THROMBOSIS RESEARCH 65; 785790,1992 0049-3848/92 $5.00 + .OOPrinted in the USA. Copyright (c) 1992 Pergamon Press Ltd. All rights reserved.
DIAGNOSTIC
EFFICACY
OF THE D-DIMER
IN DISSEMINATED
INTRAVASCULAR
COAGULATION RODGER
ASSAY
(DIC).
L. BICK AND
WILLIAM REGIONAL
CANCER
F.
BAKER
AND
BLOOD DISEASE CENTER OF KERN AND DEPARTMENT OF MEDICINE, DIVISION OF HEMATOLOGY ONCOLOGY UCLA CENTER FOR THE HEALTH SCIENCES, LOS ANGELES AND BAKERSFIELD, CALIFORNIA, USA
(Received 10.1.1991; accepted in revised form 13.11.1991 by Editor M.W. Mosesson) (Received in final form by Executive Editorial Office 24.1.1992)
ABSTRACT The D-Dimer (D-D) assay for measuring cross-linked fibrin degradation products is now available for the clinical laboratory. We combined this assay with other tests to assess patients with diagnosed or suspected DIC. Also, a small group of patients (20) with deep venous thrombosis (DVT) were studied. The D-D test, antithrombin-Ill assay, FDP titer, fibrinopeptide-A level, protamine sulfate test, fibrinogen, prothrombin time, and activated partial thromboplastin time were used. The D-D test was abnormal in 93.7%, the AT-III level was abnormal in 87.5%, the fibrinopeptide-A level was abnormal in 89.5%, and the FDP titer was elevated in 83.7% of patients with DIC. When assessing patients found not to have confirmed DIC the D-D assay was abnormal in 20%, the AT-III level was abnormal in 8%, and the fibrinopeptide-A level was elevated in 13%. We conclude the D-Dimer assay to be a useful molecular marker of hemostasis in diagnosing DIC and this test will often discriminate between those patients with or without DIC, especially when used with the AT-III and fibrinopeptide-A assays. Of the battery of tests used in this study, the most useful, in descending order of efficacy, appear to be the D-dimer assay (93.7% abnormal), the fibrinopeptide-A titer (89.5% abnormal), the AT-III level (87.5% abnormal), and the FDP titer (83.7% abnormal). Key words:
D-Dimer,
DIC 785
786
D-DIMER ASSAY
Vol. 65, No. 6
Of the global tests, the diagnostic efficacy of the prothrombin time activated partial thromboplastin time, and protamine sulfate test were no greater than chance and appear to be of little use in aiding in a diagnosis of DIC. Also, the D-Dimer assay is similar in cost to the FDP titer and is cost effective for the routine clinical laboratory.
INTRODUCTION Disseminated Intravascular Coagulation (DIC) is a common and complex problem from both the clinical and laboratory diagnostic stand-point, with many available laboratory tests being purported to be of diagnostic significance.l-4 Ddimer is a neo-antigen formed when thrombin initiates the transformation of fibrinogen to fibrin and also activates factor XIII to cross-link the fibrin thus formed; this neo-antigen is formed because of plasmin digestion of cross-linked fibrin.596 The D-dimer assay is, therefore, thought to be specific for fibrin degradation products, whereas the formation of fibrinolytic degradation products (FDP’s), the X, Y, D, and E fragments, may be either fibrinogen or fibrin derived following plasmin digestion. The presence of D-dimer implies the generation of both plasmin and thrombin, the generation of thrombin being implied by thrombin-induced activation of factor XIII to factor Xllla which then cross-links D fragment, giving the dimeric form.7 Monoclonal antibodies have been harvested against the D-dimer neo-antigen DD-3B6/22 and these antibodies are specific for cross-linked fibrin derivatives containing the D-dimer configuration.899 Following the harvesting of these monoclonal antibodies, latex agglutination procedures using latex particles coated with anti-DD-3B6/22 antibody have been developed into commercially available kits. The latex agglutination assay appears equivalent to the monoclonal antibody test, done by enzyme immunoassay,le~tf making the latex agglutination test applicable for measuring D-dimer in plasma, resulting in a clinically applicable and easily The D-dimer assay is available to potentially aid in the performed test. diagnosis of disseminated intravascular coagulation by confirming the generation of plasmin and thrombin and presence of fibrin degradation products. We have used this test as part of a battery of DIC tests to assess its potential efficacy in diagnosing patients with suspected