- Email: [email protected]
D-dieter during intra-arterial low-dose streptokinase treatment of peripheral arterial occlusive disease
Fibrinofysis(1994) 8,
Suppl 2, 105-107
CD1994Longmao Group Ltd
D-Dimer During Intra-Arterial Occlusive Disease
M. Stegnar,
Low-Dose Streptokinase
Treatment
of Peripheral
Arterial
M. Kozak, M. SaboviE
SUMMARY. In order to assess systemic and local intra-arterial
levels of D-dimer, a specific degradation product of cross-linked fibrin, blood samples were obtained before and 0.5, 1.5, 4, 8, 24, and 48 hours after the start of intra-arterial low dose streptokinase treatment (3750 IU/h) in 21 patients with angiographically documented peripheral arterial occlusive disease. Blood was sampled simultaneously from the cubital vein and from the arterial catheter located close to the occlusive thrombus. Pre-treatment D-dimer levels in arterial and venous blood were 298 and 259 ng/mL (medians), respectively. During the first day of treatment D-dimer levels in arterial blood increased on average lo-20 fold and were at all times significantly higher than D-dimer levels in venous blood (artery vs vein; 0.5 h: 414 vs 266; 1.5 h: 2640 vs 411; 4 h: 2490 vs 898; 8 h: 2640 vs 906; 24 h: 6290 vs 1060 ng/mL, medians). In 13 patients in whom recanalization was achieved D-dimer levels were higher than in 8 unsuccessfully treated patients (vein: p < 0.05; artery: not significant). Significant decreases in plasminogen, 01~antiplasmin, fibrinogen and euglobulin clot lysis time indicated fibrinolytic activation in local arterial as well as in systemic venous blood. It was concluded that higher D-dimer in the vicinity of the thrombus compared to systemic levels reflected local lysis of fibrin. Systemic levels of D-dimer might provide early information on the efficacy of the treatment. KEYWORDS.
D-dimer.
Thrombolysis.
Streptokinase.
Peripheral
arterial occlusive
disease
INTRODUCTION
PATIENTS
D-dimer, a specific degradation product of cross-linked fibrin, has been extensively studied in patients with venous thromboembolism and myocardial infarction, as a marker of intravascular thrombus formation and dissolution.‘v2 In systemic thrombolytic therapy with various thrombolytic agents it was found useful in monitoring the therapy and in predicting the therapeutic outcome.*y3 Systemic intravenous administration of streptokinase can cause marked systemic activation of fibrinolysis and can therefore be associated with serious haemorrhagic complications. Intra-arterial thrombolytic therapy delivering much lower doses of streptokinase close to the thrombus aims at localized activation of tibrinolysis at the thrombus site without systemic effects. The aim of the present study was to assess systemic and local intraarterial levels of D-dimer during intra-arterial low dose streptokinase treatment of peripheral arterial occlusive disease in order to compare them with other parameters of tibrinolytic activation and with the therapeutic outcome.
In 21 patients (5 women and 16 men, 39-80, mean 61 years old) with angiographically documented peripheral arterial occlusive disease low dose streptokinase (3750 N/h) was applied through an intra-arterial catheter located close to the occlusive thrombus. Treatment was continued until recanalization or for at most 3 days. Blood was sampled simultaneously from the cubital vein and from the arterial catheter located close to the thrombus before treatment and 0.5, 1.5, 4, 8, 24, and 48 hours after start of the treatment. Blood was collected into 0.13 mol/L trisodium citrate and centrifuged for 30 min at 2000 g and 4°C. Plasma was stored at -70°C until analyzed. D-dimer was determined by enzyme-linked imrnunosorbent assay (TintEliz@ D-dimer, Biopool). D-dimer levels in 13 apparently healthy subjects were 105 f 21 ng!mL (mean + S.D.). Fibrinogen, plasminogen activity, cr,-antiplasmin activity, and euglobulin clot lysis time were also determined in plasma. The differences between D-dimer levels in arterial and venous blood and the differences between patients with and without recanalization were tested by the Wilcoxon matched pairs signed-ranks test and the Mann-Whitney Utest, respectively.
University
Medical
Ljubljana,
Slovenia
Centre,
Tmovo
Hospital
of Internal
Medicine.
