The role of therapeutic plasma exchange in the catastrophic antiphospholipid syndrome

Transfusion and Apheresis Science 33 (2005) 11–17 intl.elsevierhealth.com/journals/tras

The role of therapeutic plasma exchange in the catastrophic antiphospholipid syndrome Imad Uthman a, Ali Shamseddine b, Ali Taher

b,*

a

b

Department of Internal Medicine, Division of Rheumatology, American University of Beirut Medical Center (AUBMC), Hamra Street, Beirut 1107 2802, Lebanon Department of Internal Medicine, Division of Hematology/Oncology, American University of Beirut Medical Center (AUBMC), Hamra Street, Beirut 1107 2802, Lebanon Received 31 May 2004; received in revised form 22 September 2004; accepted 4 October 2004

Abstract The catastrophic antiphospholipid syndrome (CAPS) is a life-threatening sub-entity of the antiphospholipid syndrome (APS) resulting in multiorgan failure and a mortality rate that may reach 50%. The optimal treatment regimen for CAPS is unknown. To evaluate the benefit of therapeutic plasma exchange (TPE) therapy in CAPS, we undertook a computer-assisted (MEDLINE, National Library of Medicine, Bethesda, MD) search of the literature to locate all cases of CAPS (case reports and reviews) treated with TPE. In view of the published literature so far, TPE has shown reasonable therapeutic benefits and improved survival for patients with CAPS. The use of this technique, along with anticoagulation and if needed pharmacological immunosuppression, should be considered for the acute management of patients who present with this life-threatening condition. Ó 2005 Elsevier Ltd. All rights reserved. Keywords: Catastrophic antiphospholipid syndrome; Therapeutic plasma exchange

1. Background Antiphospholipid syndrome (APS) is characterized by a state of hypercoagulability potentially affecting all segments of the vascular bed with *

Corresponding author. Tel.: +961 3 755 669; fax: +961 1 342 517. E-mail address: [email protected] (A. Taher).

thrombosis [1]. The APS is caused by autoantibodies to plasma phospholipids, namely anticardiolipin antibodies (ACA), lupus anticoagulant (LAC), that serve as cofactors in the common phase of the intrinsic and extrinsic coagulation cascade [1], or to plasma proteins with an affinity for anionic (phospholipid) surfaces (ß2GPI, prothrombin) [2]. The catastrophic antiphospholipid syndrome (CAPS) is a life-threatening and

1473-0502/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.transci.2004.10.025

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accelerated sub-entity of APS resulting in multiorgan failure. The disorder is clinically defined by the thrombotic occlusion in several regions of the macro- and microvascular beds, in at least three organ systems over a period of days or weeks (Ôthrombotic stormÕ) producing a clinical picture resembling that of disseminated intravascular coagulation [3]. Patients with CAPS have in common: (a) clinical evidence of multiple organ involvement developed in a very short period of time; (b) histopathological evidence of multiple small vessel occlusion (a minority also have large vessel thrombosis); and (c) laboratory confirmation of the presence of antiphospholipid antibodies (aPL), usually in high titer [4]. Furthermore, most of the catastrophic APS episodes are preceded by a precipitating event, mainly infections [5]. Although CAPS patients represent less than 1% of all patients with APS, it is a condition that requires high clinical awareness in view of its association with a high mortality rate that may reach 50% [5–7]. The optimal treatment regimen for CAPS is unknown [5], the management must have three clear aims: to treat any precipitating factors, to prevent and to treat the ongoing thrombotic events and to suppress the excessive cytokine ÔstormÕ [5,8]. There are no prospective studies on the treatment of CAPS because of the rarity of the condition [6,9]. Anticoagulation (usually intravenous heparin followed by oral anticoagulants), corticosteroids, plasma exchange, intravenous gammaglobulins and, if associated with lupus flare, cyclophosphamide, are the most commonly used treatments for CAPS patients [5]. Other reported management options include fibrinolytics, prostacyclin, defibrotide, danazol, cyclosporine, azathioprine, hemodialysis and splenectomy [6,9]. Therapeutic plasma exchange (TPE) provides an effective means of treating immune diseases by physically eliminating disease-specific free antibodies from the plasma [1]. A prerequisite of successful therapeutic TPE in immune hematology is the presence of circulating free antibodies or immune complexes directly related to the clinical picture of the disorder [1]. This technique has been used for the first time in systemic lupus erythematosus (SLE) in 1974 [10].

