Zusammenfassung: Die tiefe Venenthrombose ist in Industrieländern ein mit zunehmendem Lebensalter häufiger auftretendes Ereignis. Der Verdacht auf das Vorliegen einer hereditären thrombophilen Diathese und damit die Indikation zur Thrombophiliediagnostik ergibt sich aus dem klinischen Gesamtbild sowie den anamnestischen Informationen. Auch wenn aus Kostengründen eine nicht unmittelbar zur therapeutischen Konsequenz führende Diagnostik prinzipiell vermieden werden sollte, ist die mögliche Konsequenz für Familienangehörige zu berücksichtigen. Zudem ist eine Weiterentwicklung im Bereich der Thrombophiliediagnostik zu erwarten, die im Hinblick auf Prophylaxe und Therapie thromboembolischer Erkrankungen künftig ein differenziertes Vorgehen erlauben wird.
Da der Mangel antikoagulatorischer Proteine das unmittelbare therapeutische Vorgehen beeinflussen kann, ist die Indikation zur Bestimmung von Protein C, Protein S und Antithrombin großzügig zu stellen. Eine Thrombophiliediagnostik sollte möglichst vor Einleitung einer oralen Antikoagulation durchgeführt werden, da Normwerte für die jeweiligen Faktoren einen Defekt definitiv ausschließen und eine Festlegung für das weitere Vorgehen ermöglichen.
Auch bei Vorliegen eines hereditären Thromboserisikofaktors ist nach Erstthrombose die Dauer und Intensität der Antikoagulation in Abhängigkeit von individuellen klinischen und anamnestischen Zeichen einer thrombophilen Diathese festzulegen. Für Träger von Kombinationsdefekten geben erste Daten Hinweise auf einen möglichen Vorteil einer dauerhaften Antikoagulation bereits nach Erstthrombose bei erhöhtem Rezidivrisiko.
Auch bei Vorliegen einer Thrombophilie ist jede prolongierte Antikoagulation im Sinne einer Risiko-Nutzen-Evaluation regelmäßig zu überprüfen und kontinuierlich mit den Daten aus neuen Veröffentlichungen abzugleichen.
Thrombophilia: diagnostic steps and therapeutic consequences
after deep vein thrombosis
Summary: In developed countries there is an age dependent increasing incidence of deep vein thrombosis. Hereditary thrombophilia is usually suspected by the clinical constellation and anamnestic informations. For economical reasons usually laboratory testing should be avoided if the results will not change directly the therapeutic process. But for hereditary defects consequences for the patient in future and for relatives should be taken into account especially as more selective strategies for prophylaxis and treatment have to be expected by increasing information in that field of research.
As deficiencies of anticoagulant proteins (PC, PS, AT) have an impact on anticoagulant treatment, the indication for testing should not be held too strict. Time point for diagnostic procedures should be early after a thromboembolic event as negative results exclude hereditary defects definitely which allows the planning of the aimed treatment duration.
After first onset of deep vein thrombosis, even in presence of hereditary coagulation defects the duration of anticoagulation usually depends on the clinical and anamnestic signs for a thrombophilic tendency of the individual patient. First publications suggest the need for prolonged anticoagulation of carriers with combined defects, showing an elevated rate of re-thrombosis after the first thromboembolic event, when anticoagulation is stopped.
Every ongoing anticoagulation should be checked repeatedly in the sense of a risk -benefit evaluation even for patients with a thrombophilic tendency and should be adapted to actual publications.
Literatur
1
Baglin C, Brown K, Luddington R, Baglin T. East Anglian Thrombophilia Study
Group .
Risk of recurrent venous thromboembolism in
patients with the factor V Leiden (FVR506Q) mutation: Effect of
warfarin and prediction by precipitating factors.
Br J
Haematol.
1998;
100
764-768
2
Dahlbäck B, Carlsson M, Svensson P J.
Familial
thrombophilia due to a previously unrecognised mechanism characterized
by poor anticoagulant response to activated protein C: prediction
of a cofactor to activated protein C.
Proc Natl Acad Sci
USA.
1993;
90
1004-1008
3
De Mitrio V, Marino R, Scaraggi F A. et al .
Influence of factor VIII/ von Willebrand
complex on the activated protein C-resistance phenotype and on the
risk for venous thromboembolism in heterocygous carriers of the
factor V Leiden mutation.
Blood Coagul Fibrinolysis.
1999;
10
409-416
4
De Stefano V, Martinelli I, Mannucci P M. et al .
The risk of recurrent deep venous thrombosis
among heterozygous carriers of both factor V Leiden and the G20210A
prothrombin mutation.
N Engl J Med.
1999;
341
801-806
5
De Stefano V, Zappacosta B, Perschilli S, Rossi E, Casorelli I. et al .
Prevalence of mild hyperhomocysteinaemia
and association with thromboembolic genotypes (factor V Leiden and
prothrombin G20210A) in Italian patients with venous thromboembolic
disease.
B J Haematol.
1999;
106
564-568
6
Den Heijer M, Rosendaal F R, Blom H J.
Hyperhomocysteinemia
and venous thrombosis: a meta-analysis (Abstract).
Thromb
Haemost.
1998;
80
874-877
7
Egeberg O.
Inherited
antithrombin deficiency causing thrombophilia.
Thromb
Diath Haemorrh.
1965;
13
516-530
8
Eichinger S, Pabinger I, Stumpflen A. et al .
The risk of recurrent venous thromboembolism
in patients with and without factor V Leiden.
Thromb Haemost.