DIC. Other tests done in conjunction with the latex agglutination assay for D-dimer were the antithrombin-Ill level, FDP titer, flbrinopeptide-A level, protamine sulfate test, prothrombin time, activated partial thromboplastin time and fibrinogen level. Also, these assays were done, for comparative purposes in a population of 20 patients with documented Deep Vein Thrombosis (DVT). The results of these findings are herein reported. MATERIALS AND METHODS The D-dimer latex agglutination assay was obtained from American Diagnostica and performed according to manufacturer’s instructions. The fibrinopeptide-A assay was obtained from Mallinckrodt immunoassay systems and performed by RIA according to instructions. The protamine sulfate and FDP assays were obtained from American Dade and performed according to The antithrombin-Ill assay was obtained from KABI manufacturer’s directions. (Coatest), using the chromogenic substrate S-2236 and was performed
Vol. 65, No. 6
D-DIMER
ASSAY
787
according to manufacturer’s instructions on a multistat Ill (Instrumentation Laboratories) analyzer. The prothrombin time and activated partial thromboplastin time were both obtained from Helena Laboratories and performed according to manufacturer’s instructions. Patients studied were those routinely seen in our consultative hematology/oncology medical practice. Sixty-three patients with suspected DIC were seen and evaluated during this study. A diagnosis of DIC was based upon clinical and laboratory evidence as previously describedl* and consisted of finding the appropriate types(s) of hemorrhage / thrombosis in the appropriate clinical setting in association with characteristic abnormal laboratory findings. It was found that forty-eight patients with suspected DIC had the diagnosis confirmed based upon clinical and laboratory findings and fifteen patients initially suspected to have DIC were found to have a different hemorrhagic or thrombotic disorder based upon further clinical and laboratory evaluation. Also, twenty patients with documented deep venous thrombosis (ascending contrast venography or technetium thromboscintograms) were studied for comparative purposes with this same battery of procedures.
iDi
In patients with documented DIC it was found that the D-dimer assay was abnormally elevated (> 200 ug/dl) in 93.7%, with the mean D-dimer level being 1982 ug/dl; in those patients in whom DIC was ruled out, the D-dimer assay was abnormal in 20% with the mean level being 293 ug/dl. These differences were of significance (p = 0.040). In patients with confirmed DIC, the antithrombin-Ill level was abnormal (< 85% normal human plasma [NHP]) in 87.5% of patients, with the mean antithrombin-Ill level being 81.9% of NHP. In patients with suspected but not confirmed DIC, the mean antithrombin-III level was 105% of NHP. These differences were of significance (p < 0.0001). The FDP titer was abnormally elevated (> 40 ug/dl) in 83.7% of patients with confirmed DIC, with the mean titer being 211.9 ug/dl; in those patients with suspected, but not confirmed DIC, the FDP level was elevated in 40% and the mean FDP titer was 32.6 ug/dl. The fibrinopeptide-A titer was abnormal (> 9 ng/dl) in 89.5% of patients with confirmed DIC, with the mean level being 24.8 ng/dl, and the fibtinopeptide-A titer was abnormal in 13% of the non-confirmed DIC patients, with the mean titer being 11.6 ng/dl. The differences in FDP level and fibrinopeptide-A levels between those with or without DIC were not of statistical significance (p = 0.56 and 0.07 respectively). The protamine sulfate test was abnormal (positive) in 26% of patients with confirmed DIC and was abnormal in 13% of patients with suspected but non-confirmed DIC. In the non-confirmed patients, never were the D-dimer, antithrombin-HI, and fibrinopeptide-A results all abnormal. Of significance, in the patients who had non-confirmed DIC, only one patient had a D-dimer level of 2000 ug/dl and all other patients in this group were under 1000 ug/d. The prothrombin time and activated partial thromboplastin time were abnormal in 20% and 48% of patients with confirmed DIC. The mean D-dimer results, antithrombin-Ill results, FDP assay results, and the fibrinopeptide-A results for all three categories of patients studied (confirmed DIC, non-confirmed DIC, and DVT) are summarized in the table.
