Background

These are circulating antibodies to phospholipids associated with venous and arterial thrombosis, thrombocytopenia, and or recurrent pregnancy loss. There are seveal autoantibodies which comprise this group:

Anticardiolipins
Antiphosphatidylinositol
Antiphosphatidylglycerol
Antiphosphatidylserine

Anticardiolipins are the most commonly detected antiphospholipid antibodies. In general, to diagnose the syndrome, a positive blood test to either the lupus anticoagulant or the anticardiolipin antibody on two separate occasions at least 8 weeks apart is needed.

The Lupus-like Anticoagulant forms a heterogeneous group of IgG or IgM antibodies directed against the phospholipid or phospholipidprotein components involved in the activation of the coagulation cascade. Thus, it is a subset of the antiphospholipid antibodies. However, it is NOT associated with a clinical bleeding tendency unless an additional hemostatic abnormality is present. Instead, it is associated with arterial and venous thrombosis occurring in 25-50% of patients who carry this protein.

The diagnosis rests upon the laboratory evaluation. Cardiolipin (anionic phospholipid) has been widely used for the detection of these antibodies. The majority of these antibodies crossreact with other anioinic phospholipids, but some also react with zwetterionic phospholipids. Some of these protein substrates include prothrombin, annexin V, beta-2 glycoprotein I, protein C and S. The anionic antibodies may be IgG or IgM whereas antibodies to zwitterionic phospholipids are more frequently IgM.

OUTLINE

Epidemiology
Disease Associations
Pathogenesis
Laboratory/Radiologic/Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/ Immunohistochemistry/ Electron Microscopy
Differential Diagnosis
Prognosis
Treatment
Commonly Used Terms
Internet Links

EPIDEMIOLOGY

CHARACTERIZATION

The prevalence of antiphospholipid antibodies in women with recurrent spontaneous abortion, women with successful pregnancies, and women who have never been pregnant. Parke AL, Wilson D, Maier D. Department of Medicine, University of Connecticut School of Medicine, Farmington.

Arthritis Rheum 1991 Oct;34(10):1231-5 Abstract quote Antibodies to negatively charged phospholipids are associated with a predisposition to both arterial and venous thrombosis, recurrent fetal wastage, and thrombocytopenia. These associations have been reported in patients who do not fulfill criteria for connective tissue diseases. In this study, we determined the prevalence of antiphospholipid antibodies in 81 women who had had recurrent spontaneous abortion (3 or more fetal losses), in 88 women whose pregnancies were successful, and in 64 women who had never been pregnant. Antiphospholipid antibodies were found in 16% of women with recurrent spontaneous abortion, and at a statistically greater prevalence than in women who had successful pregnancies (7%) as well as those who had never been pregnant (3%). A false-positive VDRL and IgG anticardiolipin antibodies were more specific for fetal wastage than was either the lupus anticoagulant or IgM anticardiolipin antibodies.

 

