Antiphospholipid Antibody Syndrome. Rare Diseases of the Immune System

14. Differential Diagnosis

Domenico Prisco1, 2  , Giacomo Emmi , Elena Silvestri , Lucia Ciucciarelli , Elena Niccolai , Mario Milco D’Elios , Danilo Squatrito  and Lorenzo Emmi 


SOD Patologia Medica, Center for Autoimmune Systemic Diseases – Behçet Center and Lupus Clinic – AOU Careggi, Florence, Italy


Department of Experimental and Clinical Medicine, University of Florence, V.le L.go G. Brambilla 3, Florence, 50134, Italy


SOD Patologia Medica, Center for Autoimmune Systemic Diseases – Behçet Center and Lupus Clinic – AOU Careggi, AOU Careggi Hospital, V.le L.go G. Brambilla 3, Florence, 50134, Italy

Domenico Prisco (Corresponding author)


Giacomo Emmi


Elena Silvestri


Lucia Ciucciarelli


Elena Niccolai


Mario Milco D’Elios


Danilo Squatrito


Lorenzo Emmi



Antiphospholipid antibody syndromeDifferential diagnosisRecurrent thrombosisAtypical thrombosisMyakis criteria

14.1 Introduction

The antiphospholipid antibody syndrome (APS) is a systemic, acquired, immune-mediated systemic disease characterized by episodes of thrombosis (venous, arterial, or of the microcirculation) and/or pregnancy morbidities, associated with the persistent presence of circulating autoantibodies directed to molecular complexes consisting of phospholipids and proteins (confirmed at least in two occasions 12 weeks apart). APS should always be considered as a potential diagnosis for young patients presenting with a history of thrombotic events, especially when they occur without any obvious external trigger or any inherited thrombophilic mutation (even if 2006 criteria do not exclude APS patients with other inherited or acquired pro-thrombotic conditions) or for women with recurrent pregnancy losses or later fetal deaths. Many other disorders are able to mimic APS, so a broad range of alternative diagnoses should be investigated and ruled out during clinical workup. In 2006, new classification criteria were formulated to allow a well-defined and shared picture of the syndrome [1]. According to these criteria, it is possible to identify the following conditions:




In the first type of situations, diagnosis is relatively simple in some cases of primary APS when clinical presentation includes only acute thrombosis or pregnancy loss. However, in more complex cases special attention deserves the exclusion of certain conditions, in particular microangiopathic syndromes or systemic lupus erythematosus (SLE). In the second group the diagnosis of APS may be more complex due to nonspecific clinical manifestations; in this case, different clinical conditions must be considered before diagnosis of APS is done (e.g., an acute abdominal pain due to visceral thrombosis). In the third case the patient presents with non-criterial clinical features, due to conditions potentially associated with APS, which deserve a careful follow-up to detect early clinical criteria and to establish appropriate therapy.

A “seronegative” form of the syndrome has been described and recently revised, but we will not consider this entity in this chapter.

In this chapter we will consider these three possibilities, focusing on clinical signs and on the main aspects of the differential diagnosis. For a schematic representation of the text, see Fig. 14.1.


Fig. 14.1

Clinical suspicion for definite and non-criterial APS

14.2 Definite APS with Usual Clinical Manifestations

The clinical picture of APS is protean and very variable in the single patient, as thrombotic events can involve both arterial and venous vessels of any size and anatomical district and sometimes APS diagnosis requires a broad number of medical conditions to be ruled out (Table 14.1).

Table 14.1

Main differential diagnosis


Behçet’s syndrome

Demyelinating diseases (multiple sclerosis, Devic’s syndrome)

Microangiopathic syndromes (TTP/HUS, HELLP)a

Heparin-induced thrombocytopenia (HIT)

Disseminated intravascular coagulation (DIC)

Hyperviscosity syndromes

Sneddon’s syndrome, Susac’s syndrome, Degos disease, Moyamoya syndrome (very rare)

a TTP thrombotic thrombocytopenic purpura, HUS hemolytic uremic syndrome, HELLP hemolysis, elevated liver enzymes, and low platelets

14.2.1 Systemic Lupus Erythematosus

A particular liaison exists between APS and SLE; the 2006 International consensus conference for the first time pointed out that the definition of secondary APS is not necessary and appropriate, since SLE and APS may represent a different spectrum of the same disease [1]. In clinical practice, we often challenge the following three scenarios:




Whenever APS primarily involve the central nervous system (CNS), the main clinical challenge is the differential diagnosis with neuro-SLE, since both the conditions share similar neurological symptoms and MR findings [3]. The detection of a significant titer of specific circulating autoantibodies (e.g., anti-ribosomal P) and low complement levels should be suggestive of SLE. However, many patients with neuro-SLE show also circulating aPL; therefore, ischemic lesions seen on brain MR could be either the result of APS microthrombosis or alternatively of SLE inflammation. The discrimination between the two conditions could be very challenging for clinicians; however, this step is crucial since in the first case anticoagulants are the mainstay of therapy, while in the other SLE requires the use of high-dose steroids usually combined with immunosuppressants drugs [4].

