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The catastrophic variant of the antiphospholipid syndrome (APS) is a life‐threatening form of presentation of this syndrome that can be triggered by several factors.
To describe the characteristics of patients who developed catastrophic APS triggered during pregnancy and puerperium.
A review of the first 255 cases collected in the website‐based “CAPS Registry” was undertaken. Three new and unpublished cases of catastrophic APS developed during pregnancy and puerperium were added.
Fifteen cases were identified. The mean (range) age was 27 (17–38) years. Most patients had a previous unsuccessful obstetric history. In 7 of 14 (50%) cases with available medical history, the catastrophic APS appeared during pregnancy, in 6 (43%) during the puerperium and in 1 (7%) after curettage for a fetal death. The main clinical and serological characteristics were similar to those patients with catastrophic APS triggered by other factors, except for a history of a higher prevalence of previous abortions (p<0.01). Several specific features were found, including the HELLP (haemolysis, elevated liver enzymes, low platelets) syndrome in 8 (53%) patients, placental infarctions in 4 (27%) patients, and pelvic vein thrombosis and myometrium thrombotic microangiopathy in 1 (7%) patient each. Mortality rate was high for the mothers (46%), and for the babies (54%).
It is important to consider the possibility of the development of catastrophic APS in those patients with signs of HELLP syndrome and multiorgan failure during pregnancy or puerperium, especially in those patients with previous history of abortions and/or thrombosis.
The antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterised by a combination of arterial and/or venous thrombosis, pregnancy morbidity, usually accompanied by a mild‐to‐moderate thrombocytopenia, and raised titres of antiphospholipid antibodies (aPL)—namely, the lupus anticoagulant (LA) and/or anticardiolipin antibodies (aCL).1
The most characteristic feature of obstetrical APS is miscarriage. Currently, recurrent miscarriage is a potentially treatable condition when it is associated with aPL.2 Additionally, several other serious obstetric complications have been associated with APS, including pre‐eclampsia, fetal growth restriction, uteroplacental insufficiency, fetal distress and medically induced preterm delivery.3,4
Catastrophic APS (also known as “Asherson's syndrome”) is an unusual (<1%) but usually a life‐threatening variant of APS, characterised by rapid appearance of multiple thromboses (mainly small‐vessel thrombosis) that lead to multiorgan failure.5 Since its first description in 1992,5 several large series have been published,6,7 and more than 250 patients have been collected in the international registry of patients with catastrophic APS (Catastrophic Antiphospholipid Syndrome (CAPS) Registry. Catastrophic events may be triggered, in >50% of patients, by a recognised factor, mainly infections, trauma or surgery, anticoagulation withdrawal, malignancies and lupus “flares”, or appear infrequently during pregnancy (ie, after a caesarean section or fetal loss).
No previous publications have focused on the setting of catastrophic APS during the obstetric period. Our objective in this study was to assess the clinical and laboratory characteristics of the catastrophic APS triggered or presented during pregnancy and puerperium obstetric periods by analysing three new and unpublished cases in addition to 12 already published cases collected from the “CAPS Registry”, with special interest in maternal and fetal outcome.
We reviewed the 255 cases that were included in the website‐based CAPS Registry on 1 November 2005. This registry was created by the European Forum on Antiphospholipid Antibodies, a study group devoted to the development of multicentre projects with large populations of patients with catastrophic APS. The website contains clinical, laboratory and therapeutic data on all reported cases of patients with catastrophic APS and can be freely accessed through the internet (http://www.med.ub.es/MIMMUN/FORUM/CAPS.HTM). The sources of information are the personal communications of the physician who treated these patients and the periodically computer‐assisted search (Medline, National Library of Medicine, Bethesda, Maryland, USA) of published reports to locate all cases of patients with catastrophic APS. Patients included in the CAPS Registry fulfil the classification criteria for catastrophic APS8 (box 1). Cases were summarised using a standardised data form, including age, diagnosis of the underlying condition, time of presentation of catastrophic APS features (during pregnancy or puerperium periods), clinical manifestations, serological features, treatment and outcome.
