AUTREV-01615; No of Pages 7 Autoimmunity Reviews xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev
1
Review
4Q1
Samuele Raso a, Savino Sciascia b,c,⁎, Anna Kuzenko a, Irene Castagno a, Luca Marozio d, Maria Tiziana Bertero a
5 6 7 8
a
9
a r t i c l e
10 11 12 13
Article history: Received 14 August 2014 Accepted 2 September 2014 Available online xxxx
14 15 16 17 18 19 20 31
Keywords: Antiphospholipid syndrome Bridging therapy Anticoagulation Warfarin Thrombosis Bleeding
Clinical Immunology, AO Ordine Mauriziano, Torino, Italy Centro di Ricerche di Immunopatologia e Documentazione su Malattie Rare and Università di Torino, Torino, Italy Graham Hughes Lupus Research Laboratory, King's College London, London, UK d Department of Obstetrics and Gynaecology, Università di Torino, Torino, Italy b
a b s t r a c t
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Peri-operative management of patients on warfarin involves assessing and balancing individual risks for thromboembolism and bleeding. The timing of warfarin withdrawal and a tailored pre/postoperative management (including the substitution of heparin in place of warfarin, the so-called bridging therapy) is critical in patients with prothrombotic conditions. The antiphospholipid syndrome (APS) is the most common cause of acquired thrombophilia. In this particular subset of patients, as the risk of thrombosis is higher than in general population, bridging therapy can represent a real challenge for treating physicians. Only few studies have been designed to address this topic. We aim to report our experience and to review the available literature in the peri-procedural management of APS and antiphospholipid antibody-positive patients, reporting adverse events and attempting to identify potential risk factor associated with thrombosis or bleeding complications. © 2014 Elsevier B.V. All rights reserved.
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1. Introduction . . . . . 2. Patients and methods . 3. Autoantibodies detection 4. Results . . . . . . . . 5. Discussion . . . . . . References . . . . . . . . .
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1. Introduction
46
Peri-operative management of patients on warfarin involves assessing and balancing individual risks for thromboembolism [1,2] and bleeding [3]. Indeed, the timing of warfarin withdrawal and a tailored pre/postoperative management (the so-called bridging therapy) are critical elements to avoid thromboembolic complications. Bridging
49 50
U
45
47 48
21 22 23 24 25 26 27 28 29 30
C Contents
E
34
38 39 40 41 42 43
R O
c
35 33 32
37 36
O
F
3
Bridging therapy in antiphospholipid syndrome and antiphospholipid antibodies carriers: Case series and review of the literature☆
2
☆ All the Authors declare not to have any financial or other relationships that might lead to a conflict of interest. This manuscript has been read and approved by all Authors. The manuscript has not been published or submitted elsewhere. ⁎ Corresponding author at: Centro di Ricerche di Immunopatologia e Documentazione su Malattie Rare and Università di Torino, Torino, Italy. Piazza del Donatore di Sangue 3, Torino. E-mail address: [email protected] (S. Sciascia).
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0 0 0 0 0 0
therapy is defined as the temporary peri-operative substitution of low-molecular-weight heparin (LMWH) or unfractionated heparin (UH) in place of warfarin [4]. An effective bridging therapy approach aims to both control the thromboembolic risk that drives the need for an aggressive peri-procedural strategy (bridging therapy), and the procedural bleeding risk determines how and when anticoagulant therapy should be resumed [1,5]. Despite several strategies with various clinical indications are nowadays available [5,6], data from randomized controlled trials are still limited and the question of whether patients should undergo bridging therapy is not resolved [1,7]. Recently, Siegel et al. [6] showed an increased bleeding risk in heparin bridged patients compared with non-bridged, whereas the thrombotic risk seems not to differ between the two groups [6]. Two prospective
http://dx.doi.org/10.1016/j.autrev.2014.09.002 1568-9972/© 2014 Elsevier B.V. All rights reserved.
Please cite this article as: Raso S, et al, Bridging therapy in antiphospholipid syndrome and antiphospholipid antibodies carriers: Case series and review of the literature, Autoimmun Rev (2014), http://dx.doi.org/10.1016/j.autrev.2014.09.002
51 52 53 54 55 56 57 58 59 60 61 62 63 64
90 91 92 93 94 95
99 100 101 102 103
t1:1 t1:2 t1:3
Table 1 Demographic and immunological characteristics of the 36 patients treated with bridging therapy.
t1:5 t1:6 t1:7 t1:8 t1:9 t1:10 t1:11 t1:12 t1:13 t1:14 t1:15 t1:16 t1:17 t1:18 t1:19 t1:20 t1:21 t1:22 t1:23 t1:24 t1:25 t1:26
C
88 89
E
86 87
R
84 85
R
82 83
O
80 81
APS n. 16 F/M Age at procedure (years) Time of APS/aPL diagnosis aPL profile M I⁎ M IIa Other autoimmune diseases associated Procedures time frame Obstetrical intervention Thrombotic adverse events Hemorragic adverse events
C
78 79
APL n. 20
13/3 49 (31–73)
20/0 36 (21–53)
1992–2002
1995–2011
N
76 77
U
74 75
F
This study retrospectively included 36 consecutive patients undergoing any invasive procedure who attended Immunology Department at Ospedale Umberto I, Torino from April 2005 to June 20013. All patients tested positive at least twice for aPL and 16 of those fulfilled the current APS classification criteria [17]. Demographic, clinical and laboratory characteristics are summarized in Table 1.
72 73
O
98
71
R O
2. Patients and methods
69 70
12 (triple positivity in 9) 13 (triple positivity in 8) 2 3 68% (56% patients with SLE) 70% (25% patients with SLE) 1/2006–1/2013
4/2005–6/2013
47%
84,6%
2 venous, 1 arterial
1 venous
2
0
⁎ M I, aPL profile according to Myiakis I [17]: more than one laboratory criteria present (any combination); M IIa, profile according to Myiakis Iia [17]: LA present alone; Triple positivity: LA, aCL, anti-b2glycoprotein-I antibodies.
104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121
3. Autoantibodies detection
122
The aCL and the anti-β2GPI were detected by ELISA as described previously [19]. Plasma samples were tested for the presence of LA according to the recommended criteria from the ISTH Subcommittee on lupus anticoagulant-phospholipid-dependent antibodies [20].
123 124
4. Results
127
We retrospectively described 45 procedures in 36 aPL-positive patients: of those, 20 (55%) were aPL carriers and 16 (44%) were APS. Demographic and immunological characteristics are reported in Table 1. Overall, we described one hemorrhagic and four thrombotic events. Three thrombotic events occurred in the APS group (2 venous and 1 arterial thrombosis), while 1 venous thrombosis occurred in the aPL carrier group. Tables 2 and 3 summarized the outcomes in all APS and aPL patients, respectively. A detailed case analysis is reported in Table 4. A case-by-case analysis of patients who suffered for any adverse outcome has been performed, as follows:
128
Event 1 (patient 8): a patient with obstetric APS developed deep vein thrombosis (DVT) in the postpartum period because of fixed dose of LMWH (enoxaparin 4000 U, with weight 80 kg corresponding to 50 U/kg/die). Event 2 (patient 17): an aPL-positive patient with undifferentiated connective tissue disease (UCTD) developed a cerebral venous thrombosis (CVT) after labor, which occurred 66 hours after LMWH was stopped. Concomitant microcytic anemia (Hb 7,8) favored the adverse event. Event 3 (patient 15): a patient with thrombotic APS (DVT) in SLE (malar rash, photosensivity, arthritis, anti-nuclear antibodies, antiDNA antibodies), who was on LDA because she stopped OAT few years ago, developed DVT after necrosectomy of necrotic ulcer tissue followed by skin graft. She received LMWH (enoxiparin 40 mg OD) for 8 days. Smoke and bed rest, added to low dosage and short period of heparin prophylaxis could justify the onset of DVT. Event 4 (patient 14): a patient with thrombotic APS (pulmonary embolism) in SLE (autoimmune hemolytic anemia, arthritis, sierositis and anti-nuclear antibodies), presented hemorrhage (loss of 6 g Hb) followed by thrombotic event (myocardial infarction) after orthopedic procedure. NSAIDs post-surgery prescription and early somministration of LMWH could explain significant bleeding, whereas smoke, post-splenectomy thrombocytosis were highlighted as arterial
140
P
97
67 68
Inclusion criteria for this study were (1) confirmed aPL positivity, (2) antiaggregant or OAT because of clinical history of thrombosis and/or pregnancy morbidity and (3) bridging therapy required for invasive procedure. Included patients met all the above inclusion criteria. Thrombotic risks assessment included arterial hypertension (systolic pressure N 140 mm Hg or diastolic pressure N 90 mm Hg), obesity (body mass index N 30 kg/m2), diabetes mellitus (baseline glycemia N 126 mg/dl in at least two occasions), smoking, active or treated neoplasia, use of oral contraceptives, underlying systemic autoimmune diseases and genetic hypercoagulables states. The considered bleeding risks factors were previous hemorrhagic events, thrombocytopenia, use of non-steroidal anti-inflammatory drugs (NSAIDs), von Willebrand disease and coagulation factors deficiencies [18]. Preoperative therapy, time of stopping and LMWH doses before and after intervention were retrospectively collected. Adverse events, namely, thrombosis and bleeding, were as previously defined [18].