DISEASE ASSOCIATIONS	CHARACTERIZATION
Anti-Phospholipid Antibodies	SLE 20-35% of patients Malignancies Drugs Infections Recurrent pregnancy loss 11-22% of cases, in all trimesters
PREGNANCY LOSS
Relationship of antiphospholipid antibodies to pregnancy loss in patients with systemic lupus erythematosus: a cross-sectional study. Ginsberg JS, Brill-Edwards P, Johnston M, Denburg JA, Andrew M, Burrows RF, Bensen W, Cividino A, Long AA. Department of Medicine, McMaster University, Hamilton, Ontario, Canada.	Blood 1992 Aug 15;80(4):975-80 Abstract quote To determine whether an association exists between the presence of antiphospholipid antibodies and pregnancy loss, a cross-sectional study was performed. Consecutive women who were referred to three outpatient rheumatology clinics and who had systemic lupus erythematosus (SLE) and a history of one or more pregnancies were evaluated. Patients were interviewed to determine outcomes of all previous pregnancies. Blood was taken on two separate occasions at least 3 months apart to test for the presence of the lupus anticoagulant and anticardiolipin antibodies; on both occasions, five tests of the lupus anticoagulant, with well-defined normal ranges, and an enzyme-linked immunosorbent assay to measure IgG anticardiolipin antibodies were performed. Patients were considered to be positive for the lupus anticoagulant if one or more tests was abnormal on both occasions and positive for anticardiolipin antibodies if the test was abnormal on both occasions. Forty-two women were studied. Statistically significant associations were shown between lupus anticoagulant positivity and previous pregnancy loss (odds ratio [OR], 4.8; 95% confidence intervals [CI], 1.0 to 23.6; P = .05) and between anticardiolipin antibody positivity and previous pregnancy loss (OR, 20.0; 95% CI, 1.3 to 97.0; P = .01). All seven women with multiple episodes of pregnancy loss were lupus anticoagulant positive and four of these were also anticardiolipin antibody positive. If patients who are transiently positive for lupus anticoagulant and/or anticardiolipin antibodies are considered to be test positive, the associations with pregnancy loss are no longer statistically significant. Within the group of lupus anticoagulant-positive patients, we observed stronger associations between the presence of six or more positive tests and pregnancy loss than between the presence of two to five positive tests and pregnancy loss. No single test for the lupus anticoagulant provides a statistically significant association with pregnancy loss. The results of our study show that by performing multiple lupus anticoagulant tests and by repeating testing for lupus anticoagulant and anticardiolipin antibodies on more than one occasion, significant associations between the presence of antiphospholipid antibodies and previous pregnancy loss can be shown in patients with SLE.
The influence of antiphospholipid antibodies on the pregnancy outcome of patients with recurrent spontaneous abortion. Heilmann L, von Tempelhoff GF, Kuse S. Department of Obstetrics and Gynecology, City Hospital Ruesselsheim, Germany.	Clin Appl Thromb Hemost 2001 Oct;7(4):281-5 Abstract quote Several therapeutic regimens have been proposed for women with recurrent spontaneous abortion (RSA) and antiphospholipid antibodies (APA). Conflicting results have been reported about women with history of RSA, positive APA, and failure of standard therapy. To evaluate the use of intravenous immunoglobulin in RSA patients with APA and history of treatment failure, we initiated a study with standard therapy (aspirin and low-molecular-weight heparin) and intravenous immunoglobulin. We used an enzyme-linked immunosorbent assay (ELISA) test to screen IgG and IgM anticardiolipin antibodies, and a diluted Russel viper venom time assay for the lupus anticoagulant activity. Altogether, 66 pregnant women with positive APAs at the first visit could be included. Patients with hereditable thrombophilic factors were excluded. After confirmation of the pregnancy, women received a basis immunization of 0.3 g/kg immunoglobulin in a 4-week cycle until the 28th to 32nd week of gestation. All patients received 100 mg/d aspirin and 3,000 anti-Xa U/d certoparin. Among the 66 pregnant women, 17 were persistently autoantibody positive (25.8%), of whom 11 (16.7%) were ACA positive alone, 2 (3%) were lupus anticoagulant positive, and 4 (6.4%) had both antibody types. A total of 49 patients had positive APAs at the initial test, but were negative for ACA and lupus anticoagulant at the second test administered approximately 5 weeks after the start of therapy. We described this group in our following observation as "antibody negative." Sixteen of the 17 autoantibody-positive patients (94.1%) were delivered of live infants compared with 40 patients (81.6%) in the antibody-negative group (odds ratio [OR]: 1.2; 95% CI: 0.98 to 1.4). The overall miscarriage rate was 12.1% and the fetal loss rate was 15.2%. Four patients (25%) in the antibody-positive group developed symptoms of preeclampsia and fetal growth retardation compared with four patients (9.8%) in the antibody-negative group. In conclusion, we see a reduction of the fetal loss rate in patients with RSA and positive APA (5.8%) compared with APA-negative (18.4%) women with the same therapy (OR: 0.3; 95% CI: 0.04 to 2.3).