Definite catastrophic APS
We selected those patients who developed the catastrophic APS during pregnancy and puerperium. The list of precipitating factors in the CAPS registry was used as a guide for case identification; however, only those cases with a close relationship between pregnancy and/or puerperium and the development of the catastrophic APS event were included. Three previously unpublished cases with catastrophic APS occurring during pregnancy or puerperium were added to the review and subsequently included into the registry. The diagnosis of HELLP (haemolysis, elevated liver enzymes, low platelets) syndrome was established if patients fulfilled the laboratory criteria proposed by Sibai et al,9 including: (1) platelet count <100000/mm3, (2) aspartate aminotransferase >70 IU/l and (3) lactate dehydrogenase >600 U/l. Severity of HELLP syndrome was classified according to Martin et al's10 criteria based on platelet count. Class 1 (severe) was considered when platelet count was <50×109/mm3, class 2 (moderate) when platelet count was between 51×109 and 100×109/mm3 and class 3 (mild) when platelet count was >100×109/mm3.
In order to identify whether patients with catastrophic APS triggered during pregnancy or puerperium correspond to a special subset of patients with catastrophic APS, we compared them with the rest of patients (n=240) included in the CAPS Registry (χ2 test, SPSS V.11.0).
We analysed 15 cases of catastrophic APS that appeared during pregnancy or puerperium. (3 previously unpublished cases and 12 from the CAPS Registry5,11,12,13,14,15,16,17,18,19). ).TablesTables 1 and 22 summarise the data from these cases.
In all, 7 (47%) patients had primary APS, 7 (47%) had SLE and 1 (6%) had lupus‐like syndrome. The mean (SD, range) age at the time of the catastrophic APS event was 27 (6 (17–38)) years. Past obstetric history was available in 14 cases. Only 1 patient had a previous successful pregnancy, 9 patients had previous abortions or fetal losses, and in 4 cases11,13,16,19 there were no previous pregnancies. In 7 of the 14 (50%) cases catastrophic APS appeared during pregnancy (ranging from the 17th to 38th weeks of gestation), in 6 (43%) cases it presented during puerperium (ranging from the 2nd day until 3 weeks after delivery) and in 1 (7%) case it presented, 2 days after dilatation and curettage for a fetal death at 18 weeks of pregnancy. In 4 (26%) cases the catastrophic APS event was the first manifestation of the APS (cases 1, 6, 11 and 13). Only 6 (40%) patients fulfilled the diagnostic criteria for APS prior to the catastrophic APS event. The remaining patients had some features suggestive of APS or previous aPL‐positive determinations. At the moment of the catastrophic APS event, only 2 patients (cases 2 and 10) were under treatment (aspirin 325 mg/day and warfarin, respectively).
The main clinical symptoms were renal involvement in 11 (73%) patients (in 3 of them in the form of renal thrombotic microangiopathy (TMA)) pulmonary involvement in 11 (73%) patients (acute respiratory distress syndrome (ARDS) in four patients, respiratory failure in three, pulmonary embolism in two, and alveolar hemorrhage, pulmonary infarcts and pulmonary TMA in one case each), central nervous system (CNS) involvement in 9 (60%) patients (cerebral infarcts in five cases, encephalopathy in two cases, cerebral haemorrhage in two cases, transient ischaemic attack in one case, cerebral TMA in one case and status epilepticus in one case) and HELLP syndrome in 8 (53%) patients. Seven patients had a class 1 HELLP syndrome, whereas only 1 patient had class 2. The mean platelet count among patients with HELLP syndrome was 29000/mm3 (ranging from 6000 to 59000).
Intra‐abdominal and pelvic features included placental infarctions in 4 (27%) patients, gastrointestinal thrombosis in 4 (27%; including mesenteric and intestinal thrombosis), hepatic thrombosis in 3 (20%), adrenal involvement in 2 (13%; haemorrhage in one case and adrenal infarcts in another), portal vein thrombosis in 1 (7%), inferior vena cava thrombosis in 1 (7%), splenic infarcts in 1 (7%), pelvic vein thrombosis in 1 (7%) and myometrium TMA in 1 (7%).