D-DIMER ASSAY
788
Vol. 85, No. 6
DEEP
VENOUS THROMBOSIS PATIENTS: In assessing twenty patients with deep venous thrombosis, the D-dimer assay was abnormally elevated in 50%, with the mean level being 525 ug/dl; this is significantly different from DIC patients (p = 0.041). The antithrombin-Ill level was depressed in 30% of DVT patients with the mean antithrombin-Ill level being 84.1% of NHP. This also was significantly different from the DIC levels (p = 0.003). The fibrinopeptide-A titer was only abnormal in lo%, with a mean level of 13.3 ng/dl, and the FDP titer was abnormally elevated in 30%, with the mean level being 103 ug/dl; these findings were not significantly different from those found in DIC patients (p’ 0.05). MEAN
ASSAY
VALUES
DIAGNOSIS:
DIC
#
[48]
[15]
(201
D-DIMER
f 982.4
293.3
525
(200
AT-III
61.9
105.4
84.1
> 85%
F.P.-A
24.8
11.7
13.3
< 9 ugldL
FDP
210.9
32.6
103.7
< 40 ug/dL
PATIENTS:
NO DIC
DVT
NORMAL
ASSAY: ug/dL NHP
DISCUSSION Based upon these results, the D-dimer test done by the latex agglutination technique appears to be a useful test for assessing the probability of DIC in the appropriate clinical setting. Indeed, of the tests used in this study, it appeared to be the most reliable (specific) test for probability of being abnormal in patients with confirmed DIC. With this battery of tests, in the appropriate clinical setting, the reliability of the tests used, in descending order of reliability appear to be the D-dimer assay (abnormal in 93.7%), the fibrinopeptide-A level (abnormal in 89.5%), the antithrombin-Ill assay (abnormal However, only the in 87.5%), and the FDP titer (abnormal in 83.7%). differences in the D-dimer and antithrombin-Ill levels, when comparing DIC to The were of statistical significance. non-DIC or DIC to DVT patients, prothrombin time, activated partial thromboplastin time and the protamine sulfate test appear to be of marginal use in DIC patients. Lane and co-workers have studied the D-dimer fragment in 9 patients with DIC and found the levels to be elevated in 8 of the 9.13 Also, Elms and co-workers have assessed D-dimer in DIC patients and found the levels to be elevated in all patients.14 Boisclair and associates evaluated D-dimer and other markers of hemostasis activation in 30 patients with DIC; although measurements of fragment E antigen were more sensitive than the D-dimer assay, the D-dimer assay was found more sensitive than the thrombin-antithrombin (TAT) complex. 1s Carr and coworkers studied Ddimer and FDP in 33 patients with DIC and concluded the FDP titer to be more sensitive and the D-dimer to be the more specific of the two assays.’
Vol. 65, No. 6
D-DIMER ASSAY
789
Based upon our findings and the reports of others, it seems reasonable to conclude that the D-dimer latex agglutination test, measuring the presence of the neo-antigen DD-386122, is a very useful test which is easily done in a routine clinical laboratory and should be included in the armamentarium of tests used to confirm or rule out disseminated intravascular coagulation. Since the D-dimer test is providing the same information as both the FDP titer and the protamine sulfate or ethanol gelation test, it can replace both these tests in the diagnostic work up of a patient with suspected DIC, leading to both cost effectiveness and enhanced diagnostic efficacy.16917 REFERENCES 1.
Bick, RL. Clinical Hemostasis Practice: The Major Impact Of Laboratory Automation: Seminars Thromb. Hemostas. 9,139-171, 1983
2.
Bick, R.L., Fekete, L.F. Antithrombin Ill (AT-III) patterns in disseminated intravascular coagulation. Am J Clin Pathol 73, 577-583, 1980
3.
Bick, R.L. Disseminated intravascular coagulation: A clinical I laboratory study in 48 patients. Ann N.Y. Acad Sci 370, 843-850, 1981
4.
Baker, W.F. Clinical aspects of disseminated intravascular coagulation: clinicians point of view. Seminars Thromb Hemostas 15, l-57, 1989
5.
Plow, EF, Edgington, TS. Surface Markers of Fibrinogen Physiologic Derivatives Revealed By Antibody Probes: Thromb., 38-56, 1982
6.
Francis, CW, Marder, VJ.: A Molecular Crosslinked Fibrin: Seminars Thromb.
7.
Carr, J.M., McKinney, M. and McDonagh, J. Diagnosis of disseminated intravascular coagulation. Role of D-Dimer. Am J Clin Pathol 91, 280-287, 1989
8.
Matsumoto, T, Nishijima, Y, Teramura, Y, Fujino, K, Hibino, M, Hirata, M.:Monoclonal Antibodies to Fibrinogen-Fibrin Degradation Products Which Contain D-Domain: Thromb., 297-302,
a
and Its Seminars
Model of Plasmic Degradation Hemostas. 8, 25-35, 1982
Of
1985
9.