AUTOIMMUNE THROMBOCYTOPENIC PURPURA
Antiphospholipid antibodies and antiphospholipid syndrome in patients presenting with immune thrombocytopenic purpura: a prospective cohort study. Diz-Kucukkaya R, Hacihanefioglu A, Yenerel M, Turgut M, Keskin H, Nalcaci M, Inanc M. Divisions of Hematology and Rheumatology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Turkey.	Blood 2001 Sep 15;98(6):1760-4 Abstract quote The pathogenetic role and the clinical importance of the presence of antiphospholipid antibodies (APAs) in patients with immune thrombocytopenic purpura (ITP) are not clear. In this study, the prevalence and clinical significance of APAs were investigated in patients with ITP. Eighty-two newly diagnosed ITP patients were prospectively studied. They were evaluated for the presence of lupus anticoagulant (LA) and immunoglobulin G/M anticardiolipin antibodies (ACAs). Thirty-one patients (37.8%) were APA positive at diagnosis. No statistically significant differences were found between the APA-positive and APA-negative groups regarding gender, initial platelet counts, or response to methylprednisolone therapy. After 5 years of follow-up, cumulative thrombosis-free survival of APA-positive (n = 31) and APA-negative (n = 51) ITP patients was 39% and 97.7%, respectively. A significant difference was found between these groups by log-rank test (P =.0004). In addition, LA was an important risk marker for the development of thrombosis in ITP patients. After a median follow-up of 38 months, 14 ITP patients (45%) who had APA positivity developed clinical features (thrombosis or fetal losses) of antiphospholipid syndrome (APS). There were no differences between the APA-positive patients with and without APS regarding the initial platelet counts, response to the therapy, or ACA positivity. The positivity rate for LA was significantly higher in those patients with ITP who developed APS (chi(2): P =.0036; relative risk 7.15; 95% confidence interval, 1.7-47). In conclusion, this study indicates that a significant proportion of patients initially presenting with ITP and APA positivity developed APS. In patients with ITP, the persistent presence of APAs is an important risk factor for the development of APS.
LUPUS-LIKE ANTICOAGULANT	5-10% of SLE patients Drug therapy Phenothiazine Lymphoproliferative disorders Idiopathic
Anticardiolipin antibodies: a study in cerebral venous thrombosis. Christopher R, Nagaraja D, Dixit NS, Narayanan CP. Department of Neurochemistry, National Institute of Mental Health and Neuro Sciences, Bangalore, India.	Acta Neurol Scand 1999 Feb;99(2):121-4 Abstract quote OBJECTIVES: Anticardiolipin antibodies (aCL) have been recognized as a marker for an increased risk of thrombosis. There are no documented reports from India on the prevalence of aCL in patients with cerebral venous thrombosis (CVT). Our study aimed at establishing the prevalence of these antibodies in patients with CVT and evaluating their clinical significance. SUBJECTS AND METHODS: Thirty-one patients with CVT diagnosed by angiography and/or cranial CT were investigated for the presence of aCL along with 31 age- and sex-matched normal controls. All subjects had no overt evidence of systemic lupus erythematosis or related autoimmune disorders. The titres of IgG and IgM type of aCL were estimated in the sera using a solid phase enzyme-linked immunosorbent assay. RESULTS: Anticardiolipin antibodies were detected in 22.6% of CVT patients compared to 3.2% of normal controls (95% confidence interval (CI) 1.01 to 75.65). Five CVT patients had both IgG and IgM antibodies, and 2 had only IgG antibodies. The aCL positive group did not differ from the aCL-negative group with respect to the clinical characteristics and the demographic and risk factor profile. CONCLUSION: The findings suggest that anticardiolipin antibodies are a risk marker for cerebral venous thrombosis. Further studies on a larger group of patients are needed to establish the role of aCL in the pathogenesis of CVT.
HEPATITIS C
Anticardiolipin antibodies in patients with chronic hepatitis C virus infection: characterization in relation to antiphospholipid syndrome. Ordi-Ros J, Villarreal J, Monegal F, Sauleda S, Esteban I, Vilardell M. Department of Internal Medicine, Vall d'Hebron Hospital, Universitat Autonoma de Barcelona, Barcelona, Spain.	Clin Diagn Lab Immunol 2000 Mar;7(2):241-4 Abstract quote The antiphospholipid syndrome (APS) is usually defined by the association of clinical manifestations that comprise venous and/or arterial thrombosis, recurrent fetal losses, and thrombocytopenia, along with the presence of anticardiolipin (aCL) antibodies and/or lupus anticoagulant. Various infectious diseases can induce aCL; however, these antibodies are not usually associated with thrombotic events, as happens with autoimmune diseases, in which these antibodies need the presence of beta(2)-glycoprotein I. Levels of immunoglobulin G (IgG) and IgM aCL antibodies were determined by enzyme-linked immunosorbent assay for 243 patients with chronic hepatitis C virus (HCV) infection and 100 healthy controls. Clinical events of APS, the level of beta(2)-glycoprotein dependence of aCL, the presence of cryoglobulins and other autoantibodies, and cross-reactivity between purified aCL and HCV were evaluated. Positive results for aCL antibodies were found more frequently (3. 3%) for the patients with HCV infection than for healthy controls (0%). All positive aCL antibodies were beta(2)-glycoprotein I independent. No significant association was found between aCL antibodies and clinical manifestations of APS, neither was one found between the presence of other autoantibodies or cryoglobulins and that of aCL. Finally, no cross-reactivity between aCL antibodies and HCV antigens was observed. As previously reported, aCL antibodies seem to be an epiphenomenon, and they do not have clinical or laboratory significance in HCV patients.
