- Email: [email protected]
26. Disseminated thrombosis, an unusual and catastrophic manifestation of the antiphospholipid syndrome
A10
Abstracts/Netherlands
Journal
curve (till 48 h after acenocoumarol) after omeprazole (1.7 + 0.1, 26 + 1 h, 68 rt 3 h, respectively) and placebo (1.7 f 0.1, 25 + 1 h, 67 rt 3 h, respectively) did not differ. Conclusions: Neither the pharmacokinetics of R- and S-acenocoumarol nor their combined anticoagulant activity were affected by the short-term co-administration of omeprazole. These in viva data differ from in vitro data on the interaction between omeprazole and acenocoumarol, stressing the point that the in vivo relevance of in vitro interactions has to be confirmed. As the results of the present study also differ from a previously reported in vivo interaction between omeprazole and warfarin, the authors recommend that drug interaction studies with oral anticoagulants should not only be restricted to the use of warfarin.
24. Substantial impairment of hemostasis by the intravenous administration of a gelatin-based plasma expander. E. de Jonge, M. Levi, F. Berends, J.W. ten Cate, C.P. Stoutenbeek. Department of Intensive Care and Department of Internal Medicine, Academic Medical Center, Amsterdam, Netherlands. Background and aim: Gelatin-based plasma substitutes are frequently used for intravascular volume expansion (e.g., in bleeding patients or during complicated surgical procedures). Obviously, in these situations interference of these substitutes with the hemostatic system is undesirable. Recent reports, however, indicate that the use of gelatin-based solutions may be associated with increased bleeding. The aim of this study was to investigate the effect of a gelatin-based plasma expander on hemostasis and blood coagulation in healthy humans. Methods: We performed a double-blind, randomized, controlled cross-over study. Six healthy subjects received an 60 min infusion of either 1 1 gelofusin (gelatin 4% in NaCl 0.9%) or 1 1 NaCl 0.9% (control). After 2 wks wash-out the alternative treatment was administered. Sequential blood samples were obtained and bleeding time measurements were performed before the infusion and up to 4 h hereafter. Results: Infusion of gelatin resulted in a 1.7-fold increase in bleeding time, whereas the bleeding time after the infusion of saline remained unchanged. Aggregation studies revealed a significant impairment of ristocetin-induced platelet aggregation after infusion of gelatin, which appeared to be caused by reduced levels of von Willebrand factor. Gelofusin caused a slight prolongation of clotting times (aPTI and Py), which was not seen after the infusion of saline. Although in both groups functional levels of coagulation factors decreased, the reductions were more pronounced in the gelofusin group. After correction for plasma dilution, plasma levels of factor VIII:Rag and factor VIII:c remained significantly lower in the gelofusin group. Overall markers for thrombin generation (TAT and Fl + 2) were significantly lower in the gelofusin group, as compared with the saline group. Conclusion: Gelofusin causes a significant impairment of primary hemostasis and thrombin generation. The defect in primary hemostasis appears to be related to a reduction in von Willebrand factor, whereas the decreased thrombin generation is due to the dilution of coagulation factors in combination with a specific reduction in factor VIII complex. The effect of gelatin-based plasma expanders on hemostasis may have clinical implications, particularly in bleeding patients or in patients with an already compromised hemostatic system.