Rylatt, DB, Blake, AS, Cottis, LE, Massingham, DA, Fletcher, WA, Masci, PP, Whitaker, AN, Elms, M, Bunce, I, Webber, AJ, Wyatt, D, Bundesen, PG.: An Immunoassay for Human D-Dimer Using Monoclonal Antibodies.: Thromb. Research 31, 767-778, 1983
10.
Elms, MJ, Bunce, IH, Whitaker, AN. Rapid Products in Plasma Am. J. Clin. Pathol.
Bundesen, PG, Rylatt, DB, Webber, AJ, Masci, PP, Detection of Cross-Linked Fibrin Degradation Using Monoclonal Antibody-Coated Latex Particles: 85,360-364, 1986
790
D-DIMER ASSAY
Vol. 65, No. 6
11.
Greenberg, C.S., Devine, D.V., and McCrae, KM. Measurement of plasma fibrin D-dimer levels with the use of a monoclonal antibody coupled to latex beads. Am J Clin Pathol 87, 94-100, 1987
12.
Bick, R.L. Disseminated intravascular coagulation and related syndromes: a clinical review. Seminars Thromb Hemostas 14, 299-338, 1988
13.
Lane, DA, Preston, FE, Van Ross, ME, Kakkar, VV. Characterization Of Serum Fibrinogen and Fibrin Fragments Produced During Disseminated Intravascular Coagulation: Brit J Haematol 40, 609-815, 1978
14
Masci, PP, Elms, MJ, Bunce, IH, Bundesen, PG, Rylatt, DB, Webber, AJ, Whitaker, AN. Measurement of Crosslinked Fibrin Degradation Productsan Immunoassay Using Monoclonal Antibodies: Thromb. Haemostas. 50, 591, 1983
15
Biosclair, M.D., Lane, D.A., Wilde, J.T., Ireland, H., Preston, F.E., Ofosu, F.A. A Comparative Evaluation of Assays for markers of activated coagulation and/or fibrinolysis: thrombin-antithrombin complex, Ddimer and fibrinogen/fibrin fragment E antigen. Brit J. Haematol. 74, 471479, 1990
18.
Bick, R.L. and Baker, W.F. Diagnostic efficacy of the D-dimer assay in DIC and related disorders. Blood 88 f#5) 329a, 1988
17.
Whitaker, AN, Rowe, EA, Masci, PP, Gaffney, PJ Identification of DDimer-E Complex in Disseminated Intravascular CoagulationThromb. Research 18, 453-459, 1980
DIAGNOSTIC
EFFICACY
OF THE D-DIMER
IN DISSEMINATED
INTRAVASCULAR
COAGULATION RODGER
ASSAY
(DIC).
L. BICK AND
WILLIAM REGIONAL
CANCER
F.
BAKER
AND
BLOOD DISEASE CENTER OF KERN AND DEPARTMENT OF MEDICINE, DIVISION OF HEMATOLOGY ONCOLOGY UCLA CENTER FOR THE HEALTH SCIENCES, LOS ANGELES AND BAKERSFIELD, CALIFORNIA, USA
(Received 10.1.1991; accepted in revised form 13.11.1991 by Editor M.W. Mosesson) (Received in final form by Executive Editorial Office 24.1.1992)
ABSTRACT The D-Dimer (D-D) assay for measuring cross-linked fibrin degradation products is now available for the clinical laboratory. We combined this assay with other tests to assess patients with diagnosed or suspected DIC. Also, a small group of patients (20) with deep venous thrombosis (DVT) were studied. The D-D test, antithrombin-Ill assay, FDP titer, fibrinopeptide-A level, protamine sulfate test, fibrinogen, prothrombin time, and activated partial thromboplastin time were used. The D-D test was abnormal in 93.7%, the AT-III level was abnormal in 87.5%, the fibrinopeptide-A level was abnormal in 89.5%, and the FDP titer was elevated in 83.7% of patients with DIC. When assessing patients found not to have confirmed DIC the D-D assay was abnormal in 20%, the AT-III level was abnormal in 8%, and the fibrinopeptide-A level was elevated in 13%. We conclude the D-Dimer assay to be a useful molecular marker of hemostasis in diagnosing DIC and this test will often discriminate between those patients with or without DIC, especially when used with the AT-III and fibrinopeptide-A assays. Of the battery of tests used in this study, the most useful, in descending order of efficacy, appear to be the D-dimer assay (93.7% abnormal), the fibrinopeptide-A titer (89.5% abnormal), the AT-III level (87.5% abnormal), and the FDP titer (83.7% abnormal). Key words:
D-Dimer,
DIC 785
786
D-DIMER ASSAY
Vol. 65, No. 6
Of the global tests, the diagnostic efficacy of the prothrombin time activated partial thromboplastin time, and protamine sulfate test were no greater than chance and appear to be of little use in aiding in a diagnosis of DIC. Also, the D-Dimer assay is similar in cost to the FDP titer and is cost effective for the routine clinical laboratory.