Oxidized Low-Density Lipoprotein and Autoimmune Antibodies in Patients With Antiphospholipid Syndrome With a History of Thrombosis Dandan Zhao, MD, PhD Hirokazu Ogawa, MD Xiang Wang, MD Gregory S. Cameron, PhD Darric E. Baty, MD Jeffrey S. Dlott, MD and Douglas A. Triplett, MD, FACP	Am J Clin Pathol 2001;760-767 Abstract quote The prevalence and clinical significance of plasma oxidized low-density lipoprotein (oxLDL) and antibodies against oxLDL (anti-oxLDL) were evaluated in patients with antiphospholipid syndrome (APS). OxLDL and IgG anti-oxLDL were determined by enzyme-linked immunosorbent assay in plasma samples from 80 patients with APS. Positive values (mean + 3 SD) for oxLDL and anti-oxLDL were found in 21 (26%) and 19 (24%) of 80 patients with APS, respectively. These values were significantly higher than those in healthy subjects. Levels of oxLDL and anti-oxLDL antibodies in subgroupings of patients with APS who had experienced thrombotic events were compared. There were significant differences among the groups for the levels of both oxLDL and anti-oxLDL antibodies. Pairwise comparisons between the groups yielded similar but not identical results. There was a significant, positive correlation between levels of plasma oxLDL and anti-oxLDL. These results suggest that elevated levels of plasma oxLDL and anti-oxLDL may be risk factors and potential markers for thrombosis, especially for arterial thrombotic events, in patients with APS.
STROKE
Antiphospholipid antibodies and subsequent thrombo-occlusive events in patients with ischemic stroke. Levine SR, Brey RL, Tilley BC, Thompson JL, Sacco RL, Sciacca RR, Murphy A, Lu Y, Costigan TM, Rhine C, Levin B, Triplett DA, Mohr JP; APASS Investigators. Department of Neurology, Mt Sinai School of Medicine, New York, NY 10029-6574, USA.	JAMA. 2004 Feb 4;291(5):576-84 Abstract quote.   CONTEXT: The presence of antiphospholipid antibodies (aPL) has been associated with vascular occlusive events. However, the role of aPL in predicting ischemic events, particularly recurrent ischemic stroke, is controversial. OBJECTIVE: To evaluate the effect of baseline aPL positivity (ie, positivity for anticardiolipin antibodies [aCL], lupus anticoagulant antibodies [LA], or both) on subsequent thrombo-occlusive events, including recurrent stroke. DESIGN, SETTING, AND PARTICIPANTS: The Antiphospholipid Antibodies and Stroke Study (APASS), a prospective cohort study within the Warfarin vs Aspirin Recurrent Stroke Study (WARSS), a randomized double-blind trial (N = 2206) conducted at multiple US clinical sites from June 1993 through June 2000 and comparing adjusted-dose warfarin (target international normalized ratio, 1.4-2.8) and aspirin (325 mg/d) for prevention of recurrent stroke or death. APASS participants were 1770 (80%) WARSS participants who consented to enroll in the APASS, with usable baseline blood samples drawn prior to randomization to the WARSS and analyzed for aPL status within 90 days of index stroke by a central independent laboratory. Quality assurance was performed on approximately 10% of samples by a second independent laboratory. MAIN OUTCOME MEASURE: Two-year rate of the composite end point of death from any cause, ischemic stroke, transient ischemic attack, myocardial infarction, deep vein thrombosis, pulmonary embolism, and other systemic thrombo-occlusive events. The primary analysis assessed the outcome associated with aPL positivity within each WARSS treatment group separately, after risk-factor adjustment (since these aPL-positive vs aPL-negative comparisons were not randomized). RESULTS: Of the 1770 APASS patients, 720 (41%) were classified as aPL-positive and 1050 (59%) as aPL-negative. There was no increased risk of thrombo-occlusive events associated with baseline aPL status in patients treated with either warfarin (relative risk [RR], 0.99; 95% confidence interval [CI], 0.75-1.31; P =.94), or aspirin (RR, 0.94; 95% CI, 0.70-1.28; P =.71). The overall event rate was 22.2% among aPL-positive and 21.8% among aPL-negative patients. There was no treatment x aPL interaction (P =.91). Patients with baseline positivity for both LA and aCL antibodies tended to have a higher event rate (31.7%) than did patients who tested negative for both antibodies (24.0%) (unadjusted RR, 1.36; 95% CI, 0.97-1.92; P =.07). Classification and regression tree analyses did not identify a specific LA test or aCL isotype or titer that was associated with increased risk of thrombo-occlusive event. CONCLUSIONS: The presence of aPL (either LA or aCL) among patients with ischemic stroke does not predict either increased risk for subsequent vascular occlusive events over 2 years or a differential response to aspirin or warfarin therapy. Routine screening for aPL in patients with ischemic stroke does not appear warranted.

