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Tissue factor pathway inhibitor (TFPI) and its response to heparin in patients with spontaneous deep vein thrombosis
THROMBOSIS RESEARCH 72; 467470,1993 00493848193 $6.00 + .OO Printed in the USA. Copyright (c) 1993 Pergamon Press Ltd. All rights reserved.
BRIEF COMMUNICATION TISSUE FACTOR PATHWAY INHIBITOR (TFPI) AND ITS RESPONSE TO HEPARIN IN PATIENTS WITH SPONTANEOUS DEEP VEIN THROMBOSIS Jan Holst, Bengt Lindblad, Eva Wedeberg, David Bergqvist, *Ole Nordfang, *Per B 0stergaard and *Ulla Hedner. Department of Surgery, Lund University, Malmo General Hospital, Malmo, Sweden, *Nova Nordisk A/S, Gentofte, Denmark
(Received
22.4.1993;
accepted
in revised form 25.8.1993
by Editor M.F. Scully)
The serine protease inhibitor Tissue Factor Pathway Inhibitor (TFPI) may be an important regulator of the extrinsic pathway in vivo (1, 2). After forming a complex with FXa it effectively neutralises the catalytic activity of the FVIIa-TF complex and thus halts the formation of thrombin (3) generated through the extrinsic pathway. So far no patient with deep vein thrombosis (DVT) has been detected with a lack of or defective TFPI (4, 5). TFPI is functionally related to heparin. Heparinisation is known to increase pTFP1 in healthy volunteers (6) and in some patients with intestinal malignancies (7). MATERIALS AND METHODS Twenty nine patients were admitted to the department of Emergency Internal Medicine at Malmii General Hospital with symptoms and signs of DVT. A diagnostic phlebography was performed. Patients with a prior history of recurrent DVT, trauma, immobilisation, pregnancy or malignancy were not included in the study. Plasma-TFPI was measured in a two stage chromogenic assay (8), antithrombin III (ATIII) on an ACL 300 (Research Instrument, Instrumentation Laboratory, Italy). Anti-FXa, anti-FIIa and APTT were measured as previously described (9). A baseline plasma sample was obtained immediately after the phlebography was performed. No further samples were taken from the patients with a negative phlebogram. The second plasma sample was drawn 60 min after heparinization. Two therapy strategies were used; both started with a bolus iv injection of 5000 IU standard heparin and were continued with either continuous iv-infusion (target prolongation of APTT of 2-3 fold) or with 250 IU/kg bw subcutaneously (SC)twice daily (target prolongation of APTT with 1.5-2 fold prior to the second injection). A third plasma sample was drawn after the heparin therapy was substituted with warfarin. The fourth sample was obtained during convalescence, approximately a month after the patient had been discharged from the hospital. Key words: TFPI, Heparin, Spontaneous Deep Vein Thrombosis Corresponding author: J Holst, Dept of Surgery, Malmo General Hospital, Lund University, S-214 01 Malmo, Sweden
Vol. 72, No. 5
TFPI, HEPARIN, VENOUS THROMBOSIS
468
RESULTS Fourteen patients had a DVT (mean age 67, SD 16), 7 women and 8 men. 15 patients had a negative phlebogram, in this group sex, age, smoking habits and the onset of symptoms did not statistically differ from the group with DVT. Among the patients with positive phlebography 8 patients received the continuous iv-infusion of heparin and 6 patients heparin subcutaneously. The results with regard to pTFP1 and AT111did not statistically differ between the two groups receiving different heparin regimes. Therefore they are presented as one group. No individual poor responders was identified in either group. The baseline p.TFPI values were 1.3 (SD 0.3) and 1.2 U/ml (SD 0.3) for the patients with positive and negative phlebography respectively. In the second sample (drawn 60 min after the heparin therapy was started) pTFP1 was 2.8 (SD 0.7 U/ml), the third and fourth were 1.4 (SD 0.4) and 1.2 U/ml (SD 0.2) respectively. .KI’..IIlevels were within the reference values in all samples for patients with and without DVT (Fig 1). In the baseline sample of the patients with and without (data not shown) DVT, .antiZXa, anti: FIIa and APT’ were within the reference values. In the second sample from the patients with DVT, a prolongation was observed in all assays but was almost normalised at the third. By the fourth sample anti-FXa, anti-FIIa and APTT were completely normalised (Table 1).
