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Prosthetic graft thrombosis associated with lupus anticoagulant
EurJ Vasc Surg 2, 57-60 (1988)
CASE REPORT
Prosthetic Graft Thrombosis Associated with Lupus Anticoagulant Simon Ashley, Anton Kruger, K. Wendy M c M u l l e n and Simon Darke Royal Victoria Hospital, Boscombe, Bournemouth BHI 4JG, U.K.
Introduction
Case I
The presence of an unique in vitro coagulation inhibitor in two patients with systemic lupus erythematosis (SLE) was first described by Conley and H a r t m a n n (1952). 1 A similar p h e n o m e n o n in a patient without SLE was subsequently described by Frick (1955). 2 The term "lupus anticoagulant" (LA) was introduced in 19 72 by Feinstein and Rapaport. 3 For the clinician the term "lupus anticoagulant" is misleading because this inhibitor of coagulation tests only rarely interferes with haemostasis in vivo. Furthermore it is not confined to patients with lupus. Its clinical implications, paradoxically,, are concerned with spontaneous venous and arterial thrombosis. 4 The identification of lupus anticoagulant is hallmarked by the prolongation of phospholipid-dependent coagulation tests, which are not corrected by the addition of normal plasma but which will become normal with the addition of platelet phospholipid. This is due to the action of immunoglobulins of the IgG or IgM class, with affinity for phospholipid (platelet factor III), s hence the alternative term "lupus antibody". We report two patients with peripheral vascular disease who underwent aorta-bifemoral and femoropopliteal bypass respectively, who were incidentally found to have LA. Both procedures were technically straightforward and a successful outcome was anticipated. Both patients suffered from u n e x p e c t e d - - a n d in one case repeated--graft thrombosis. We have been unable to find similar cases reported within the literature.
A 75-year-old lady presented with intermittent claudication and ischaemic rest pain affecting her right leg and gangrene in the big toe. She suffered with hypertension, angina and had had a mild cerebro-vascular accident 7 years previously. She had occlusion of the superficial femoral artery in the affected limb, confirmed by arteriography, which also demonstrated patency of all three calf vessels. This was treated by a technically straightforward femoro-popfiteal bypass using a PTFE graft from high in the common femoral artery to a popliteal artery of reasonable calibre above the knee. The patient had previously had bilateral varicose vein surgery. Twenty-four hours postoperatively the graft thrombosed, and in spite of repeated attempts flow was not reestablished and she subsequently required an above-knee amputation. Routine preoperative screening investigations had revealed an abnormal clotting screen in which the activated partial thromboplastin time (APTT) was slightly prolonged against controls and which did not correct with the addition of normal plasma. (APTT patient--72s, control 38s, Prothrombin, thrombin and bleeding times normal.) Further laboratory tests confirmed the presence of a lupus coagulant. Six months later she presented again with a critically ischaemic left foot due to an occluded superficial femoral artery. Arteriography revealed a similar appearance to the opposite side. In view of the previous experience she was started on Prednisolone 20 mg daily, with a return to normal of her clotting studies prior to surgery.
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S. Ashley e t al.
A femoro-popliteal bypass using externally supported PTFE was performed successfully and remains patent 9 months later. The patient has been maintained on longterm Warfarin therapy.
Case 2 A 52-year-old female presented with buttock and thigh claudication and ischaemic rest pain in her right foot and gangrenous second and third toes. She was a heavy smoker. Peripheral pulses were absent on the right side and arteriogram confirmed aorto-iliac atheroma with occlusion of the right c o m m o n iliac artery. The femoral and more distal vessels were patent. She underwent an aorto-bifemoral "piggy-back" bypass using a 16 x 8 m m woven Dacron prosthesis, with immediate restoration of foot pulses. Postoperative recovery was uneventful. Three months later she presented with an acutely ischaemic right leg due to occlusion of the right limb of the graft. This was treated by emergency thrombectomy. Although no immediate cause for the thrombotic event was evident a Dacron patch angioplasty to the distal anastomosis was fashioned. This restored pulses to her right limb but 2 4 h later the left limb of the bypass occluded, although the limb itself was immediately viable. Her clotting screen showed a prolonged APTT (patient 62, control 37s, not corrected by normal plasma, Prothrombin, thrombin and bleeding times normal) and further laboratory tests suggested this to be due to Lupus anticoagulant. Anti-DNA antibodies were also demonstrated. She was started on Prednisolone, 4 0 m g daily and Heparinised. One week later the right limb of her graft once more thrombosed and both legs became critically ischaemic. She underwent urgent bilateral graft thrombectomies with immediately satisfactory results. Flow down the left limb was not sustained however. Attempted plasmapheresis had to be abandoned due to bleeding from one of her groin wounds, requiring transfusion. In view of this, treatment with a prostacyclin infusion was started at a dose of 10 ng/kg body wt/min. Two days later a successful left femoral thrombembolectomy was performed. Heparin and Prostcycline infusions were continued 48 h postoperatively and she was started on long-term Warfarin. The graft is still patent to date, 6 months later. Apart from some partial necrosis in the forefoot and a lateral popliteal nerve palsy in the left limb, recovery has been satisfactory.