T
96
randomized trials (PERIOP-2 and BRIDGE) attempting to address this uncertainty are ongoing [8]. All together, due to the lack of sound evidence, an individualized approach and involvement of the patient in decision making process is at present advised [7]. The antiphospholipid syndrome (APS) is the most common cause of acquired thrombophilia [7,9,10], characterized by the association of antiphospholipid antibodies (aPL) with thrombosis and/or pregnancy loss [11]. Thrombotic events can affect venous, arterial side or the microvascular district. In the presence of aPL, the therapeutic approach is influenced by the presence of previous clinical manifestations [2]. For aPL carriers, without history of vascular and/or obstetric events, thromboprophylaxis in acute high-risk situations is highly recommended. Secondary thromboprophylaxis in APS with thrombosis is provided using oral anticoagulant (OAT), normally lifelong. Therapy in pregnant women with APS aims to improve both maternal and fetal outcomes; APS patients with a history of pregnancy morbidity but no vascular thrombosis are usually treated with prophylactic doses of LMWH plus low-dose aspirin (LDA). Patients with a history of thrombotic events should receive full antithrombotic doses of LMWH plus LDA. For all cases anticoagulation for 6 weeks of postpartum is warranted [11,12]. Bridging therapy in APS patients has been evaluated in only few studies designed to address this topic [13,14]. In this particular subset of patients, as the risk of thrombosis is higher than in general population [15], bridging therapy can represent a real challenge for treating physicians [16]. This case study aimed to report our experience in the periprocedural management in a cohort of APS and aPL-positive patients attending the Immunology Department, reporting adverse events and attempting to identify potential risk factor associated with thrombosis or bleeding complications.
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S. Raso et al. / Autoimmunity Reviews xxx (2014) xxx–xxx
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2
Please cite this article as: Raso S, et al, Bridging therapy in antiphospholipid syndrome and antiphospholipid antibodies carriers: Case series and review of the literature, Autoimmun Rev (2014), http://dx.doi.org/10.1016/j.autrev.2014.09.002
125 126
129 130 131 132 133 134 135 136 137 138 139
141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162
U
Table 2 Clinical characteristics, peri-procedural management and outcome of APS patients.
N
t2:4 t2:5 t2:6 t2:7
Patient no.
Age (procedure)
Sex
Diagnosis and treatment before procedure
t2:8 t2:9 t2:10 t2:11 t2:12 t2:13 t2:14 t2:15 t2:16 t2:17 t2:18 t2:19 t2:20 t2:21 t2:22 t2:23 t2:24 t2:25 t2:26 t2:27 t2:28 t2:29 t2:30 t2:31 t2:32 t2:33 t2:34 t2:35 t2:36 t2:37 t2:38 t2:39 t2:40 t2:41 t2:42 t2:43 t2:44 t2:45 t2:46
1 2
46 33
F F
O-APS on LDA O-APS + UCTD on LDA
ACLM+ LAC+ACL-G+ B2GPI-G+
3
34
F
4
41
F
O-APS + SLE on LDA T-APS + S.SJOGREN
5
39
F
6
35
F
7
35
F
T-APS + SLE on LDA T-APS + UCTD on LDA T-O-APS + SLEon LDA
8
32
F
O-APS on LDA
9 10
39 31
F M
11/1st procedure 11/2nd procedure 12
57
F
60
F
60
F
13
39
F
O-APS on LDA T-APS + SLE on OAT T-APS + SLE on LDA T-APS + SLE on LDA T-APS + SLE on LDA OT-APS on LDA
14/1st procedure
64
M
T-APS + SLE on OAT
14/2nd procedure 15/1st procedure 15/2nd procedure 16
68
M
75
F
76
F
64
M
T-APS + on OAT T-APS + on LDA T-APS + on LDA T-APS + on LDA
Apl profile (closer to procedure)
Procedure
LMWH interruption before and after procedure
LMWH doses before and after intervention
Thrombosis risk factors
Bleeding risk factors
Thrombotic and hemorrhagic event
Diagnosis treatment after procedure
CS SL
1/1 1/0
b100 UI/kg × 1/100 UI/kg × 1 b100 UI/kg × 1/100 UI/kg × 1
– –
– –
O-APS on LDA O-APS + UCTD on LD
LAC+ACLG+ACLM+ B2GPI-G+B2GPI-M + ACLG+B2GPI-M+
CS
1/2
100 UI/kg × 1/100 UI/kg × 1
– Steroid Treatment/thrombotic events familiarity HTA Smoke
Thrombocytopenia
–
O-APS + SLE on LDA
2/0
b100 UI/kg × 1/100 UI/kg × 1
Protein S Deficiency
–
–
LAC+ACL-GB2GPI-G
SL
100 UI/kg × 2/100 UI/kg × 2
Smoke
–
–
T-APS + S.SJOGREN in OAE T-APS + SLE on OAT
LAC+ACL-G+ B2GPI-G+ LAC+ACL-G+ B2GPI-G+ LAC+ACL-G+ B2GPI-G+ B2GPI-G + LAC+ACL-GB2GPI-G
CS
b100 UI/kg × 1/100 UI/kg × 1
Smoke – Thrombotic events familiarity HTA – obesity- steroid therapy PreviousDVT
–
–
T-APS + UCTD on LDA
–
–
T-O-APS + SLEon LD
–
DVT
O-APS on OAT
100 UI/kg × 1/100 UI/kg × 2 100 UI/kg × 1/100 UI/kg × 1
Smoke, Overweight HTA, Obesity
– –
– –
O-APS on LDA T-APS on OAT
C
O
R SL
R
E 1/1
1/1
C
CS
1/1
IL
2/0
100 UI/kg × 2/100 UI/kg × 2
CS Surgery
1/0 1/0
LAC+
Surgery
0/0
100 UI/kg × 1/100 UI/kg × 1
HTA, Obesity
–
–
T-APS + SLE on LDA
LAC+
Surgery
0/0
100 UI/kg × 1/100 UI/kg × 1
HTA, Obesity
–
–
T-APS + SLE on LDA
LAC+ACL-M+ B2GPI-M+ LAC+ACL-G +
Surgery
1/0
b100 UI/kg × 1/100 UI/kg × 1
–
–
T-APS + SLE on LDA
1/0
100 UI/kg × 2/100 UI/kg × 2
–
–
OT-APS on LDA
LAC+ACLG+ACLM+
Voluntary Interruption of pregnancy Surgery
Obesity/Steroid treatment –
1/1
100 UI/kg × 2/100 UI/kg × 1
NSAD
LAC+ACLG+ACLM+
Surgery
0/1
100 UI/kg × 1/100 UI/kg × 1
ACS/Local bleeding, loss of 6 g Hb –
T-APS + SLE on OAT + Clopidogrel
SLE SLE
LAC+ACLG+B2GPIG+
Surgery
0/1
−/b100 UI/kg × 1
Smoke, steroid therapy, (anemia post bleeding) Smoke, steroid therapy Smoke
SLE
LAC+ACLG+B2GPIG+
Surgery
1/1
−/b100 UI/kg × 1
Smoke
–
SLE
LAC +
Surgery
3/1
100 UI/kg × 1/100 UI/kg × 1
HTA,Overweight, Steroid therapy
–
T
b100 UI/kg × 1/100 UI/kg × 1
E
D
P
R O
O –
F
S. Raso et al. / Autoimmunity Reviews xxx (2014) xxx–xxx
Please cite this article as: Raso S, et al, Bridging therapy in antiphospholipid syndrome and antiphospholipid antibodies carriers: Case series and review of the literature, Autoimmun Rev (2014), http://dx.doi.org/10.1016/j.autrev.2014.09.002
t2:1 t2:2
T-APS + SLE on OAT T-APS + SLE on LDA
DVT
T-APS + SLE on LDA
–
T-APS + SLE on LDA
3
4
N
C
O
R
R
E
C
Table 3 Clinical Characteristics, peri-procedural management and outcome of antiphsopholipid antibody-positive patients.
T
t3:4 t3:5 t3:6
Patient no.