2. Case series and reports The objective of this paper is to assess the role of TPE in the management of the CAPS by reviewing published case reports and reviews. We undertook a computer-assisted (MEDLINE, National Library of Medicine, Bethesda, MD) search of the literature to locate all cases of CAPS (case reports and reviews) published, in all languages, from 1980 till up to 2004, using the key words: antiphospholipid syndrome, CAPS, therapeutic plasma exchange, plasmapheresis, and apheresis. Out of 50 articles identified using this search module, 37 references were found to be relevant to our review. Table 1 summarizes the published cases of CAPS treated with TPE [6,9,11–26]. In a retrospective (non-randomized) review in 1996, Asherson and Piette described 31 patients with APS and multi-organ failure [14], of the 13 patients who underwent TPE, 9 (69%) survived; among the remaining 18 patients who were not treated with TPE, only four (23%) survived. The authors concluded that TPE appears useful in some patients who are refractory to full anticoagulation [14]. Following this report, two large series were published also by Asherson et al. on a series of 50 and 80 patients respectively [6,9]. In the first series [6] published in 1998, Asherson et al. analyzed the clinical and laboratory characteristics of 50 patients with CAPS. TPE was associated with the highest treatment success rate, recovery occurred in 13 out of 20 patients (65%), as compared to 22 of the 35 (63%) patients who received anticoagulation, 19 of the 35 (54%) who received steroids, 4 of the 8 (50%) who received intravenous gammaglobulins, and 7 of the 17 (41%) who received cyclophosphamide [6]. Among the 20 patients who received the combination of anticoagulation, steroids, and TPE or intravenous gammaglobulins, recovery occurred in 14 (70%) patients [6]. In the second larger series, 80 episodes of CAPS were analyzed [9]. Anticoagulation was the most frequent treatment, used in 67 of 80 episodes (84%), TPE was used in 16 patients (20%) [9], most patients, however, received a combination of nonsurgical therapies. After mixing treatment results from the 1998 and the 2001 series for a global anal-

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Table 1 Previous case reports of TPE in the management of CAPS References

Number of patients treated with TPE

Primary diagnosis

Clinical course

[11]

2

SjogrenÕs syndrome and APS with multiple-organ disease characterized by a non-inflammatory vasculopathy

Marked improvement in thrombotic diathesis after TPE

[12]

2

SLE with neurological complications Thrombotic thrombocytopenic purpura (TTP) unresponsive to corticosteroids

IV cyclophosphamide Recovery

[13]

1

CAPS: Thrombotic events, hemolytic anemia with thrombocytopenia, high levels of IgG and IgM ACA associated with LAC

TPE and steroid therapy offered some benefit in the acute phase, but these were ineffective as maintenance therapy

[27]

1

APS with serious, non-inflammatory, thrombotic macroangiopathy and uremic–hemolytic syndrome during oral anticoagulant therapy

The patient died despite treatment with aspirin, intravenous dipyridamole and a total of 14 fresh frozen plasma exchange (PEX)

[14]

13

CAPS

See text

[15]

1

APS with history of a spontaneous abortion HELLP syndrome

An artificial abortion, anticoagulation therapy, and TPE were performed concomitantly with corticosteroid therapy She responded to the therapy, a remission was obtained

[16]

1

APS with extensive bone marrow necrosis

Treatment with steroids, transfusion, and TPE with some clinical improvement but her pancytopenia did not respond and necessitated frequent transfusions

[17]

1

APS Transverse myelitis with flaccid paraparesis

Steroids, heparin, ticlopidine Resolution of clinical symptoms

[18]