TFPI U/ml 3.50
-
3,25
-
3,00
-
ATIII % l-
120
110
100
2,75
_-__
-
TFPI; posphlebography
90 2so
-
2,25
-
8.
ATIII; pas phlehography
f3
TFPI; neg phlebography
ATIII;
neg phlebography
70 2,00
-
1,751,50-
1,25 -
1.ooFirst
Second
Third
Fourth FIG
1.
Plasma-TFPI and AT111 levels in bloodsamples from patients with spontaneous DVT. The baseline sample was obtained imediately after the phlebography. At this first time point pTFP1 and AT111 levels in the patients with (n=14) and without (n=lS) DVT are shown. At the following time points only results from the patients with DVT are shown. The second sample was obtained 60 min after the injection of unfractionated heparin, the third sample was drawn after the heparin therapy was substituted by warfarin and the fourth was a convalescence sample. All values expressed as mean and SD.
Vol. 72, No. 5
TFPI, HEPARIN, VENOUS THROMBOSIS
Anti-FXa (Anti-FXa IU/ml)
Observation Baseline Second Third Fourth
mean SD mean SD mean SD mean SD
Anti-FIIa (Anti-FIIa U/ml) 0.05 0.05 0.5 0.2 0.1
0.1 0.05 0.01
469
APTT (set) 44.3 5.4 160.3 46.4 84.9 41.7 54.3 14.5
DISCUSSION TFPI is produced by endothelial cells (IO) and the non circulating pool is presumably bound to the luminal surface. When the negatively charged heparin molecules are administered, a displacement of the TFPI molecule most probably occurs and is reflected as an increase of pTFPI(5). It is not known whether the heparin molecules also may induce an increased protein production or how the synthesis of TFPI in general is regulated. In patients with certain intestinal malignancies elevated pTFP1 levels have been observed. These patients also respond with a higher increase of pTFP1 when treated with heparin (7). Such patients are in general more prone to thrombotic events (11). One might argue that they have an ongoing low grade disseminated intravasalcular coagulation (DIC) (12). This elevation of pTFP1 is not likely to be a reflection of the body’s strive for homeostasis since different malignant cellines in vitro are known to produce TFPI (13, 14, 15). In patients with septicaemia and trauma induced DIC, both low (16) and high (17) levels of TFPI are reported. Clinical (18) and experimental (19) reports on ARDS have found elevation of TFPI in broncheo alveolar lavage. So far no patient with DVT with low levels or defective TFPI has been reported (3, 4). Venous occlusion test has also failed to detect fluctuations of pTFPI(5). The present study essentially confirms previous findings. Plasma-TFPI was the same in patients with a positive phlebography and in those with a negative phlebography. The mean pTFP1 increase was ~210% following the standard heparin regimes. This increase is somewhat less compared to what has been found in previous reports (6). The peak values ranged from 150 to 300%. The different pharmacokinetics from iv and SCheparin therapy probably accounts for the wide range observed. Increased TFPI activity was observed in the plasma when the patients were heparinised measured as anti-FXa, anti-FIIa or APTT. As the anticoagulation parameters decreased, as a reflection of heparin elimination, pTFP1 also decreased. This observation, in patients with DVT, has not been reported before but might have been expected from studies on healthy volunteers (20) and experimental animal studies (unpublished data). Warfarin is known to cause no fluctuations in pTFPI(21), which is also observed in this study. The pathophysiological role of TFPI is still obscure. This could be interpreted in principally three different ways; firstly, TFPI is merely an old phylogenetic remnant, secondly, lack of or defective TFPI is not compatible with life or thirdly, the scientific society is still looking in the wrong place. In conclusion Plasma-TFPI in patients with phlebographically confirmed spontaneous DVT was normal as compared to healthy volunteers. Plasma-TFPI-levels varied in parallel with the antiFXa and anti-FIIa-levels during heparin therapy. Acknowledgement The assistance of Dr S Lindgren, Dept of Medicine and Dr C Tornquist, Dept of Radiology are greatly acknowledged. This study was supported by grants from Swedish Medical Research Council 00759.