Discussion The prevalence of LA is highest in patients with SLE, in EurJ Vasc Surg Vol 2, February 1988
w h o m it is found in about 10% of cases, 6 although it has been described in other auto-immune conditions, e.g. rheumatoid arthritis, Addison's disease, Raynaud's, and ulcerative colitis. LA also occurs in isolation and in one series of 219 cases, 45% had no clinical evidence of SLE or SLE-like disease, even though 29% of this group had a positive anti-nuclear antibody (ANA) determination. 7 Others have stated that as m a n y as 6 0 - 9 0 % of patients with LA have antinuclear antibody.8 LA m a y also occur as a part of drug-related lupus syndromes, especially associated with phenothiazines ~ and procainamide 7 and has been reported in the Acquired I m m u n e Deficiency Syndrome. 10 The presence of LA can be suspected w h e n the activated partial thromboplastin time is prolonged with no correction by a mixture of normal plasma. 11 (When prolongation is due to clotting factor deficiency, it is corrected by normal plasma.) Blood coagulation is the result of the interaction of numerous clotting factors, m a n y of which are present in blood in trace amounts. This is precipitated by the absorber and concentrator on a surface such as exposed phospholipid on the surface of activated platelets. Lupus anticoagulants are immunoglobulins, usually polyclonal, 12 with affinity for negatively charged phospholipids. It is postulated that they impede in vitro coagulation by neutralising this catalytic surface. The reason why this does not occur in vivo remains obscure but it probably relates to platelet activity. 13 Tests used to detect lupus anticoagulant reflect to some extent the conversion of prothrombin to thrombin by Factor Xa. Factor Xa m a y be generated via the intrinsic p a t h w a y (APTT) or the extrinsic p a t h w a y (PT or expressed as ratio of test sample: control, International normalised ratio (INR)), depending on the test system used. The realisation that the lupus anticoagulant interferes with the phospholipid contribution to coagulation in vitro has led to the development of assays made more sensitive by reducing the concentration of phospholipids used. The lower the concentration of phospholipid available, the more likely the reactive surface can become saturated with the immunoglobulin, thus inhibiting normal coagulation. It is, in effect, a titration between available phospholipid and LA. The Kaolin clotting time uses the activation of the intrinsic pathway and is performed without addition of phospholipid and depends on the relatively small amounts inherently present. In the presence of LA the test will be prolonged because of the relative paucity of available phospholipid. The prothombin time uses the initiation of the extrinsic pathway and requires the addition of tissue thromboplastin which is massively rich in phospholipid. Thus the prothrombin time will be normal or only slightly prolonged unless the added thrombo-
Prosthetic Graft Thrombosis
plastin is diluted. This forms the basis of the s u p p l e m e n t a r y tests u s e d to detect lupus a n t i c o a g u l a n t . Despite this in vitro clotting a b n o r m a l i t y LA is r a r e l y associated w i t h a bleeding t e n d e n c y in vivo. Bowie e t al. (1963)14 first described t h e o c c u r r e n c e of t h r o m b o t i c c o m p l i c a t i o n s in patients w i t h SLE a n d LA. Lechner a n d P a b i n g e r - F a s c h i n g , 4 r e v i e w i n g the literat u r e in 1 9 8 5 , observed t h a t of 2 5 9 p a t i e n t s w i t h LA, 85 (32.8%) h a d developed thrombosis, i n c l u d i n g spont a n e o u s t h r o m b o s i s of o t h e r w i s e h e a l t h y cerebral a n d p e r i p h e r a l arteries a n d p e r i p h e r a l as well as visceral v e n o u s t h r o m b o s i s . A n o t h e r a s s o c i a t i o n h a s b e e n t h a t of a n increased risk of r e c u r r e n t a b o r t i o n s due to p l a c e n t a l infarction in p a t i e n t s w i t h LA. is One of the striking p a t h o l o g i c a l features of a r t e r i a l a n d v e n o u s t h r o m b o s i s in