of Medicine
50 11997) Al-A44
25. Coagalation factor XI: rather a tibrinolytic inhibitor than a coagulation factor. M.C. Minnema, M. Levi, J.C.M. Meijers, B.J. Biemond, B.N. Bouma, H. ten Cate. Department of Internal Medicine, Academic Medical Center, and Sloteruaart Ziekenhuis, Amsterdam; Department of Hematology, University Hospital. Utrecht, Netherlands. Background and aim: Recent studies have shown a prominent role of the tissue factor-dependent (extrinsic) pathway in the activation of coagulation, whereas the intrinsic pathway appears not to be involved in coagulation activation in vivo. The role of factor XI in this concept, however, is not clear, since a deficiency of this factor is related to a (mild) bleeding tendency. Recent in vitro observations have indicated that factor XI may be important in the activation of a novel, important inhibitor of the fibrinolytic system, thrombin-activatable fibrinolytic inhibitor (TAFI). Hence, factor XI may be of importance for the inhibition of fibrinolysis rather than the activation of coagulation. The aim of this study was to investigate the effect of in vivo inhibition of factor XI on endogenous fibrinolytic activity in an experimental thrombosis model in rabbits. Merhods: Standard lz51-fibrinogen labeled thrombi were preformed in jugular veins of New Zealand rabbits. Thrombi were formed from blood that was preincubated with either a polyclonal goat-anti-rabbit factor XI antibody (0.1 mg/ml) or a control antibody. Experiments were performed with subsequent systemic administration of either the anti-factor XI antibody (1 or 7.5 mg/kg) or the control antibody. Endogenous thrombolysis at 2 h after thrombus formation was assessed by measuring the decrease in lz51-fibrinogen in the clot. Results: The systemic administration of 1 or 7.5 mg/kg anti-factor XI antibody to rabbits resulted in a reduction of plasma factor XI activity of 15 and 80%, respectively. Incorporation of anti-factor XI antibody in clots in the absence of systemic antifactor XI antibody resulted in an almost 2-fold increase in endogenous thrombolysis (11.3 f 0.9 vs 6.3 _+ 0.6% in controls, P < 0.05). Systemic administration of anti-factor XI antibodies resulted in a small further increase in thrombolysis of these clots to 12.1 + 0.8% (1 mg/kg anti-factor XI antibody) or 15.3 + 1.4% (7.5 mg/kg anti-factor XI antibody). Conclusion: Inhibition of factor XI activity by means of anti-factor XI antibodies in rabbits resulted in enhanced endogenous thrombolysis. This facilitation of fibrinolysis is particularly present in clots that are formed from blood in the absence of factor XI activity and appears to be amplified in a situation with systemic factor XI deficiency. In vivo, factor XI may rather act as an inhibitor of fibrinolysis than as a coagulation factor, which may explain the bleeding tendency that is caused by factor XI de& ciency.
26. Diiminated thrombosis, an anusual and catastrophic manifestation of the antiphospholipid syndrome. C.G. Schaar I, 3. ’ DepartE.P.M. Boets ‘, H.K, Ronday 3 and F.C. Breedveld ment of Internal Medicine, ’ Department of Ophthalmology, 3 Department of Rheumatology, University Hospital, Leiden, Netherlands. A 16-year-old Caucasian girl was transferred to our hospital because of progressive renal failure and antiphospholipid syn-
Abstracts/Netherlands
Journal
drome. In 1992 she experienced unexplained intermittent ataxia, her lab results showed autoimmune thrombocytopenia (8 I. log/l), false positive syphilis serology (VDRL 1:2, TPHA and FTA-ABS negative) and a prolonged AFIT of 54 s. Neither finding was explained or investigated. In 1995 an extensive investigation was initiated after she presented with a perforated nasal septum and an elevated ESR (100 mm). There was no evidence of Wegener’s granulomatosis, ANF was weakly positive, anti-ds-DNA was negative and there were high titers of IgM and IgG anticardiolipin antibodies. She was transferred to our hospital because of rapidly progressive renal failure and mental confusion; intravenous heparin was initiated on suspicion of renal thrombotic microangiopathy. On admission she was lethargic, hypertensive (160/105 mmHg), has right temporal episcleritis with normal visual acuity, extensive livedo reticularis with shallow leg ulcers and a systolic murmur was heard at the apex of the heart. There was no history of hair loss, light sensitivity, arthralgia or Raynaud’s phenomenon; there were no nailbed splinter haemorrhages. Fundoscopy revealed normal papillae, normal maculae, cotton wool exudates, intratinal haemorrhages and many areas of choroidal paleness. An abdominal ultrasound showed no sign of renal vein thrombosis. On suspicion of lupus nephritis methylprednisolone was initiated. Her hospital course was stormy. Four days after admission she complained of severe bone pains, became blind and soporous, oliguric renal failure developed, together with severe thrombocytopenia (9.10’/1) which necessitated cessation of heparin. A NMR of the brain showed several old cerebellar infarcts, bone marrow biopsy disclosed ischaemic megakaryocytes and the skin ulcer biopsy showed thrombotic microangiopathy without any signs of vasculitis. Blood cultures remained sterile. On the echocardiogram mitral valve insufficiency due to diffuse valve thickening was seen. There was no