Age (procedure)
sex
Diagnosis and Treatment before procedure
Apl Profile (closer to procedure)
Procedure
LMWH interruption before and after procedure
LMWH doses before and after intervention
t3:7 t3:8 t3:9 t3:10 t3:11 t3:12 t3:13 t3:14 t3:15 t3:16 t3:17 t3:18 t3:19 t3:20 t3:21 t3:22 t3:23 t3:24 t3:25 t3:26 t3:27 t3:28 t3:29 t3:30 t3:31 t3:32 t3:33 t3:34 t3:35
17 18/1st procedure 18/2nd procedure 19 20 21 22/1st procedure
39 32 37 41 38 37 53
F F F F F F F
APL + UCTD APL + SLE on LDA APL + SLE APL on LDA APL on LDA APL + UCTD on LDA APL + UCTD on LDA
LAC+ ACLG + ACLG + ACLM+B2GPIM+ ACLM+B2GPIM+ LAC+B2GPIM+ LAC+ACLG+B2GPIG+
IL CS CS SL CS CS Surgery
2/1 1/1 0/3 1/1 1/1 1/1 2/2
100 UI/kg × 1/100 UI/kg × 1 b100 UI/kg × 1/b100 UI/kg × −/b100 UI/kg × 1 b100 UI/kg × 1/b100 UI/kg × b100 UI/kg × 1/b100 UI/kg × b100 UI/kg × 1/b100 UI/kg × −/100 UI/kg × 1
22/2nd procedure 23/1st procedure
39 34
F F
APL on LDA APL + SLE on LDA
CS SL
1/1 1/2
23/2nd procedure 24
36 32
F F
APL + SLE on LDA APL + SLE on LDA
CS Surgery
25 26 27
36 30 28
F F F
APL + UCTD on LDA APL + on LDA APL + SLE on LDA
LAC+B2GPIG+ LAC+ACLG+B2GPIG+ B2GPIM+ LAC+B2GPIG+ LAC+ACLG+B2GPIG+ B2GPIM+ LAC+ACLG+B2GPIG+ LAC+ACLM + LAC+B2GPIG+
28/1st procedur
36
F
APL + UCTD on LDA
28/2nd procedure
40
F
29 30/1st procedure 30/2nd procedure 31/1st procedure
33 38 40 32
31/2nd procedure
35
Thrombosis risk factors
Bleeding Risk Factors
Thrombotic and Hemorrhagic event
Diagnosis Treatment after Procedure
– – – – – – Thrombocytopenia
CVST – – Bleeding – – –
T-APS + UCTD on OAT APL + SLE on LDA APL + SLE APL on LDA APL APL + UCTD APL + UCTD on LDA
b100 UI/kg × 1/b100 UI/kg × 1 b100 UI/kg × 1/100 UI/kg × 1
– Overweight Overweight – Overweight – Obesity, Smoke, HTA, (cancer) Steroid Therapy Steroid Therapy
– –
– –
APL APL + SLE on LDA
1/1 1/2
b100 UI/kg × 1/b100 UI/kg × 1 b100 UI/kg × 1/100 UI/kg × 1
Steroid Therapy Obesity, HTA
– Thrombocytopenia
– –
APL + SLE on LDA APL + SLE on LDA
CS CS IL
0/2 2/1 3/1
100 UI/kg × 1/100 UI/kg × 1 b100 UI/kg × 1/100 UI/kg × 1 100 UI/kg × 1/100 UI/kg × 1
– – –
– – –
APL + UCTD APL + on LDA APL + SLE on LDA
LAC+ACLG+B2GPIG+
IL
2/1
100 UI/kg × 1/100 UI/kg × 1
–
APL + UCTD on LDA
APL + UCTD on LDA
LAC+ACLG+B2GPIG+
CS
0/1
100 UI/kg × 1/100 UI/kg × 1
–
–
APL + UCTD on LDA
F F F F
APL APL APL APL
CS CS CS SL
1/1 2/1 1/1 2/1
100 100 100 100
– – – –
– – – –
APL + on LDA APL + on LDA APL+ APL + UCTD on LDA
F
APL + UCTD on LDA
ACLG + ACLM+B2GPIM+ LAC+ACLM+B2GPIM+ LAC+ACLG+ACLM+ B2GPI-G+B2GPI-M + LAC+ACLG+ACLM+ B2GPI-G+B2GPI-M +
– – Steroid Therapy, Smoke Smoke,Protein S Deficiency Smoke,Protein S Deficiency – – – –
IL
1/1
b100 UI/kg × 1/b100 UI/kg × 1
Steroid Therapy
–
–
+ + + +
on LDA on LDA on LDA UCTD on LDA
E
D
1 1 1 1
P
UI/kg UI/kg UI/kg UI/kg
× × × ×
R O
1/100 UI/kg × 1 1/100 UI/kg × 2 1/100 UI/kg × 1 1/b100 UI/kg × 1
O –
F
S. Raso et al. / Autoimmunity Reviews xxx (2014) xxx–xxx
Please cite this article as: Raso S, et al, Bridging therapy in antiphospholipid syndrome and antiphospholipid antibodies carriers: Case series and review of the literature, Autoimmun Rev (2014), http://dx.doi.org/10.1016/j.autrev.2014.09.002
t3:1 t3:2
U
t3:42 t3:43 t3:44 t3:45 t3:46 t3:47 t3:48 t3:49 t3:50 t3:51 t3:52 t3:53 t3:54 t3:55 t3:56 t3:57 t3:58 t3:59 t3:60 t3:61 t3:62 t3:63 t3:64 t3:65 t3:66 t3:67 t3:68
32 33 34/1st procedure 34/2nd procedure 35 36
36 47 21 22 57 38
F F F F F F
APL APL APL APL APL APL
+ + + + + +
O-APS, obstetric antiphospholipid syndrome T-APS, thrombotic antiphospholipid syndrome SLE, systemic lupus erythematosus UCTD, undifferentiated connective tissue disease HTA, arterial hypertension ACS, acute coronary syndrome NSAD, non-steroid anti-inflammatory drugs LDA, low dose aspirin OAT, oral anticoagulant therapy LDA, low dose aspirin OAT, oral anticoagulant therapy LAC, lupus anticoagulant ACLG, IgG anti-cardiolipina ACLM, IgM anti-cardiolipina B2GPI-G, IgG anti-B2GPI B2GPI-M, IgM anti-B2GPI TRIPLE CS, cesarean section SL, spontaneous labor IL, induced labor DVT, deep venous thrombosis CVST, cerebral venous sinus thrombosis LMWH, interruption before and after procedure 0 b 12H (1) 12–24H (2) 25–48H (3) N48H
on LDA on LDA SLE on LDA SLE on LDA UCTD on LDA on LDA
ACLM+ ACLG + LAC+ LAC+ LAC+ LAC+ACLG+B2GPIG+
CS CS CS Surgery Surgery IL
1/1 1/1 1/1 1/1 1/1 1/1
100 UI/kg × 1/100 UI/kg × 1 100 UI/kg × 1/100 UI/kg × 1 100 UI/kg × 1/100 UI/kg × 1 100 UI/kg × 1/100 UI/kg × 1 100 UI/kg × 1/100 UI/kg × 1 b100 UI/kg × 1/b100 UI/kg × 1
– Smoke – – Protein S Deficiency –
– – – – – –
– – – – – –
APL+ APL + APL + APL + APL + APL +
R SLE on LDA SLE on LDA UCTD on LDA on LDA
U
N
C
O
R
R
S. Raso et al. / Autoimmunity Reviews xxx (2014) xxx–xxx
Please cite this article as: Raso S, et al, Bridging therapy in antiphospholipid syndrome and antiphospholipid antibodies carriers: Case series and review of the literature, Autoimmun Rev (2014), http://dx.doi.org/10.1016/j.autrev.2014.09.002
t3:36 t3:37 t3:38 t3:39 t3:40 t3:41
E
C
T
E
D P
R O
O
F
5
C Myiakis IIa aPL with UCTD on LDA
N Triple positivity T-APS with SLE on LDA
17
15
197
This report describes a cohort of APS and aPL-positive patients requiring bridging therapy for surgery or invasive procedure. To the best of our knowledge, we report the largest study addressing the topic of bridging therapy in aPL-positive patients. Bridging therapy in APS and aPL carriers represents a challenge for many reasons. Several factors such as stasis, endothelial injury and aPL related hypercoagulability may contribute to the development of postoperative thromboembolic events. APS patients may have increased risk of postoperative thrombosis, making prophylaxis with heparin or warfarin in patients with APS mandatory [13]. Besides, surgery itself is an established trigger factor for CAPS, severe microvascular form that affects multiple organ systems, and it is fatal in approximately half of patients [21]. SLE, associated to APS (in 50% of cases), provides an increased risk of thrombosis [22,23] and immunosuppressive therapy may complicate the management of peri-operative period. Young people are generally affected, and fertility is not compromised in APS patients: for those reasons, delivery and cesarean section deserve particular attention in these patients. Indeed, labor and cesarean section accounts for a high percentage of total procedures (69%) in our cohort. As combination of LDA and heparin is considered the standard of care to minimize the risk of maternal thromboembolism and it has been proven to improve fetal-maternal outcome in aPL pregnancy [24] , optimal timing for stopping them is essential for a correct management and to plan intervention such as epidural procedures. It is generally accepted that aspirin could be stopped at least 10 days before delivery (normally at 34° weeks of gestation), despite the possibility of using of aspirin during the delivery is still under debate [25,26]. LMWH should be suspended 12–24 hours before neuraxial anesthesia (depending on dosage of heparin) and resumed 12 hours after catheter removal [24]. In APS and aPL-positive patients, LMWH should be continued for 6– 8 weeks after delivery [26]. It is usually suggested to induce the delivery as an effective strategy to optimize the timing for stopping heparin, aiming to reduce the risks for both thrombotic and hemorrhagic complications related to the puerperium. This can also reduce the need for cesarean section, which may require general anesthesia, known as a potential cause of complication and increased risk of death [26]. In this study, despite the heterogeneity of the study population, when analyzing the patients who suffered for adverse events, it is possible draw to some general considerations. First, all patients with adverse events were LA positive (aPL profile including triple positivity, Miyakis I or IIa [19]). LA is considered the strongest risk factor among aPL for thrombosis [27], and a special attention is required when a thrombo-prophylaxis is planned in patients with LA, especially when associated with multiple positivity. However, we think that the presence of LA might have had a role in inducing thrombosis, while the association with the hemorrhagic event is more difficult to be interpreted. Second, the co-existence of anemia and thromboembolism seems to be evident in cases 17 and 14. An association between anemia (defined as b 9 g/dl) and CVT has been recognized by Stolz et al. [28]. In our cohort, case 17 presented with a severe microcytic anemia (Hb 7,8 g/dl at the time of CVT). However, it worth noting that this happened in the absence of thrombocytosis, which is frequently seen in iron deficiency anemia and could justify an hypercoagulability. In case 14, several risk factors coexisted, for both bleeding or thrombotic complication. SLE itself is strong risk for thromboembolic event, while an early re-introduction of LMWH and the use of NSAIDs in analgesic therapy enabled bleeding. In the same patients, a severe blood loss occurred, and this has been linked with the occurrence of myocardial infarction [29,30]. This case highlights the concept that major attention should be paid in aPL-positive patients also when assessing the bleeding