I05
AND METHODS
106 D-Dimer During Thrombolysis
levels in arterial blood (948 ng/mL) and venous blood (819 ng/mL, all values medians). In 13 patients with arteriographicallyconfirmed recanalization D-dimer levels either in venous (p < 0.05 at 24 h) or in arterial blood (not significant) were higher than in 8 unsuccessfully treated patients (Fig. 1). During the first day of treatment venous D-dimer levels over 1000 ng/mL were observed more frequently in patients with recanalization (24165 measurements) than in unsuccessfully treated patients (5/38 measurements, p < 0.05). In all patients treatment-dependent reduction of plasminogen, cr,-antiplasmin, fibrinogen and euglobulin clot lysis time, indicating tibrinolytic activation, was observed both in arterial and venous blood. During the first day of treatment the decrease in the variables measured was significantly greater in local arterial blood and appeared earlier than in venous blood. After 24 h the variables reached approximately the same levels.
ARTER
6000
5000
4000 3000
2000
i-
1000
5 ;0 VEI
E ‘T 5000
p-zo.05
n
A
4000
3000
2000
DISCUSSION
1000
0
0
24
40
hours of treatment
Fig. I D-dimer levels in local atrerial (upper panel) and systemic venous blood (lower panel) in 21 patients with peripheral arterial occlusive disease treated with intra-arterial low dose streptokinase (hatched). From 0.5 h to 24 h of treatment alterial D-dimer levels were significantly higher than venous D-dimer levels. In 13 successfully treated patients (open symbols) higher D-dimer levels were observed in arterial (not significant) and venous blood @ < 0.05 at 24 h) compared to 8 unsuccessfully treated patients (closed symbols). Medians are shown.
The study Committee.
was
approved
by
the
State
Ethical
RESULTS In all patients pretreatment D-dimer levels in venous (259 ng/mL) and arterial blood (298 ng/mL) were on average 2-3 fold higher than in apparently healthy subjects. From 0.5 h to 24 h of treatment, D-dimer levels in arterial blood increased on average lo-20 fold and were at all times significantly higher than D-dimer in venous blood (artery vs vein; 0.5 h: 414 vs 266 ng/mL, p < 0.01; 1.5 h: 2640 vs 411 ng/m.L, p C 0.001; 4 h: 2490 vs 898 rig/m.... p < 0.05; 8 h: 2640 vs 906 ng/mL, p < 0.05; 24 h: 6290 vs 1060 ng/mL, p = 0.08). At 48 h of treatment Ddimer decreased to approximately the same
In the present study intra-arterial fibrinolysis close to the occlusive thrombus in peripheral arteries is reported. Fibrinolytic activation during in&a-arterial low dose streptokinase treatment was assessed by the levels of Ddimer. During the first day of treatment significantly higher D-dimer levels were observed in local arterial than in systemic venous blood and were attributed to local lysis of fibrin. Decreases in plasminogen, ar,-antiplasmin, fibrinogen and euglobulin clot lysis time were also greater in arterial blood indicating enhanced local activation near the thrombus. Later on, the differences between arterial fibrinolytic parameters faded away, and venous presumably due to increased distance between the catheter tip and/or better outflow due to partial or complete lysis of the thrombus. An increase in D-dimer levels and a decrease in other fibrinolytic parameters measured were also observed in venous blood, confirming previous reports on the systemic effect of local intra-arterial treatment of peripheral arterial occlusive disease.4*5 The main reason for the significant increase in D-dimer in systemic blood was considered to be lysis of the thrombus, which is huge in peripheral arteries compared to e.g. the thrombus in coronary arteries. Higher D-dimer levels in successfully treated patients supported this presumption. Evaluation of the D-dimer assay as a diagnostic, prognostic and monitoring tool in procedures on occluded peripheral arteries is in its infancy and the present results are conflicting. In this study increased D-dimer levels in venous blood (> 150 ng/mL) prior to treatment were observed in all but one patient, but there was no difference between patients with or without recanalization. However, during the first day of treatment higher Ddimer levels in arterial and in venous blood were observed in successfully treated patients, implying that the amount of fibrin dissolved was greater than in patients without recanalization. In patients undergoing percu-
Fibrinolysis
taneous transh.uninal angioplasty significantly higher Ddimer levels were observed before and shortly after the procedure in patients subsequently suffering thrombotic reocclusion than in patients with patency of the dilated arterial segment.6 On the contrary, the lowest initial Ddimer was seen in the only patient who suffered rethrombosis within 24 hours after local application of recombinant human tissue-type plasminogen activator.’ In conclusion, D-dimer reflected local lysis of fibrin in arterial blood close to the thrombus in the course of intra-arterial low dose streptokinase treatment. Systemic levels of D-dimer might provide early information on the efficacy of the treatment.