470
TFPI, HEPARIN, VENOUS THROMBOSIS
Vol. 72, No. 5
REFERENCES 1 RAPAPORT SI. The extrinsic pathway inhibitor, a regulator of the tissue factor-dependent blood coagulation. Thromb Haemost, 66, 6-15, 1991 2 SANDSET PM, ABILDGAARD U. Extrinsic Pathway Inhibitor - The key to feedback control of blood coagulation initiated by tissue thromboplastin. Haemost, 21, 219-39, 1991 3 WARN-CRAMER BJ, RAO LVM, MAKI, SL RAPAPORT SI. Modifications of extrinsic pathway inhibitor (EPI) and factor Xa that effect their ability to interact and to inhibit factor VIItissue factor: evidence for a two step model of inhibition, Thromb Heamost, 60,453-6, 1988 4 SANDSET PM. Studies of extrinsic coagulation inhibitor. Thesis, University of Oslo, 1989. 5 NOVOTNY WF, BROWN SG, GIRARD TJ, MILETICH JP, BROZE GJ Jr. Plasma LACI antigen in patient samples. Blood, 74 (suppl 1) 209a, (abst), 1989. 6 SANDSET PM, ABILDGAARD U, LARSEN ML. Heparin induces release of extrinsic coagulation pathway inhibitor (EPI). Thromb Res, 50,803-13, 1988 7 LINDAHL AK, ABILDGAARD U, STOCKE G. Release of extrinsic pathway inhibitor after heparin injection: increased response in cancer patients. Thromb Res, 59, 651-59, 1990. 8 SANDSET PM, ABILDGAARD U, PETTERSEN M. A sensitive assay of extrinsic coagulation pathway inhibitor (EPI) in plasma and plasma fractions. Thromb Res, 47, 389-400, 1987. 9 MATZSCH T, BERGQVIST D, HEDNER U, 0STERGAARD PB. Effects of an enzymatically depolymerized heparin as compared with conventional heparin. Thromb Haemost, 57, 97-101, 1987. 10 BAJAJ MS, KUPPUSWAMY MN, SAITO H, SPITZER SG, BAJAJ SP. Cultured normal hepatocytes do not synthetize lipoprotein-associated coagulation inhibitor: Evidence that endothelium is the principal site of its synthesis. Proc Nat1 Acad Sci USA, 87, 8869-73, 1990. 11 RICKLES FR, EDWARDS RL. Activation of blood coagulation in cancer Trousseau’s syndrome revisited. Blood, 62, 14-3 1, 1983. 12 BICK RL. Dissiminated intravascular coagulation and related syndromes: a clinical review. Sem Thromb Haemost, 14, 65-81, 1988. 13 BROZE GJ Jr, MILETICH JP. Isolation of the tissue factor inhibitor produced in HepG2 hepatoma cells. Proc Nat1 Acad Sci USA, 84, 1886-90, 1987. 14 NORDFANG 0, NIELSEN LS, JACOBSEN PB. Purification and cloning of extrinsic pathway inhibitor from HeLa cells. Biotech o Plasma Proteins, 98 (abst), 1990. 15 RANA SV, REIMERS HJ, PATHIKONDA MS, BAJAJ SP. Expression of the tissue factor and factor VIIa/tissue factor inhibitor activity in endotoxin or phorbol ester stimulated U937 monocyte-like cells. Blood, 71, 259-62, 1988. 16 BAJAJ MS, RANA SV, WYSOLMERSKI RB, BAJAJ SP. Inhibitor of the factor VIIa-tissue factor complex is reduced in patients with dissiminated intravascular coagulation but not in patients with severe hepatocellular disease. J Clin Invest, 79, 1874-79, 1987. 17 ANDERSSON TR, BELL H, SANDSET PM, 0DEGAARD OR, AAMODT L-M. New coagulation inhibitor levels in pneumonia, dissiminated intravascular coagulation and liver disease. Thromb Haemost, 58, 305A (abst), 1987. 