proteinuria, only erythocyturia without casts. There was no deficiency of protein C, S, no APC resistance, no cryoglobulins, and no heparin-induced thrombocytopenia; the level of schistocytes was never raised. No renal biopsy could be taken because of hypertension and severe thrombocytopenia. A diagnosis of catastrophic primary antiphospholipid syndrome was made on the basis of widespread intravascular thrombosis (skin, eyes, CNS, bone marrow and kidney) in the absence of SLE and/or vasculitis. After restarting anticoagulation (heparin and phenprocoumon) she made a full recovery: her creatinine clearance stabilised at 50 ml/min. She regained normal visual acuity though follow-up fluorescence angiograms show large areas of choroidal nonperfusion corresponding with paracentral scotomas; a psychoneurological examination shows signs of intellectual deterioration. Conclusion: Antiphospholipid syndrome is a thrombophilic disorder that leads to both venous and arterial occlusions, Most thrombotic episodes are localized, seldom widespread and lifethreatening. Early recognition and anticoagulative treatment can prevent recurrent thrombotic episodes. 27. Assessment of prevention of venous thromboembolism university hospital. A.J. Verheul ‘, M.C.H. Janssen I,
in a
B. Boll *,
of Medicine
50 (1997)
Al -A44
H. Wollersheim ‘, I. Novakova 3, Th. Thien ‘. Deparmtents
All
of
’ General Internal Medicine, 2 Surgery and ’ Haematology, Uniuersity Hospital, Nijmegen, Netherlands. Background: Clinical decisions concerning the prevention of
venous thromboembolism (VTE) in patients at high risk should be part of the routine of almost all practicing physicians. Certain factors are known to increase the risk of VTEZ.Although numerous methods of prophylaxis for VTE have been studied, an organized strategy or guidelines for the prevention of VTE did not yet evolve. Aim of the study: To assess common practice of VTE-prophylaxis in a university hospital with attention to the influence of risk factors on prophylaxis for individual cases. Materials/ Methods: A standard questionnaire was developed to enquire on the ruling practice and attitude towards VTE prophylaxis. On 33 wards of 25 clinical departments a resident and a nurse were interviewed, guided by the questionnaire. They were asked whether VTE prophylaxis is actually used on the ward, who initiates prophylaxis, which prophylactic regimens were installed, which risk factors and contraindications are recognized and whether prophylaxis is adjusted according to these risk factors and contraindications. Results: Thirty-three doctors and 31 nurses were interviewed. All responders claimed that they employ VTE prophylaxis. At the departments of surgery, orthopedics, intensive care. rheumatology, urology and gynaecology a standard protocol is used. At the other departments there is no protocol. There is no consensus in allocating level of risk to individual cases. The most important nominated risk factors are operation (lOO%), immobilization (lOO%), previous VTE (82%), inherited thrombophilia (79%), malignancy (64%) and obesity (48%). Despite the knowledge VTE prophylaxis is seldom adjusted when these factors are present. Contraindications for prophylaxis are coagulation deficiencies (58%). recent cerebral haemorrhage (39%) and gastrointestinal bleeding (30%). Early ambulation is indicated as VTE prophylaxis by all of the responders. The most commonly used medicine is low molecular weight heparin in a variable dosage. Compression stockings are used in only 16%. Conclusion: In spite of being aware of risk factors, similar patients are treated widely different by different clinicians. Therefore, it is important not only to formally assess each individual patient’s VTE risk, but also to prescribe prophylaxis accordingly by using a risk stratification form based on the accepted risk factors. 28. The use of novel laboratory tests for the hypercoaguiable state in malignant disease. W.H.E. Waale, R. van Oerle, L. van Pampus, K. Hamuly&. Department of Haematology, Unioersity Hospital, Maastricht, Netherlands. Background: Thromboembolic complications are common in
patients with malignant disease. Novel laboratory methods are available that might be useful in the elucidation of the mechanisms responsible for the hypercoagulable state in malignant disease. Methods: In this pilot study we measured the thrombin potential (ETP) according to Hemker et al. (Thromb. Haemostas. 1993;70:617-624), FVIIa levels (Philippou et al, Blood, in press)
Abstracts/Netherlands
Journal
curve (till 48 h after acenocoumarol) after omeprazole (1.7 + 0.1, 26 + 1 h, 68 rt 3 h, respectively) and placebo (1.7 f 0.1, 25 + 1 h, 67 rt 3 h, respectively) did not differ. Conclusions: Neither the pharmacokinetics of R- and S-acenocoumarol nor their combined anticoagulant activity were affected by the short-term co-administration of omeprazole. These in viva data differ from in vitro data on the interaction between omeprazole and acenocoumarol, stressing the point that the in vivo relevance of in vitro interactions has to be confirmed. As the results of the present study also differ from a previously reported in vivo interaction between omeprazole and warfarin, the authors recommend that drug interaction studies with oral anticoagulants should not only be restricted to the use of warfarin.