REFERENCES 1.
2.
3.
4.
ACKNOWLEDGEMENTS 5.
The study was supported by the Ministry for Science and Technology of the Republic of Slovenia, grant no. P35270-0312. D-dimer kits were a generous gift of Dr. M. R&by.
107
6.
Bounameaux H, de Moerloose P, Perrier A. Reber G 1994 Plasma measurement of D-dimer as a diagnostic aid in suspected venous thromboembolism: an overview. Thromb Haemostas 71: l-6 Lew A S, Berberian F L, cerrek A B, Lee S T, Sah P K, Ganz F W 1986 Elevated serum d-dimer: a degradation product of cross linked fibrin (XDP) after intravenous streptokinase during acute myocardial infarction. J Am Co11 Cardiol 7: 1320-1324 Faivre R, Mirshani M, Ducellier D, Soria C, Soria I, Mirshani M, Kieffer Y, Bassand I P, Caen I, Maurat J P 1988 Evolution of plasma specific fibrin degradation products during thrombolytic therapy in patients with thmmho-embolism. Thmmb Res 50: 583-589 Berridge D C, Eamshaw J J, Westby J C, Makin G S, Hopkinson B R 1989 Fibrinolytic profiles in local low-dose thrombolysis with streptokinase and recombinant tissue plasminogen activator. Thmmb Haemostas 61: 275-278 Koppensteiner R, Speiser W, Minar E, Ahmadi R, Ehringer H 1990 D-dimer in local thrombolytic therapy with low-doses of recombinant human tissue-type plasminogen activator (e-PA) in patients with peripheral arterial occlusive disease. Thromb Haemostas 64: 192- 195 Jorgensen B, Nielsen D J 1993 Value of D-dimer measurement in arterial thromhosis and after angioplasty. Fibrinolysis 7, suppl 2: 23-27
Suppl 2, 105-107
CD1994Longmao Group Ltd
D-Dimer During Intra-Arterial Occlusive Disease
M. Stegnar,
Low-Dose Streptokinase
Treatment
of Peripheral
Arterial
M. Kozak, M. SaboviE
SUMMARY. In order to assess systemic and local intra-arterial
levels of D-dimer, a specific degradation product of cross-linked fibrin, blood samples were obtained before and 0.5, 1.5, 4, 8, 24, and 48 hours after the start of intra-arterial low dose streptokinase treatment (3750 IU/h) in 21 patients with angiographically documented peripheral arterial occlusive disease. Blood was sampled simultaneously from the cubital vein and from the arterial catheter located close to the occlusive thrombus. Pre-treatment D-dimer levels in arterial and venous blood were 298 and 259 ng/mL (medians), respectively. During the first day of treatment D-dimer levels in arterial blood increased on average lo-20 fold and were at all times significantly higher than D-dimer levels in venous blood (artery vs vein; 0.5 h: 414 vs 266; 1.5 h: 2640 vs 411; 4 h: 2490 vs 898; 8 h: 2640 vs 906; 24 h: 6290 vs 1060 ng/mL, medians). In 13 patients in whom recanalization was achieved D-dimer levels were higher than in 8 unsuccessfully treated patients (vein: p < 0.05; artery: not significant). Significant decreases in plasminogen, 01~antiplasmin, fibrinogen and euglobulin clot lysis time indicated fibrinolytic activation in local arterial as well as in systemic venous blood. It was concluded that higher D-dimer in the vicinity of the thrombus compared to systemic levels reflected local lysis of fibrin. Systemic levels of D-dimer might provide early information on the efficacy of the treatment. KEYWORDS.
D-dimer.
Thrombolysis.
Streptokinase.