 

PATHOGENESIS	CHARACTERIZATION
Lupus anticoagulant	Reacts with the negatively charged phospholipid portion of the prothrombin activator complex to produce prolongation of the in vitro clotting assays such as aPTT, dilute RVV, kaolin clotting time, and PT
Complement mediated injury	J Rheumatol 2000;27:Suppl 58:20 APL antibodies bind to complexes comprising a protein cofactor and surface phospholipids-leading to platelet aggregation and endothelial dysfunction Damaging endothelium exposes hidden antigens which may lead to development of antibodies
	Possible that APL antibodies are directed against a complex antigen of which beta2-glycoprotein-1 is an essential component In patients with infections such as syphilis and HIV, the APL antibodies bind directly to the phospholipid even in the absence of beta2-glycoprotein APL antibodies directed against phosphatidylethanolamine or cardiolipin could downregulate the expression of anticoagulant activities of the protein C pathway, creating a state of relative activated protein C resistance Since beta2 glycoprotein is a natural anticoagulant by virtue of a lipid-binding inhibitor or platelet aggregation and of prothrombin APL antibodies may be directed against heparin sulfate in the region recognized by antithrombin III, thereby promoting coagulation by preventing heparin-induced formation of antithrombin III-thrombin complexes
Paraoxonase activity is dramatically decreased in patients positive for anticardiolipin antibodies. Lambert M, Boullier A, Hachulla E, Fruchart JC, Teissier E, Hatron PY, Duriez P. Department of Internal Medicine, Huriez Hospital, University Hospital, University of Lille 2, France.	Lupus 2000;9(4):299-300 Abstract quote It has been reported that paraoxonase 1 (PON1) activity inhibits low-density lipoprotein (LDL) oxidation and modulates the risk of coronary heart disease. This study shows that autoantibodies (IgG) directed against modified LDL were increased in 71 patients positive for anticardiolipin antibodies. In a representative subgroup of these patients (n = 36) PON1 activity was dramatically decreased and the prevalence of the RR genotype of this enzyme tended to be increased in patients who had developed arterial thrombosis. This study suggests that PON1 abnormalities play a role in the antiphospholipid syndrome.
Antiphosphatidylethanolamine antibodies contribute to the diagnosis of antiphospholipid syndrome in patients with systemic lupus erythematosus. Balada E, Ordi-Ros J, Paredes F, Villarreal J, Mauri M, Vilardell-Tarres M. Department of Internal Medicine, Hospital Vall d'Hebron, Universidad Autonoma de Barcelona, Spain.	Scand J Rheumatol 2001;30(4):235-41 Abstract quote OBJECTIVE: To evaluate the correlation between antiphosphatidylethanolamine antibodies (aPE) and some antiphospholipid antibodies (aPL)-related clinical manifestations in patients with systemic lupus erythematosus (SLE). METHODS: Patients with SLE (n=217) were tested for the presence of aPE, anticardiolipin antibodies (aCL), and lupus anticoagulant (LA). The prospective aPL-related clinical manifestations studied were: thrombosis, thrombocytopenia, recurrent fetal losses, heart valvulopathies, hemolytic anemia, livedo reticularis, and pulmonary hypertension. RESULTS: A total of 109 SLE patients (50.23%) were IgG aPE-positive; 17.51% presented aPE as the sole autoantibody and had some clinical features of aPL-related clinical manifestations. IgG aPE were associated to the presence of heart valvulopathies (p=0.002). A statistical difference was also found when considering high levels of IgG aPE (O.D.>0.600) in patients with livedo reticularis (p=0.008). CONCLUSION: The evaluation of IgG aPE may allow us to detect some more patients with aPL-related clinical manifestations in the SLE population, aPE correlated particularly with valvulopathies and livedo reticularis.
Anti-tissue factor pathway inhibitor activity in patients with primary antiphospholipid syndrome. Adams MJ, Donohoe S, Mackie IJ, Machin SJ. Haematology Department, University College London, London, UK.	Br J Haematol 2001 Aug;114(2):375-9 Abstract quote The association between antiphospholipid antibodies and an increased risk of thrombosis in antiphospholipid syndrome (aPS) patients is probably caused by numerous mechanisms, including the effects of antibodies to phospholipid-binding proteins such as beta(2)-glycoprotein I and prothrombin. In this study, we investigated the inhibition of tissue factor pathway inhibitor (TFPI) in 33 patients with primary antiphospholipid syndrome (PAPS). TFPI was measured in PAPS patients using an amidolytic assay, dependent on the generation of activated factor X (Fxa), and this was compared with 55 healthy subjects. Functional levels of TFPI (mean +/- SD) were significantly lower in PAPS patients (0.89 +/- 0.37 U/ml) than the control group (1.05 +/- 0.15 U/ml) (P = 0.02). The difference was caused by a subset of five patients who had TFPI levels below the lower 99% confidence interval of the normal reference range, representing increased FXa generation in the assay system. IgG fractions were isolated from these five patients and five control subjects, then incorporated into normal plasma to measure FXa generation in the TFPI assay system. FXa generation was increased when polyclonal rabbit anti-human TFPI IgG (P < 0.0001) or PAPS IgG (P = 0.0001) were added to normal plasma, demonstrating inhibition of TFPI. The apparent anti-TFPI activity demonstrated in the five subjects with PAPS in this study may represent a significant new mechanism for thrombosis in patients with aPS, as it implies that increased tissue factor FVIIa-mediated thrombin generation might occur.