24. Substantial impairment of hemostasis by the intravenous administration of a gelatin-based plasma expander. E. de Jonge, M. Levi, F. Berends, J.W. ten Cate, C.P. Stoutenbeek. Department of Intensive Care and Department of Internal Medicine, Academic Medical Center, Amsterdam, Netherlands. Background and aim: Gelatin-based plasma substitutes are frequently used for intravascular volume expansion (e.g., in bleeding patients or during complicated surgical procedures). Obviously, in these situations interference of these substitutes with the hemostatic system is undesirable. Recent reports, however, indicate that the use of gelatin-based solutions may be associated with increased bleeding. The aim of this study was to investigate the effect of a gelatin-based plasma expander on hemostasis and blood coagulation in healthy humans. Methods: We performed a double-blind, randomized, controlled cross-over study. Six healthy subjects received an 60 min infusion of either 1 1 gelofusin (gelatin 4% in NaCl 0.9%) or 1 1 NaCl 0.9% (control). After 2 wks wash-out the alternative treatment was administered. Sequential blood samples were obtained and bleeding time measurements were performed before the infusion and up to 4 h hereafter. Results: Infusion of gelatin resulted in a 1.7-fold increase in bleeding time, whereas the bleeding time after the infusion of saline remained unchanged. Aggregation studies revealed a significant impairment of ristocetin-induced platelet aggregation after infusion of gelatin, which appeared to be caused by reduced levels of von Willebrand factor. Gelofusin caused a slight prolongation of clotting times (aPTI and Py), which was not seen after the infusion of saline. Although in both groups functional levels of coagulation factors decreased, the reductions were more pronounced in the gelofusin group. After correction for plasma dilution, plasma levels of factor VIII:Rag and factor VIII:c remained significantly lower in the gelofusin group. Overall markers for thrombin generation (TAT and Fl + 2) were significantly lower in the gelofusin group, as compared with the saline group. Conclusion: Gelofusin causes a significant impairment of primary hemostasis and thrombin generation. The defect in primary hemostasis appears to be related to a reduction in von Willebrand factor, whereas the decreased thrombin generation is due to the dilution of coagulation factors in combination with a specific reduction in factor VIII complex. The effect of gelatin-based plasma expanders on hemostasis may have clinical implications, particularly in bleeding patients or in patients with an already compromised hemostatic system.
