ABSTRACT
D-dimer measurement is commonly included in the diagnostic workup of patients with suspected acute symptomatic deep venous thrombosis and pulmonary embolism. As a haemostatic marker, it could be theoretically useful in other thromboembolic disorders, such as acute cerebrovascular events. In this review we summarize published literature on D-dimer testing in acute ischemic stroke and cerebral sinus and venous thrombosis (CSVT), discussing possible clinical diagnostic and therapeutical applications. In ischemic stroke, mounting evidence suggests a possible role of D-dimer in the acute diagnosis of ischemic stroke subtypes, especially in identifying tromboembolic and lacunar stroke. Its prognostic role still remains unclear, due to conflicting data. D-dimer could be also an useful screening test for excluding CSVT in patients presenting with acute headache, making the presence of cerebral thrombosis unlikely with low plasma levels. In this clinical setting sensitivity and negative predictive value are comparable to that reported in the diagnosis of acute thromboembolic disease. However, more studies are needed to confirm these recent findings as well as management studies to correctly introduce D-dimer measurement in clinical daily practice of ischemic stroke and CSVT.
KEYWORDS
D-dimer - ischemic stroke - cerebral sinus and venous thrombosis - deep venous thrombosis - diagnosis - prognosis
REFERENCES
-
1
Rylatt D B, Blake A S, Cottis L E et al..
An immunoassay for human D-dimer using monoclonal antibodies.
Thromb Res.
1983;
31
767-778
-
2
Van der Graaf F, van den Borne H, van der Kolk M, de Wild P J, Janssen GWT, van Uum AHM.
Exclusion of deep venous thrombosis with D-dimer testing. Comparison of 13 D-dimer methods in 99 outpatients suspected of deep venous thrombosis using venography as reference standard.
Thromb Haemost.
2000;
83
191-198
-
3
Gaffney P J, Creighton L J, Callus M J, Thorpe R.
Monoclonal antibodies to cross-linked fibrin degradation products (XL-FDP)-Evolution in a variety of clinical conditions.
Br J Haematol.
1988;
68
91-96
-
4 World Health Organization .World Health Report 2002. Geneva, Switzerland; WHO 2002
-
5
Adams Jr H P, Adams R J, Brott T Stroke Council of the American Stoke Association et al..
Guidelines for the early management of patients with ischemic stroke. A scientific statement from the Stroke Council of the American Stroke Association.
Stroke.
2003;
34
1056-1083
-
6
Johnson C J, Kittner S J, McCarter R J et al..
Interrater reliability of an etiologic classification of ischemic stroke.
Stroke.
1995;
26
46-51
-
7
Bamford J, Sandercock P, Dennis M et al..
Classification and natural history of clinically identifiable subtypes of cerebral infarction.
Lancet.
1991;
337
1521-1526
-
8
Adams Jr H P, Bendixen B H, Kappelle L J et al..
Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment.
Stroke.
1993;
24
35-41
-
9
Kolominsky-Rabas P L, Weber M, Gefeller O, Neundoerfer B, Heuschmann P U.
Epidemiology of ischemic stroke subtypes according to TOAST criteria. Incidence, recurrence, and long-term survival in ischemic stroke subtypes: a population-based study.
Stroke.
2001;
32
2735-2740
-
10
Feinberg W M, Bruck D C, Ring M E, Corrigan Jr J J.
Hemostatic markers in acute stroke.
Stroke.
1989;
20
592-597
-
11
Fon E A, Mackey A, Cote R et al..
Hemostatic markers in acute transient ischemic attacks.
Stroke.
1994;
25
282-286
-
12
Fisher M, Francis R.
Altered coagulation in cerebral ischemia. Platelet, thrombin, and plasmin activity.
Arch Neurol.
1990;
47
1075-1079
-
13
Cotè R, Wolfson C, Solymoss S et al..
Hemostatic markers in patients at risk of cerebral ischemia.
Stroke.
2000;
31
1856-1862
-
14
Ono N, Koyama T, Suehiro A, Oku K, Fujikake K, Kakishita E.
Clinical significance of new coagulation and fibrinolytic markers in ischemic stroke patients.
Stroke.
1991;
22
1369-1373
-
15
Gaines K J, Chesney C, Vander Zwaag R, Cape C.
Racial difference in coagulation studies in stroke.
Neurol Res.
1992;
14(Suppl)
103-108
-
16
Kataoka S, Hirose G, Hori A, Shirakawa T, Saigan T.
Activation of thrombosis and fibrinolysis following brain infarction.
J Neurol Sci.
2000;
181
82-88
-
17
Takano K, Yamaguchi T, Kato H, Omae T.
Activation of coagulation in acute cardioembolic stroke.
Stroke.
1991;
22
12-16
-
18
Takano K, Yamaguchi T, Uchida K.
Markers of a hypercoagulable state following acute ischemic stroke.
Stroke.