1997;
774
624-628
9
Giorlami A, Simioni P, Scarano L, Carraro G.
Prothrombin and the
prothrombin 20 210 G to A polymorphism: their relationship
with hypercoagulabity and thrombosis.
Blood Rev.
1999;
13
205-210
10
Griffin J H, Evatt B, Zimmerman T S, Kleiss A J, Wideman C.
Efficiency
of protein C in congenital thrombotic disease.
J Clin
Invest.
1981;
68
1370-1373
11
Kluijtmans L AJ, den Heijer M, Reitsma P H, Sandra H G, Blom H J, Rosendaal F R.
Thermolabile
Methalenthetrahydrofolate Reductase and Factor V Leiden in the Risk
of Deep-Vein Thrombosis.
Thromb Haemost.
1998;
79
254-258
12
Koster T, Blann A D, Briët E, Vandenbrouke J P, Rosendaal F R.
Role
of clotting factor VIII in effect of von Willebrand factor on occurrence
of deep-vein thrombosis (Abstract).
Lancet.
1995;
345
152-155
13
Koster T, Rosendaal F R, Briët E.
Protein
C deficiency in a controlled series of unselected outpatients: an
infrequent but clear risk factor for venous thrombosis (Leiden Thrombophilia
Study) (Abstract).
Blood.
1995;
85
2756-2761
14
Koster T, Rosendaal F R, De Ronde H, Briët E, Vandenbrouke J P, Bertina R M.
Venous thrombosis
due to a poor anticoagulant response to activated protein C: Leiden
Thrombophilia Study.
Lancet.
1993;
342
1503-1506
15
Kraaijenhaagen R A, in`t Anker P S, Koopmann M N. et al .
High plasma concentration of F VIII is
a major risc factor for venous thromboembolism.
Thromb
Haemost.
2000;
83
5-9
16
Kyrle P A, Minar E, Bialoncyk C.
High
levels of Factor VIII and the risk of recurrent venous thromboembolism.
N
Engl J Med.
2000;
343
457-462
17
Margaglione M, D¿Andrea G, Colaizzo D. et al .
Coexistence of factor V Leiden and Faktor
II A20210 mutations and recurrent venous thromboembolism.
Thromb
Haemost.
1999;
82
1583-1587
18
Martinelli I, Mannoucci P M, de Stefano V, Taioli E, Rossi V, Crosti F, Paciaroni K, Leone G, Faioni M.
Different risks of thrombosis
in four coagulation defects associated with inherited thrombophilia:
A study of 150 families.
Blood.
1998;
92
1353-1358
19
Poort S R, Rosendaal F R, Reitsma P H, Bertina R M.
A commongenetic
variation in the 3’-untranslated region of the prothrombin
gene isassociated with elevated plasma prothrombin levels and an
increase invenous thrombosis (Abstract).
Blood.
1996;
88
3698-3603
20
Rosendaal F R, Koster T, Vandenbrouke J P, Reitsma P H.
High risk
of thrombosis in patients homozygous for factor V Leiden (activated
protein C resistance) (Abstract).
Blood.
1995;
85
1504-1508
21
Rosendaal F R.
Thrombosis
in the young: epidemiology and risk factors, a focus on venous thrombosis
(Abstract).
Thromb Haemost.
1997;
78
1-6
22
Ryan D H, Creowther M A, Ginsberg J S, Francis C W.
Relation of
Factor V Leiden genotype to risk for acute deep venous thrombosis
after joint replacement surgery.
Ann Intern Med.
1998;
128
270-276
23
Sanson B J, Simioni P, Tormene D.
The
incidence of venous thromboembolism in asymptomatic carriers of
a deficiency of antithrombin, proteinc, or protein s: a prospective
cohort study.
Blood.
1999;
94
3702-3706
24
Sarasin F P, Bounameaux H.
Decision analysis
model of prolonged oral anticoagulant treatment in factor V Leiden
carriers with first episode of deep vein thrombosis.
BMJ.
1998;
316
95-99
25
Schwartz H P, Fischer M, Hopmeier P, Batard M A, Griffin J H.
Plasma
protein S deficiency in familial thrombotic disease.
Blood.
1984;
64
1297-1300
26
Soria J M, Almasy L, Souto J C. et al .
Linkage analysis demonstrates that the
prothrombin G202010A mutation jointly influences plasma prothrombin
levels and risk of thrombosis.
Blood.
2000;
95
2780-2785
27
Souto J C, Mateo J, Soria J M. et al .
Homocygotes for prothrombin gene 20 210
A allele in a thrombophilic family without clinical manifestations
of venous thromboembolism.
Haematologica.
1999;
84
627-632
28
Svensson P J, Benoni G, Fredin H. et al .
Female gender and resistance to activated
protein C(FV:Q 506) as potential risk factors for thrombosis after
elective hip arthroplasty.
Thromb Haemost.
1997;
78
993-996
29
Van der Meer F JM, Koster T, Vandenbrouke J P, Briët E, Rosendaal F R.
The
Leiden thrombophilia study (LETS).
Thrombosis and Haemostasis.
1997;
78
631-635
30
Woolson S T, Zehnder L L, Maloney W J.
Factor
V Leiden and the risk of proximal venous thrombosis after total
hip arthroplasty.
J Arthroplasty.
1998;
13
207-210
Korrespondenz
Professor Dr. med. H. Völler
Klinik am See, Reha-Zentrum für Innere
Medizin
15562 Rüdersdorf/Berlin
Phone: +49/33638/78623
Fax: +49/33638/78624
Email: heinz.voeller@klinikamsee.com