18 IDELL S, JAMES KK, LEVIN EG, SCHWARTZ BS, MANCHANDA N, MAUNDER RJ, MARTIN TR, MCLARTY DS. Local abnormalities in coagulation and fibrinolytic pathways predispose to alveloar fibrin deposits in the adult respiratory distress syndrome. J Clin Invest, 84, 695-705, 1989. 19 IDELL S, PETERS J, JAMES KK, FAIR DS, COALSON JJ. Local abnormalities in coagulation and fibrinolytic pathways that promote alvelolar fibrin deposition in the lungs of baboons with diffuse alveolar damage. J Clin Invset, 84, 181-93,1989. 20 HOLST J, LINDBLAD B, BERGQVIST D, HEDNER U, GARRE K, NORDFANG, 0sTERGAARD P. Effect of protamine sulfate on Tissue Factor Pathway Inhibitor (TFPI) released by iv or SCstandard or low molecular weight heparin. Thromb Haemost, 69, 1114 (abst #2042), 1993. 21 ABILDGAARD u, SANDSET PM, ANDERSSON TR, ODEGAARD OR, ROSEN S. The inhibitor of FVIIa in plasma measured with a sensitive chromgenic substrate assay. Comparison with antithrombin, protein C, heparin cofactor II in a clinical material. Folia Haematol (Leipz), 115, 274-77, 1988.
BRIEF COMMUNICATION TISSUE FACTOR PATHWAY INHIBITOR (TFPI) AND ITS RESPONSE TO HEPARIN IN PATIENTS WITH SPONTANEOUS DEEP VEIN THROMBOSIS Jan Holst, Bengt Lindblad, Eva Wedeberg, David Bergqvist, *Ole Nordfang, *Per B 0stergaard and *Ulla Hedner. Department of Surgery, Lund University, Malmo General Hospital, Malmo, Sweden, *Nova Nordisk A/S, Gentofte, Denmark
(Received
22.4.1993;
accepted
in revised form 25.8.1993
by Editor M.F. Scully)
The serine protease inhibitor Tissue Factor Pathway Inhibitor (TFPI) may be an important regulator of the extrinsic pathway in vivo (1, 2). After forming a complex with FXa it effectively neutralises the catalytic activity of the FVIIa-TF complex and thus halts the formation of thrombin (3) generated through the extrinsic pathway. So far no patient with deep vein thrombosis (DVT) has been detected with a lack of or defective TFPI (4, 5). TFPI is functionally related to heparin. Heparinisation is known to increase pTFP1 in healthy volunteers (6) and in some patients with intestinal malignancies (7). MATERIALS AND METHODS Twenty nine patients were admitted to the department of Emergency Internal Medicine at Malmii General Hospital with symptoms and signs of DVT. A diagnostic phlebography was performed. Patients with a prior history of recurrent DVT, trauma, immobilisation, pregnancy or malignancy were not included in the study. Plasma-TFPI was measured in a two stage chromogenic assay (8), antithrombin III (ATIII) on an ACL 300 (Research Instrument, Instrumentation Laboratory, Italy). Anti-FXa, anti-FIIa and APTT were measured as previously described (9). A baseline plasma sample was obtained immediately after the phlebography was performed. No further samples were taken from the patients with a negative phlebogram. The second plasma sample was drawn 60 min after heparinization. Two therapy strategies