14.2.2 Behçet’s Syndrome

Neuro-Behçet (NB) represents an important differential diagnosis for APS with predominant cerebral involvement. Of note both diseases can be responsible for cerebral venous sinus thrombosis and parenchymal lesions [5]. NB brain inflammatory lesions are typically located deeply at the level of basal ganglia and brainstem, while APS usually involves the subcortical and periventricular white matter areas. Differential diagnosis between the two conditions is crucial because in NB immunosuppressive treatment is required [6]. Moreover, a particular subset of Behçet patients is indeed very prone to vascular thrombosis that in these cases could represent the main clinical manifestation, further complicating the differential diagnosis with APS. Due to their primary inflammatory vascular origin, the thrombotic events in Behçet syndrome are usually better responsive to corticosteroid or immunosuppressive drugs than to anticoagulation [7]. Noteworthy the inappropriate use of anticoagulants in Behçet could be very dangerous when these drugs are used in patients with clinically occult pulmonary artery aneurisms, since the risk of rupture is very high in this setting [8]. Oral aphthosis is the most frequent clinical sign in Behçet; however, it lacks specificity due to its high frequency in the general and otherwise healthy population. Moreover, about 5 % percent of Behçet patients lack oral aphtosis. The same considerations are valid for HLA- B51 antigen, often wrongly used as a Behçet diagnostic biomarker, due to its high prevalence in Behçet patients, but aphtosis can also be found in approximately 30 % of unaffected people. HLA-B51 screening test and other laboratory investigations are not included in the classification criteria, since the diagnosis/classification of Behçet currently relies only on clinical findings [9]. Moreover, aPL could be present at low titer in Behçet patients. However, recurrent oral and genital (bipolar) aphthosis and uveitis when present are pathognomonic for Behcet’s disease and point to the correct diagnosis.

14.2.3 Demyelinating Diseases (Multiple Sclerosis and Neuromyelitis Optica)

Multiple sclerosis (MS) lesions can be hardly differentiated from neuro-APS on brain MR, since their radiologic morphology and location could be similar in the two conditions [10]. A further complication is represented by the not unusual finding of ANA and aPL positivity in MS patients, although often at very low titer. Lesions involving the periventricular and corpus callosum areas are more suggestive of SM than APS; moreover, the detection of oligoclonal bands from cephalospinal fluid further supports the diagnosis of demyelinating disease [11]. Neuromyelitis optica (NMO), previously named Devic’s syndrome, is a recently recognized disease, now considered a separate disorder from MS, since it recognizes a different inflammatory pathway. The presence of aquaporin-4 (anti-NMO) antibodies is considered the main pathogenetic player and a very useful diagnostic tool at the same time. The diagnosis of NMO should be suspected in patients who present with optic neuritis, usually more severe than in MS, and/or with longitudinally extended transverse myelitis, defined as a spinal inflammatory lesion involving at least three consecutive vertebrae. In this scenario testing patients for anti-NMO antibodies is strongly recommended [12]. NMO can coexist with SLE and APS in the same patient and this overlap created some degree of confusion in the past. Indeed, some neurological symptoms have been ascribed to SLE/APS rather than to NMO. This is the case, for example, of transverse myelitis frequently reported as an APS complication (among non-criteria clinical clues) but often with no data available on anti-NMO status. Recognizing NMO typical ocular/spinal pattern is hence considered fundamental for further investigating the presence of circulating anti-NMO, since this lead to the correct treatment with plasmapheresis or eventually with other immunosuppressive approach [13].

14.2.4 Microangiopathic Syndromes

Catastrophic antiphospholipid syndrome (CAPS), thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), and hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome all belong to the group of thrombotic microangiopathy syndromes; these disorders are histologically characterized by small vessel occlusion with hyaline thrombi and fibrin deposition, various degree of platelet consumption, intravascular hemolysis with red cells fragmentation producing schistocytes, and clinical/laboratoristic findings of organ dysfunction. Since aPL have been not infrequently detected in such conditions and since conversely APS does not uncommonly show some degree of microangiopathic involvement, the term MAPS (microangiopathic antiphospholipid syndrome) has been proposed as an “umbrella” to include many conditions [1415].