INTRODUCTION Disseminated Intravascular Coagulation (DIC) is a common and complex problem from both the clinical and laboratory diagnostic stand-point, with many available laboratory tests being purported to be of diagnostic significance.l-4 Ddimer is a neo-antigen formed when thrombin initiates the transformation of fibrinogen to fibrin and also activates factor XIII to cross-link the fibrin thus formed; this neo-antigen is formed because of plasmin digestion of cross-linked fibrin.596 The D-dimer assay is, therefore, thought to be specific for fibrin degradation products, whereas the formation of fibrinolytic degradation products (FDP’s), the X, Y, D, and E fragments, may be either fibrinogen or fibrin derived following plasmin digestion. The presence of D-dimer implies the generation of both plasmin and thrombin, the generation of thrombin being implied by thrombin-induced activation of factor XIII to factor Xllla which then cross-links D fragment, giving the dimeric form.7 Monoclonal antibodies have been harvested against the D-dimer neo-antigen DD-3B6/22 and these antibodies are specific for cross-linked fibrin derivatives containing the D-dimer configuration.899 Following the harvesting of these monoclonal antibodies, latex agglutination procedures using latex particles coated with anti-DD-3B6/22 antibody have been developed into commercially available kits. The latex agglutination assay appears equivalent to the monoclonal antibody test, done by enzyme immunoassay,le~tf making the latex agglutination test applicable for measuring D-dimer in plasma, resulting in a clinically applicable and easily The D-dimer assay is available to potentially aid in the performed test. diagnosis of disseminated intravascular coagulation by confirming the generation of plasmin and thrombin and presence of fibrin degradation products. We have used this test as part of a battery of DIC tests to assess its potential efficacy in diagnosing patients with suspected DIC. Other tests done in conjunction with the latex agglutination assay for D-dimer were the antithrombin-Ill level, FDP titer, flbrinopeptide-A level, protamine sulfate test, prothrombin time, activated partial thromboplastin time and fibrinogen level. Also, these assays were done, for comparative purposes in a population of 20 patients with documented Deep Vein Thrombosis (DVT). The results of these findings are herein reported. MATERIALS AND METHODS The D-dimer latex agglutination assay was obtained from American Diagnostica and performed according to manufacturer’s instructions. The fibrinopeptide-A assay was obtained from Mallinckrodt immunoassay systems and performed by RIA according to instructions. The protamine sulfate and FDP assays were obtained from American Dade and performed according to The antithrombin-Ill assay was obtained from KABI manufacturer’s directions. (Coatest), using the chromogenic substrate S-2236 and was performed
Vol. 65, No. 6
D-DIMER
ASSAY
787
according to manufacturer’s instructions on a multistat Ill (Instrumentation Laboratories) analyzer. The prothrombin time and activated partial thromboplastin time were both obtained from Helena Laboratories and performed according to manufacturer’s instructions. Patients studied were those routinely seen in our consultative hematology/oncology medical practice. Sixty-three patients with suspected DIC were seen and evaluated during this study. A diagnosis of DIC was based upon clinical and laboratory evidence as previously describedl* and consisted of finding the appropriate types(s) of hemorrhage / thrombosis in the appropriate clinical setting in association with characteristic abnormal laboratory findings. It was found that forty-eight patients with suspected DIC had the diagnosis confirmed based upon clinical and laboratory findings and fifteen patients initially suspected to have DIC were found to have a different hemorrhagic or thrombotic disorder based upon further clinical and laboratory evaluation. Also, twenty patients with documented deep venous thrombosis (ascending contrast venography or technetium thromboscintograms) were studied for comparative purposes with this same battery of procedures.