were used; both started with a bolus iv injection of 5000 IU standard heparin and were continued with either continuous iv-infusion (target prolongation of APTT of 2-3 fold) or with 250 IU/kg bw subcutaneously (SC)twice daily (target prolongation of APTT with 1.5-2 fold prior to the second injection). A third plasma sample was drawn after the heparin therapy was substituted with warfarin. The fourth sample was obtained during convalescence, approximately a month after the patient had been discharged from the hospital. Key words: TFPI, Heparin, Spontaneous Deep Vein Thrombosis Corresponding author: J Holst, Dept of Surgery, Malmo General Hospital, Lund University, S-214 01 Malmo, Sweden
Vol. 72, No. 5
TFPI, HEPARIN, VENOUS THROMBOSIS
468
RESULTS Fourteen patients had a DVT (mean age 67, SD 16), 7 women and 8 men. 15 patients had a negative phlebogram, in this group sex, age, smoking habits and the onset of symptoms did not statistically differ from the group with DVT. Among the patients with positive phlebography 8 patients received the continuous iv-infusion of heparin and 6 patients heparin subcutaneously. The results with regard to pTFP1 and AT111did not statistically differ between the two groups receiving different heparin regimes. Therefore they are presented as one group. No individual poor responders was identified in either group. The baseline p.TFPI values were 1.3 (SD 0.3) and 1.2 U/ml (SD 0.3) for the patients with positive and negative phlebography respectively. In the second sample (drawn 60 min after the heparin therapy was started) pTFP1 was 2.8 (SD 0.7 U/ml), the third and fourth were 1.4 (SD 0.4) and 1.2 U/ml (SD 0.2) respectively. .KI’..IIlevels were within the reference values in all samples for patients with and without DVT (Fig 1). In the baseline sample of the patients with and without (data not shown) DVT, .antiZXa, anti: FIIa and APT’ were within the reference values. In the second sample from the patients with DVT, a prolongation was observed in all assays but was almost normalised at the third. By the fourth sample anti-FXa, anti-FIIa and APTT were completely normalised (Table 1).
TFPI U/ml 3.50
-
3,25
-
3,00
-
ATIII % l-
120
110
100
2,75
_-__
-
TFPI; posphlebography
90 2so
-
2,25
-
8.
ATIII; pas phlehography
f3
TFPI; neg phlebography
ATIII;
neg phlebography
70 2,00
-
1,751,50-
1,25 -
1.ooFirst
Second
Third
Fourth FIG
1.
Plasma-TFPI and AT111 levels in bloodsamples from patients with spontaneous DVT. The baseline sample was obtained imediately after the phlebography. At this first time point pTFP1 and AT111 levels in the patients with (n=14) and without (n=lS) DVT are shown. At the following time points only results from the patients with DVT are shown. The second sample was obtained 60 min after the injection of unfractionated heparin, the third sample was drawn after the heparin therapy was substituted by warfarin and the fourth was a convalescence sample. All values expressed as mean and SD.
