marker for reocclusion [32]. markers of hemostatic activation: applications in the diagnosis of - Fl+2 is useful for diagnosis .not only of hypercoa- thrombosis and vascular and thrombotic disorders. Clin Appl gulable but also of hypocoagulable slates [4,23]. Thrombosis/Hemostasis 1995; 1:87-102. 6. Ofusu FA. Molecular markers of in vivo coagulation and It can be used for monitoring Of thrombin generati- thrombosis. In: L. Poller, editor. Recent Advances in Blood Co- on during anticoagulant therapy with coumarins and · agulation No. 6. Edinburgh (UK): Churchill Livingstone, 1993, heparins [33,34,35]. 51-68. 7. Bruhn HD. Pathophysiology and diagnosis of prethrombosis Fl+2 is, like TAT, a good parameter for monitoring Labmed 1993;17:158-64. therapy of DIG [35]. 8. Hassouna HI. Laboratory evaluation of hemostatic disorders. - Preoperative plasma levels of Fl+2 may indicate Hematology/Oncology Clinics of North America 1993;7:1161- the incidence of deep venous thrombosis after high 1249. 9. Bredbacka S, Blombäck M, Wiman B, Pelzer H. Laboratory risk surgery, e.g. total hip replacement [38]. methods for detecting disseminated intravascular coagulation D-Dimer and PAP are markers of activation of (DIG): new aspects. Acta Anaestesiol Scand 1992;36:128-33. fibrinolysis 10. Hock JA, Sturk A, ten Gate JW, Lamping RJ, Berends F, Born JJ. Laboratory and clinical evaluation of an assay of thrombin-anti- - D-Dimer is useful for diagnosis of secondary fibri- thrombin III complexes in plasma. Clin Chem 1988;34:2058-62. nolysis in response to activation of coagulation 11. Pelzer H, Pilgrim A, Schwarz A, Merte D, Keuper H. Hock H. [25]. Determination of a2-antiplasmin-plasmin complex in human plas- D-Dimer is the best laboratory parameter for exclu- ma with an enzyme-linked immunosorbent assay. Fibrinolysis 1993;7:69-74. sion of deep-vein thrombosis and pulmonary embo- 12. Pelzer H, Schwarz A, Stueber W. Determination of human pro- lism. It can serve as diagnostic parameter for DIG thrombin activation fragment 1+2 in plasma with an antibody [2]- against a synthetic peptide. Thromb Haemostas 1991:65:153-159. 13. Bruhn HD, Conard J, Mannucci PM, Monteagudo J, Pelzer H, - PAP can be used in the diagnosis of hypofibrinoly- Reverter JC, Samama M, Tripodi A, Wagner C. Multicentric eva- tic and hyperfibrinolytic states [27]. luation of a new assay for prothrombin fragment F 1+2 determina- PAP is useful for the monitoring of DIG being a tion. Thromb Haemostas 1992;68:413-7. 14. Alving BM. The hypercoagulable states. Hosp Pract prognostic marker for such condition. It is also a 1993;28:109-21. prognostic marker for bad outcome (e.g. AMI) in 15. Mammen EF, Fujii Y. Hypercoagulable states. Lab Med patients with unstable angina pectoris [37]. 1989;20:611-6. 16. Schwartz RS, Bauer KA, Rosenberg RD, Kavanaugh EJ. Davies DC, Bogdanoff DA. Clinical experience with antithrombin III concentrate in treatment of congenital and acquired deficiency References of antithrombin. Am J Med 1989;87 (Suppl 3 B):53S-60S. 1. Furie B, Furie BC. Molecular and cellular biology of blood co- 17. Hopmeier P. The clinical significance of a deficiency in anti- agulation. N Engl J Med 1992;326:800-6. thrombin III, protein C or protein S. Lab Med 1993:17:277-88. 2. Bick RL, Pegram M. Syndromes of hypercoagulability and 18. Miiller-Berghaus G. Pathophysiologic and biochemical events thrombosis: A review. Sem Thromb Hemost 1994;20:109-32. in disseminated intravascular coagulation dysregulation of proagu- 3. Bauer KA. Laboratory markers of coagulation activation. Arch lant and anticoagulant pathways. Sem Thromb Hemostas Pathol Lab Med 1993; 117:17-77. 1989;15:58-87.