Other manifestations were skin involvement in 5 (33%) patients (livedo reticularis in two cases, and skin ulcers, skin thrombosis and digital necrosis in one case), heart involvement in 3 (20%) patients in the form of myocardial infarction, valve disease and myocardial TMA in one case each, deep vein thrombosis in 3 (20%) patients, bone marrow involvement in 2 (13%) patients (bone marrow necrosis in one and bone marrow hypoplasia in the other) and bone necrosis in 1 (7%) patient.
Severe thrombocytopenia was found in 2 (13%) patients without HELLP syndrome, schistocytes were found in 3 (20%) patients, disseminated intravascular coagulation (DIC) features in 3 (20%), haemolytic anaemia in 2 (13%) and severe pancytopenia in 2 (13%). In all, 14 (93%) patients were positive for aCL, 12 (80%) for the IgG isotype and 4 (27%) for the IgM isotype. LA was found in 10 (73%) patients, and anti‐β2 glycoprotein I (GPI) antibodies in 3 (20%).
A total of 6 (40%) patients (cases 2, 6, 9, 10, 11 and 13) were under anticoagulation treatment (low molecular weight heparin) before a catastrophic APS event. Specific treatment for the catastrophic APS events was available in 14 cases. In all, 11 (79%) out of 14 patients received anticoagulation, 10 (71%) steroids, 4 (29%) plasma exchange, 3 (21%) dialysis, 3 (21%) cyclophosphamide, 3 (21%) intravenous immunoglobulins, 2 (14%) fresh frozen plasma and 1 (7%) fibrinolysis.
In all, 7 (46%) mothers died due to the catastrophic APS. Fetal outcome was available in 13 cases. Only 6 (46%) babies survived (3 of them were premature newborns), whereas 7 (54%) babies died. Neither the mothers nor the babies had different outcomes regarding the previous presence of HELLP syndrome or the treatment received (non‐statistically significant differences), including the combined therapies (anticoagulation and plasma exchange). Regarding the babies who survived, in 2 cases their mothers had received plasma exchange. However, in 2 of the babies who died, their mothers had also received plasma exchange therapy.
Fifteen patients with catastrophic APS events associated with pregnancy or puerperium were compared with 240 patients with catastrophic APS events not associated with pregnancy or puerperium that were included in the CAPS Registry (table 33).). In the former group, there was a higher prevalence of previous abortions (p<0.001). In those patients with catastrophic APS events not related to pregnancy or puerperium, there was a higher prevalence of cardiac involvement (p=0.02) and livedo reticularis (p=0.025), and they had a higher prevalence of catastrophic events as the initial manifestation of APS (p=0.05).
Pregnancy is a well‐recognised hypercoagulable state that encompasses a period of 10–11 months (including puerperium). This hypercoagulability is explained by many factors, including alterations in coagulation proteins (increased levels of factors II, V, VII, VIII, X and XII as well as von Willebrand factor, and decreased levels of protein S and activated protein C) and alterations in fibrinolytic systems (low plasma fibrinolytic activity during pregnancy, labour and delivery), with a decreased activity of tissue plasminogen activator.20,21 The presence of microparticles derived from maternal endothelial cells, platelets and placental trophoblasts may also contribute to the procoagulant situation.20 Additionally, the reduction of venous flow in lower extremities as a result of compression by the gravid uterus and the prolonged bed rest (especially during labour and postpartum) induces venous stasis and contributes to the formation of thrombosis. The risk of venous thrombosis is 5–6‐fold higher during pregnancy compared with non‐pregnant women of similar age.21 Despite this situation, deep venous thrombosis is not commonly reported during pregnancy, occurring in 1 in 1000 to 1 in 2000 pregnancies;21 however, this prevalence may be higher in the presence of any thrombophilic factor.