patients w i t h LA is the a b s e n c e of i n f l a m m a t i o n ( " v a s culitis") or o t h e r a b n o r m a l i t i e s such as a t h e r o m a in t h e vessel wall. 16 It seems t h a t the t h r o m b o s i s results from a d i s t u r b a n c e of blood c o a g u l a t i o n or from a f u n c t i o n a l dist u r b a n c e of t h e e n d o t h e l i a l cell (loss of " r e s i s t a n c e to t h r o m b o s i s " ) b u t the precise m e c h a n i s m r e m a i n s speculative. One t h e o r y is based o n the o b s e r v a t i o n t h a t p r o s t a cycline release w a s inhibited from e n d o t h e l i a l cells of r a t a o r t a by a n IgG fraction o b t a i n e d from the s e r u m of a p a t i e n t w i t h LA, r e c u r r e n t a b o r t i o n s a n d arterial t h r o m bosis. 17 This result h a s been confirmed b y o t h e r studies. 18-2° T h e a u t h o r s suggest t h a t a n a n t i b o d y in these patients m a y interfere w i t h t h e p r o d u c t i o n or release of p r o s t a c y c l i n e by the vessel wall, possibly b y interfering w i t h t h e availability of a r a c h i d o n i c acid. H o w e v e r , m o r e r e c e n t work, using c u l t u r e d h u m a n e n d o t h e l i a l cells, h a s d e m o n s t r a t e d no effect for l u p u s a n t i c o a g u l a n t on the p r o d u c t i o n 21 or release of prostacycline.22 Other p r o p o s e d theories of LA-associated t h r o m b o genicity i n c l u d e increased platelet a d h e s i v e n e s s a n d r e d u c e d fibrinolytic activity,23 inhibition of p r o t e i n C activ a t i o n 24 a n d p r o m o t i o n of e n d o t h e l i a l cell p r o c o a g u l a n t a c t i v i t y , as T r e a t m e n t of t h r o m b o s i s in p a t i e n t s w i t h LA is empirical a n d b a s e d o n a n e c d o t a l experience. It w o u l d a p p e a r t h a t t r e a t m e n t w i t h H e p a r i n a n d oral a n t i c o a g u lants is effective in the p r e v e n t i o n or e x t e n s i o n or rec u r r e n c e of t h r o m b o s i s a n d once a p a t i e n t with LA h a s developed thrombosis, l o n g - t e r m oral a n t i c o a g u l a t i o n is advised. 7 Platelet suppressive agents h a v e been used in patients w i t h LA b u t their precise role is u n c e r t a i n . Since m a n y patients w i t h LA a n d t h r o m b o s i s h a v e a n u n d e r lying a u t o i m m u n e disorder, t r e a t m e n t w i t h steroids or i m m u n o s u p p r e s s i v e agents h a s been considered. T h e r e h a v e b e e n reports of live births o c c u r r i n g in w o m e n w i t h LA a n d r e c u r r e n t abortions, given P r e d n i s o l o n e 26,27 in c o m b i n a t i o n w i t h low dose of aspirin. Suppression of t h e a n t i b o d y w a s observed in m a n y cases. In theory, p l a s m a pheresis, by r e m o v i n g the a b n o r m a l c i r c u l a t i n g i m m u n o -
59
globin, m a y be beneficial b u t its clinical place is u n p r o ven. Prosthetic graft t h r o m b o s i s in patients w i t h LA, such as o c c u r r e d in t h e p a t i e n t s r e p o r t e d here, h a s n o t previously b e e n reported. A l t h o u g h the c a u s a l relationship b e t w e e n LA a n d t h e graft t h r o m b o s i s is speculative, the c i r c u m s t a n c e s do s t r o n g l y suggest t h a t this w a s the case. A successful o u t c o m e was e v e n t u a l l y achieved in both patients by using a c o m b i n a t i o n of steroids, a n t i c o a g u lants and, in o n e patient, a p r o s t a c y c l i n e infusion, a l t h o u g h the relative benefits of these m e a s u r e s are difficult to assess. It r e m a i n s to be seen w h e t h e r the t h e r a peutic m a n o e u v r e s described will prove to be of benefit to similar patients in t h e future. Lupus a n t i c o a g u l a n t m a y be a n i m p o r t a n t t h r e a t to p a t i e n t s u n d e r g o i n g i n s e r t i o n of prosthetic v a s c u l a r grafts. Its presence should be considered a n d excluded by careful e v a l u a t i o n of the r o u t i n e p r e o p e r a t i v e c o a g u l a tion screen.