iDi
In patients with documented DIC it was found that the D-dimer assay was abnormally elevated (> 200 ug/dl) in 93.7%, with the mean D-dimer level being 1982 ug/dl; in those patients in whom DIC was ruled out, the D-dimer assay was abnormal in 20% with the mean level being 293 ug/dl. These differences were of significance (p = 0.040). In patients with confirmed DIC, the antithrombin-Ill level was abnormal (< 85% normal human plasma [NHP]) in 87.5% of patients, with the mean antithrombin-Ill level being 81.9% of NHP. In patients with suspected but not confirmed DIC, the mean antithrombin-III level was 105% of NHP. These differences were of significance (p < 0.0001). The FDP titer was abnormally elevated (> 40 ug/dl) in 83.7% of patients with confirmed DIC, with the mean titer being 211.9 ug/dl; in those patients with suspected, but not confirmed DIC, the FDP level was elevated in 40% and the mean FDP titer was 32.6 ug/dl. The fibrinopeptide-A titer was abnormal (> 9 ng/dl) in 89.5% of patients with confirmed DIC, with the mean level being 24.8 ng/dl, and the fibtinopeptide-A titer was abnormal in 13% of the non-confirmed DIC patients, with the mean titer being 11.6 ng/dl. The differences in FDP level and fibrinopeptide-A levels between those with or without DIC were not of statistical significance (p = 0.56 and 0.07 respectively). The protamine sulfate test was abnormal (positive) in 26% of patients with confirmed DIC and was abnormal in 13% of patients with suspected but non-confirmed DIC. In the non-confirmed patients, never were the D-dimer, antithrombin-HI, and fibrinopeptide-A results all abnormal. Of significance, in the patients who had non-confirmed DIC, only one patient had a D-dimer level of 2000 ug/dl and all other patients in this group were under 1000 ug/d. The prothrombin time and activated partial thromboplastin time were abnormal in 20% and 48% of patients with confirmed DIC. The mean D-dimer results, antithrombin-Ill results, FDP assay results, and the fibrinopeptide-A results for all three categories of patients studied (confirmed DIC, non-confirmed DIC, and DVT) are summarized in the table.
D-DIMER ASSAY
788
Vol. 85, No. 6
DEEP
VENOUS THROMBOSIS PATIENTS: In assessing twenty patients with deep venous thrombosis, the D-dimer assay was abnormally elevated in 50%, with the mean level being 525 ug/dl; this is significantly different from DIC patients (p = 0.041). The antithrombin-Ill level was depressed in 30% of DVT patients with the mean antithrombin-Ill level being 84.1% of NHP. This also was significantly different from the DIC levels (p = 0.003). The fibrinopeptide-A titer was only abnormal in lo%, with a mean level of 13.3 ng/dl, and the FDP titer was abnormally elevated in 30%, with the mean level being 103 ug/dl; these findings were not significantly different from those found in DIC patients (p’ 0.05). MEAN
ASSAY
VALUES
DIAGNOSIS:
DIC
#
[48]
[15]
(201
D-DIMER
f 982.4
293.3
525
(200
AT-III
61.9
105.4
84.1
> 85%
F.P.-A
24.8
11.7
13.3
< 9 ugldL
FDP
210.9
32.6
103.7
< 40 ug/dL
PATIENTS:
NO DIC
DVT
NORMAL
ASSAY: ug/dL NHP
DISCUSSION Based upon these results, the D-dimer test done by the latex agglutination technique appears to be a useful test for assessing the probability of DIC in the appropriate clinical setting. Indeed, of the tests used in this study, it appeared to be the most reliable (specific) test for probability of being abnormal in patients with confirmed DIC. With this battery of tests, in the appropriate clinical setting, the reliability of the tests used, in descending order of reliability appear to be the D-dimer assay (abnormal in 93.7%), the fibrinopeptide-A level (abnormal in 89.5%), the antithrombin-Ill assay (abnormal However, only the in 87.5%), and the FDP titer (abnormal in 83.7%). differences in the D-dimer and antithrombin-Ill levels, when comparing DIC to The were of statistical significance. non-DIC or DIC to DVT patients, prothrombin time, activated partial thromboplastin time and the protamine sulfate test appear to be of marginal use in DIC patients. Lane and co-workers have studied the D-dimer fragment in 9 patients with DIC and found the levels to be elevated in 8 of the 9.13 Also, Elms and co-workers have assessed D-dimer in DIC patients and found the levels to be elevated in all patients.14 Boisclair and associates evaluated D-dimer and other markers of hemostasis activation in 30 patients with DIC; although measurements of fragment E antigen were more sensitive than the D-dimer assay, the D-dimer assay was found more sensitive than the thrombin-antithrombin (TAT) complex. 1s Carr and coworkers studied Ddimer and FDP in 33 patients with DIC and concluded the FDP titer to be more sensitive and the D-dimer to be the more specific of the two assays.’