1992;
23
194-198
-
19
Altes A, Abellan M T, Mateo J, Avila A, Marti-Vilalta J L, Fontcuberta J.
Hemostatic disturbances in acute ischemic stroke: a study of 86 patients.
Acta Haematol.
1995;
94
10-15
-
20
Ince B, Bayram C, Harmanci H, Ulutin T.
Hemostatic markers in ischemic stroke of undetermined etiology.
Thromb Res.
1999;
96
169-174
-
21
Yamamoto Y, Oiwa K, Hayashi M, Imai K, Nakamura T.
Coagulation and fibrinolytic activation in lacunar infarct patients.
Rinsho Shinkeigaku.
1999;
39
1104-1108
-
22
Yamazaki M, Uchiyama S, Maruyama S.
Alterations of haemostatic markers in various subtypes and phases of stroke.
Blood Coagul Fibrinolysis.
1993;
4
707-712
-
23
Ageno W, Finazzi S, Steidl L et al..
Ischemic subtypes plasma measurement of D-Dimer levels for the early diagnosis of ischemic stroke subtypes.
Arch Intern Med.
2002;
162
2589-2593
-
24
Lip GYH, Lowe GDO, Rumley A, Dunn F G.
Increased markers of thrombogenesis in chronic atrial fibrillation: effects of warfarin treatment.
Br Heart J.
1995;
73
527-533
-
25
Hacke W, Kaste M, Fieschi C For the ECASS Group. et al..
Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke: the European Cooperative Acute Stroke Study.
JAMA.
1995;
274
1017-1025
-
26
Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Diseases and Stroke rt-PA Stroke Study Group.
N Engl J Med.
1995;
333
1581-1587
-
27
Fassbender K, Dempfle C E, Mielke O et al..
Changes in coagulation and fibrinolysis markers in acute ischemic stroke treated with recombinant tissue plasminogen activator.
Stroke.
1999;
30
2101-2104
-
28
The Ancrod Stroke Study Investigators .
Ancrod for the treatment of acute ischemic brain infarction.
Stroke.
1994;
25
1755-1759
-
29
Sherman D G, Atkinson R P, Chippendale T et al..
Intravenous ancrod for treatment of acute ischemic stroke: the STAT Study: a randomized controlled trial: Stroke Treatment with Ancrod Trial.
JAMA.
2000;
283
2395-2403
-
30
Pollak V E, Glas Greenwalt P, Olinger C P, Wadhwa N K, Myre S A.
Ancrod causes rapid thrombolysis in patients with acute stroke.
Am J Med Sci.
1990;
299
319-325
-
31
Dempfle C E, Argiriou S, Kucher K, Muller-Peltzer H, Rubsamen K, Heene D L.
Analysis of fibrin formation and proteolysis during intravenous administration of ancrod.
Blood.
2000;
96
2793-2802
-
32
Hankey G, Warlow C.
Treatment and secondary prevention of stroke: evidence, costs, and effects on individuals and populations.
Lancet.
1999;
354
1457-1463
-
33
Sacco R L, Wolf P A, Kannel W B, McNamara P M.
Survival and recurrence following stroke: the Framingham Study.
Stroke.
1982;
13
290-296
-
34
Burn J, Dennis M, Bamford J, Sandercock P, Wade D, Warlow C.
Long-term risk of recurrent stroke after a first-ever stroke: the Oxfordshire Community Stroke Project.
Stroke.
1994;
25
333-337
-
35
Hart R, Benavente O, McBride R, Pearce L.
Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis.
Ann Intern Med.
1999;
131
492-501
-
36
Thompson S G, Kienast J, Pyke SDM, Haverkate F, van de Loo JCW.
Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris.
N Engl J Med.
1995;
332
635-641
-
37
Ridker P M, Hennekens C H, Cerskus A, Stampfer M H.
Plasma concentration of cross-linked fibrin degradation product (D-dimer) and the risk of future myocardial infarction among apparently healthy men.
Circulation.
1994;
90
2236-2240
-
38
Lowe GDO, Yarnell JWG, Sweetnam P M, Rumley A, Thomas H F, Elwood P C.
Fibrin D-dimer, tissue plasminogen activator, tissue plasminogen activator inhibitor, and the risk of major ischaemic heart disease in the Caerphilly Study.
Thromb Haemost.
1998;
79
129-133
-
39
Lowe GDO, Yarnell JWG, Rumley A, Baiton D, Sweetnam P M.
C-reactive protein, fibrin D-dimer, and incident ischemic heart disease in the Speedwell study: are inflammation and fibrin turnover linked in pathogenesis?.
Arterioscler Thromb Vasc Biol.
2001;
21
603-610
-
40
Moss A J, Goldstein R E, Marder V J et al..
Thrombogenic factors and recurrent coronary events.
Circulation.
1999;
99
2517-2522
-
41
Smith F B, Lee A J, Fowkes FGR, Price J F, Rumley A, Lowe GDO.
Hemostatic factors as predictors of ischemic heart disease and stroke in the Edinburgh Artery Study.