Vol. 72, No. 5
TFPI, HEPARIN, VENOUS THROMBOSIS
Anti-FXa (Anti-FXa IU/ml)
Observation Baseline Second Third Fourth
mean SD mean SD mean SD mean SD
Anti-FIIa (Anti-FIIa U/ml) 0.05 0.05 0.5 0.2 0.1
0.1 0.05 0.01
469
APTT (set) 44.3 5.4 160.3 46.4 84.9 41.7 54.3 14.5
DISCUSSION TFPI is produced by endothelial cells (IO) and the non circulating pool is presumably bound to the luminal surface. When the negatively charged heparin molecules are administered, a displacement of the TFPI molecule most probably occurs and is reflected as an increase of pTFPI(5). It is not known whether the heparin molecules also may induce an increased protein production or how the synthesis of TFPI in general is regulated. In patients with certain intestinal malignancies elevated pTFP1 levels have been observed. These patients also respond with a higher increase of pTFP1 when treated with heparin (7). Such patients are in general more prone to thrombotic events (11). One might argue that they have an ongoing low grade disseminated intravasalcular coagulation (DIC) (12). This elevation of pTFP1 is not likely to be a reflection of the body’s strive for homeostasis since different malignant cellines in vitro are known to produce TFPI (13, 14, 15). In patients with septicaemia and trauma induced DIC, both low (16) and high (17) levels of TFPI are reported. Clinical (18) and experimental (19) reports on ARDS have found elevation of TFPI in broncheo alveolar lavage. So far no patient with DVT with low levels or defective TFPI has been reported (3, 4). Venous occlusion test has also failed to detect fluctuations of pTFPI(5). The present study essentially confirms previous findings. Plasma-TFPI was the same in patients with a positive phlebography and in those with a negative phlebography. The mean pTFP1 increase was ~210% following the standard heparin regimes. This increase is somewhat less compared to what has been found in previous reports (6). The peak values ranged from 150 to 300%. The different pharmacokinetics from iv and SCheparin therapy probably accounts for the wide range observed. Increased TFPI activity was observed in the plasma when the patients were heparinised measured as anti-FXa, anti-FIIa or APTT. As the anticoagulation parameters decreased, as a reflection of heparin elimination, pTFP1 also decreased. This observation, in patients with DVT, has not been reported before but might have been expected from studies on healthy volunteers (20) and experimental animal studies (unpublished data). Warfarin is known to cause no fluctuations in pTFPI(21), which is also observed in this study. The pathophysiological role of TFPI is still obscure. This could be interpreted in principally three different ways; firstly, TFPI is merely an old phylogenetic remnant, secondly, lack of or defective TFPI is not compatible with life or thirdly, the scientific society is still looking in the wrong place. In conclusion Plasma-TFPI in patients with phlebographically confirmed spontaneous DVT was normal as compared to healthy volunteers. Plasma-TFPI-levels varied in parallel with the antiFXa and anti-FIIa-levels during heparin therapy. Acknowledgement The assistance of Dr S Lindgren, Dept of Medicine and Dr C Tornquist, Dept of Radiology are greatly acknowledged. This study was supported by grants from Swedish Medical Research Council 00759.
470
TFPI, HEPARIN, VENOUS THROMBOSIS
Vol. 72, No. 5