1

APS and SLE Refractory venous thrombosis in her legs and relapsing thrombocytopenia and renal thrombotic microangiopathy

Cryosupernatant TPE was effective and improved both the refractory venous thrombosis in her legs and relapsing thrombocytopenia

[19]

1

APS, SLE, severe thrombocytopenia refractory to treatment with corticosteroid, anticoagulant, and antiplatelet drugs

TPE led to recovery from severe refractory thrombocytopenia, accompanied by a decrease in the serum beta2 glycoprotein I antibody level

[6]

20

[20]

1

CAPS

See text

APS and pulmonary capillaritis APS presented with hemoptysis and respiratory failure

Prompt response to methylprednisolone, cyclophosphamide and TPE (continued on next page)

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Table 1 (continued) References

Number of patients treated with TPE

Primary diagnosis

Clinical course

[2]

2

CAPS associated with fulminant thrombotic diatheses

Both patients were treated with TPE, which resulted in a marked decrease in antibody titer accompanied by an improved clinical outcome in one patient. In the second patient, the outcome was poor despite TPE

[28]

1

A 7-year-old girl with SLE and CAPS, presented with convulsions, and loss of consciousness. MRI of brain revealed multiple hemorrhagic infarcts

Successful treatment with TPE, anticoagulation, and subsequent cyclophosphamide-pulse therapy

[9]

16

CAPS

See Section 3

[21]

1

SLE and RaynaudÕs phenomenon and APS and skin vasculitis

Partial remission was achieved after 9 immunoadsorption sessions, as documented by marked improvement of skin lesions and an increase of capillary density in the nailfold area

[22]

1

APS and multiple arterial thromboses

Steroids, anticoagulation, TPE No reccurence of thrombotic events

[23]

1

APS Proteinuria, thrombosis, thrombocytopenia refractory to anticoagulation and prednisolone

Double-filtration TPE and cyclophosphamide Decrease in titers of ß2GPI and IgG ACA and no more thrombosis occurred

[24]

1

APS (myocardial infarction, acute respiratory distress syndrome, septic shock)

Failed treatment with heparin TPE, immunoglobulins, cyclophosphamide, antibiotics were used, this led to a rapid decrease of aPL antibodies and clinical improvement

[25]

1

SLE and APS and post-partum acute renal failure, hemorrhagic stroke associated with pre-eclampsia/HELLP syndrome

Treatment with fresh frozen plasma and TPE Her clinical condition stabilized, and laboratory results improved, with normalization of liver function and platelet count

[26]

1

APS (multi-organ failure (kidneys, lungs, brain), microangiopathic thromboses in the kidney, strongly positive LAC, thrombocytopenia, livedo reticularis)

Anticoagulation, and TPE At the time of discharge, she was ambulatory and her mental status had returned to baseline

ysis of 125 episodes, the authors found a mortality rate of 38% in patients treated with anticoagulation versus 75% in its absence (p = 0.0012). In contrast, no associated treatment demonstrated additional benefit. Neither the concomitant use of steroids nor attempts at achieving a prompt reduction of aPL (with TPE and/or immunoglobu-

lins) significantly improved mortality, contrary to the 1998 report for the latter [9]. In addition to the above large series a number of case reports appeared in the English language literature, describing successful use of TPE in the APS [11–13,15–26]. Several cases were reported of treatment of refractory thrombocytopenia in

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association with APS and SLE [12,13,19,23], hemolysis, elevated liver enzymes, and low platelet counts syndrome (HELLP) syndrome [15,25], multi-organ thrombosis and failure [2,11], transverse myelitis [17], extensive bone marrow necrosis [16], pulmonary capillaritis [20], skin vasculitis [21], multiple arterial thrombosis [22], myocardial infarction, acute respiratory distress syndrome, septic shock [24], microangiopathic thromboses in the kidneys [18,26,27], and tonic convulsion with loss of consciousness with multiple hemorrhagic infarcts in the brain [28]. TPE, in association with anticoagulation and other immunosuppressive therapies, was effective in controlling the clinical symptoms of the majority of the above cases and led to a significant drop in aPL antibodies titers [11,14,29–31]. In one patient, continued TPE, 3 times weekly over a 3-year period, was associated with continued clinical improvement [6].