Arterioscler Thromb Vasc Biol.
1997;
17
3321-3325
-
42
Feinberg W M, Erickson L P, Bruck D, Kittelson J.
Hemostatic markers in acute ischemic stroke: association with stroke type, severity, and outcome.
Stroke.
1996;
27
1296-1300
-
43
Lip GYH, Blann A D, Farooqi I S, Zarifis J, Sagar G, Beevers D G.
Sequential alterations in haemorheology, endothelial dysfunction, platelet activation and thrombogenesis in relation to prognosis following acute stroke: The West Birmingham Stroke Project.
Blood Coagul Fibrinolysis.
2002;
13
339-347
-
44
Di Napoli M, Papa F. For the Villa Pini Stroke Data Bank Investigators .
Inflammation, hemostatic markers, and antithrombotic agents in relation to long-term risk of new cardiovascular events in first-ever ischemic stroke patients.
Stroke.
2002;
33
1763-1771
-
45
Bruno A, McConnell J P, Cohen S N et al..
Plasma thrombosis markers following cerebral infarction in African Americans.
Thromb Res.
2005;
115
73-77
-
46
Barber M, Langhorne P, Rumley A, Lowe GDO, Stott D J.
Hemostatic function and progressing ischemic stroke. D-dimer predicts early clinical progression.
Stroke.
2004;
35
1421-1425
-
47
Scandinavian Stroke Study Group .
Multicenter trial of hemodilution in ischemic stroke-back ground and study protocol.
Stroke.
1985;
16
885-890
-
48
van Swieten J C, Koudstaal P J, Visser M C, Schouten H J, van Gijn J.
Intraobserver agreement for the assessment of handicap in stroke patients.
Stroke.
1988;
19
604-607
-
49 Wade D. Measurement in Neurological Rehabilitation. 1st ed. Oxford/New York/Tokyo; Oxford University Press 1992
-
50
Tombul T, Atbas C, Anlar O.
Hemostatic markers and platelet aggregation factors as predictive markers for type of stroke and neurological disability following cerebral infarction.
J Clin Neurosci.
2005;
12
429-434
-
51
Stam J.
Cerebral venous and sinus thrombosis: incidence and causes.
Adv Neurol.
2003;
92
225-232
-
52
Bousser M G, Chiras J, Bories J, Castaigne P.
Cerebral venous thrombosis-a review of 38 cases.
Stroke.
1985;
16
199-213
-
53
Stam J.
Thrombosis of the cerebral veins and sinuses.
N Engl J Med.
2005;
352
1791-1798
-
54
Stam J.
The treatment of cerebral venous sinus thrombosis.
Adv Neurol.
2003;
92
233-240
-
55
Wildberger J E, Mull M, Kilbinger M, Schon S, Vorwerk D.
Cerebral sinus thrombosis: rapid test diagnosis by demonstration of increased plasma D-dimer levels (SimpliRED) [in German].
Rofo.
1997;
167
527-529
-
56
Talbot K, Wright M, Keeling D.
Normal d-dimer levels do not exclude the diagnosis of cerebral venous sinus thrombosis.
J Neurol.
2002;
249
1603-1604
-
57
Tardy B, Tardy-Poncet B, Viallon A et al..
D-dimer levels in patients with suspected acute cerebral venous thrombosis.
Am J Med.
2002;
113
238-241
-
58
Lalive P H, de Moerloose P, Lovblad K, Sarasin F P, Mermillod B, Sztajzel R.
Is measurement of D-dimer useful in the diagnosis of cerebral venous thrombosis?.
Neurology.
2003;
61
1057-1060
-
59
Kosinski C M, Mull M, Schwarz M et al..
Do normal D-dimer levels reliably exclude cerebral sinus thrombosis?.
Stroke.
2004;
35
2820-2825
-
60
Wijdicks E F, Scott J P.
Pulmonary embolism associated with acute stroke.
Mayo Clin Proc.
1997;
72
297-300
-
61
Stein P D, Hull R D, Patel K C et al..
D-dimer for the exclusion of acute venous thrombosis and pulmonary embolism: a systematic review.
Ann Intern Med.
2004;
140
589-602
-
62
Harvey R L, Roth E J, Yarnold P R, Durham J R, Green D.
Deep vein thrombosis in stroke: the use of plasma D-dimer level as a screening test in the rehabilitation setting.
Stroke.
1996;
27
1516-1520
-
63
Kelly J, Rudd A, Lewis R R, Hunt B J.
Venous thromboembolism after acute stroke.
Stroke.
2001;
32
262-267
-
64
Kelly J, Rudd A, Lewis R R et al..
Screening for proximal deep vein thrombosis after acute ischemic stroke: a prospective study using clinical factors and plasma D-dimers.
J Thromb Haemost.
2004;
2
1321-1326
Walter AgenoM.D.
Department of Internal Medicine 1, University of Insubria
Viale Borri, 57, 21100 Varese, Italy