198
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t4:15 t4:16 t4:17 t4:18 t4:19 t4:20 t4:21 t4:22 t4:23 t4:24 t4:25
O
CVT
R
T-APS with UCTD on OAT No Microcytic anemia Hb 7,8 g, pregnancy 100 × 1/100 × 1 46/20
−/b100 × 1 DVT
Skin graft after necrosectomy of necrotic tissue Labor
−/12
DVT Local bleeding, loss of 6 g Hb/MI Labor Orthopedic surgery Triple positivity Myiakis I
U 8 14
t4:7 t4:8 t4:9 t4:10 t4:11 t4:12 t4:13 t4:14
O-APS on LDA T-APS with SLE on OAT
thrombotic risk factors. Treatment after procedure changed from OAT 195 to OAT + LDA. 196 SLE, systemic lupus erythematosus O-APS, obstetric APS T -APS, thrombotic APS LDA, low-dose aspirin OAT, oral anticoagulation therapy MI, myocardial infarction DVT, deep venous thrombosis CVT, cerebral venous thrombosis NSAID, non-steroidal anti-inflammatory drugs PE, pulmonary thromboembolism Myiakis I: more than one laboratory criteria present (any combination); IIa: LA present alone; IIb: aCL antibody present alone; IIc: anti-b2glycoprotein-I antibody present alone. Triple positivity: LA, aCL, anti-b2glycoprotein-I antibodies
T-APS with SLE on OAT No
O/T-APS on OAT T-APS with SLE on OAT + LDA + Clopidogrel No NSAID post surgery
Pregnancy Smoke, bed rest, post-splenectomy thrombocytosis, previous PE, steroid therapy Smoke, bed rest, previous DVT b100 × 1/100 × 1 100 × 2/100 × 2 31/11 12/4
LMWH interruption before and after intervention (hours) Adverse events Procedures aPL profile Diagnosis and treatment before procedure Patient no. t4:4 t4:5 t4:6
t4:1 t4:2
Table 4 Clinical Characteristics, peri-procedural management and outcome of patients who experienced adverse events.
LMWH doses before and after intervention (UI/kg/die)
Thrombotic risk factors
Diagnosis and treatment after procedure
S. Raso et al. / Autoimmunity Reviews xxx (2014) xxx–xxx
Bleeding risk factors
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Please cite this article as: Raso S, et al, Bridging therapy in antiphospholipid syndrome and antiphospholipid antibodies carriers: Case series and review of the literature, Autoimmun Rev (2014), http://dx.doi.org/10.1016/j.autrev.2014.09.002
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[1] Baron TH, Kamath PS, McBane RD. Antithrombotic therapy and invasive procedures. N Engl J Med 2013;369:1079–80. [2] Reynaud Q, Lega JC, Mismetti P, Chapelle C, Wahl D, Cathebras P, et al. Risk of venous and arterial thrombosis according to type of antiphospholipid antibodies in adults without systemic lupus erythematosus: a systematic review and meta-analysis. Autoimmun Rev 2014;13:595–608. [3] Hammerstingl C, Tripp C, Schmidt H, von der Recke G, Omran H. Periprocedural bridging therapy with low-molecular-weight heparin in chronically anticoagulated patients with prosthetic mechanical heart valves: experience in 116 patients from the prospective BRAVE registry. J Heart Valve Dis 2007;16:285–92. [4] Ortel TL. Perioperative management of patients on chronic antithrombotic therapy. Hematology Am Soc Hematol Educ Program 2012;2012:529–35. [5] Patel JP, Arya R. The current status of bridging anticoagulation. Br J Haematol 2014; 164:619–29. [6] Siegal D, Yudin J, Kaatz S, Douketis JD, Lim W, Spyropoulos AC. Periprocedural heparin bridging in patients receiving vitamin K antagonists: systematic review and meta-analysis of bleeding and thromboembolic rates. Circulation 2012;126:1630–9. [7] Spyropoulos AC, Douketis JD. How I treat anticoagulated patients undergoing an elective procedure or surgery. Blood 2012;120:2954–62.
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[8] Gallego P, Apostolakis S, Lip GY. Bridging evidence-based practice and practicebased evidence in periprocedural anticoagulation. Circulation 2012;126:1573–6. [9] Chang HH, Chiang BL. The diagnosis and classification of autoimmune coagulopathy: an updated review. Autoimmun Rev 2014;13:587–90. [10] Comarmond C, Cacoub P. Antiphospholipid syndrome: from pathogenesis to novel immunomodulatory therapies. Autoimmun Rev 2013;12:752–7. [11] Ruiz-Irastorza G, Crowther M, Branch W, Khamashta MA. Antiphospholipid syndrome. Lancet 2010;376:1498–509. [12] Erkan D, Aguiar CL, Andrade D, Cohen H, Cuadrado MJ, Danowski A, et al. 14th International Congress on Antiphospholipid Antibodies Task Force Report on Antiphospholipid Syndrome Treatment Trends. Autoimmun Rev 2014;13:685–96. [13] Erkan D, Leibowitz E, Berman J, Lockshin MD. Perioperative medical management of antiphospholipid syndrome: hospital for special surgery experience, review of literature, and recommendations. J Rheumatol 2002;29:843–9. [14] Akkara Veetil BM, Bongartz T. Perioperative care for patients with rheumatic diseases. Nat Rev Rheumatol 2012;8:32–41. [15] Bazzan M, Vaccarino A, Stella S, Bertero MT, Carignola R, Montaruli B, et al. Thrombotic recurrences and bleeding events in APS vascular patients: a review from the literature and a comparison with the APS Piedmont Cohort. Autoimmun Rev 2013; 12:826–31. [16] Pengo V, Banzato A, Denas G, Jose SP, Bison E, Hoxha A, et al. Correct laboratory approach to APS diagnosis and monitoring. Autoimmun Rev 2013;12:832–4. [17] Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006;4:295–306. [18] Tosetto A, Castaman G, Rodeghiero F. Bleeders, bleeding rates, and bleeding score. J Thromb Haemost 2013;11(Suppl. 1):142–50. [19] Sciascia S, Cosseddu D, Montaruli B, Kuzenko A, Bertero MT. Risk Scale for the diagnosis of antiphospholipid syndrome. Ann Rheum Dis 2011;70:1517–8. [20] Pengo V. ISTH guidelines on lupus anticoagulant testing. Thromb Res 2012; 130(Suppl. 1):S76–7. [21] Sciascia S, Lopez-Pedrera C, Roccatello D, Cuadrado MJ. Catastrophic antiphospholipid syndrome (CAPS). Best Pract Res Clin Rheumatol 2012;26:535–41. [22] Ramagopalan SV, Wotton CJ, Handel AE, Yeates D, Goldacre MJ. Risk of venous thromboembolism in people admitted to hospital with selected immunemediated diseases: record-linkage study. BMC Med 2011;9:1. [23] Tosetto A, Iorio A, Marcucci M, Baglin T, Cushman M, Eichinger S, et al. Predicting disease recurrence in patients with previous unprovoked venous thromboembolism: a proposed prediction score (DASH). J Thromb Haemost 2012;10:1019–25. [24] Ateka-Barrutia O, Khamashta MA. The challenge of pregnancy for patients with SLE. Lupus 2013;22:1295–308. [25] Sibai BM, Caritis SN, Thom E, Shaw K, McNellis D. Low-dose aspirin in nulliparous women: safety of continuous epidural block and correlation between bleeding time and maternal-neonatal bleeding complications. National Institute of Child Health and Human Developmental Maternal-Fetal Medicine Network. Am J Obstet Gynecol 1995;172:1553–7. [26] Horlocker TT, Wedel DJ, Benzon H, Brown DL, Enneking FK, Heit JA, et al. Regional anesthesia in the anticoagulated patient: defining the risks (the second ASRA Consensus Conference on Neuraxial Anesthesia and Anticoagulation). Reg Anesth Pain Med 2003;28:172–97. [27] Galli M, Luciani D, Bertolini G, Barbui T. Lupus anticoagulants are stronger risk factors for thrombosis than anticardiolipin antibodies in the antiphospholipid syndrome: a systematic review of the literature. Blood 2003;101:1827–32. [28] Stolz E, Valdueza JM, Grebe M, Schlachetzki F, Schmitt E, Madlener K, et al. Anemia as a risk factor for cerebral venous thrombosis? An old hypothesis revisited Results of a prospective study. J Neurol 2007;254:729–34. [29] da Silveira AD, Ribeiro RA, Rossini AP, Stella SF, Ritta HA, Stein R, et al. Association of anemia with clinical outcomes in stable coronary artery disease. Coron Artery Dis 2008;19:21–6. [30] Blanco M, Castillo J. Stroke in 2012: major advances in the treatment of stroke. Nat Rev Neurol 2013;9:68–70.