3. Discussion In the largest series on the treatment of CAPS, Asherson et al. analyzed the outcome of 130 CAPS patients, and found that only anticoagulation had a significant effect against death [5,6,9]. In his evaluation TPE with fresh frozen plasma was recommended if features of microangiopathic haemolytic anaemia (i.e., schistocytes) appeared [5]. These conclusions however should be taken with caution for several reasons, including: first, this is a retrospective uncontrolled observation which suffers from the fact that patients may be different in many baseline characteristics, second the total number of patients who were treated with TPE was not large enough (only 36 out of 130 patients), third the clinical manifestations of the disease are quite heterogeneous, and finally what makes the situation more complicated is the fact that TPE is used alongside with other therapeutic modalities which makes the evaluation of the effectiveness of each therapy very difficult. On the other hand, in our literature review, TPE was successfully used in conjunction with anticoagulation, in a number of CAPS patients. Out of 21 patients treated with TPE, 16 had suc-

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cessful control of the syndrome, 3 partial response and only 2 patients failed to respond. Therefore this therapeutic modality remains an option in the management of patients with CAPS until more prospective controlled studies become available which will confirm or not its effectiveness. Although CAPS has not been assigned an indication category by the American Society for Apheresis [32], or by the American Association of Blood Banks [33], there is reasonable evidence so far towards including this condition in these indications. Therefore, in view of the seriousness of this condition and the high mortality rate associated with it, all available measures that may save the patientÕs life should be used as early as possible in the course of the disease. In the absence of welldesigned randomized controlled trials, CAPS cannot be included among the category I indications, however we may suggest including it, either in the category II or III indications [32,33]. TPE is a relatively safe and well-tolerated procedure. In a large survey by McLeod et al., the overall incidence of adverse effects associated with TPE was 4.75% of mostly reversible adverse effects [32,34]. The incidence of selected specific adverse events were transfusion reaction: 1.6%; citraterelated nausea and/or vomiting: 1.2%; systolic blood pressure <80 mmHg: 1.0%; vasovagal nausea and/ or vomiting: 0.5%; pallor and/or diaphoresis: 0.5%; pulse >120: 0.4%; respiratory distress: 0.3%; tetany or seizure: 0.2%; and chills or rigors: 0.2% [34]. In the majority of the case reports we reviewed, TPE was well tolerated with no serious adverse effects reported. One possible way to decrease further the risk of transfusion/allergic reaction induced by exposure to plasma used as replacement would be to use a 5% serum albumin; this strategy has proven to be as effective and safer in conditions such as thrombotic thrombocytopenic purpura [35].

4. Conclusion The CAPS is a life-threatening medical condition characterized by Ôthrombotic stormÕ and high levels of circulating aPL antibodies. In the absence of randomized clinical trials, no treatment is yet

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considered optimal for this disease. Despite all available therapeutic options at this time, the mortality is still high (greater than 50%) [36]. TPE is a valuable therapeutic and well-tolerated procedure, which has proven its efficacy in the elimination of disease-specific free antibodies from the plasma of patients with autoimmune conditions [10,37]. In view of the published literature so far, TPE has shown reasonable therapeutic benefits and improved survival for patients with CAPS. Therefore, the use of this technique, along with anticoagulation and if needed pharmacological immunosuppression, should be considered for the acute management of patients who present with this life-threatening condition.