Thrombophilic disorders notably increase gestational vascular complications, leading to pre‐eclampsia, retardation of fetal growth, placental abruption, placental thrombosis and recurrent miscarriages. Several thrombophilic disorders have been described during pregnancy, including antithrombin deficiency, protein S and protein C deficiency, factor V Leiden and prothrombin gene mutation, hyperhomocysteinaemia and aPL, among others.22 Routine assessment of these factors is not currently recommended in healthy pregnant women. It is only indicated in those women with previous thrombosis and/or recurrent pregnancy losses.22
HELLP syndrome is a manifestation of pre‐eclampsia occurring in approximately 0.6% of all pregnancies.23 It involves smaller terminal arterioles and is a process with characteristic histological features. The microangiopathic haemolytic anaemia and the raised liver enzymes are explained by platelet‐fibrin deposits and thrombi causing fragmentation of red cells as they pass through interrupted arterioles and hepatic sinusoid blood flow restrictions, respectively. Thrombocytopenia is due to the increased consumption of platelets after their adhesion to damaged endothelium and intravascular aggregation.24
The real incidence of HELLP syndrome in APS is difficult to estimate. Around 50 well‐documented cases are reported with both conditions. Von Tempelhoff et al25 studied several thrombophilic factors, including LA and aCL, in a series of 32 patients with HELLP syndrome. Of these, 17 (53%) patients were positive for LA and 15 (47%) were positive for aCL. Thuong et al26 described 16 episodes of HELLP in 15 patients with APS. In 8 of these cases, HELLP syndrome revealed an APS (patients with previously unknown APS). In all, 11 (69%) and 3 (19%) patients had pre‐eclampsia and eclampsia, respectively. In a significant proportion of cases (44%) HELLP syndrome occurred during the second trimester, and in 12% during 18–20 weeks of gestation. The authors concluded that HELLP appears in a more severe form in early stages of pregnancy in patients with APS than in the general population.
In the present study, we found eight patients with HELLP syndrome; most of them were classifiable as class 1 (severe) HELLP syndrome. This is, however, not a very helpful classification tool in this particular group of patients (SLE, aPL, related septic process, etc). Nonetheless, severe HELLP syndrome seems to be a major feature of catastrophic APS during the obstetric period. This is supported by data observed in six of eight collected cases with HELLP syndrome. In the case described by Hochfeld et al,12 HELLP syndrome was characterised by a persistent thrombocytopenia. In the case described by Kupferminc et al,13 HELLP syndrome improved only after plasma exchange sessions. Portal and hepatic vein thrombosis and an inferior vena cava thrombosis accompanied the HELLP syndrome in the patient documented by Kitchens et al.14 In the case described by Koenig et al,18 the patient had abdominal pain, requiring a laparotomy, which did not reveal any abnormality. Only a CT scan revealed concomitant hepatic infarctions. Interestingly, in the case described by Sinha et al,16 the HELLP syndrome deteriorated despite the termination of pregnancy. Finally, in our first case, HELLP had an unsatisfactory course in relation to surgical wound infection and haematoma formation.
As these microangiopathic disorders share several clinical and serological characteristics, the differential diagnosis in pregnant patients may be difficult, but necessary, because it carries different therapeutic strategies—eg, plasma exchange sessions for those cases with thrombotic thrombocytopenic purpura (TTP) and prompt delivery for those cases of HELLP syndrome. There are several clinical features that may differentiate each disorder. In TTP, the involvement of the CNS is higher than in HELLP syndrome, which involves mainly liver parenchyma. TTP induces a more severe thrombocytopenia and haemolytic anemia than HELLP syndrome. Anti‐thrombin and D‐dimers are normal in TTP, whereas they are abnormal in patients with HELLP syndrome. In some severe HELLP syndrome and pre‐eclampsia cases, diverse organs may be affected, leading to acute renal failure, myocardial dysfunction, DIC, ascites, pulmonary oedema, cerebral oedema, subcapsular liver haematoma and ARDS, among others.26 There are additional diagnostic challenges for clinicians. Patients with catastrophic APS develop a wide spectrum of clinical and haematological features including CNS involvement, HELLP syndrome, DIC27 and microangiopathic thrombosis. In patients with catastrophic APS, combined treatments are needed, including, in many cases, plasma exchange sessions, as well as termination of pregnancy in those cases with related pre‐eclampsia or eclampsia.
Catastrophic APS during pregnancy or puerperium represents almost 6% of all cases (15/255) described with catastrophic APS. This represents a life‐threatening situation with a high mortality rate in these young women of childbearing age. This also represents a unique scenario where many factors may participate as additional potential trigger factors, including infections such as endometritis, caesarean wound or episiotomy wound infection or mastitis, lupus flares, anticoagulation withdrawal during the actual labour, among others.
