in the antiphospholipid syndrome

Reyhan D‹Z KÜÇÜKKAYA

Division of , Department of Internal Medicine, Istanbul University, Istanbul School of Medicine, Istanbul, TURKEY

Turk J Hematol 2006;23(1): 5-14

INTRODUCTION her autoimmune disorders, especially with systemic erythematosus (SLE)[8]. Besi- Antiphospholipid antibodies (aPLA) are des these autoimmune conditions, aPLA may heterogenous antibodies directed against be present in healthy individuals, in patients phospholipid– complexes. Antiphosp- with hematologic and solid malignancies, in holipid syndrome (APS) is diagnosed when ar- patients with certain infections [syphilis, lep- terial and/or or recurrent rosy, human immunodeficiency virus (HIV), fetal loss occurs in a patient in whom scre- cytomegalovirus (CMV), Epstein-Barr virus ening for aPLA are positive. Because both (EBV), etc.], and in patients being treated thrombosis and fetal loss are common in the with some drugs (phenothiazines, procaina- population, persistent positivity of aPLA is mide, phenytoin etc.). Those antibodies are important. This syndrome is predominant in defined as “alloimmune aPLA”, and they are females (female to male ratio is 5 to 1), espe- generally transient and not associated with cially during the childbearing years[1-7]. the clinical findings of APS[9]. A minority of As in the other autoimmune disorders, APS patients may acutely present with mul- aPLA and APS may accompany other autoim- tiple simultaneous vascular occlusions affec- mune and certain situations. APS is ting small vessels predominantly, and this is referred to as “primary” when it occurs alone termed as “catastrophic APS (CAPS)”[1-7]. or “secondary” when it is associated with ot- Milestones in the Antiphospholipid Syndrome History

Antifosfolipid sendromu The first antiphospholipid antibodies we- Anahtar Kelimeler: Antifosfolipid sendromu, Antifosfolipid re discovered by Wasserman et al.[10] in antikorlar, Tromboz. 1906. Wasserman developed a complement- Key Words: Antiphospholipid syndrome, Antiphospholipid fixation test by incubating the serum of pati- antibadies, Thrombosis. ents with a saline extract of obtained from fetuses with congenital syphilis. This