References
1 CONLEYCL, HARTMANNRD. A haemorrhagic disorder caused by circulating anticoagulant in patients with DLE. ] Clin Invest 1952;3: 621-622. 2 FRICKPG. Acquired circulatory anticoagulants in systemic "collagen disease". Autoimmune thromboplastin deficiency. Blood 1955; 10:691-706. 3 FEINSTEINDI, RAPAPORTSL Acquired inhibitors of blood coagulation. Prog Haemost Thromb 1972;1:75-95. 4 LECHNERK, PABINGER-FusCHINGE. Lupus anticoagulants and thrombosis. Haemastasis 1985; 15:254-262. 5 THIAGARAJANP, SHAPIROSS, DE MARCOL. Monoclonal immunoglobin M coagulation inhibitor via phospholipid specificity. ] Clin Invest 1980;66:397-405. 6 SHAPIROS, THIAGARAJANP. Lupus anticoagulants. Prog Haemost Thromb 1982;6:263-285. 7 GASTINEUADA, KAZONIERFi, NICHOLSWL. Lupus anticoagulant: an analysis of the clinical and laboratory features of 219 cases. Ann J Haemato11985;19:265-273.
8 EDITORIAL.Lupus anticoagulant. Lancet 1984;i: l l 57-1158. 9 MUCHJR, HERBSTKD, RAPAPORTSL Thrombosis in patients with the lupus anticoagulant. Ann Int Med 1980;92:156-159. 10 COHENAi, PHILLIPSTM, KESSLERCM. Circulating coagulation inhibitors in the acquired immune deficiency syndrome. Ann lnt Med 1986;104:175. 11 GREEND, HORGIEC, KAZONIERFJ et al. Report of the working party on acquired inhibitor of coagulation: studies on tbe "lupus" anticoagulant. Thromb Haemost 1983 ;49:144-146. 12 LECHNER K. Acquired inhibitors in non-haemophiliac patients. Haemostasis 1974; 3:65-93. 13 VERMYLENJ, BLOCKMANSD, SPITZB, DECKMYNH. Thrombosis and Immune Disorders. In: Clinics in Haematology London: Saunders & Co, May 1986;394-412. 14 BOWIEEJW, THOMPSONJH.JR, PASCUZZOLA et al. Thrombosis in systemic lupus erythematosis despite circulating anticoagulants. ] Lab CI Med 1963;62:416-430. 15 LUBBEWF, BUTLERWD, PALMERSJ et al. Lupus anticoagulation in pregnancy. Br J Obs Gyn 1984;91:357-363. 16 ASHERSONRA, MACKWORTH-YoIJNGCG, HAt~RISFaN et HI. Multiple venous and arterial thrombosis associated with the lupus antiEurJ Vasc Surg Vol 2, February 1988
60
17 18 19 20 21
22
S. Ashley e t al.
coagulant and antibodies to cardiolipin in the absence of SLE. Rheumatol Inter 1985; 5: 91-93. CAr~EKaSLO, MACHINSJ, DEMONPt et al. Thrombosis, intrauterine death and lupus anticoagulant: detection of immunoglobin interfering with prostacycline formation. Lancet 1981 ;i:244. ELDORA, ELIASM. Thromboembolic events in patients with "lupus" type anticoagulant. Thromb Haemost 1983;50:345. MARCHES!D, PARLTARUA, FRAMPTONGet al. Thrombotic tendency in systemic lupus erythematosus. Lancet 1981;i:719. VILA L, DE CASTELLARNAUC, BORR~LLMet al. Lupus anticoagulant and vascular prostacycline production. Thromb Haemost 1985;54: 38. RUSTIN MHA, BULL HA, DOWD PM, ISENBURG DA, 8NAITH ML, MACHIN SJ, Presence of the lupus anticoagulant in patients with systemic lupus erythematosis does not cause inhibition of prostacyclin production. Thromb Haemost 1987;58:1428',[Abstract page 390]. PETRAmNOLOW, BOVILLE, HOAKJ. The lupus anticoagulant does
EurJ Vasc Surg Vol 2, February 1988
not inhibit the release prostacyclin ti:om human endothelial cells. Tbromb Haemost 1987;58:1429;[Abstract page 390]. 23 ANYLEs-CANoE, SUTTON Y, CLAUVELJP. Predisposing factors to thrombosis in systemic lupus erythematosus. J Lab Clin Med 1979;2: 312-313. 24 CARIOUR, TOSELEMG, SORIAC, CAENJ. Inhibition of protein C activation by endothelial cells in the presence of lupus anticoagulant. N Eng J Med1986;314:l19 3-1194.