Table 5 Characteristics of activation of coagulation and fibrinolysis TAT . F1+2 D-Dimer PAP Thrombin-antithrom- Prothrombin fragment Degradation product Plasmin-Gt2-antiplas- bin 111 complex 1+2 of crosslinked fibrin min complex
Reference range """"< 4.1 pg/l 0.4-1.1 nmol/l " < 78 Mg/l 120-700 pg/l Biological halt-life 10-15 min 90 min 8 hours 12 hours Indications Diagnosis of hyper- Diagnosis of hyperco- Diagnosis of secon- Diagnosis of hypo- coagulable states agulable and hypo- dary fibrinolysis in re- fibrinolytic and hyper- coagulable states sponse to activation fibrinolytic states of coagulation Monitoring of therapy . Monitoring of anti- Diagnosis of primary in DIC, tumors and coagulant therapy Exclusion of deep hyperfibrinolysis risk -pregnancies • Oral anticoagulant vein thrombosis therapy ' (DVT) and pulmonary Monitoring of therapy Prognostic marker for '· Heparin embolism (PE) in DIC and progno- reocclusion after suc- stic marker cessful fibrinolytic Monitoring of therapy Diagnosis of DIC therapy of myocardial in DIC, tumors and Prognostic marker I infarction risk pregnancies for AMI in unstable angina
J Lab Med 1997; 21 (6): 314-322 321 R Dati et al.: Activation markers of coagulation and fibrinolysis
19. Bick RL. Disseminated intravascular coagulation: objective cri- levels demonstrate hypcrcoagulability induced during loco-regional teria for clinical and laboratory diagnosis and assessment of thera- thrombolytic therapy with rt-PA. Thromb Res I994;73: 109-115. pcmic response. Clin Appl Thrombosis/Hemostasis 1995; 1:3-23. 30. Szeczeklik A, Dropinski J, Radwan J, Krazanowski M. Persi- 20. Schmaler AH. Disseminated intravascular coagulation: patho- stent generation of thrombin after acute myocardial infarction. Ar- genesis and management. J Intensive Care Med I99I;6:209-28. teriosclerosis Thrombosis 1992; 12:548-53. 21. Ferro D, Quintarolli C, Valesini G, Violi R Lupus anticoagulant 31. Biasucci LM, Meijer P, Liuzzo G, Scabbia EV, Maseri A, Kluft and increased thrombin generation in patients with systemic lupus C. Thrombin-antithrpmbin III complexes during thrombolytic crythcmatosus. Blood 1994;83:304. therapy with rt-PA in acute myocardial infarction. Fibrinolysis 22. Amelsberg A, Zuborn KH, Gartner V, Kiehne KH, Preuße AK, 1992; 3 (Suppl):71-2. Bruhn HD. Influence of heparin treatment on biochemical markers 32. Gulba DC, Dansel WG, Simon R, Jost S, Barthels M, Amende of an activation of the coagulation system. Thromb Res I, Rafflenbeul W, Lichtlen PR. Role of thrombolysis and thrombin in 1992;66:121-31. patients with acute coronary occlusion during percutaneous translu- 23. Bruhn HD. Licbsch J, Wagner C. Documentation of hypercoa- minal coronary angioplasty. J Am Coll Cardiol 1990; 16:563-8. gulability by measurement of prothrombin fragment F 1+2 when 33. Takano K, lino K, Ibayashi S, Tagawa K, Sadoshima S, Fujis- introducing oral anticoagulant therapy. Thromb Res 1992;68:317-9. hima M. Hypercoagulable state under low-intensity warfarin anti- 24. Takahashi H, Wada K, Satoh N, Takakuwa E, Furuta R, Yoshi- coagulation assessed with hemostatic markers in cardiac disorders. no N, Shibata A. Evaluation of oral anticoagulant therapy by mea- Am J Cardiol 1994; 74:935-9. suring plasma prothrombin fragment 1+2. Blood Coag Fibrinol 34. Van Wersch JWJ, van Mourik-Alderliesten CH, Coremans A. 1993:4:435-9. Comparison of markers of coagulation activation in patients under 25. Gabazza EC, Taguchi O, Yamakami T, Machishi M, Ibata H, oral anticoagulation at different levels. Eur J Clin Chem Clin Bio- Suzuki S. Evaluating prethrombotic state in lung .cancer using chem 1992;30:461-6. molecular markers. Chest 1993; 103:196-200. 