5 Diz Küçükkaya R. Thrombosis in the antiphospholipid syndrome

test became the basis of the VDRL (Venereal of the “autoimmune” aPLA, other phospholi- Research Laboratory) test which is pid-binding including prothrombin, now also used for non-specific aPLA scre- , protein S, and annexin V have be- ening. Mass screening of Wasserman test en described as playing a similar role. showed that many patients with autoimmu- In 1998, preliminary classification crite- ne diseases had “false-positive” results. Mary ria for the classification of “definite” APS we- Pangborn[11] in 1946 isolated “cardiolipin” re described at an international meeting in from the bovine as an antigenic target Sapporo, Japan[1]. Clinical criteria included the for Wasserman test. In 1972, Feinstein vascular thrombosis and morbi- and Rapaport[12] showed an association bet- dity. Laboratory criteria were established as ween false-positive syphilis screening tests the detection of LAs, and presence of anticar- and the presence of a circulating anticoagu- diolipin IgG and IgM antibodies (Table 1). Ac- lant, termed as “lupus (LA)”. cording to these criteria, “definite” APS is Actually it is a misnomer, as more than 50% considered if a patient has at least one clini- of the patients with LA do not have SLE, and cal and one laboratory criteria[1]. Validation although LA acts as an anticoagulant in vit- studies showed that Sapporo criteria have ro, in vivo it is paradoxically associated with 71% sensitivity and 98% specificity in the di- thrombotic events. In 1980, Perumal Thiaga- agnosis of “definite” APS patients[21]. rajan[13] demonstrated that an Immunoglo- buline M (IgM) antibody with LA activity Antiphospolipid Antibodies (aPLA) cross-reacted with negatively charged phosp- Antiphospholipid antibodies are a hetero- holipids. In 1983 Harris and colleagues[14] geneous family of immunoglobulins. Despite described a radioimmunoassay for anticardi- their name, aPLA do not bind to phospholi- olipin antibodies (ACLA) that was conside- pids alone, but are directed to plasma prote- rably more sensitive than previous tests. ins which are complexed with negatively Subsequently an -linked immunosor- charged phospholipids. Although several an- bent assay (ELISA) test for ACLA was develo- ti-phospholipid antibodies are defined, in ped[15]. The clinical associations of thrombo- two of those (ACLA and LA) clinical studies sis and fetal loss were found to be similar in confirmed an association with the clinical patients with ACLA and LA. In 1985 Graham complications of APS. Hughes et al.[16] introduced the term “anti- cardiolipin syndrome”, which was soon Anticardiolipin antibodies are measured changed to “antiphospholipid syndrome” in by ELISA, and reported by GPL ad MPL units [22] 1987[17]. In the first APS classification arteri- for IgG and IgM ACLA, respectively . In pa- al thrombosis, venous thrombosis, recurrent tients with APS, ACLA are not simply direc- fetal loss and were regar- ted to the cardiolipin antigen, it recognizes ded as clinical criteria; LA positivity and mo- β2-GPI –cardiolipin complexes in the ELISA derate or high ACLA IgG/IgM positivity were microplates. Since low titer ACLA may be regarded as laboratory criteria. present in the normal population, moderate (20-80 GPL, 20-50 MPL) to high positive (mo- In 1990, two groups independently de- re than 80 GPL or 50 MPL) results are ne- monstrated that ACLA required protein co- eded for the diagnosis of APS[23]. factors for binding to the phospholi- pids[18,19]. The most common of these prote- Lupus are screened by ins was β2-glycoprotein (GP)-I which binds to phospholipid-dependent tests the anionic phospholipids and also posses- (e.g. activated partial thromboplastin time, ses an anticoagulant activity[20]. Although kaolin clotting time, Russell’s viper venom β2-glycoprotein-I is the predominant target clotting time, dilute prothrombin time, or textarin time). Prolonged screening test sho-

6 Turk J Hematol 2006;23(1):5-14 Thrombosis in the antiphospholipid syndrome Diz Küçükkaya R.

Table 1. Sapporo criteria for the classification of the APS[1]*

A. Clinical criteria: 1. Vascular thrombosis: One or more clinical episodes of arterial, venous, or small vessel thrombosis, in any tissue or organ. Thrombosis must be confirmed by imaging studies or histopathology. 2. Pregnancy morbidity: a. One or more unexplained deaths of a morphologically normal fetus at or beyond 10th week of ges- tation, or b. One or more premature births of a morphologically normal neonate at or before 34th week of ges- tation because of severe pre-eclampsia, or severe , or c. Three or more unexplained consecutive abortions before the 10th week of gestation. B. Laboratory criteria: 1. Anticardiolipin IgG or IgM antibodies present at moderate or high levels in the blood on two or more occasions at least six weeks apart, 2. Lupus anticoagulants present in plasma on two or more occasions at least six weeks apart, detected ac- cording to the guidelines of the International Society on Thrombosis and . * Definite antiphospholipid syndrome (APS) is considered to be present if at least one of the clinical and one of the labora- tory criteria are met. uld not be corrected by mixing of normal Although it has been shown that both an- plasma (mixing studies), but rather by addi- ti-β2-GPI and anti-prothrombin antibodies tion of phospholipid (phospholipid neutrali- might be associated with clinical features of zation procedure). For the diagnosis of LA, APS, most of these studies are retrospective, other including specific fac- and these antibodies are not included in the tor inhibitors should be excluded[24]. Sapporo criteria[1].