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risk. Indeed, the major bleeding indirectly influenced damage in patient 14 (triggering the onset of a thrombotic event) and, after all, it resulted in a change of treatment (fromOAT to OAT + LDA). Moreover, the index event reported in this study impact on the diagnosis and consequently on the treatment of patient 8 (OAPS to O-T APS) and 17 (from UCTD with aPL positivity to UCTD associated to APS). No CAPS, the most dangerous complication of APS, was observed in our cohort. One can speculate that this can be due to a sufficiently intensive thrombo-prophylactic management; however, it is not possible to rule out that the our cohort was not wide enough to observe the occurrence of this rare condition (less than 1% of all APS patients). We acknowledge that this study suffers for some limitations. Our cohort appears to be very heterogeneous, showing additional risk factors such SLE, corticosteroid therapy, thrombocytopenia and renal diseases, or cancer. Besides, different types of surgical procedures have been taken into account: renal biopsy, orthopedic, cardiovascular, abdominal, cutaneous and gynecologic surgery. Unlike other patient population studies for BT, it should be remembered that thrombotic risk may involve both venous and arterial side in aPL patients. In conclusion, the heterogeneity and the complexity of the cases make difficult to outline management recommendations. However, on the basis of our experience, we suggest that a multidisciplinary evaluation of the single case before procedure, aiming to tailor the tromboprophylaxis management can be an effective strategy to reduce adverse events. Probably in some patients conventional doses of heparin may result in a “under-coagulation” (patients 8 and 15); for that reason, a weight adjusted prophylactic dose of 100 U/kg can be suggested [4]. Larger, prospective studies are warranted to further evaluate the correlation between hemorrhagic adverse events and subsequent damage accrual in APS patients.
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Please cite this article as: Raso S, et al, Bridging therapy in antiphospholipid syndrome and antiphospholipid antibodies carriers: Case series and review of the literature, Autoimmun Rev (2014), http://dx.doi.org/10.1016/j.autrev.2014.09.002
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Contents lists available at ScienceDirect
Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev
1
Review
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Samuele Raso a, Savino Sciascia b,c,⁎, Anna Kuzenko a, Irene Castagno a, Luca Marozio d, Maria Tiziana Bertero a
5 6 7 8
a
9
a r t i c l e
10 11 12 13
Article history: Received 14 August 2014 Accepted 2 September 2014 Available online xxxx
14 15 16 17 18 19 20 31
Keywords: Antiphospholipid syndrome Bridging therapy Anticoagulation Warfarin Thrombosis Bleeding
Clinical Immunology, AO Ordine Mauriziano, Torino, Italy Centro di Ricerche di Immunopatologia e Documentazione su Malattie Rare and Università di Torino, Torino, Italy Graham Hughes Lupus Research Laboratory, King's College London, London, UK d Department of Obstetrics and Gynaecology, Università di Torino, Torino, Italy b
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Peri-operative management of patients on warfarin involves assessing and balancing individual risks for thromboembolism and bleeding. The timing of warfarin withdrawal and a tailored pre/postoperative management (including the substitution of heparin in place of warfarin, the so-called bridging therapy) is critical in patients with prothrombotic conditions. The antiphospholipid syndrome (APS) is the most common cause of acquired thrombophilia. In this particular subset of patients, as the risk of thrombosis is higher than in general population, bridging therapy can represent a real challenge for treating physicians. Only few studies have been designed to address this topic. We aim to report our experience and to review the available literature in the peri-procedural management of APS and antiphospholipid antibody-positive patients, reporting adverse events and attempting to identify potential risk factor associated with thrombosis or bleeding complications. © 2014 Elsevier B.V. All rights reserved.
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1. Introduction . . . . . 2. Patients and methods . 3. Autoantibodies detection 4. Results . . . . . . . . 5. Discussion . . . . . . References . . . . . . . . .
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1. Introduction
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Peri-operative management of patients on warfarin involves assessing and balancing individual risks for thromboembolism [1,2] and bleeding [3]. Indeed, the timing of warfarin withdrawal and a tailored pre/postoperative management (the so-called bridging therapy) are critical elements to avoid thromboembolic complications. Bridging
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Bridging therapy in antiphospholipid syndrome and antiphospholipid antibodies carriers: Case series and review of the literature☆
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☆ All the Authors declare not to have any financial or other relationships that might lead to a conflict of interest. This manuscript has been read and approved by all Authors. The manuscript has not been published or submitted elsewhere. ⁎ Corresponding author at: Centro di Ricerche di Immunopatologia e Documentazione su Malattie Rare and Università di Torino, Torino, Italy. Piazza del Donatore di Sangue 3, Torino. E-mail address: [email protected] (S. Sciascia).
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therapy is defined as the temporary peri-operative substitution of low-molecular-weight heparin (LMWH) or unfractionated heparin (UH) in place of warfarin [4]. An effective bridging therapy approach aims to both control the thromboembolic risk that drives the need for an aggressive peri-procedural strategy (bridging therapy), and the procedural bleeding risk determines how and when anticoagulant therapy should be resumed [1,5]. Despite several strategies with various clinical indications are nowadays available [5,6], data from randomized controlled trials are still limited and the question of whether patients should undergo bridging therapy is not resolved [1,7]. Recently, Siegel et al. [6] showed an increased bleeding risk in heparin bridged patients compared with non-bridged, whereas the thrombotic risk seems not to differ between the two groups [6]. Two prospective
http://dx.doi.org/10.1016/j.autrev.2014.09.002 1568-9972/© 2014 Elsevier B.V. All rights reserved.
Please cite this article as: Raso S, et al, Bridging therapy in antiphospholipid syndrome and antiphospholipid antibodies carriers: Case series and review of the literature, Autoimmun Rev (2014), http://dx.doi.org/10.1016/j.autrev.2014.09.002
51 52 53 54 55 56 57 58 59 60 61 62 63 64
90 91 92 93 94 95
99 100 101 102 103
t1:1 t1:2 t1:3
Table 1 Demographic and immunological characteristics of the 36 patients treated with bridging therapy.
t1:5 t1:6 t1:7 t1:8 t1:9 t1:10 t1:11 t1:12 t1:13 t1:14 t1:15 t1:16 t1:17 t1:18 t1:19 t1:20 t1:21 t1:22 t1:23 t1:24 t1:25 t1:26
C
88 89
E
86 87
R
84 85
R
82 83
O
80 81
APS n. 16 F/M Age at procedure (years) Time of APS/aPL diagnosis aPL profile M I⁎ M IIa Other autoimmune diseases associated Procedures time frame Obstetrical intervention Thrombotic adverse events Hemorragic adverse events
C
78 79
APL n. 20
13/3 49 (31–73)
20/0 36 (21–53)
1992–2002
1995–2011
N
76 77
U
74 75
F
This study retrospectively included 36 consecutive patients undergoing any invasive procedure who attended Immunology Department at Ospedale Umberto I, Torino from April 2005 to June 20013. All patients tested positive at least twice for aPL and 16 of those fulfilled the current APS classification criteria [17]. Demographic, clinical and laboratory characteristics are summarized in Table 1.
72 73
O
98
71
R O
2. Patients and methods
69 70
12 (triple positivity in 9) 13 (triple positivity in 8) 2 3 68% (56% patients with SLE) 70% (25% patients with SLE) 1/2006–1/2013
4/2005–6/2013
47%
84,6%
2 venous, 1 arterial
1 venous
2
0
⁎ M I, aPL profile according to Myiakis I [17]: more than one laboratory criteria present (any combination); M IIa, profile according to Myiakis Iia [17]: LA present alone; Triple positivity: LA, aCL, anti-b2glycoprotein-I antibodies.
104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121
3. Autoantibodies detection
122
The aCL and the anti-β2GPI were detected by ELISA as described previously [19]. Plasma samples were tested for the presence of LA according to the recommended criteria from the ISTH Subcommittee on lupus anticoagulant-phospholipid-dependent antibodies [20].