 

LABORATORY/ RADIOLOGIC/ OTHER TESTS	CHARACTERIZATION
Distribution of lupus anticoagulant and anticardiolipin antibody isotypes in a population with antiphospholipid syndrome. Guglielmone HA, Fernandez EJ. Unidad de Hemostasia y Trombosis, Laboratorio de Analisis Clinicos Especializados, Facultad de Ciencias Quimicas, Universidad Nacional de Cordoba, Argentina.	J Rheumatol 1999 Jan;26(1):86-90 Abstract quote OBJECTIVE: To analyze the distribution of lupus anticoagulant (LAC) and anticardiolipin antibody (aCL) isotypes in a population with antiphospholipid syndrome and to explore whether there is an association with the site of thrombotic episodes and the number of recurrent spontaneous abortions. METHODS: Ninety-two patients (73 female, 19 male) with positive LAC and/or aCL were included as 2 groups: (1) 20 patients with secondary antiphospholipid syndrome (APS) (16 had thrombotic episodes and 4 thrombocytopenia); (2) 72 patients with primary APS (31 presented thrombotic episodes and 41 had recurrent spontaneous abortion). RESULTS: In Group 1 seven of 20 (35%) patients with secondary APS had IgG aCL, 9 (45%) had both IgG/IgM aCL, and 2 (10%) had IgM aCL; the remaining patients had combinations of aCL isotypes. In Group 2 patients with primary APS, IgG aCL was positive in 41%, IgG/IgM mixture in 21%, and 15% of patients had combinations of the 3 isotypes. Sixteen of 20 (80%) patients with secondary disease and 37 of 72 (51%) with primary disease tested positive for LAC. CONCLUSION: The presence of one or any mixture of isotype of aCL with or without LAC is not associated with the site of thrombosis (venous or arterial). On the contrary, in the patients with primary APS, the presence of the 3 aCL isotypes plus LAC was associated with a higher number of recurrent spontaneous abortions compared to other possible combinations of aCL isotypes.
IgG subclass distribution of antibodies against beta(2)-GP1 and cardiolipin in patients with systemic lupus erythematosus and primary antiphospholipid syndrome, and their clinical associations. Samarkos M, Davies KA, Gordon C, Walport MJ, Loizou S. 5th Department of Internal Medicine, Evangelismos Hospital, Athens, Greece.	Rheumatology (Oxford) 2001 Sep;40(9):1026-32 Abstract quote OBJECTIVES: To determine the immunoglobulin G (IgG) subclass distribution of anticardiolipin (aCL) and anti-beta(2)-glycoprotein 1 (beta(2)-GP1) antibodies (abeta(2)-GP1), and to examine possible associations between the different abeta(2)-GP1 and aCL subclasses and the main clinical manifestations of the antiphospholipid syndrome (APS). METHODS: We studied 130 patients with systemic lupus erythematosus and 35 patients with primary APS. We used enzyme-linked immunosorbent assays to measure IgG aCL and abeta(2)-GP1 and to determine the IgG subclass distribution of these two autoantibodies. RESULTS: When the number of patients positive for each subclass was examined, IgG(3) and IgG(2) aCL were more frequent (63.5 and 54.1% of patients were positive for the two subclasses, respectively), while for abeta(2)-GP1 IgG(2) was the most prevalent subclass (81.8% of patients were positive). IgG(2) aCL was significantly associated with arterial thrombosis (P=0.023) and fetal loss (P=0.013), and IgG(3) aCL was significantly associated with arterial thrombosis (P=0.0003) and fetal loss (P=0.045). IgG(2) abeta(2)-GP1 was associated with venous thrombosis (P=0.012) and IgG(3) abeta(2)-GP1 was associated with venous thrombosis (P=0.036) and fetal loss (P=0.024). CONCLUSIONS: The IgG(2) predominance of abeta(2)-GP1 suggests that the antibody response against beta(2)-GP1 may be T-cell-independent. As IgG(2) and IgG(3) differ in their effector functions, their association with the same clinical manifestations (i.e. thrombosis and fetal loss) suggests that more than one mechanism may be involved in the pathogenesis of thrombosis and fetal loss in APS.
Laboratory Markers
Prolonged PTT is first clue- PTT prolonged at least 5 seconds above upper normal limit	Mixing Study for Prolonged PTT 1. Do a 1:1 mixing study with one part of patient plasma mixed with one part of normal plasma. a. If the PTT remains prolonged at least 5 seconds above normal limit, suspect LA 2. At least 2 specific one-stage assays for factors of the intrinsic system reveal apparent factor deficiencies of less than 50% of normal (Factors VIII, IX, XI, XII) 3. As the patient plasma is increasingly diluted in these assays (ie beyond 1:5 or 1:10), the measured activity of one or more of these factors appears to increase. 4. If no other apparent causes of the abnormal coagulation studies can be identified. Proceed to Russell Viper Venom Test (RVVT) A dilute RVVT has been shown to correct the abnormality of the LA. RVVT directly activates Factor X a. Normal RVVT suggests a deficiency of Factor VII activity 5. Additional Tests
	NOTE: Resting or activated platelets substituted for the exogenous phospholipid has been shown to correct the abnormality.
Specific Laboratory Identification	It may be identified in three ways:
Serologically false positive test for syphilis using VDRL	This test is a flocculation assay using carbon particles coated with cholesterol, lecithin, and cardiolipin Antibodies directed against the phospholipid beta2 glycoprotein complex also binds to the cardiolipin antigen
Lupus anticoagulant assay	Prolongation of the APTT not corrected by normal plasma
Cardiolipin assay with the use of cardiolipin or other negatively charged phospholipids as antigens
COMPARISON OF TESTS
Assessing the usefulness of anticardiolipin antibody assays: a cautious approach is suggested by high variation and limited consensus in multilaboratory testing. Favaloro EJ, Silvestrini R. Department of Haematology, Institute of Clinical Pathology and Medical Research, Westmead Hospital, Western Sydney Area Health Service, New South Wales, Australia	Am J Clin Pathol 2002 Oct;118(4):548-57 Abstract quote An anticardiolipin antibody (ACA) assay has become a laboratory standard for the detection of antiphospholipid antibodies. We evaluated data from a quality assurance program to assess ACA assay usefulness. Cross-laboratory (n = 56) testing of 12 serum samples yielded interlaboratory coefficients of variation (CVs) for lgG ACA and IgM ACA that were higher than 50% in 17 (71%) of 24 cases. The situation for testing consensus was of equal concern. Total consensus occurred in 6 (25%) of 24 cases. General consensus (interlaboratory agreement, 90% or more) was obtained in 10 (42%) of 24 cases. In the majority of test cases, laboratories could not agree on whether a serum sample tested was ACA-positive or ACA-negative. Differing method-related issues also were evident; some methods tended toward higher or lower ACA values. Method-based majority consensus differed from participant majority consensus on many test occasions. Exceedingly high interlaboratory result variation, combined with a general lack of test result grading consensus and method-based variation, indicate that a cautious clinical approach toward laboratory findings is prudent. Laboratory tests should be repeated at least once before making a clinical diagnosis of any anti-phospholipid syndrome-like disorder.