Peripheral
arterial occlusive
disease
INTRODUCTION
PATIENTS
D-dimer, a specific degradation product of cross-linked fibrin, has been extensively studied in patients with venous thromboembolism and myocardial infarction, as a marker of intravascular thrombus formation and dissolution.‘v2 In systemic thrombolytic therapy with various thrombolytic agents it was found useful in monitoring the therapy and in predicting the therapeutic outcome.*y3 Systemic intravenous administration of streptokinase can cause marked systemic activation of fibrinolysis and can therefore be associated with serious haemorrhagic complications. Intra-arterial thrombolytic therapy delivering much lower doses of streptokinase close to the thrombus aims at localized activation of tibrinolysis at the thrombus site without systemic effects. The aim of the present study was to assess systemic and local intraarterial levels of D-dimer during intra-arterial low dose streptokinase treatment of peripheral arterial occlusive disease in order to compare them with other parameters of tibrinolytic activation and with the therapeutic outcome.
In 21 patients (5 women and 16 men, 39-80, mean 61 years old) with angiographically documented peripheral arterial occlusive disease low dose streptokinase (3750 N/h) was applied through an intra-arterial catheter located close to the occlusive thrombus. Treatment was continued until recanalization or for at most 3 days. Blood was sampled simultaneously from the cubital vein and from the arterial catheter located close to the thrombus before treatment and 0.5, 1.5, 4, 8, 24, and 48 hours after start of the treatment. Blood was collected into 0.13 mol/L trisodium citrate and centrifuged for 30 min at 2000 g and 4°C. Plasma was stored at -70°C until analyzed. D-dimer was determined by enzyme-linked imrnunosorbent assay (TintEliz@ D-dimer, Biopool). D-dimer levels in 13 apparently healthy subjects were 105 f 21 ng!mL (mean + S.D.). Fibrinogen, plasminogen activity, cr,-antiplasmin activity, and euglobulin clot lysis time were also determined in plasma. The differences between D-dimer levels in arterial and venous blood and the differences between patients with and without recanalization were tested by the Wilcoxon matched pairs signed-ranks test and the Mann-Whitney Utest, respectively.
University
Medical
Ljubljana,
Slovenia
Centre,
Tmovo
Hospital
of Internal
Medicine.
I05
AND METHODS
106 D-Dimer During Thrombolysis
levels in arterial blood (948 ng/mL) and venous blood (819 ng/mL, all values medians). In 13 patients with arteriographicallyconfirmed recanalization D-dimer levels either in venous (p < 0.05 at 24 h) or in arterial blood (not significant) were higher than in 8 unsuccessfully treated patients (Fig. 1). During the first day of treatment venous D-dimer levels over 1000 ng/mL were observed more frequently in patients with recanalization (24165 measurements) than in unsuccessfully treated patients (5/38 measurements, p < 0.05). In all patients treatment-dependent reduction of plasminogen, cr,-antiplasmin, fibrinogen and euglobulin clot lysis time, indicating tibrinolytic activation, was observed both in arterial and venous blood. During the first day of treatment the decrease in the variables measured was significantly greater in local arterial blood and appeared earlier than in venous blood. After 24 h the variables reached approximately the same levels.
ARTER
6000
5000
4000 3000
2000
i-
1000
5 ;0 VEI
E ‘T 5000
p-zo.05
n
A
4000
3000
2000
DISCUSSION
1000
0
0
24
40
hours of treatment
Fig. I D-dimer levels in local atrerial (upper panel) and systemic venous blood (lower panel) in 21 patients with peripheral arterial occlusive disease treated with intra-arterial low dose streptokinase (hatched). From 0.5 h to 24 h of treatment alterial D-dimer levels were significantly higher than venous D-dimer levels. In 13 successfully treated patients (open symbols) higher D-dimer levels were observed in arterial (not significant) and venous blood @ < 0.05 at 24 h) compared to 8 unsuccessfully treated patients (closed symbols). Medians are shown.