REFERENCES 1 RAPAPORT SI. The extrinsic pathway inhibitor, a regulator of the tissue factor-dependent blood coagulation. Thromb Haemost, 66, 6-15, 1991 2 SANDSET PM, ABILDGAARD U. Extrinsic Pathway Inhibitor - The key to feedback control of blood coagulation initiated by tissue thromboplastin. Haemost, 21, 219-39, 1991 3 WARN-CRAMER BJ, RAO LVM, MAKI, SL RAPAPORT SI. Modifications of extrinsic pathway inhibitor (EPI) and factor Xa that effect their ability to interact and to inhibit factor VIItissue factor: evidence for a two step model of inhibition, Thromb Heamost, 60,453-6, 1988 4 SANDSET PM. Studies of extrinsic coagulation inhibitor. Thesis, University of Oslo, 1989. 5 NOVOTNY WF, BROWN SG, GIRARD TJ, MILETICH JP, BROZE GJ Jr. Plasma LACI antigen in patient samples. Blood, 74 (suppl 1) 209a, (abst), 1989. 6 SANDSET PM, ABILDGAARD U, LARSEN ML. Heparin induces release of extrinsic coagulation pathway inhibitor (EPI). Thromb Res, 50,803-13, 1988 7 LINDAHL AK, ABILDGAARD U, STOCKE G. Release of extrinsic pathway inhibitor after heparin injection: increased response in cancer patients. Thromb Res, 59, 651-59, 1990. 8 SANDSET PM, ABILDGAARD U, PETTERSEN M. A sensitive assay of extrinsic coagulation pathway inhibitor (EPI) in plasma and plasma fractions. Thromb Res, 47, 389-400, 1987. 9 MATZSCH T, BERGQVIST D, HEDNER U, 0STERGAARD PB. Effects of an enzymatically depolymerized heparin as compared with conventional heparin. Thromb Haemost, 57, 97-101, 1987. 10 BAJAJ MS, KUPPUSWAMY MN, SAITO H, SPITZER SG, BAJAJ SP. Cultured normal hepatocytes do not synthetize lipoprotein-associated coagulation inhibitor: Evidence that endothelium is the principal site of its synthesis. Proc Nat1 Acad Sci USA, 87, 8869-73, 1990. 11 RICKLES FR, EDWARDS RL. Activation of blood coagulation in cancer Trousseau’s syndrome revisited. Blood, 62, 14-3 1, 1983. 12 BICK RL. Dissiminated intravascular coagulation and related syndromes: a clinical review. Sem Thromb Haemost, 14, 65-81, 1988. 13 BROZE GJ Jr, MILETICH JP. Isolation of the tissue factor inhibitor produced in HepG2 hepatoma cells. Proc Nat1 Acad Sci USA, 84, 1886-90, 1987. 14 NORDFANG 0, NIELSEN LS, JACOBSEN PB. Purification and cloning of extrinsic pathway inhibitor from HeLa cells. Biotech o Plasma Proteins, 98 (abst), 1990. 15 RANA SV, REIMERS HJ, PATHIKONDA MS, BAJAJ SP. Expression of the tissue factor and factor VIIa/tissue factor inhibitor activity in endotoxin or phorbol ester stimulated U937 monocyte-like cells. Blood, 71, 259-62, 1988. 16 BAJAJ MS, RANA SV, WYSOLMERSKI RB, BAJAJ SP. Inhibitor of the factor VIIa-tissue factor complex is reduced in patients with dissiminated intravascular coagulation but not in patients with severe hepatocellular disease. J Clin Invest, 79, 1874-79, 1987. 17 ANDERSSON TR, BELL H, SANDSET PM, 0DEGAARD OR, AAMODT L-M. New coagulation inhibitor levels in pneumonia, dissiminated intravascular coagulation and liver disease. Thromb Haemost, 58, 305A (abst), 1987. 18 IDELL S, JAMES KK, LEVIN EG, SCHWARTZ BS, MANCHANDA N, MAUNDER RJ, MARTIN TR, MCLARTY DS. Local abnormalities in coagulation and fibrinolytic pathways predispose to alveloar fibrin deposits in the adult respiratory distress syndrome. J Clin Invest, 84, 695-705, 1989. 19 IDELL S, PETERS J, JAMES KK, FAIR DS, COALSON JJ. Local abnormalities in coagulation and fibrinolytic pathways that promote alvelolar fibrin deposition in the lungs of baboons with diffuse alveolar damage. J Clin Invset, 84, 181-93,1989. 20 HOLST J, LINDBLAD B, BERGQVIST D, HEDNER U, GARRE K, NORDFANG, 0sTERGAARD P. Effect of protamine sulfate on Tissue Factor Pathway Inhibitor (TFPI) released by iv or SCstandard or low molecular weight heparin. Thromb Haemost, 69, 1114 (abst #2042), 1993. 21 ABILDGAARD u, SANDSET PM, ANDERSSON TR, ODEGAARD OR, ROSEN S. The inhibitor of FVIIa in plasma measured with a sensitive chromgenic substrate assay. Comparison with antithrombin, protein C, heparin cofactor II in a clinical material. Folia Haematol (Leipz), 115, 274-77, 1988.