References [1] von Baeyer H. Plasmapheresis in immune hematology: review of clinical outcome data with respect to evidencebased medicine and clinical experience. Therap Apher Dial 2003;7(1):127–40. [2] Flamholz R, Tran T, Grad GI, Mauer AM, Olopade OI, Ellman MH, et al. Therapeutic plasma exchange for the acute management of the catastrophic antiphospholipid syndrome: beta(2)-glycoprotein I antibodies as a marker of response to therapy. J Clin Apher 1999;14(4):171–6. [3] Levine JS, Branch DW, Rauch J. The antiphospholipid syndrome. N Engl J Med 2002;346(10):752–63. [4] Asherson RA. The catastrophic antiphospholipid syndrome. J Rheumatol 1992;19(4):508–12. [5] Asherson RA, Cervera R, de Groot PG, Erkan D, Boffa MC, Piette JC, et al. Catastrophic antiphospholipid syndrome: international consensus statement on classification criteria and treatment guidelines. Lupus 2003;12(7):530–4. [6] Asherson RA, Cervera R, Piette JC, Font J, Lie JT, Burcoglu A, et al. Catastrophic antiphospholipid syndrome. Clinical and laboratory features of 50 patients. Medicine (Baltimore) 1998;77(3):195–207. [7] Cervera R, Piette JC, Font J, Khamashta MA, Shoenfeld Y, Camps MT, et al. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1000 patients. Arthr Rheum 2002;46(4):1019–27. [8] Kitchens CS. Thrombotic storm: when thrombosis begets thrombosis. Am J Med 1998;104(4):381–5. [9] Asherson RA, Cervera R, Piette JC, Shoenfeld Y, Espinosa G, Petri MA, et al. Catastrophic antiphospholipid syndrome: clues to the pathogenesis from a series of 80 patients. Medicine (Baltimore) 2001;80(6):355–77. [10] Wallace DJ. Apheresis for lupus erythematosus. Lupus 1999;8(3):174–80.

[11] Ingram SB, Goodnight Jr SH, Bennett RM. An unusual syndrome of a devastating noninflammatory vasculopathy associated with anticardiolipin antibodies: report of two cases. Arthr Rheum 1987;30(10):1167–72. [12] Hess DC, Sethi K, Awad E. Thrombotic thrombocytopenic purpura in systemic lupus erythematosus and antiphospholipid antibodies: effective treatment with plasma exchange and immunosuppression. J Rheumatol 1992; 19(9):1474–8. [13] Ruffatti A, De Silvestro G, Ghirardello A, Calligaro A, Del Ross T, Thiene G, et al. A catastrophic antiphospholipid syndrome: the importance of high levels of warfarin anticoagulation. J Int Med 1994;235(1):81–3. [14] Asherson RA, Piette JC. The catastrophic antiphospholipid syndrome 1996: acute multi-organ failure associated with antiphospholipid antibodies: a review of 31 patients. Lupus 1996;5(5):414–7. [15] Nagayama K, Izumi N, Miyasaka Y, Saito K, Ono K, Noguchi O, et al. Hemolysis, elevated liver enzymes, and low platelets syndrome associated with primary antiphospholipid antibody syndrome. Int Med 1997;36(9): 661–6. [16] Paydas S, Kocak R, Zorludemir S, Baslamisli F. Bone marrow necrosis in antiphospholipid syndrome. J Clin Pathol 1997;50(3):261–2. [17] Ruiz-Arguelles GJ, Guzman-Ramos J, Flores-Flores J, Garay-Martinez J. Refractory hiccough heralding transverse myelitis in the primary antiphospholipid syndrome. Lupus 1998;7(1):49–50. [18] Akioka Y, Hattori M, Konomoto T, Takahashi K, Nagafuchi H, Shiraga H, et al. Cryosupernatant plasma exchange in the treatment of antiphospholipid antibody syndrome with lupus nephritis. Ther Apher 1998;2(3): 236–9. [19] Satomi A, Koiwa F, Ogata H, Kinugasa E, Akizawa T, Ideura T. Plasma exchange for thrombocytopenia in antiphospholipid syndrome: a case report. Ther Apher 1998;2(2):157–9. [20] Waterer GW, Latham B, Waring JA, Gabbay E. Pulmonary capillaritis associated with the antiphospholipid antibody syndrome and rapid response to plasmapheresis. Respirology 1999;4(4):405–8. [21] Braun N, Junger M, Klein R, Gutenberger S, Guagnin M, Risler T. Dextran sulfate (Selesorb) plasma apheresis improves vascular changes in systemic lupus erythematosus. Ther Apher 2002;6(6):471–7. [22] Sachais BS, Thompson JE, Strobl FJ. Use of plasma exchange, steroids, and anticoagulation in a patient with multiple arterial thromboses and IgM anticardiolipin antibodies. J Clin Apher 2002;17(3):138–9. [23] Otsubo S, Nitta K, Yumura W, Nihei H, Mori N. Antiphospholipid syndrome treated with prednisolone, cyclophosphamide and double-filtration plasmapheresis. Int Med 2002;41(9):725–9. [24] Koschmieder S, Miesbach W, Fauth F, Bojunga J, Scharrer I, Brodt HR. Combined plasmapheresis and immunosuppression as rescue treatment of a patient with catastrophic antiphospholipid syndrome occurring despite