Vol. 65, No. 6
D-DIMER ASSAY
789
Based upon our findings and the reports of others, it seems reasonable to conclude that the D-dimer latex agglutination test, measuring the presence of the neo-antigen DD-386122, is a very useful test which is easily done in a routine clinical laboratory and should be included in the armamentarium of tests used to confirm or rule out disseminated intravascular coagulation. Since the D-dimer test is providing the same information as both the FDP titer and the protamine sulfate or ethanol gelation test, it can replace both these tests in the diagnostic work up of a patient with suspected DIC, leading to both cost effectiveness and enhanced diagnostic efficacy.16917 REFERENCES 1.
Bick, RL. Clinical Hemostasis Practice: The Major Impact Of Laboratory Automation: Seminars Thromb. Hemostas. 9,139-171, 1983
2.
Bick, R.L., Fekete, L.F. Antithrombin Ill (AT-III) patterns in disseminated intravascular coagulation. Am J Clin Pathol 73, 577-583, 1980
3.
Bick, R.L. Disseminated intravascular coagulation: A clinical I laboratory study in 48 patients. Ann N.Y. Acad Sci 370, 843-850, 1981
4.
Baker, W.F. Clinical aspects of disseminated intravascular coagulation: clinicians point of view. Seminars Thromb Hemostas 15, l-57, 1989
5.
Plow, EF, Edgington, TS. Surface Markers of Fibrinogen Physiologic Derivatives Revealed By Antibody Probes: Thromb., 38-56, 1982
6.
Francis, CW, Marder, VJ.: A Molecular Crosslinked Fibrin: Seminars Thromb.
7.
Carr, J.M., McKinney, M. and McDonagh, J. Diagnosis of disseminated intravascular coagulation. Role of D-Dimer. Am J Clin Pathol 91, 280-287, 1989
8.
Matsumoto, T, Nishijima, Y, Teramura, Y, Fujino, K, Hibino, M, Hirata, M.:Monoclonal Antibodies to Fibrinogen-Fibrin Degradation Products Which Contain D-Domain: Thromb., 297-302,
a
and Its Seminars
Model of Plasmic Degradation Hemostas. 8, 25-35, 1982
Of
1985
9.
Rylatt, DB, Blake, AS, Cottis, LE, Massingham, DA, Fletcher, WA, Masci, PP, Whitaker, AN, Elms, M, Bunce, I, Webber, AJ, Wyatt, D, Bundesen, PG.: An Immunoassay for Human D-Dimer Using Monoclonal Antibodies.: Thromb. Research 31, 767-778, 1983
10.
Elms, MJ, Bunce, IH, Whitaker, AN. Rapid Products in Plasma Am. J. Clin. Pathol.
Bundesen, PG, Rylatt, DB, Webber, AJ, Masci, PP, Detection of Cross-Linked Fibrin Degradation Using Monoclonal Antibody-Coated Latex Particles: 85,360-364, 1986
790
D-DIMER ASSAY
Vol. 65, No. 6
11.
Greenberg, C.S., Devine, D.V., and McCrae, KM. Measurement of plasma fibrin D-dimer levels with the use of a monoclonal antibody coupled to latex beads. Am J Clin Pathol 87, 94-100, 1987
12.
Bick, R.L. Disseminated intravascular coagulation and related syndromes: a clinical review. Seminars Thromb Hemostas 14, 299-338, 1988
13.
Lane, DA, Preston, FE, Van Ross, ME, Kakkar, VV. Characterization Of Serum Fibrinogen and Fibrin Fragments Produced During Disseminated Intravascular Coagulation: Brit J Haematol 40, 609-815, 1978
14
Masci, PP, Elms, MJ, Bunce, IH, Bundesen, PG, Rylatt, DB, Webber, AJ, Whitaker, AN. Measurement of Crosslinked Fibrin Degradation Productsan Immunoassay Using Monoclonal Antibodies: Thromb. Haemostas. 50, 591, 1983
15
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