 

CLINICAL VARIANTS/GROSS DISEASE	CHARACTERIZATION
Criteria for the diagnosis of antiphospholipid syndrome in patients presenting with dermatologic symptoms. Kriseman YL, Nash JW, Hsu S. Department of Dermatology, Baylor College of Medicine, Houston, TX 77030, USA.	J Am Acad Dermatol. 2007 Jul;57(1):112-5. Epub 2007 Apr 30. Abstract quote The antiphospholipid syndrome (APS) is an autoimmune disorder characterized by the occurrence of arterial and/or venous thromboembolic events and obstetric complications in the setting of circulating antiphospholipid antibodies. Dermatologic manifestations are commonly seen in APS with almost half of the patients exhibiting varied conditions such as ulceration, splinter hemorrhages, and livedo reticularis. In this paper, we report the case of a 12-year-old boy who was diagnosed with APS after presenting with livedo reticularis and positive antiphospholipid antibodies. We discuss the difficulty of diagnosing APS in patients presenting solely with dermatologic complaints, as these skin manifestations are not specific enough for APS to be included in the Sapporo diagnostic criteria. Proposed revisions to the Sapporo criteria to increase its specificity and sensitivity are also addressed.
Pathogenic antibodies in women with obstetric features of antiphospholipid syndrome who have negative test results for lupus anticoagulant and anticardiolipin antibodies. Silver RM, Pierangeli SS, Edwin SS, Umar F, Harris EN, Scott JR, Branch DW. Department of Obstetrics and Gynecology, University of Utah School of Medicine, Salt Lake City 84132, USA.	Am J Obstet Gynecol 1997 Mar;176(3):628-33 Abstract quote OBJECTIVE: Our goal was to determine whether women with clinical features of antiphospholipid syndrome but negative test results for lupus anticoagulant and anticardiolipin antibodies have pathogenic antibodies not identified by currently used methods. STUDY DESIGN: Sera were obtained from women with clinical features associated with antiphospholipid antibodies who had negative test results for lupus anticoagulant and anticardiolipin antibodies (antiphospholipid syndrome-like). We studied (1) the effect of passive immunization with their purified immunoglobulin G fraction on murine pregnancy (n = 35) and (2) the presence of antiphospholipid antibodies other than lupus anticoagulant or anticardiolipin antibodies (n = 39). Sera were also retested for anticardiolipin antibodies and lupus anticoagulant. RESULTS: Fetal loss occurred in 235 of 1088 (22%) pups in 137 mice immunized with immunoglobulin G fraction from antiphospholipid syndrome-like women compared with 23 of 402 (6%) pups in 53 control mice. Immunoglobulin G from 11 study patients resulted in the loss of at least one third of the exposed pups. Five women had positive levels of antiphosphatidylserine antibodies (>99th percentile). All levels were low positive, and three women also had low-positive levels of anticardiolipin antibodies on repeat testing. Five of the 11 (45%) women whose immunoglobulin G fractions caused at least 33% fetal loss also had positive test results for antiphospholipid antibodies. CONCLUSIONS: A subset of women with clinical disorders suspicious for antiphospholipid syndrome but who had negative test results for lupus anticoagulant and anticardiolipin antibodies by current methods have serum immunoglobulin G that is pathogenic to murine pregnancy. Testing for pathogenic immunoglobulin G may provide additional means to identify women with an as yet uncharacterized immune condition. The clinical relevance of low levels of antiphospholipid antibodies in these women remains unproved.
Extensive cutaneous necrosis associated with anticardiolipin antibodies. Paira S, Roverano S, Zunino A, Oliva ME, Bertolaccini ML. Rheumatology Department, Hospital JM Cullen, Santa Fe, Republica Argentina.	J Rheumatol 1999 May;26(5):1197-200 Abstract quote Extensive cutaneous necrosis (ECN) associated with antiphospholipid antibodies is a rare presentation. We describe 2 patients with ECN and high titers of anticardiolipin antibodies. The mechanism by which these antibodies act has not been established and there is still controversy regarding treatment of these patients without established guidelines. In the few documented cases the use of pulse steroid therapy, anticoagulants, fibrinolytic agents, plasmapheresis, or a combination of them has shown some benefit. Early recognition and treatment of the antiphospholipid syndrome may limit the extent of thrombotic complications that can result in tissue necrosis.
Widespread cutaneous necrosis occurring in association with the antiphospholipid syndrome: a report of two cases. Creamer D, Hunt BJ, Black MM. St John's Institute of Dermatology and Department of Haematology, St Thomas' Hospital, London SE1 7EH, U.K.	Br J Dermatol 2000 Jun;142(6):1199-203 Abstract quote The antiphospholipid syndrome is an acquired prothrombotic state where thrombosis and/or pregnancy loss is related to the presence of antiphospholipid antibodies. Cutaneous necrosis secondary to intravascular thrombosis of small dermal vessels is a recognized but rare association with antiphospholipid syndrome. We report two patients with high circulating levels of anticardiolipin antibodies who developed widespread cutaneous necrosis as the first clinical manifestation of the antiphospholipid syndrome. The exact mechanism by which antiphospholipid antibodies mediate thrombosis is uncertain; however, proposed mechanisms of activity include endothelial cell activation, altered endothelial production of prostacyclin, activation of platelets, and modulation of the protein C and S pathways.
Foetal loss, liver necrosis and acute lupus erythematosus in a patient with antiphospholipid antibody syndrome. Fehr T, Cathomas G, Weber C, Fontana A, Schaffner A. Medical Clinic B, University Hospital, Zurich, Switzerland	Lupus 2001;10(8):576-9 Abstract quote The antiphospholipid antibody syndrome (APS) is characterized by arterial or venous thromboses and recurrent foetal loss. It occurs as primary disease, but also in the context of systemic lupus erythematosus (SLE). Whereas primary APS induces a thrombotic microangiopathy without significant inflammatory reaction, secondary APS in SLE is usually associated with vasculitis. Here we report a patient with APS who presented with acute diarrhoea and then developed a HELLP-like syndrome characterized by a spontaneous abortion, multifocal hepatic necroses and thrombocytopenia. Thereafter an acute flare of SLE with arthralgias, pleuritis, skin rash and glomerulitis occurred. Clinical amelioration was only achieved by combining curettage, anticoagulation and immunosuppression, a treatment taking into account the pathogenesis of HELLP-like disease, APS and SLE. To our knowledge this is the first reported case of APS associated with combined acute manifestations of these three syndromes triggered by a presumable intestinal infection.