I. Uthman et al. / Transfusion and Apheresis Science 33 (2005) 11–17

[25]

[26]

[27]

[28]

[29]

[30]

anticoagulation: a case report. Blood Coagul Fibrinol 2003;14(4):395–9. Roberts G, Gordon MM, Porter D, Jardine AG, Gibson IW. Acute renal failure complicating HELLP syndrome, SLE and anti-phospholipid syndrome: successful outcome using plasma exchange therapy. Lupus 2003;12(4):251–7. Moll S, Kudrik FJ, Thomas DB. Catastrophic antiphospholipid antibody syndrome. Am J Hematol 2003;72(4):278–9. Vivaldi P, Andreotti C, Mazzon C, Pedrazzoli M. A ‘‘primitive’’ catastrophic antiphospholipid syndrome. Haematologica 1994;79(2):173–6. Miyamae T, Imagawa T, Ito S, Katakura S, Mori M, Ibe M, et al. Effective combination therapy of plasma exchange and subsequent cyclophosphamide pulses for catastrophic antiphospholipid antibody syndrome: a case report. Ryumachi 1999;39(3):591–7. Frampton G, Cameron JS, Thom M, Jones S, Raftery M. Successful removal of anti-phospholipid antibody during pregnancy using plasma exchange and low-dose prednisolone. Lancet 1987;2(8566):1023–4. Fulcher D, Stewart G, Exner T, Trudinger B, Jeremy R. Plasma exchange and the anticardiolipin syndrome in pregnancy. Lancet 1989;2(8655):171.

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[31] Kobayashi S, Tamura N, Tsuda H, Mokuno C, Hashimoto H, Hirose S. Immunoadsorbent plasmapheresis for a patient with antiphospholipid syndrome during pregnancy. Ann Rheum Dis 1992;51(3):399–401. [32] McLeod BC. Introduction to the third special issue: clinical applications of therapeutic apheresis. J Clin Apher 2000; 15(1–2):1–5. [33] Smith JW, Weinstein R. For The AHCKL. Therapeutic apheresis: a summary of current indication categories endorsed by the AABB and the American Society for Apheresis. Transfusion 2003;43(6):820–2. [34] McLeod BC, Sniecinski I, Ciavarella D, Owen H, Price TH, Randels MJ, et al. Frequency of immediate adverse effects associated with therapeutic apheresis. Transfusion 1999;39(3):282–8. [35] Bandarenko N, Brecher ME. United States Thrombotic Thrombocytopenic Purpura Apheresis Study Group (US TTP ASG): multicenter survey and retrospective analysis of current efficacy of therapeutic plasma exchange. J Clin Apher 1998;13(3):133–41. [36] Asherson RA, Cervera R. Catastrophic antiphospholipid syndrome. Curr Rheumatol Rep 2003;5(5):395–400. [37] Koo AP. Therapeutic apheresis in autoimmune and rheumatic diseases. J Clin Apher 2000;15(1–2):18–27.