25 TANNENBAUMSH, FINKOR, CINESDB. Antibody and immune complexes induce tissue factor production by human endothelial cells. ] lmmunol 1986;137:1532-1537. 26 LUBBWF, B~:TLERWS, PALMERSJ et al. Fetal survival after Prednisone suppression of maternal lupus anticoagulant. Lancet 1983;i: 1361-1363. 27 FARQIYtIARSONRG, PEARSONJF, JOHN L. Lupus anticoagulant and pregnancy management. Lancet 1984;ii:228-229. Received 2 September 1987
CASE REPORT
Prosthetic Graft Thrombosis Associated with Lupus Anticoagulant Simon Ashley, Anton Kruger, K. Wendy M c M u l l e n and Simon Darke Royal Victoria Hospital, Boscombe, Bournemouth BHI 4JG, U.K.
Introduction
Case I
The presence of an unique in vitro coagulation inhibitor in two patients with systemic lupus erythematosis (SLE) was first described by Conley and H a r t m a n n (1952). 1 A similar p h e n o m e n o n in a patient without SLE was subsequently described by Frick (1955). 2 The term "lupus anticoagulant" (LA) was introduced in 19 72 by Feinstein and Rapaport. 3 For the clinician the term "lupus anticoagulant" is misleading because this inhibitor of coagulation tests only rarely interferes with haemostasis in vivo. Furthermore it is not confined to patients with lupus. Its clinical implications, paradoxically,, are concerned with spontaneous venous and arterial thrombosis. 4 The identification of lupus anticoagulant is hallmarked by the prolongation of phospholipid-dependent coagulation tests, which are not corrected by the addition of normal plasma but which will become normal with the addition of platelet phospholipid. This is due to the action of immunoglobulins of the IgG or IgM class, with affinity for phospholipid (platelet factor III), s hence the alternative term "lupus antibody". We report two patients with peripheral vascular disease who underwent aorta-bifemoral and femoropopliteal bypass respectively, who were incidentally found to have LA. Both procedures were technically straightforward and a successful outcome was anticipated. Both patients suffered from u n e x p e c t e d - - a n d in one case repeated--graft thrombosis. We have been unable to find similar cases reported within the literature.
A 75-year-old lady presented with intermittent claudication and ischaemic rest pain affecting her right leg and gangrene in the big toe. She suffered with hypertension, angina and had had a mild cerebro-vascular accident 7 years previously. She had occlusion of the superficial femoral artery in the affected limb, confirmed by arteriography, which also demonstrated patency of all three calf vessels. This was treated by a technically straightforward femoro-popfiteal bypass using a PTFE graft from high in the common femoral artery to a popliteal artery of reasonable calibre above the knee. The patient had previously had bilateral varicose vein surgery. Twenty-four hours postoperatively the graft thrombosed, and in spite of repeated attempts flow was not reestablished and she subsequently required an above-knee amputation. Routine preoperative screening investigations had revealed an abnormal clotting screen in which the activated partial thromboplastin time (APTT) was slightly prolonged against controls and which did not correct with the addition of normal plasma. (APTT patient--72s, control 38s, Prothrombin, thrombin and bleeding times normal.) Further laboratory tests confirmed the presence of a lupus coagulant. Six months later she presented again with a critically ischaemic left foot due to an occluded superficial femoral artery. Arteriography revealed a similar appearance to the opposite side. In view of the previous experience she was started on Prednisolone 20 mg daily, with a return to normal of her clotting studies prior to surgery.
0950-821X/88/010057+04503.00/0
© 1988 Grune & Stratton Ltd
58
S. Ashley e t al.
A femoro-popliteal bypass using externally supported PTFE was performed successfully and remains patent 9 months later. The patient has been maintained on longterm Warfarin therapy.