of Medicine
50 11997) Al-A44
25. Coagalation factor XI: rather a tibrinolytic inhibitor than a coagulation factor. M.C. Minnema, M. Levi, J.C.M. Meijers, B.J. Biemond, B.N. Bouma, H. ten Cate. Department of Internal Medicine, Academic Medical Center, and Sloteruaart Ziekenhuis, Amsterdam; Department of Hematology, University Hospital. Utrecht, Netherlands. Background and aim: Recent studies have shown a prominent role of the tissue factor-dependent (extrinsic) pathway in the activation of coagulation, whereas the intrinsic pathway appears not to be involved in coagulation activation in vivo. The role of factor XI in this concept, however, is not clear, since a deficiency of this factor is related to a (mild) bleeding tendency. Recent in vitro observations have indicated that factor XI may be important in the activation of a novel, important inhibitor of the fibrinolytic system, thrombin-activatable fibrinolytic inhibitor (TAFI). Hence, factor XI may be of importance for the inhibition of fibrinolysis rather than the activation of coagulation. The aim of this study was to investigate the effect of in vivo inhibition of factor XI on endogenous fibrinolytic activity in an experimental thrombosis model in rabbits. Merhods: Standard lz51-fibrinogen labeled thrombi were preformed in jugular veins of New Zealand rabbits. Thrombi were formed from blood that was preincubated with either a polyclonal goat-anti-rabbit factor XI antibody (0.1 mg/ml) or a control antibody. Experiments were performed with subsequent systemic administration of either the anti-factor XI antibody (1 or 7.5 mg/kg) or the control antibody. Endogenous thrombolysis at 2 h after thrombus formation was assessed by measuring the decrease in lz51-fibrinogen in the clot. Results: The systemic administration of 1 or 7.5 mg/kg anti-factor XI antibody to rabbits resulted in a reduction of plasma factor XI activity of 15 and 80%, respectively. Incorporation of anti-factor XI antibody in clots in the absence of systemic antifactor XI antibody resulted in an almost 2-fold increase in endogenous thrombolysis (11.3 f 0.9 vs 6.3 _+ 0.6% in controls, P < 0.05). Systemic administration of anti-factor XI antibodies resulted in a small further increase in thrombolysis of these clots to 12.1 + 0.8% (1 mg/kg anti-factor XI antibody) or 15.3 + 1.4% (7.5 mg/kg anti-factor XI antibody). Conclusion: Inhibition of factor XI activity by means of anti-factor XI antibodies in rabbits resulted in enhanced endogenous thrombolysis. This facilitation of fibrinolysis is particularly present in clots that are formed from blood in the absence of factor XI activity and appears to be amplified in a situation with systemic factor XI deficiency. In vivo, factor XI may rather act as an inhibitor of fibrinolysis than as a coagulation factor, which may explain the bleeding tendency that is caused by factor XI de& ciency.
26. Diiminated thrombosis, an anusual and catastrophic manifestation of the antiphospholipid syndrome. C.G. Schaar I, 3. ’ DepartE.P.M. Boets ‘, H.K, Ronday 3 and F.C. Breedveld ment of Internal Medicine, ’ Department of Ophthalmology, 3 Department of Rheumatology, University Hospital, Leiden, Netherlands. A 16-year-old Caucasian girl was transferred to our hospital because of progressive renal failure and antiphospholipid syn-
Abstracts/Netherlands
Journal
drome. In 1992 she experienced unexplained intermittent ataxia, her lab results showed autoimmune thrombocytopenia (8 I. log/l), false positive syphilis serology (VDRL 1:2, TPHA and FTA-ABS negative) and a prolonged AFIT of 54 s. Neither finding was explained or investigated. In 1995 an extensive investigation was initiated after she presented with a perforated nasal septum and an elevated ESR (100 mm). There was no evidence of Wegener’s granulomatosis, ANF was weakly positive, anti-ds-DNA was negative and there were high titers of IgM and IgG anticardiolipin antibodies. She was transferred to our hospital because of rapidly progressive renal failure and mental confusion; intravenous heparin was initiated on suspicion of renal thrombotic microangiopathy. On admission she was lethargic, hypertensive (160/105 mmHg), has right temporal episcleritis with normal visual acuity, extensive livedo reticularis with shallow leg ulcers and a systolic murmur was heard at the apex of the heart. There was no history of hair loss, light sensitivity, arthralgia or Raynaud’s phenomenon; there were no nailbed splinter haemorrhages. Fundoscopy revealed normal papillae, normal maculae, cotton wool exudates, intratinal haemorrhages and many areas of choroidal paleness. An abdominal ultrasound showed no sign of renal vein thrombosis. On suspicion of lupus nephritis methylprednisolone was initiated. Her hospital course was stormy. Four days after admission she complained of severe bone pains, became blind and soporous, oliguric renal failure developed, together with severe