35. Brack MJ, Hubner PJB, Gershlich AH. Anticoagulation after 26. Gabazza EC, Taguchi O, Yamakami T, Machishi M, Ibata H, intracoronary stent insertion. B r Heart J 1994;72:294-6. Tsutsui K, Suzuki S. Coagulation - fibrinolysis system and markers 36. Wada H, Minamikawa K, Wakita Y, Nakase T, Kaneko T, of collagen metabolism in lung cancer. Cancer 1992;70:2631-6. Okiwa M, Tamaki S, Deguchi A, Mori Y, Deguchi K, Shirakawa S, 27. Kario K, Matsuo T, Kodama K, Malsuo M, Yamamoto K, Suzuki K. Hemostatic study before onset of disseminated intravas- Kobayashi H. Imbalance between thrombin and plasmin activity in cular coagulation. Am J Hematol 1993;43:190-4. disseminated intravascular coagulation. Haemostasis 1992;22:179- 37. Biasucci LM, Liuzzo G, Monaco C, Quaranta G, Caligiuri G, 86. Rebuzzi AG, van de Greef W, Maseri A, Kluft C. Plasmin-antiplas- 28. Seite R, Rappe N, Kraus M, Immel A, Wolf M, Maasberg M, min complexes in prognostic evaluation of patients with unstable Egbring R, Pfab R, Havemann K. Activation of coagulation and fi- angina. Fibrinolysis 1994;2(Suppl.): 126-7. brinolysis in patients with lung cancer: relation to tumour stage-and 38. Cofrancesco E, Cortellaro M, Corradi A, Ravasi F, Bertocchi F. prognosis. Blood Coag Fibrinol 1993;4:249-54. Coagulation activation markers in the prediction of venous thrombosis 29. Garcia-Avello A, Garcia-Frade LJ, Gandarias C, Ocana J, after elective hip surgery. Thromb Haemostas 1997; 77;267-9. Cancelas JA, Lasso M. High. F 1.2 fragment of prothrombin, 39. Matthias FR.' Blood coagulation disorders. Berlin (DE): Sprin- thrombin-antithrombin III complex (TAT) and soluble fibrin plasma ger Verlag, 1987, 87.
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Wulf B. Storch
Grundlagen und neue Anwendungen in der klinischen Immunologie 2., neubearbeitete und erweiterte Auflage 1997. Ca. 320 Seiten mit ca. 200 Abbildungen, davon ca. 145 farbig. 17 24 cm. Gebunden. Ca. DM 198,-/öS 1445,-/sFr 182,50 ISBN 3-89412-329-X
Immunfluoreszenz - eine Labormethode zum mikroskopischen Nach- weis von Antigenen und Antikörpern. Sie wird z. B. zum Erregernachweis in histologischen und zytologischen Präparaten und zur Tumorzelldiffe- renzierung eingesetzt. Darüber hinaus kommt ihr eine entscheidende Bedeutung bei der Diagnose von Autoimmunkrankheiten zu. Die Immunfluoreszenzfibel - ein reich bebildertes Handbuch für die täg- liche praktische Arbeit im Labor - wurde 1979 in ihrer ersten Auflage be- gründet. Auf kaum einem Gebiet der Medizin sind so viele neue Erkennt- nisse zu verzeichnen wie in der Immunologie . Die zweite Auflage des Werkes geht sowohl auf Nachweismethoden ein, die bereits zum festen Bestandteil der Routinediagnostik geworden sind, als auch auf neueste Forschungsergebnisse wie die Entdeckung der Antikörper gegen den Auerbach-Plexus und gegen Podozyten. Der Einsatz moderner techni- scher Verfahren wie konfokale Laserscanning-Mikroskope oder neuerer Fluorochrome ermöglicht in einzigartiger Weise den simultanen und empfindlichen Nachweis verschiedener Substanzen. In der Hand des Erfahrenen ist die Immunfluoreszenz daher durch keine andere Such- methode zu ersetzen.
Preisstand: 1. Februar 1997 Blackwell Wissenschafts-Verlag Berlin · Wien Kurfürstendamm 57 · D-10707 Berlin Tel.: 030/32 79 06-27/28 · Fax: 030/32 79 06-44 e-mail: [email protected] · Internet: http://www.blackwis.com