β2-GPI is a plasma protein with high affi- Other aPLA (antibodies directed to zwitte- nity for negatively charged phospholipids. It rionic phospholipids, anti-phosphatidylseri- has been shown that most of the ACLA are ne, anti-phosphatidylinositol, anti-phospha- β2-GPI-dependent[18,19]. Since β2-GPI neut- tidylglycerol, etc) may be detected in patients ralizes negatively charged phospholipids and with APS. The clinical importance of other inhibits coagulation cascade, the presence of aPLA are unclear in the absence of a positive anti-β2-GPI antibodies may predispose to LA and/or ACLA test[1]. thrombosis. There are also some aPLA that can bind Anti-prothrombin antibodies may be pre- directly to negatively charged phospholipids [4-6] sent in 50-90% of APS patients . Anti- themselves. These aPLA do not require a prothrombin antibodies may cause hypoth- phospholipid binding protein (i.e. β2-GPI). rombinemia and may be associated with ble- They may be seen in patients with infectious eding symptoms in patients with APS. Bajaj diseases such as syphilis, HIV and EBV in- [25] et al. showed that anti-prothrombin anti- fections, and usually do not cause a throm- bodies are non-neutralizing antibodies, which botic complication. Routine screening tests bound prothrombin without inhibiting its may not distinguish infection-induced (so- conversion to . They suggested that called “non-pathogenic”) anti-cardiolipin an- resulted from the ra- tibodies[3]. Infection-induced anti-cardiolipin pid clearance of prothrombin/anti-prothrom- antibodies are usually temporary. bin antibody complexes from the circulation.

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Pathophysiology of Thrombosis in the the subgroup of patients with arterial invol- APS vement compared to the patients with veno- us involvement[31]. Antiphospholipid antibodies, which are obtained from patients with APS have been Since APS is an extremely heterogeneous shown to play a direct role in the develop- disorder with a broad spectrum of clinical ment of thrombotic complications in animal presentation, determination of the patients models[26]. APS is regarded as an antibody- who have high risk of thrombosis is very im- mediated prothrombotic disorder. Although portant. Although many epidemiological stu- several hypotheses have been proposed, the dies showed an increased risk of thrombosis exact pathophysiologic mechanisms causing in patients positive for aPLA, some patients thrombotic complications of APS have not with high titers of aPLA did not develop been clarified. thrombosis, even in long-term follow-up. These facts supported the hypothesis that In vitro studies showed that aPLA may ac- there were additional inherited or acquired tivate endothelial cells, inhibite protein C thrombogenic factors, that influenced the de- and protein S activity, activate , inc- velopment of thrombosis in those patients rease tissue factor expression, and impair (“double or multiple hit” hypothesis)[2]. the fibrinolytic activity[2,3,6]. In the last deca- de, more studies have been focused on inte- In the last decades, several genetic disor- raction between aPLA and Endothelial Cells ders have been identified in patients with (EC). It has been shown that binding of aPLA thrombosis, especially with venous thrombo- [32] activates EC, which results in the expression embolism . Natural anticoagulant (protein of P-selectin, Intercellular Cell Adhesion Mo- C, protein S, antithrombin) deficiencies, fac- lecule-1 (ICAM-1), and vascular cell adhesion tor V G1691A (FV Leiden) and pro- molecule-1, and induces thrombosis in ani- thrombin G20210A (PT G20210A) (proth- mal models[26-29]. Combes et al.[30] showed rombin G20210A mutation were the most that in vitro generation of endothelial micro- common causes of hereditary . particles was increased in patients with lu- It has been shown that natural anticoagu- pus anticoagulants. lant deficiencies are quite rare in patients with APS. Several studies investigating the Besides these in vitro studies, we have re- role of Leiden mutation and proth- cently demonstrated that endothelial functi- rombin G20210A mutation in patients with ons determined by brachial artery ultraso- APS gave conflicting results[33-40]. It is unc- und were impaired in patients with primary lear whether the presence of these [31] APS . In this study we evaluated brachial increased the thrombotic risk in APS pati- artery responses to the ischemia (endotheli- ents. um-dependent dilatation) and to sublingual nitroglycerin administration (endothelium- Factor XIII Val34Leu polymorphism is a independent dilatation) in primary APS pati- newly described polymorphism which is loca- ents (n= 31) and matched healthy controls ted in the three amino acids away from the (n= 27). There was no significant difference thrombin activation site of the factor XIII-A between primary APS patients and healthy subunit. It has been reported that the pre- controls with respect to basal brachial artery sence of Leu may decrease both arteri- diameter. Although endothelium-indepen- al and venous thrombosis risk, and increase dent dilatation responses are similar, endot- tendency. In a cohort of 60 APS pa- helium-dependent dilatation responses were tients with thrombosis, 22 aPLA-positive pa- significantly lower in primary APS patients tients without thrombosis and 126 healthy than in controls. Impaired endothelium-de- controls, we could not find any effect of fac- tor XIII Val34Leu polymorphism on the pendent responses were more prominent in thrombosis in patients with APS[41].