Case 2 A 52-year-old female presented with buttock and thigh claudication and ischaemic rest pain in her right foot and gangrenous second and third toes. She was a heavy smoker. Peripheral pulses were absent on the right side and arteriogram confirmed aorto-iliac atheroma with occlusion of the right c o m m o n iliac artery. The femoral and more distal vessels were patent. She underwent an aorto-bifemoral "piggy-back" bypass using a 16 x 8 m m woven Dacron prosthesis, with immediate restoration of foot pulses. Postoperative recovery was uneventful. Three months later she presented with an acutely ischaemic right leg due to occlusion of the right limb of the graft. This was treated by emergency thrombectomy. Although no immediate cause for the thrombotic event was evident a Dacron patch angioplasty to the distal anastomosis was fashioned. This restored pulses to her right limb but 2 4 h later the left limb of the bypass occluded, although the limb itself was immediately viable. Her clotting screen showed a prolonged APTT (patient 62, control 37s, not corrected by normal plasma, Prothrombin, thrombin and bleeding times normal) and further laboratory tests suggested this to be due to Lupus anticoagulant. Anti-DNA antibodies were also demonstrated. She was started on Prednisolone, 4 0 m g daily and Heparinised. One week later the right limb of her graft once more thrombosed and both legs became critically ischaemic. She underwent urgent bilateral graft thrombectomies with immediately satisfactory results. Flow down the left limb was not sustained however. Attempted plasmapheresis had to be abandoned due to bleeding from one of her groin wounds, requiring transfusion. In view of this, treatment with a prostacyclin infusion was started at a dose of 10 ng/kg body wt/min. Two days later a successful left femoral thrombembolectomy was performed. Heparin and Prostcycline infusions were continued 48 h postoperatively and she was started on long-term Warfarin. The graft is still patent to date, 6 months later. Apart from some partial necrosis in the forefoot and a lateral popliteal nerve palsy in the left limb, recovery has been satisfactory.
Discussion The prevalence of LA is highest in patients with SLE, in EurJ Vasc Surg Vol 2, February 1988
w h o m it is found in about 10% of cases, 6 although it has been described in other auto-immune conditions, e.g. rheumatoid arthritis, Addison's disease, Raynaud's, and ulcerative colitis. LA also occurs in isolation and in one series of 219 cases, 45% had no clinical evidence of SLE or SLE-like disease, even though 29% of this group had a positive anti-nuclear antibody (ANA) determination. 7 Others have stated that as m a n y as 6 0 - 9 0 % of patients with LA have antinuclear antibody.8 LA m a y also occur as a part of drug-related lupus syndromes, especially associated with phenothiazines ~ and procainamide 7 and has been reported in the Acquired I m m u n e Deficiency Syndrome. 10 The presence of LA can be suspected w h e n the activated partial thromboplastin time is prolonged with no correction by a mixture of normal plasma. 11 (When prolongation is due to clotting factor deficiency, it is corrected by normal plasma.) Blood coagulation is the result of the interaction of numerous clotting factors, m a n y of which are present in blood in trace amounts. This is precipitated by the absorber and concentrator on a surface such as exposed phospholipid on the surface of activated platelets. Lupus anticoagulants are immunoglobulins, usually polyclonal, 12 with affinity for negatively charged phospholipids. It is postulated that they impede in vitro coagulation by neutralising this catalytic surface. The reason why this does not occur in vivo remains obscure but it probably relates to platelet activity. 13 Tests used to detect lupus anticoagulant reflect to some extent the conversion of prothrombin to thrombin by Factor Xa. Factor Xa m a y be generated via the intrinsic p a t h w a y (APTT) or the extrinsic p a t h w a y (PT or expressed as ratio of test sample: control, International normalised ratio (INR)), depending on the test system used. The realisation that the lupus anticoagulant interferes with the phospholipid contribution to coagulation in vitro has led to the development of assays made more sensitive by reducing the concentration of phospholipids used. The lower the concentration of phospholipid available, the more likely the reactive surface can become saturated with the immunoglobulin, thus inhibiting normal coagulation. It is, in effect, a titration between available phospholipid and LA. The Kaolin clotting time uses the activation of the intrinsic pathway and is performed without addition of phospholipid and depends on the relatively small amounts inherently present. In the presence of LA the test will be prolonged because of the relative paucity of available phospholipid. The prothombin time uses the initiation of the extrinsic pathway and requires the addition of tissue thromboplastin which is massively rich in phospholipid. Thus the prothrombin time will be normal or only slightly prolonged unless the added thrombo-
Prosthetic Graft Thrombosis