The relatively small number of patients with catastrophic APS during the obstetric period makes it difficult to definitely conclude whether this group corresponds to or singles out a different subset of patients with catastrophic APS. However, these patients seem to have a higher prevalence of previous abortions than the non‐pregnant patients with catastrophic APS.
On the basis of present data and as per previous guidelines for the treatment of catastrophic APS,8 we propose the following scheme for the management of catastrophic APS during pregnancy (management of catastrophic APS during puerperium could be similar to that in other scenarios). First, it is essential to prevent any potential trigger factor, mainly infections, and to maintain an adequate anticoagulation in those patients with previous thromboses and aPL. The second aspect is to evaluate fetus maturation. When pulmonary fetal maturation is ready, a prompt delivery is recommended. In those cases with HELLP or other microangiopathic features, plasma exchange sessions are certainly strongly indicated. Plasma exchange sessions have been used previously in mothers with other life‐threatening conditions.28,29 The remaining therapeutic measures recommended in catastrophic APS are also useful, specially steroids and intravenous immunoglobulins. It is important to bear in mind that pre‐term delivery is the strongest risk factor for an adverse neonatal outcome, but it can be life saving for the mother and the fetus.
In conclusion, it is important to consider the possibility of the development of catastrophic APS in those patients with signs of TMA (with or without HELLP syndrome) and/or multiorgan failure during pregnancy or puerperium, particularly in those patients with a history of abortions and/or thrombosis.
aCL - anticardiolipin antibodies
aPL - antiphospholipid antibodies
APS - antiphospholipid syndrome
CAPS Registry - Catastrophic Antiphospholipid Syndrome Registry
CNS - central nervous system
DIC - disseminated intravascular coagulation
HELLP - haemolysis, elevated liver enzymes, low platelets
LA - lupus anticoagulant
TMA - thrombotic microangiopathy
TTP - thrombotic thrombocytopenic purpura
THE CATASTROPHIC ANTIPHOSPHOLIPID SYNDROME REGISTRY PROJECT GROUP (EUROPEAN FORUM ON ANTIPHOSPHOLIPID ANTIBODIES)
Coordinators: Ricard Cervera, Jean‐Charles Piette, Yehuda Shoenfeld, Silvia Bucciarelli, Josep Font and Ronald A Asherson.
The members of the Catastrophic APS Registry Project Group who contributed to this study are as follows:
Mary‐Carmen Amigo, Rheumatology Department, Instituto Nacional de Cardiología; Leonor Barile‐Fabris, Rheumatology Department, Hospital de Especialidades, Centro Medico la Raza IMSS, Mexico City, Mexico; Jean‐Jacques Boffa, Deparment of Nephrology, Hôpital Tenon, Paris, France; Marie‐Claire Boffa, Hôpital Pitié‐Salpêtrière, Paris, France; Ignacio Chávez, Mexico City, Mexico; Joab Chapman, Neuroimmunology Service, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Christopher Davidson, Department of Cardiology, Royal Sussex Hospital, Brighton, UK; Alex E Denes, Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, USA; Ronald HWM Derksen, Department of Rheumatology and Clinical Immunology, University Medical Centre, Utrecht, The Netherlands; JF Diaz Coto, Caja Costarricense del Seguro Social, San Jose, Costa Rica; Patrick Disdier, Service de Medecine Interne, Centre Hospitalier Universitaire Timone, Marseille, France; Rita M Egan, Department of Medicine, University of Kentucky Medical Center, Lexington, USA; M. Ehrenfeld, Chaim Sheba Medical Center and Tel‐Aviv University, Tel‐Hashomer, Israel; R Enriquez, Nephrology Section, Hospital General de Elx, Spain; Doruk Erkan, Hospital for Special Surgery, and Weill Medical College of Cornell University, New York, USA,; Leslie S Fang, Renal Associates, Massachusetts General Hospital and Harvard Medical School, Boston, USA; Mario García‐Carrasco, Benemérita Universidad Autónoma