123 124
4. Results
127
We retrospectively described 45 procedures in 36 aPL-positive patients: of those, 20 (55%) were aPL carriers and 16 (44%) were APS. Demographic and immunological characteristics are reported in Table 1. Overall, we described one hemorrhagic and four thrombotic events. Three thrombotic events occurred in the APS group (2 venous and 1 arterial thrombosis), while 1 venous thrombosis occurred in the aPL carrier group. Tables 2 and 3 summarized the outcomes in all APS and aPL patients, respectively. A detailed case analysis is reported in Table 4. A case-by-case analysis of patients who suffered for any adverse outcome has been performed, as follows:
128
Event 1 (patient 8): a patient with obstetric APS developed deep vein thrombosis (DVT) in the postpartum period because of fixed dose of LMWH (enoxaparin 4000 U, with weight 80 kg corresponding to 50 U/kg/die). Event 2 (patient 17): an aPL-positive patient with undifferentiated connective tissue disease (UCTD) developed a cerebral venous thrombosis (CVT) after labor, which occurred 66 hours after LMWH was stopped. Concomitant microcytic anemia (Hb 7,8) favored the adverse event. Event 3 (patient 15): a patient with thrombotic APS (DVT) in SLE (malar rash, photosensivity, arthritis, anti-nuclear antibodies, antiDNA antibodies), who was on LDA because she stopped OAT few years ago, developed DVT after necrosectomy of necrotic ulcer tissue followed by skin graft. She received LMWH (enoxiparin 40 mg OD) for 8 days. Smoke and bed rest, added to low dosage and short period of heparin prophylaxis could justify the onset of DVT. Event 4 (patient 14): a patient with thrombotic APS (pulmonary embolism) in SLE (autoimmune hemolytic anemia, arthritis, sierositis and anti-nuclear antibodies), presented hemorrhage (loss of 6 g Hb) followed by thrombotic event (myocardial infarction) after orthopedic procedure. NSAIDs post-surgery prescription and early somministration of LMWH could explain significant bleeding, whereas smoke, post-splenectomy thrombocytosis were highlighted as arterial
140
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67 68
Inclusion criteria for this study were (1) confirmed aPL positivity, (2) antiaggregant or OAT because of clinical history of thrombosis and/or pregnancy morbidity and (3) bridging therapy required for invasive procedure. Included patients met all the above inclusion criteria. Thrombotic risks assessment included arterial hypertension (systolic pressure N 140 mm Hg or diastolic pressure N 90 mm Hg), obesity (body mass index N 30 kg/m2), diabetes mellitus (baseline glycemia N 126 mg/dl in at least two occasions), smoking, active or treated neoplasia, use of oral contraceptives, underlying systemic autoimmune diseases and genetic hypercoagulables states. The considered bleeding risks factors were previous hemorrhagic events, thrombocytopenia, use of non-steroidal anti-inflammatory drugs (NSAIDs), von Willebrand disease and coagulation factors deficiencies [18]. Preoperative therapy, time of stopping and LMWH doses before and after intervention were retrospectively collected. Adverse events, namely, thrombosis and bleeding, were as previously defined [18].
T
96
randomized trials (PERIOP-2 and BRIDGE) attempting to address this uncertainty are ongoing [8]. All together, due to the lack of sound evidence, an individualized approach and involvement of the patient in decision making process is at present advised [7]. The antiphospholipid syndrome (APS) is the most common cause of acquired thrombophilia [7,9,10], characterized by the association of antiphospholipid antibodies (aPL) with thrombosis and/or pregnancy loss [11]. Thrombotic events can affect venous, arterial side or the microvascular district. In the presence of aPL, the therapeutic approach is influenced by the presence of previous clinical manifestations [2]. For aPL carriers, without history of vascular and/or obstetric events, thromboprophylaxis in acute high-risk situations is highly recommended. Secondary thromboprophylaxis in APS with thrombosis is provided using oral anticoagulant (OAT), normally lifelong. Therapy in pregnant women with APS aims to improve both maternal and fetal outcomes; APS patients with a history of pregnancy morbidity but no vascular thrombosis are usually treated with prophylactic doses of LMWH plus low-dose aspirin (LDA). Patients with a history of thrombotic events should receive full antithrombotic doses of LMWH plus LDA. For all cases anticoagulation for 6 weeks of postpartum is warranted [11,12]. Bridging therapy in APS patients has been evaluated in only few studies designed to address this topic [13,14]. In this particular subset of patients, as the risk of thrombosis is higher than in general population [15], bridging therapy can represent a real challenge for treating physicians [16]. This case study aimed to report our experience in the periprocedural management in a cohort of APS and aPL-positive patients attending the Immunology Department, reporting adverse events and attempting to identify potential risk factor associated with thrombosis or bleeding complications.
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S. Raso et al. / Autoimmunity Reviews xxx (2014) xxx–xxx
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Please cite this article as: Raso S, et al, Bridging therapy in antiphospholipid syndrome and antiphospholipid antibodies carriers: Case series and review of the literature, Autoimmun Rev (2014), http://dx.doi.org/10.1016/j.autrev.2014.09.002
125 126
129 130 131 132 133 134 135 136 137 138 139
141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162
U
Table 2 Clinical characteristics, peri-procedural management and outcome of APS patients.
N
t2:4 t2:5 t2:6 t2:7
Patient no.
Age (procedure)
Sex
Diagnosis and treatment before procedure
t2:8 t2:9 t2:10 t2:11 t2:12 t2:13 t2:14 t2:15 t2:16 t2:17 t2:18 t2:19 t2:20 t2:21 t2:22 t2:23 t2:24 t2:25 t2:26 t2:27 t2:28 t2:29 t2:30 t2:31 t2:32 t2:33 t2:34 t2:35 t2:36 t2:37 t2:38 t2:39 t2:40 t2:41 t2:42 t2:43 t2:44 t2:45 t2:46
1 2
46 33
F F
O-APS on LDA O-APS + UCTD on LDA
ACLM+ LAC+ACL-G+ B2GPI-G+
3
34
F
4
41
F
O-APS + SLE on LDA T-APS + S.SJOGREN
5
39
F
6
35
F
7
35
F
T-APS + SLE on LDA T-APS + UCTD on LDA T-O-APS + SLEon LDA
8
32
F
O-APS on LDA
9 10
39 31
F M
11/1st procedure 11/2nd procedure 12
57
F
60
F
60
F
13
39
F
O-APS on LDA T-APS + SLE on OAT T-APS + SLE on LDA T-APS + SLE on LDA T-APS + SLE on LDA OT-APS on LDA
14/1st procedure
64
M
T-APS + SLE on OAT
14/2nd procedure 15/1st procedure 15/2nd procedure 16
68
M
75
F
76
F
64
M
T-APS + on OAT T-APS + on LDA T-APS + on LDA T-APS + on LDA
Apl profile (closer to procedure)
Procedure
LMWH interruption before and after procedure
LMWH doses before and after intervention
Thrombosis risk factors
Bleeding risk factors
Thrombotic and hemorrhagic event
Diagnosis treatment after procedure
CS SL
1/1 1/0
b100 UI/kg × 1/100 UI/kg × 1 b100 UI/kg × 1/100 UI/kg × 1
– –
– –
O-APS on LDA O-APS + UCTD on LD
LAC+ACLG+ACLM+ B2GPI-G+B2GPI-M + ACLG+B2GPI-M+
CS
1/2
100 UI/kg × 1/100 UI/kg × 1
– Steroid Treatment/thrombotic events familiarity HTA Smoke
Thrombocytopenia
–
O-APS + SLE on LDA
2/0
b100 UI/kg × 1/100 UI/kg × 1
Protein S Deficiency
–
–
LAC+ACL-GB2GPI-G
SL
100 UI/kg × 2/100 UI/kg × 2
Smoke
–
–
T-APS + S.SJOGREN in OAE T-APS + SLE on OAT
LAC+ACL-G+ B2GPI-G+ LAC+ACL-G+ B2GPI-G+ LAC+ACL-G+ B2GPI-G+ B2GPI-G + LAC+ACL-GB2GPI-G
CS
b100 UI/kg × 1/100 UI/kg × 1
Smoke – Thrombotic events familiarity HTA – obesity- steroid therapy PreviousDVT
–
–
T-APS + UCTD on LDA
–
–
T-O-APS + SLEon LD
–
DVT
O-APS on OAT
100 UI/kg × 1/100 UI/kg × 2 100 UI/kg × 1/100 UI/kg × 1
Smoke, Overweight HTA, Obesity
– –
– –
O-APS on LDA T-APS on OAT
C
O
R SL
R
E 1/1
1/1
C
CS
1/1
IL
2/0
100 UI/kg × 2/100 UI/kg × 2
CS Surgery
1/0 1/0
LAC+
Surgery
0/0
100 UI/kg × 1/100 UI/kg × 1
HTA, Obesity
–
–
T-APS + SLE on LDA
LAC+
Surgery
0/0
100 UI/kg × 1/100 UI/kg × 1
HTA, Obesity
–
–
T-APS + SLE on LDA
LAC+ACL-M+ B2GPI-M+ LAC+ACL-G +
Surgery
1/0
b100 UI/kg × 1/100 UI/kg × 1
–
–
T-APS + SLE on LDA
1/0
100 UI/kg × 2/100 UI/kg × 2
–
–
OT-APS on LDA
LAC+ACLG+ACLM+
Voluntary Interruption of pregnancy Surgery
Obesity/Steroid treatment –
1/1
100 UI/kg × 2/100 UI/kg × 1
NSAD
LAC+ACLG+ACLM+
Surgery
0/1
100 UI/kg × 1/100 UI/kg × 1
ACS/Local bleeding, loss of 6 g Hb –
T-APS + SLE on OAT + Clopidogrel
SLE SLE
LAC+ACLG+B2GPIG+
Surgery
0/1
−/b100 UI/kg × 1
Smoke, steroid therapy, (anemia post bleeding) Smoke, steroid therapy Smoke
SLE
LAC+ACLG+B2GPIG+
Surgery
1/1
−/b100 UI/kg × 1
Smoke
–
SLE
LAC +
Surgery
3/1
100 UI/kg × 1/100 UI/kg × 1
HTA,Overweight, Steroid therapy
–
T
b100 UI/kg × 1/100 UI/kg × 1
E
D
P
R O
O –
F
S. Raso et al. / Autoimmunity Reviews xxx (2014) xxx–xxx
Please cite this article as: Raso S, et al, Bridging therapy in antiphospholipid syndrome and antiphospholipid antibodies carriers: Case series and review of the literature, Autoimmun Rev (2014), http://dx.doi.org/10.1016/j.autrev.2014.09.002
t2:1 t2:2
T-APS + SLE on OAT T-APS + SLE on LDA
DVT
T-APS + SLE on LDA
–
T-APS + SLE on LDA
3
4
N
C
O
R
R
E
C
Table 3 Clinical Characteristics, peri-procedural management and outcome of antiphsopholipid antibody-positive patients.