 

HISTOLOGICAL TYPES	CHARACTERIZATION
General-SKIN	J Am Acad Dermatol 2999;42:903 Hum Pathol 1995;26:716 Br J Dermatol 1999;140:725 Pan dermal and subcutaneous arterial and venous thrombi-bland thrombosis most common Intramural lymphocytic infiltrate may be present Reactive angioendotheliomatosis resembling stasis dermatitis may be present in the lower extremities and acral sites associated with luminal thrombosis and glomeruloid like proliferations
VARIANTS
Livedoid vasculopathy
Perniotic nodules
Purpuric cutaneous infarction	Clin Rheumatol 1996;15:394
Degos-disease like skin infarcts	Heal to form porcelain scars
Papules and nodules

 

PROGNOSIS AND TREATMENT	CHARACTERIZATION
PROGNOSIS	Predictors of thrombosis include: IgG subtype Presence of antibodies to beta2 glycoprotein Simultaneous presence of circulating lupus anticoagulant and high titres of both anticardiolipin antibody and antibodies to beta2 glycoprotein-1
Outcome of patients with anticardiolipin antibodies: a 10 year follow-up of 52 patients. Shah NM, Khamashta MA, Atsumi T, Hughes GR. Lupus Research Unit, Rayne Institute, St. Thomas' Hospital, London, UK.	Lupus 1998;7(1):3-6 Abstract quote We report a 10-year follow-up on 52 patients with raised levels of anticardiolipin antibodies (aCL) who were first seen at our tertiary referral centre in 1986. The clinical and serological features of these 52 patients are described. Thirty-one patients had the antiphospholipid syndrome (APS) in 1986. Nine of these patients (29%) had further thrombotic events during the follow-up period. Of the other 21 aCL positive patients without clinical manifestations of APS, 11 (52%) developed the syndrome over this period. Five patients (10%) died during the follow-up. Close monitoring of patients with connective tissue diseases and aCL is essential as the likelihood of developing antiphospholipid syndrome is high.
TREATMENT
Antiphospholipid antibody-associated recurrent pregnancy loss: treatment with heparin and low-dose aspirin is superior to low-dose aspirin alone. Kutteh WH. Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center at Dallas 75235-9032, USA.	Am J Obstet Gynecol 1996 May;174(5):1584-9 Abstract quote OBJECTIVE: The purpose of this study was to compare the use of low-dose aspirin alone with heparin and low-dose aspirin in the treatment of the antiphospholipid antibody syndrome. STUDY DESIGN: A prospective, single-center trial included 50 patients who were alternately assigned to treatment. Each patient had at least three consecutive spontaneous pregnancy losses, positive antiphospholipid antibodies on two occasions, and a complete evaluation. Data were compared by chi(2) analysis and Fisher's exact test. RESULTS: Viable infants were delivered of 11 of 25 (44%) women treated with aspirin and 20 of 25 (80%) women treated with heparin and aspirin (p < 0.05). There were no significant differences between the low-dose aspirin and the heparin plus low-dose aspirin groups with respect to gestational age at delivery (37.8 +/- 2.1 vs 37.2 +/- 3.4 weeks), number of cesarean sections (18% vs 20%), or complications. CONCLUSION: Heparin plus low-dose aspirin provides a significantly better pregnancy outcome than low-dose aspirin alone does for antiphospholipid antibody-associated recurrent pregnancy loss.
Therapeutic plasma exchange for the acute management of the catastrophic antiphospholipid syndrome: beta(2)-glycoprotein I antibodies as a marker of response to therapy. Flamholz R, Tran T, Grad GI, Mauer AM, Olopade OI, Ellman MH, McKinsey JF, Jeon HR, Baron JM, Baron BW. Department of Pathology-Blood Bank, The University of Chicago, Chicago, IL 60637, USA.	J Clin Apheresis 1999;14(4):171-6 Abstract quote We describe two patients with the catastrophic antiphospholipid syndrome associated with elevation of beta(2)-glycoprotein I antibodies and fulminant thrombotic diatheses. Both patients were treated with therapeutic plasma exchange (TPE), which resulted in a marked decrease in antibody titer accompanied by an improved clinical outcome in one patient (IgG antibody). In the second patient, the outcome was poor despite TPE (IgA antibody). There were no significant complications of TPE in either case. Because of the fulminant nature of the catastrophic antiphospholipid syndrome, we conclude that a trial of TPE is warranted for the acute management. Further studies are needed to clarify which patients may benefit from this treatment.

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Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
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Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
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