de Puebla, Puebla, Mexico; John T Grandone, Neenah, Wisconsin, USA; José A. Gómez‐Puerta, Department of Autoimmune Diseases, Hospital Clinic, Barcelona, Catalonia, Spain Anagha Gurjal, Division of Hematology/Oncology, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan, USA; Fernanda Falcini, Department of Paediatrics, University of Florence, Italy Gilles Hayem, Department of Rheumatology, CHU Bichat‐Claude‐Bernard, Paris, France; Graham R V Hughes, Lupus Research Unit, The Rayne Institute, St Thomas' Hospital, London, UK; Sohail Inam, Riyadh Armed Forces Hospital Riyadh, Saudi Arabia; K Shashi Kant, Department of Internal Medicine, University of Cincinnati College of Medicine, Ohio, USA; Munther A. Khamashta, Lupus Research Unit, The Rayne Institute, St Thomas' Hospital, London, UK; Craig S Kitchens, Department of Medicine, University of Florida, Gainesville, USA; Michael J Kupferminc, Department of Obstetrics and Gynaecology, Lis Maternity Hospital, Tel Aviv University, Tel Aviv, Israel; Gabriela de Larrañaga, Hospital Muñiz, Buenos Aires, Argentina; Roger A Levy, Department of Rheumatology, Faculdade de Ciencias Medicas, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil; Michael D. Lockshin, Hospital for Special Surgery, New York, USA; Siu Fai Lui, Department of Medicine, Prince of Wales Hospital and Chinese University of Hong Kong, Shatin, Hong Kong; Peter J Maddison, Gwynedd Rheumatology Service, Ysbyty Gwynedd, Bangor, UK; Yoseph A Mekori, Department of Medicine, Meir Hospital, Kfar Saba, Israel; Takako Miyamae, Department of Paediatrics, Yokohama City University School of Medicine, Yokohama, Japan; John Moore, Department of Haematology, St Vincents Hospital, Sydney, Australia; Haralampos M. Moutsopoulos, Department of Pathophysiology, Medical School, National University of Athens, Athens, Greece; Francisco J Muñoz‐Rodríguez, Department of Autoimmune Diseases, Hospital Clinic, Barcelona, Catalonia, Spain; Jacek Musial, Jagiellonian University School of Medicine, Krakow, Poland; Ayako Nakajima, Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan; Michael C Neuwelt, Medical Service, VA Palo Alto Health Care System, USA; Ann Parke, Department of Internal Medicine, Division of Rheumatic Diseases, University of Connecticut Health Center, Connecticut, USA; Jean‐Charles Piette, Hôpital Pitié‐Salpêtrière, Paris, France; Sonja Praprotnik, Univerisity Clinical Center, Department of Rheumatology, Ljubljana, Slovenia; Bernardino Roca, Department of Internal Medicine, Hospital General de Castelló, Castelló, Spain; Jorge Rojas‐Rodriguez, Department of Rheumatology, Specialties Hospital, Manuel Avila Camacho National Medical Centre, Puebla, Mexico; R. Roldan, Rheumatology Department, Hospital Reina Sofia, Cordoba, Spain; Allen D Sawitzke, Division of Rheumatology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, USA; Cees G Schaar, Department of Haematology, Leiden University Medical Centre, The Netherlands; Yehuda Shoenfeld, Chaim‐Sheba Medical Centre, Tel‐Hashomer, Israel; Alenka Šipek‐Dolnicar Department of Rheumatology, University Medical Center, Ljubljana, Slovenia; Alex C Spyropoulos, Clinical Thrombosis Center, Albuquerque, New Mexico, USA; Renato Sinico, Nephrology and Dialysis Unit and Center of Clinical Immunology and Rheumatology, San Carlo Borromeo Hospital, Milan, Italy; Ljudmila Stojanovich, Clinical‐Hospital Center “Bezhanijska Kosa”, Belgrade, Yugoslavia; Daryl Tan, Singapore General Hospital, Singapore; Maria Tektonidou, Department of Pathophysiology, Medical School, National University of Athens, Athens, Greece; Carlos Vasconcelos, Hospital General de San Antonio, Porto, Portugal; Marcos Paulo Veloso, Hospital Universitario Clementino Fraga Filho, Rio de Janeiro, Brazil; and Margaret Wislowska, Outpatients Department of Rheumatology, Central Clinical Hospital, Warsaw, Poland.
Competing interests: None declared.
Funding: Supported in part by grant p1030280 from ISCIII of Spain.