T
t3:4 t3:5 t3:6
Patient no.
Age (procedure)
sex
Diagnosis and Treatment before procedure
Apl Profile (closer to procedure)
Procedure
LMWH interruption before and after procedure
LMWH doses before and after intervention
t3:7 t3:8 t3:9 t3:10 t3:11 t3:12 t3:13 t3:14 t3:15 t3:16 t3:17 t3:18 t3:19 t3:20 t3:21 t3:22 t3:23 t3:24 t3:25 t3:26 t3:27 t3:28 t3:29 t3:30 t3:31 t3:32 t3:33 t3:34 t3:35
17 18/1st procedure 18/2nd procedure 19 20 21 22/1st procedure
39 32 37 41 38 37 53
F F F F F F F
APL + UCTD APL + SLE on LDA APL + SLE APL on LDA APL on LDA APL + UCTD on LDA APL + UCTD on LDA
LAC+ ACLG + ACLG + ACLM+B2GPIM+ ACLM+B2GPIM+ LAC+B2GPIM+ LAC+ACLG+B2GPIG+
IL CS CS SL CS CS Surgery
2/1 1/1 0/3 1/1 1/1 1/1 2/2
100 UI/kg × 1/100 UI/kg × 1 b100 UI/kg × 1/b100 UI/kg × −/b100 UI/kg × 1 b100 UI/kg × 1/b100 UI/kg × b100 UI/kg × 1/b100 UI/kg × b100 UI/kg × 1/b100 UI/kg × −/100 UI/kg × 1
22/2nd procedure 23/1st procedure
39 34
F F
APL on LDA APL + SLE on LDA
CS SL
1/1 1/2
23/2nd procedure 24
36 32
F F
APL + SLE on LDA APL + SLE on LDA
CS Surgery
25 26 27
36 30 28
F F F
APL + UCTD on LDA APL + on LDA APL + SLE on LDA
LAC+B2GPIG+ LAC+ACLG+B2GPIG+ B2GPIM+ LAC+B2GPIG+ LAC+ACLG+B2GPIG+ B2GPIM+ LAC+ACLG+B2GPIG+ LAC+ACLM + LAC+B2GPIG+
28/1st procedur
36
F
APL + UCTD on LDA
28/2nd procedure
40
F
29 30/1st procedure 30/2nd procedure 31/1st procedure
33 38 40 32
31/2nd procedure
35
Thrombosis risk factors
Bleeding Risk Factors
Thrombotic and Hemorrhagic event
Diagnosis Treatment after Procedure
– – – – – – Thrombocytopenia
CVST – – Bleeding – – –
T-APS + UCTD on OAT APL + SLE on LDA APL + SLE APL on LDA APL APL + UCTD APL + UCTD on LDA
b100 UI/kg × 1/b100 UI/kg × 1 b100 UI/kg × 1/100 UI/kg × 1
– Overweight Overweight – Overweight – Obesity, Smoke, HTA, (cancer) Steroid Therapy Steroid Therapy
– –
– –
APL APL + SLE on LDA
1/1 1/2
b100 UI/kg × 1/b100 UI/kg × 1 b100 UI/kg × 1/100 UI/kg × 1
Steroid Therapy Obesity, HTA
– Thrombocytopenia
– –
APL + SLE on LDA APL + SLE on LDA
CS CS IL
0/2 2/1 3/1
100 UI/kg × 1/100 UI/kg × 1 b100 UI/kg × 1/100 UI/kg × 1 100 UI/kg × 1/100 UI/kg × 1
– – –
– – –
APL + UCTD APL + on LDA APL + SLE on LDA
LAC+ACLG+B2GPIG+
IL
2/1
100 UI/kg × 1/100 UI/kg × 1
–
APL + UCTD on LDA
APL + UCTD on LDA
LAC+ACLG+B2GPIG+
CS
0/1
100 UI/kg × 1/100 UI/kg × 1
–
–
APL + UCTD on LDA
F F F F
APL APL APL APL
CS CS CS SL
1/1 2/1 1/1 2/1
100 100 100 100
– – – –
– – – –
APL + on LDA APL + on LDA APL+ APL + UCTD on LDA
F
APL + UCTD on LDA
ACLG + ACLM+B2GPIM+ LAC+ACLM+B2GPIM+ LAC+ACLG+ACLM+ B2GPI-G+B2GPI-M + LAC+ACLG+ACLM+ B2GPI-G+B2GPI-M +
– – Steroid Therapy, Smoke Smoke,Protein S Deficiency Smoke,Protein S Deficiency – – – –
IL
1/1
b100 UI/kg × 1/b100 UI/kg × 1
Steroid Therapy
–
–
+ + + +
on LDA on LDA on LDA UCTD on LDA
E
D
1 1 1 1
P
UI/kg UI/kg UI/kg UI/kg
× × × ×
R O
1/100 UI/kg × 1 1/100 UI/kg × 2 1/100 UI/kg × 1 1/b100 UI/kg × 1
O –
F
S. Raso et al. / Autoimmunity Reviews xxx (2014) xxx–xxx
Please cite this article as: Raso S, et al, Bridging therapy in antiphospholipid syndrome and antiphospholipid antibodies carriers: Case series and review of the literature, Autoimmun Rev (2014), http://dx.doi.org/10.1016/j.autrev.2014.09.002
t3:1 t3:2
U
t3:42 t3:43 t3:44 t3:45 t3:46 t3:47 t3:48 t3:49 t3:50 t3:51 t3:52 t3:53 t3:54 t3:55 t3:56 t3:57 t3:58 t3:59 t3:60 t3:61 t3:62 t3:63 t3:64 t3:65 t3:66 t3:67 t3:68
32 33 34/1st procedure 34/2nd procedure 35 36
36 47 21 22 57 38
F F F F F F
APL APL APL APL APL APL
+ + + + + +
O-APS, obstetric antiphospholipid syndrome T-APS, thrombotic antiphospholipid syndrome SLE, systemic lupus erythematosus UCTD, undifferentiated connective tissue disease HTA, arterial hypertension ACS, acute coronary syndrome NSAD, non-steroid anti-inflammatory drugs LDA, low dose aspirin OAT, oral anticoagulant therapy LDA, low dose aspirin OAT, oral anticoagulant therapy LAC, lupus anticoagulant ACLG, IgG anti-cardiolipina ACLM, IgM anti-cardiolipina B2GPI-G, IgG anti-B2GPI B2GPI-M, IgM anti-B2GPI TRIPLE CS, cesarean section SL, spontaneous labor IL, induced labor DVT, deep venous thrombosis CVST, cerebral venous sinus thrombosis LMWH, interruption before and after procedure 0 b 12H (1) 12–24H (2) 25–48H (3) N48H
on LDA on LDA SLE on LDA SLE on LDA UCTD on LDA on LDA
ACLM+ ACLG + LAC+ LAC+ LAC+ LAC+ACLG+B2GPIG+
CS CS CS Surgery Surgery IL
1/1 1/1 1/1 1/1 1/1 1/1
100 UI/kg × 1/100 UI/kg × 1 100 UI/kg × 1/100 UI/kg × 1 100 UI/kg × 1/100 UI/kg × 1 100 UI/kg × 1/100 UI/kg × 1 100 UI/kg × 1/100 UI/kg × 1 b100 UI/kg × 1/b100 UI/kg × 1
– Smoke – – Protein S Deficiency –
– – – – – –
– – – – – –
APL+ APL + APL + APL + APL + APL +
R SLE on LDA SLE on LDA UCTD on LDA on LDA
U
N
C
O
R
R
S. Raso et al. / Autoimmunity Reviews xxx (2014) xxx–xxx
Please cite this article as: Raso S, et al, Bridging therapy in antiphospholipid syndrome and antiphospholipid antibodies carriers: Case series and review of the literature, Autoimmun Rev (2014), http://dx.doi.org/10.1016/j.autrev.2014.09.002
t3:36 t3:37 t3:38 t3:39 t3:40 t3:41
E
C
T
E
D P
R O
O
F
5
C Myiakis IIa aPL with UCTD on LDA
N Triple positivity T-APS with SLE on LDA
17
15
197
This report describes a cohort of APS and aPL-positive patients requiring bridging therapy for surgery or invasive procedure. To the best of our knowledge, we report the largest study addressing the topic of bridging therapy in aPL-positive patients. Bridging therapy in APS and aPL carriers represents a challenge for many reasons. Several factors such as stasis, endothelial injury and aPL related hypercoagulability may contribute to the development of postoperative thromboembolic events. APS patients may have increased risk of postoperative thrombosis, making prophylaxis with heparin or warfarin in patients with APS mandatory [13]. Besides, surgery itself is an established trigger factor for CAPS, severe microvascular form that affects multiple organ systems, and it is fatal in approximately half of patients [21]. SLE, associated to APS (in 50% of cases), provides an increased risk of thrombosis [22,23] and immunosuppressive therapy may complicate the management of peri-operative period. Young people are generally affected, and fertility is not compromised in APS patients: for those reasons, delivery and cesarean section deserve particular attention in these patients. Indeed, labor and cesarean section accounts for a high percentage of total procedures (69%) in our cohort. As combination of LDA and heparin is considered the standard of care to minimize the risk of maternal thromboembolism and it has been proven to improve fetal-maternal outcome in aPL pregnancy [24] , optimal timing for stopping them is essential for a correct management and to plan intervention such as epidural procedures. It is generally accepted that aspirin could be stopped at least 10 days before delivery (normally at 34° weeks of gestation), despite the possibility of using of aspirin during the delivery is still under debate [25,26]. LMWH should be suspended 12–24 hours before neuraxial anesthesia (depending on dosage of heparin) and resumed 12 hours after catheter removal [24]. In APS and aPL-positive patients, LMWH should be continued for 6– 8 weeks after delivery [26]. It is usually suggested to induce the delivery as an effective strategy to optimize the timing for stopping heparin, aiming to reduce the risks for both thrombotic and hemorrhagic complications related to the puerperium. This can also reduce the need for cesarean section, which may require general anesthesia, known as a potential cause of complication and increased risk of death [26]. In this study, despite the heterogeneity of the study population, when analyzing the patients who suffered for adverse events, it