8 Turk J Hematol 2006;23(1):5-14 Thrombosis in the antiphospholipid syndrome Diz Küçükkaya R.

Clinical Manifestations of APS vascular occlusions affecting small vessels predominantly, and this is termed as “ca- Thrombotic complications are the major tastrophic APS (CAPS)”. Precipitating factors causes of morbidity and mortality in pati- have been identified in the majority of the ents with APS. APS may affect any system CAPS patients, such as infections, , and organ in the body including heart, bra- pregnancy, SLE flares, withdrawal of antico- in, kidney, skin, , and placenta (Table agulation therapy, and trauma. CAPS defini- 2)[2-7]. Although the thrombosis may occur tion requires thrombotic involvement of at in any site of the vascular tree venous least three different organ systems over a thrombosis is encountered most commonly. period of days or weeks. Clinical manifesta- About 2/3 of the thrombotic events are ve- tions of CAPS are related to the extent of or- nous, mainly deep and superficial in gan involvement and cytokine release of af- the lower extremity; the remaining 1/3 are fected tissues. Renal dysfunction (70%), pul- seen in the arterial system. In patients with monary involvement such as adult respira- APS, the risk of the thrombotic recurrence is tory distress syndrome (ARDS) and pulmo- high compared to patients without APS, es- nary embolism (66%), skin involvement pecially after the discontinuation of oral an- such as skin necrosis and ticoagulant therapy[2-6]. APS patients may (66%), central nervous system manifestati- acutely present with multiple simultaneous

Table 2. Clinical manifestations of the APS

System Findings Cardiovascular Acute coronary syndromes, angina pectoris, cardiac valve involvement, non-bacterial system thrombotic endocarditis, atherosclerosis, peripheral arterial disease, myocarditis intermittent claudication Arterial system Thrombosis in the large, medium or small arteries Venous system Thrombosis in the large, medium or small veins Cerebrovascular Transient ischemic attack, cerebral arterial occlusion, chorea, convulsions, dementia, transverse myelitis encephalopathy, migraine, Sneddon’s syndrome, pseudo-tumor cerebri, cerebral venous thrombosis, mononeuritis multiplex Obstetrical Fetal loss, pre-eclampsia, eclampsia, HELLP syndrome, fetal growth retardation, utero-placental insufficiency, infertility Hematological Thrombocytopenia, autoimmune hemolytic anemia, thrombotic thrombocytopenic , hemolytic uremic syndrome Dermatological Livedo reticularis, Reynaud’s phenomenon, leg ulcers, purpura, acrocyanosis, cutaneous infarcts, digital gangrenes, Degos’s disease, anetoderma Ophthalmological Retinal, arterial and venous thrombosis, amaurosis fugax, transient or persistent visual loss, photophobia Gastrointestinal Budd-Chiari’s syndrome, mesentery embolism, nodular regenerative hyperplasia of the liver, intestinal vaso-occlusive disease, ischemic colitis, pancreatitis, hepatic or splenic infarct Pulmonary , pulmonary hypertension, alveolar hemorrhage, fibrosing alveolitis, respiratory distress syndrome Renal Renal thrombosis, renal arterial thrombosis, acute or chronic renal failure, hypertension, hematuria, nephrotic syndrome Psychiatric Psychosis, cognitive dysfunction