plastin is diluted. This forms the basis of the s u p p l e m e n t a r y tests u s e d to detect lupus a n t i c o a g u l a n t . Despite this in vitro clotting a b n o r m a l i t y LA is r a r e l y associated w i t h a bleeding t e n d e n c y in vivo. Bowie e t al. (1963)14 first described t h e o c c u r r e n c e of t h r o m b o t i c c o m p l i c a t i o n s in patients w i t h SLE a n d LA. Lechner a n d P a b i n g e r - F a s c h i n g , 4 r e v i e w i n g the literat u r e in 1 9 8 5 , observed t h a t of 2 5 9 p a t i e n t s w i t h LA, 85 (32.8%) h a d developed thrombosis, i n c l u d i n g spont a n e o u s t h r o m b o s i s of o t h e r w i s e h e a l t h y cerebral a n d p e r i p h e r a l arteries a n d p e r i p h e r a l as well as visceral v e n o u s t h r o m b o s i s . A n o t h e r a s s o c i a t i o n h a s b e e n t h a t of a n increased risk of r e c u r r e n t a b o r t i o n s due to p l a c e n t a l infarction in p a t i e n t s w i t h LA. is One of the striking p a t h o l o g i c a l features of a r t e r i a l a n d v e n o u s t h r o m b o s i s in patients w i t h LA is the a b s e n c e of i n f l a m m a t i o n ( " v a s culitis") or o t h e r a b n o r m a l i t i e s such as a t h e r o m a in t h e vessel wall. 16 It seems t h a t the t h r o m b o s i s results from a d i s t u r b a n c e of blood c o a g u l a t i o n or from a f u n c t i o n a l dist u r b a n c e of t h e e n d o t h e l i a l cell (loss of " r e s i s t a n c e to t h r o m b o s i s " ) b u t the precise m e c h a n i s m r e m a i n s speculative. One t h e o r y is based o n the o b s e r v a t i o n t h a t p r o s t a cycline release w a s inhibited from e n d o t h e l i a l cells of r a t a o r t a by a n IgG fraction o b t a i n e d from the s e r u m of a p a t i e n t w i t h LA, r e c u r r e n t a b o r t i o n s a n d arterial t h r o m bosis. 17 This result h a s been confirmed b y o t h e r studies. 18-2° T h e a u t h o r s suggest t h a t a n a n t i b o d y in these patients m a y interfere w i t h t h e p r o d u c t i o n or release of p r o s t a c y c l i n e by the vessel wall, possibly b y interfering w i t h t h e availability of a r a c h i d o n i c acid. H o w e v e r , m o r e r e c e n t work, using c u l t u r e d h u m a n e n d o t h e l i a l cells, h a s d e m o n s t r a t e d no effect for l u p u s a n t i c o a g u l a n t on the p r o d u c t i o n 21 or release of prostacycline.22 Other p r o p o s e d theories of LA-associated t h r o m b o genicity i n c l u d e increased platelet a d h e s i v e n e s s a n d r e d u c e d fibrinolytic activity,23 inhibition of p r o t e i n C activ a t i o n 24 a n d p r o m o t i o n of e n d o t h e l i a l cell p r o c o a g u l a n t a c t i v i t y , as T r e a t m e n t of t h r o m b o s i s in p a t i e n t s w i t h LA is empirical a n d b a s e d o n a n e c d o t a l experience. It w o u l d a p p e a r t h a t t r e a t m e n t w i t h H e p a r i n a n d oral a n t i c o a g u lants is effective in the p r e v e n t i o n or e x t e n s i o n or rec u r r e n c e of t h r o m b o s i s a n d once a p a t i e n t with LA h a s developed thrombosis, l o n g - t e r m oral a n t i c o a g u l a t i o n is advised. 7 Platelet suppressive agents h a v e been used in patients w i t h LA b u t their precise role is u n c e r t a i n . Since m a n y patients w i t h LA a n d t h r o m b o s i s h a v e a n u n d e r lying a u t o i m m u n e disorder, t r e a t m e n t w i t h steroids or i m m u n o s u p p r e s s i v e agents h a s been considered. T h e r e h a v e b e e n reports of live births o c c u r r i n g in w o m e n w i t h LA a n d r e c u r r e n t abortions, given P r e d n i s o l o n e 26,27 in c o m b i n a t i o n w i t h low dose of aspirin. Suppression of t h e a n t i b o d y w a s observed in m a n y cases. In theory, p l a s m a pheresis, by r e m o v i n g the a b n o r m a l c i r c u l a t i n g i m m u n o -
59
globin, m a y be beneficial b u t its clinical place is u n p r o ven. Prosthetic graft t h r o m b o s i s in patients w i t h LA, such as o c c u r r e d in t h e p a t i e n t s r e p o r t e d here, h a s n o t previously b e e n reported. A l t h o u g h the c a u s a l relationship b e t w e e n LA a n d t h e graft t h r o m b o s i s is speculative, the c i r c u m s t a n c e s do s t r o n g l y suggest t h a t this w a s the case. A successful o u t c o m e was e v e n t u a l l y achieved in both patients by using a c o m b i n a t i o n of steroids, a n t i c o a g u lants and, in o n e patient, a p r o s t a c y c l i n e infusion, a l t h o u g h the relative benefits of these m e a s u r e s are difficult to assess. It r e m a i n s to be seen w h e t h e r the t h e r a peutic m a n o e u v r e s described will prove to be of benefit to similar patients in t h e future. Lupus a n t i c o a g u l a n t m a y be a n i m p o r t a n t t h r e a t to p a t i e n t s u n d e r g o i n g i n s e r t i o n of prosthetic v a s c u l a r grafts. Its presence should be considered a n d excluded by careful e v a l u a t i o n of the r o u t i n e p r e o p e r a t i v e c o a g u l a tion screen.