is possible draw to some general considerations. First, all patients with adverse events were LA positive (aPL profile including triple positivity, Miyakis I or IIa [19]). LA is considered the strongest risk factor among aPL for thrombosis [27], and a special attention is required when a thrombo-prophylaxis is planned in patients with LA, especially when associated with multiple positivity. However, we think that the presence of LA might have had a role in inducing thrombosis, while the association with the hemorrhagic event is more difficult to be interpreted. Second, the co-existence of anemia and thromboembolism seems to be evident in cases 17 and 14. An association between anemia (defined as b 9 g/dl) and CVT has been recognized by Stolz et al. [28]. In our cohort, case 17 presented with a severe microcytic anemia (Hb 7,8 g/dl at the time of CVT). However, it worth noting that this happened in the absence of thrombocytosis, which is frequently seen in iron deficiency anemia and could justify an hypercoagulability. In case 14, several risk factors coexisted, for both bleeding or thrombotic complication. SLE itself is strong risk for thromboembolic event, while an early re-introduction of LMWH and the use of NSAIDs in analgesic therapy enabled bleeding. In the same patients, a severe blood loss occurred, and this has been linked with the occurrence of myocardial infarction [29,30]. This case highlights the concept that major attention should be paid in aPL-positive patients also when assessing the bleeding
198
E
D
P
R O
O
F
5. Discussion
T
C
E
R
t4:15 t4:16 t4:17 t4:18 t4:19 t4:20 t4:21 t4:22 t4:23 t4:24 t4:25
O
CVT
R
T-APS with UCTD on OAT No Microcytic anemia Hb 7,8 g, pregnancy 100 × 1/100 × 1 46/20
−/b100 × 1 DVT
Skin graft after necrosectomy of necrotic tissue Labor
−/12
DVT Local bleeding, loss of 6 g Hb/MI Labor Orthopedic surgery Triple positivity Myiakis I
U 8 14
t4:7 t4:8 t4:9 t4:10 t4:11 t4:12 t4:13 t4:14
O-APS on LDA T-APS with SLE on OAT
thrombotic risk factors. Treatment after procedure changed from OAT 195 to OAT + LDA. 196 SLE, systemic lupus erythematosus O-APS, obstetric APS T -APS, thrombotic APS LDA, low-dose aspirin OAT, oral anticoagulation therapy MI, myocardial infarction DVT, deep venous thrombosis CVT, cerebral venous thrombosis NSAID, non-steroidal anti-inflammatory drugs PE, pulmonary thromboembolism Myiakis I: more than one laboratory criteria present (any combination); IIa: LA present alone; IIb: aCL antibody present alone; IIc: anti-b2glycoprotein-I antibody present alone. Triple positivity: LA, aCL, anti-b2glycoprotein-I antibodies
T-APS with SLE on OAT No
O/T-APS on OAT T-APS with SLE on OAT + LDA + Clopidogrel No NSAID post surgery
Pregnancy Smoke, bed rest, post-splenectomy thrombocytosis, previous PE, steroid therapy Smoke, bed rest, previous DVT b100 × 1/100 × 1 100 × 2/100 × 2 31/11 12/4
LMWH interruption before and after intervention (hours) Adverse events Procedures aPL profile Diagnosis and treatment before procedure Patient no. t4:4 t4:5 t4:6
t4:1 t4:2
Table 4 Clinical Characteristics, peri-procedural management and outcome of patients who experienced adverse events.
LMWH doses before and after intervention (UI/kg/die)
Thrombotic risk factors
Diagnosis and treatment after procedure
S. Raso et al. / Autoimmunity Reviews xxx (2014) xxx–xxx
Bleeding risk factors
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Please cite this article as: Raso S, et al, Bridging therapy in antiphospholipid syndrome and antiphospholipid antibodies carriers: Case series and review of the literature, Autoimmun Rev (2014), http://dx.doi.org/10.1016/j.autrev.2014.09.002
199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258
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290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 370
F
O
R O
276 277
[1] Baron TH, Kamath PS, McBane RD. Antithrombotic therapy and invasive procedures. N Engl J Med 2013;369:1079–80. [2] Reynaud Q, Lega JC, Mismetti P, Chapelle C, Wahl D, Cathebras P, et al. Risk of venous and arterial thrombosis according to type of antiphospholipid antibodies in adults without systemic lupus erythematosus: a systematic review and meta-analysis. Autoimmun Rev 2014;13:595–608. [3] Hammerstingl C, Tripp C, Schmidt H, von der Recke G, Omran H. Periprocedural bridging therapy with low-molecular-weight heparin in chronically anticoagulated patients with prosthetic mechanical heart valves: experience in 116 patients from the prospective BRAVE registry. J Heart Valve Dis 2007;16:285–92. [4] Ortel TL. Perioperative management of patients on chronic antithrombotic therapy. Hematology Am Soc Hematol Educ Program 2012;2012:529–35. [5] Patel JP, Arya R. The current status of bridging anticoagulation. Br J Haematol 2014; 164:619–29. [6] Siegal D, Yudin J, Kaatz S, Douketis JD, Lim W, Spyropoulos AC. Periprocedural heparin bridging in patients receiving vitamin K antagonists: systematic review and meta-analysis of bleeding and thromboembolic rates. Circulation 2012;126:1630–9. [7] Spyropoulos AC, Douketis JD. How I treat anticoagulated patients undergoing an elective procedure or surgery. Blood 2012;120:2954–62.
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R
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R
268 269
N C O
266 267
U
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D
289
261 262
T
288 Q2
risk. Indeed, the major bleeding indirectly influenced damage in patient 14 (triggering the onset of a thrombotic event) and, after all, it resulted in a change of treatment (fromOAT to OAT + LDA). Moreover, the index event reported in this study impact on the diagnosis and consequently on the treatment of patient 8 (OAPS to O-T APS) and 17 (from UCTD with aPL positivity to UCTD associated to APS). No CAPS, the most dangerous complication of APS, was observed in our cohort. One can speculate that this can be due to a sufficiently intensive thrombo-prophylactic management; however, it is not possible to rule out that the our cohort was not wide enough to observe the occurrence of this rare condition (less than 1% of all APS patients). We acknowledge that this study suffers for some limitations. Our cohort appears to be very heterogeneous, showing additional risk factors such SLE, corticosteroid therapy, thrombocytopenia and renal diseases, or cancer. Besides, different types of surgical procedures have been taken into account: renal biopsy, orthopedic, cardiovascular, abdominal, cutaneous and gynecologic surgery. Unlike other patient population studies for BT, it should be remembered that thrombotic risk may involve both venous and arterial side in aPL patients. In conclusion, the heterogeneity and the complexity of the cases make difficult to outline management recommendations. However, on the basis of our experience, we suggest that a multidisciplinary evaluation of the single case before procedure, aiming to tailor the tromboprophylaxis management can be an effective strategy to reduce adverse events. Probably in some patients conventional doses of heparin may result in a “under-coagulation” (patients 8 and 15); for that reason, a weight adjusted prophylactic dose of 100 U/kg can be suggested [4]. Larger, prospective studies are warranted to further evaluate the correlation between hemorrhagic adverse events and subsequent damage accrual in APS patients.
E
259 260
7
Please cite this article as: Raso S, et al, Bridging therapy in antiphospholipid syndrome and antiphospholipid antibodies carriers: Case series and review of the literature, Autoimmun Rev (2014), http://dx.doi.org/10.1016/j.autrev.2014.09.002
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