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ons such as cerebral, arterial and venous who presented with thrombocytopenia and thrombosis, convulsions, and encephalo- had positive tests for aPLA had increased pathy (60%), and cardiac manifestations risk of thrombosis. We have proposed that such as valve involvements and myocardial measurement of aPLA, especially LA in pati- infarctions (53%) are the major clinical fin- ents with initial diagnosis of ITP may identify dings. Thrombocytopenia, usually severe a subgroup of patients with higher risk of de- thrombocytopenia is present (60%). Hemoly- veloping APS[47]. sis and disseminated intravascular coagula- tion (DIC) may occur. Recommendations for The severity of thrombocytopenia may af- the treatment of CAPS are intravenous he- fect the development of thrombosis in pati- parin, plasmapheresis, and steroids. Treat- ents with APS. When the APS patients were ment of CAPS should include the precipita- divided into three groups according to plate- ting conditions such as the treatment of in- let counts as non-thrombocytopenic, mode- 3 fections with appropriate antibiotics and the rately (50.000-100.000/mm ), and severely 3 treatment of SLE flares. The mortality rate is thrombocytopenic (below 50.000/mm ), the quite high (more than 50%) even in presu- rates of thrombosis development were found [44,45] mably properly treated patients[42,43]. as 40%, 32%, and 9%, respectively . On the other hand, this data shows that mode- Although in the general population preg- rate thrombocytopenia does not prevent de- nancy loss is most frequent during the first velopment of thrombosis in patients with nine weeks of gestation, the risk of preg- APS, and anti-thrombotic prophylaxis sho- nancy loss in patients with APS is greatest uld be considered in those patients[44-47]. after the 10th week of gestation. Besides the fetal losses, it is now clear that aPLA may ca- Although thrombocytopenia is a common use pre-eclampsia, eclampsia, fetal growth finding in patients with APS, bleeding comp- retardation, utero-placental insufficiency, lications are very rare, even in severe throm- , and reproductive failure. bocytopenia. The presence of bleeding symp- Pregnancy morbidity in women with APS toms in an APS patient with moderate may result from impaired placental circulati- thrombocytopenia should alert to considera- on due to placental thrombosis, impaired tion of the presence of anti-prothrombin an- throphoblastic invasion, and hormone pro- tibodies and other diseases which may affect [1,2,8] duction . hemostasis such as DIC, uremia etc. Severe Thrombocytopenia is reported in about thrombocyopenia may require therapy. Tre- 20-40% of patients with APS, is usually mild atment strategies in those patients are simi- (70.000-120.000/mm3), and does not requ- lar to those in patients with ITP. ire any clinical intervention. Severe throm- Interestingly there are a few case reports 3 bocytopenia (lower than 50.000/mm ) is se- describing the correction of thrombocytope- [44-46] en in only 5-10% of the patients . Altho- nia with aspirin[48,49], [50,51], and ugh thrombocytopenia has been defined as a anti-malarial drugs[52]. It has been suggested clinical criterion in the first classification of that inhibition of activation, aggrega- APS, it is not included in the preliminary tion, and platelet consumption may help to classification of definite APS recently propo- increase platelet count in those patients. sed in Sapporo[1]. The patients who had aP- LA and thrombocytopenia as the only clinical Management of Thrombotic manifestation in the absence of other APS Complications in APS findings were defined as “probable” or “pos- Management of patients with aPLA ma- sible” APS. In a recent prospective study, ho- inly depends on the presence of clinical wever, we have demonstrated that the immu- symptoms and findings: ne (ITP) patients