thrombocytopenia (9.10’/1) which necessitated cessation of heparin. A NMR of the brain showed several old cerebellar infarcts, bone marrow biopsy disclosed ischaemic megakaryocytes and the skin ulcer biopsy showed thrombotic microangiopathy without any signs of vasculitis. Blood cultures remained sterile. On the echocardiogram mitral valve insufficiency due to diffuse valve thickening was seen. There was no proteinuria, only erythocyturia without casts. There was no deficiency of protein C, S, no APC resistance, no cryoglobulins, and no heparin-induced thrombocytopenia; the level of schistocytes was never raised. No renal biopsy could be taken because of hypertension and severe thrombocytopenia. A diagnosis of catastrophic primary antiphospholipid syndrome was made on the basis of widespread intravascular thrombosis (skin, eyes, CNS, bone marrow and kidney) in the absence of SLE and/or vasculitis. After restarting anticoagulation (heparin and phenprocoumon) she made a full recovery: her creatinine clearance stabilised at 50 ml/min. She regained normal visual acuity though follow-up fluorescence angiograms show large areas of choroidal nonperfusion corresponding with paracentral scotomas; a psychoneurological examination shows signs of intellectual deterioration. Conclusion: Antiphospholipid syndrome is a thrombophilic disorder that leads to both venous and arterial occlusions, Most thrombotic episodes are localized, seldom widespread and lifethreatening. Early recognition and anticoagulative treatment can prevent recurrent thrombotic episodes. 27. Assessment of prevention of venous thromboembolism university hospital. A.J. Verheul ‘, M.C.H. Janssen I,
in a
B. Boll *,
of Medicine
50 (1997)
Al -A44
H. Wollersheim ‘, I. Novakova 3, Th. Thien ‘. Deparmtents
All
of
’ General Internal Medicine, 2 Surgery and ’ Haematology, Uniuersity Hospital, Nijmegen, Netherlands. Background: Clinical decisions concerning the prevention of
venous thromboembolism (VTE) in patients at high risk should be part of the routine of almost all practicing physicians. Certain factors are known to increase the risk of VTEZ.Although numerous methods of prophylaxis for VTE have been studied, an organized strategy or guidelines for the prevention of VTE did not yet evolve. Aim of the study: To assess common practice of VTE-prophylaxis in a university hospital with attention to the influence of risk factors on prophylaxis for individual cases. Materials/ Methods: A standard questionnaire was developed to enquire on the ruling practice and attitude towards VTE prophylaxis. On 33 wards of 25 clinical departments a resident and a nurse were interviewed, guided by the questionnaire. They were asked whether VTE prophylaxis is actually used on the ward, who initiates prophylaxis, which prophylactic regimens were installed, which risk factors and contraindications are recognized and whether prophylaxis is adjusted according to these risk factors and contraindications. Results: Thirty-three doctors and 31 nurses were interviewed. All responders claimed that they employ VTE prophylaxis. At the departments of surgery, orthopedics, intensive care. rheumatology, urology and gynaecology a standard protocol is used. At the other departments there is no protocol. There is no consensus in allocating level of risk to individual cases. The most important nominated risk factors are operation (lOO%), immobilization (lOO%), previous VTE (82%), inherited thrombophilia (79%), malignancy (64%) and obesity (48%). Despite the knowledge VTE prophylaxis is seldom adjusted when these factors are present. Contraindications for prophylaxis are coagulation deficiencies (58%). recent cerebral haemorrhage (39%) and gastrointestinal bleeding (30%). Early ambulation is indicated as VTE prophylaxis by all of the responders. The most commonly used medicine is low molecular weight heparin in a variable dosage. Compression stockings are used in only 16%. Conclusion: In spite of being aware of risk factors, similar patients are treated widely different by different clinicians. Therefore, it is important not only to formally assess each individual patient’s VTE risk, but also to prescribe prophylaxis accordingly by using a risk stratification form based on the accepted risk factors. 28. The use of novel laboratory tests for the hypercoaguiable state in malignant disease. W.H.E. Waale, R. van Oerle, L. van Pampus, K. Hamuly&. Department of Haematology, Unioersity Hospital, Maastricht, Netherlands. Background: Thromboembolic complications are common in
patients with malignant disease. Novel laboratory methods are available that might be useful in the elucidation of the mechanisms responsible for the hypercoagulable state in malignant disease. Methods: In this pilot study we measured the thrombin potential (ETP) according to Hemker et al. (Thromb. Haemostas. 1993;70:617-624), FVIIa levels (Philippou et al, Blood, in press)