References
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8 EDITORIAL.Lupus anticoagulant. Lancet 1984;i: l l 57-1158. 9 MUCHJR, HERBSTKD, RAPAPORTSL Thrombosis in patients with the lupus anticoagulant. Ann Int Med 1980;92:156-159. 10 COHENAi, PHILLIPSTM, KESSLERCM. Circulating coagulation inhibitors in the acquired immune deficiency syndrome. Ann lnt Med 1986;104:175. 11 GREEND, HORGIEC, KAZONIERFJ et al. Report of the working party on acquired inhibitor of coagulation: studies on tbe "lupus" anticoagulant. Thromb Haemost 1983 ;49:144-146. 12 LECHNER K. Acquired inhibitors in non-haemophiliac patients. Haemostasis 1974; 3:65-93. 13 VERMYLENJ, BLOCKMANSD, SPITZB, DECKMYNH. Thrombosis and Immune Disorders. In: Clinics in Haematology London: Saunders & Co, May 1986;394-412. 14 BOWIEEJW, THOMPSONJH.JR, PASCUZZOLA et al. Thrombosis in systemic lupus erythematosis despite circulating anticoagulants. ] Lab CI Med 1963;62:416-430. 15 LUBBEWF, BUTLERWD, PALMERSJ et al. Lupus anticoagulation in pregnancy. Br J Obs Gyn 1984;91:357-363. 16 ASHERSONRA, MACKWORTH-YoIJNGCG, HAt~RISFaN et HI. Multiple venous and arterial thrombosis associated with the lupus antiEurJ Vasc Surg Vol 2, February 1988
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coagulant and antibodies to cardiolipin in the absence of SLE. Rheumatol Inter 1985; 5: 91-93. CAr~EKaSLO, MACHINSJ, DEMONPt et al. Thrombosis, intrauterine death and lupus anticoagulant: detection of immunoglobin interfering with prostacycline formation. Lancet 1981 ;i:244. ELDORA, ELIASM. Thromboembolic events in patients with "lupus" type anticoagulant. Thromb Haemost 1983;50:345. MARCHES!D, PARLTARUA, FRAMPTONGet al. Thrombotic tendency in systemic lupus erythematosus. Lancet 1981;i:719. VILA L, DE CASTELLARNAUC, BORR~LLMet al. Lupus anticoagulant and vascular prostacycline production. Thromb Haemost 1985;54: 38. RUSTIN MHA, BULL HA, DOWD PM, ISENBURG DA, 8NAITH ML, MACHIN SJ, Presence of the lupus anticoagulant in patients with systemic lupus erythematosis does not cause inhibition of prostacyclin production. Thromb Haemost 1987;58:1428',[Abstract page 390]. PETRAmNOLOW, BOVILLE, HOAKJ. The lupus anticoagulant does
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not inhibit the release prostacyclin ti:om human endothelial cells. Tbromb Haemost 1987;58:1429;[Abstract page 390]. 23 ANYLEs-CANoE, SUTTON Y, CLAUVELJP. Predisposing factors to thrombosis in systemic lupus erythematosus. J Lab Clin Med 1979;2: 312-313. 24 CARIOUR, TOSELEMG, SORIAC, CAENJ. Inhibition of protein C activation by endothelial cells in the presence of lupus anticoagulant. N Eng J Med1986;314:l19 3-1194.
25 TANNENBAUMSH, FINKOR, CINESDB. Antibody and immune complexes induce tissue factor production by human endothelial cells. ] lmmunol 1986;137:1532-1537. 26 LUBBWF, B~:TLERWS, PALMERSJ et al. Fetal survival after Prednisone suppression of maternal lupus anticoagulant. Lancet 1983;i: 1361-1363. 27 FARQIYtIARSONRG, PEARSONJF, JOHN L. Lupus anticoagulant and pregnancy management. Lancet 1984;ii:228-229. Received 2 September 1987