10 Turk J Hematol 2006;23(1):5-14 Thrombosis in the antiphospholipid syndrome Diz Küçükkaya R.

a. aPLA-positive individuals with no the treatment are not clear. In the first studi- APS symptoms or findings: It is known that es, it has been suggested that high intensity aPLA may be present in 1-5% of healthy in- (INR > 3) oral anticoagulant therapy should dividuals[53]. If aPLA-positive individuals ha- be used in APS[58,60]. Recent studies howe- ve no history or findings of APS, treatment ver, showed that high intensity oral antico- should not be considered[3,4,54,55]. Although agulant therapy is not superior to conventi- some investigators recommend prophylactic onal dose oral anticoagulant therapy (INR 2- therapy for aPLA-positive individuals if they 3) for the prevention of thrombosis in those face acquired thrombotic risk (puerperal pe- patients[2,3,7,61-64]. Ames et al.[63] also sho- riod, surgery, immobilization etc.)[7,54], there wed that high intensity oral anticoagulant are no prospective or controlled studies in- therapy might increase bleeding complicati- vestigating the effectiveness of anti-thrombo- ons in patients with APS. Coexistence of tic prophylaxis in those individuals. thrombocytopenia is the major cause for ble- eding. The duration of oral anticoagulant b. Primary prophylaxis of thrombosis therapy is another debated issue. Although in aPLA-positive patients: Although many life-long therapy was recommended in the experts recommend using anti-thrombotic first studies recent prospective studies have prophylaxis in aPLA-positive patients who yielded no firm conclusions. The current re- fullfill Sapporo APS criteria and have no his- commendation from the American College of tory of thrombosis, there are only a few stu- Chest Physicians for anticoagulant therapy dies addressing this issue. The diffucult po- for APS patients who sustain a venous int is to define thrombotic risk in aPLA-posi- thrombo-embolic event is warfarin with tar- tive patients who had no thrombosis. Erkan get INR of 2.5 (Grade 1A) for 12 months[65]. et al.[56] showed that APS patients with fetal The thrombotic risk modification including losses were also at high risk of thrombosis, cessation of smoking, discontinuation of hor- and they recommended prophylactic aspirin mone replacement therapy, correction of therapy, 325 mg/day. Petri et al.[57] reported body mass index etc. is also very important that hydroxychloroquine might have a pro- in the management of thrombosis in those tective effect against thrombosis in secon- patients. dary APS (SLE-APS) patients. In a prospecti- ve study, 82 ITP patients were evaluated for d. Treatment of arterial thrombosis in aPLA and it was found that a significant por- APS: Acute coronary syndromes, transient tion of patients who had aPLA positivity de- ischemic attacks, and cerebral arterial veloped APS in 5 years of follow-up. It has thrombosis are the most common causes of been reported that LA was an important risk arterial involvement in patients with APS. factor for the development of thrombosis in Morbidity and mortality are high in arterial ITP patients[47]. involvement. In APS patients with acute coro- nary syndromes, high intensity oral antico- c. Treatment of venous thrombosis in agulant therapy is recommended. The effecti- APS: Treatment of the first venous thrombo- veness of additional aspirin therapy is deba- tic attack is similar to that in idiopathic ve- ted[7]. In the (APASS) Antiphospholipid Anti- nous thrombosis. Heparin and oral antico- body in Study Group study[64], APS agulation therapy are routinely used for this patients with stroke were randomized to eit- purpose. Recurrency of thrombosis is higher her aspirin (325 mg daily) or warfarin (targe- in patients with APS compared to patients ted INR 2.2), and were compared for the risk with no aPLA and venous thrombosis[58], es- of recurrent stroke. The APASS study found pecially in the first six months of thrombosis no significant difference between the two and after the cessation of the therapy[58-60]. arms. It is important to determine other However, the duration and the intensity of systemic findings to decide the treatment mo-

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