The study Committee.
was
approved
by
the
State
Ethical
RESULTS In all patients pretreatment D-dimer levels in venous (259 ng/mL) and arterial blood (298 ng/mL) were on average 2-3 fold higher than in apparently healthy subjects. From 0.5 h to 24 h of treatment, D-dimer levels in arterial blood increased on average lo-20 fold and were at all times significantly higher than D-dimer in venous blood (artery vs vein; 0.5 h: 414 vs 266 ng/mL, p < 0.01; 1.5 h: 2640 vs 411 ng/m.L, p C 0.001; 4 h: 2490 vs 898 rig/m.... p < 0.05; 8 h: 2640 vs 906 ng/mL, p < 0.05; 24 h: 6290 vs 1060 ng/mL, p = 0.08). At 48 h of treatment Ddimer decreased to approximately the same
In the present study intra-arterial fibrinolysis close to the occlusive thrombus in peripheral arteries is reported. Fibrinolytic activation during in&a-arterial low dose streptokinase treatment was assessed by the levels of Ddimer. During the first day of treatment significantly higher D-dimer levels were observed in local arterial than in systemic venous blood and were attributed to local lysis of fibrin. Decreases in plasminogen, ar,-antiplasmin, fibrinogen and euglobulin clot lysis time were also greater in arterial blood indicating enhanced local activation near the thrombus. Later on, the differences between arterial fibrinolytic parameters faded away, and venous presumably due to increased distance between the catheter tip and/or better outflow due to partial or complete lysis of the thrombus. An increase in D-dimer levels and a decrease in other fibrinolytic parameters measured were also observed in venous blood, confirming previous reports on the systemic effect of local intra-arterial treatment of peripheral arterial occlusive disease.4*5 The main reason for the significant increase in D-dimer in systemic blood was considered to be lysis of the thrombus, which is huge in peripheral arteries compared to e.g. the thrombus in coronary arteries. Higher D-dimer levels in successfully treated patients supported this presumption. Evaluation of the D-dimer assay as a diagnostic, prognostic and monitoring tool in procedures on occluded peripheral arteries is in its infancy and the present results are conflicting. In this study increased D-dimer levels in venous blood (> 150 ng/mL) prior to treatment were observed in all but one patient, but there was no difference between patients with or without recanalization. However, during the first day of treatment higher Ddimer levels in arterial and in venous blood were observed in successfully treated patients, implying that the amount of fibrin dissolved was greater than in patients without recanalization. In patients undergoing percu-
Fibrinolysis
taneous transh.uninal angioplasty significantly higher Ddimer levels were observed before and shortly after the procedure in patients subsequently suffering thrombotic reocclusion than in patients with patency of the dilated arterial segment.6 On the contrary, the lowest initial Ddimer was seen in the only patient who suffered rethrombosis within 24 hours after local application of recombinant human tissue-type plasminogen activator.’ In conclusion, D-dimer reflected local lysis of fibrin in arterial blood close to the thrombus in the course of intra-arterial low dose streptokinase treatment. Systemic levels of D-dimer might provide early information on the efficacy of the treatment.
REFERENCES 1.
2.
3.
4.
ACKNOWLEDGEMENTS 5.
The study was supported by the Ministry for Science and Technology of the Republic of Slovenia, grant no. P35270-0312. D-dimer kits were a generous gift of Dr. M. R&by.
107
6.
Bounameaux H, de Moerloose P, Perrier A. Reber G 1994 Plasma measurement of D-dimer as a diagnostic aid in suspected venous thromboembolism: an overview. Thromb Haemostas 71: l-6 Lew A S, Berberian F L, cerrek A B, Lee S T, Sah P K, Ganz F W 1986 Elevated serum d-dimer: a degradation product of cross linked fibrin (XDP) after intravenous streptokinase during acute myocardial infarction. J Am Co11 Cardiol 7: 1320-1324 Faivre R, Mirshani M, Ducellier D, Soria C, Soria I, Mirshani M, Kieffer Y, Bassand I P, Caen I, Maurat J P 1988 Evolution of plasma specific fibrin degradation products during thrombolytic therapy in patients with thmmho-embolism. Thmmb Res 50: 583-589 Berridge D C, Eamshaw J J, Westby J C, Makin G S, Hopkinson B R 1989 Fibrinolytic profiles in local low-dose thrombolysis with streptokinase and recombinant tissue plasminogen activator. Thmmb Haemostas 61: 275-278 Koppensteiner R, Speiser W, Minar E, Ahmadi R, Ehringer H 1990 D-dimer in local thrombolytic therapy with low-doses of recombinant human tissue-type plasminogen activator (e-PA) in patients with peripheral arterial occlusive disease. Thromb Haemostas 64: 192- 195 Jorgensen B, Nielsen D J 1993 Value of D-dimer measurement in arterial thromhosis and after angioplasty. Fibrinolysis 7, suppl 2: 23-27