Thrombotic Thrombocytopenic Purpura

TTP, also named Moschowitz syndrome, is clinically characterized by severe neurological involvement, fever, thrombocytopenia, microangiopathic hemolytic anemia, and more rarely kidney dysfunction. Useful tools to diagnose this condition are the presence of schistocytes, elevated levels of circulating ultra large von Willebrand factor (ULVWF) multimers, and, in acquired autoimmune type, the detection of antibodies against the metalloproteinase-disintegrin ADAMTS13 [16]. Differential diagnosis could be hard since aPL have been occasionally reported in TTP patients; diagnostic clues helping in differential diagnosis are the rarity of severe episodes of thrombocytopenia in APS, while the occurrence of hemolytic anemia, the presence of schistocytes on peripheral blood smear, the elevated LDH levels, and the detection of ULVWF further support the diagnosis of TTP.

Hemolytic Uremic Syndrome

HUS is a disorder characterized by thrombocytopenia and microangiopathic anemia with microvascular thrombosis, tissue ischemia with necrosis, and renal failure. It has been distinguished into diarrhea-associated HUS, the most frequent and usually linked to Shiga-like toxin-producing bacteria (STEC-HUS), and diarrhea-nonassociated or atypical HUS. The latter constitutes only 5–10 % of HUS in children, but the majority of HUS in adults. Despite its rarity, atypical HUS is endowed with a very intriguing pathogenesis, since it can be triggered by genetical defect or by the presence of circulating proteins affecting the complement system [1718]. Clinical features suggesting HUS are the rapid onset of renal failure and the presence of microangiopathic anemia associated with thrombocytopenia; in the typical presentation the temporal occurrence of a previous episode of diarrhea as well as the absence of aPL further supports the diagnosis.

Hemolysis Elevated Liver Enzymes and Low Platelets

HELLP syndrome can complicate pregnancy, even in pregnant women with history of APS or aPL positivity. This condition is more common in multiparous women; 70 % of cases occur between the 27th and the 37th week of gestation, while in the remaining 30 % diagnosis is made during the postpartum period. The HELLP syndrome is characterized by upper right quadrant abdominal pain, nausea, vomiting, generalized edema, signs of hemolysis, elevated liver enzymes, severe thrombocytopenia, and renal dysfunction; noteworthy, severe hypertension is not usually found in HELLP syndrome, and this can help distinguish it from preeclampsia, even if the two conditions can coexist in 70–80 % of cases [19]. This scenario is even more complicated considering that some APS patients can experience HELLP syndrome during pregnancy, indicating that probably circulating aPL can affect the occurrence of HELLP in predisposed women [20].

For the main causes of recurrent miscarriage, see Fig. 14.2.


Fig. 14.2

Differential diagnosis between microangiopathies, DIC, and HIT

14.2.5 Heparin-Induced Thrombocytopenia

Another condition that must be considered in the differential diagnosis of APS is heparin-induced thrombocytopenia (HIT), clinically characterized by thrombocytopenia and thrombotic events and histologically by multiple thrombotic occlusions of small vessels [21]. This entity should be suspected early during heparin treatment and always considered as potentially fatal. Two forms of HIT have been described: type I HIT, not immune-mediated, has a favorable prognosis since it is not associated with thrombotic events; type II HIT, with an underlying immunological mechanism, is associated with microthrombosis involving multiple anatomical sites. Type I HIT occurs in approximately 10 % of patients undergoing both unfractionated heparin (UH) or low molecular weight heparin (LMWH) treatment and is thought to be caused by direct platelet activation from heparin. It occurs very early usually within the first 4/5 days of therapy and resolves without treatment and without any complication. Type II HIT is conversely a dreaded complication, potentially involving 1–5 % of patients undergoing heparin therapy. Approximately 50 % of patients with type II HIT may experience thrombotic events affecting both the arterial and the venous vascular district. The risk of mortality in such cases is estimated to be about 20–30 %. The likelihood of developing type II HIT is considered to be between 10 and 40 times higher when unfractionated heparin is used compared to LMWH. It should be suspected when the platelet count falls by about 50 % compared to baseline after 5–15 days from the beginning of heparin therapy. Type II HIT can present in three ways: (a) production of specific antiplatelet antibodies without thrombocytopenia; (b) antibodies associated with thrombocytopenia but not with thrombotic complications; and (c) antibodies, thrombocytopenia, and thrombosis. The pathogenesis of HIT has been recently better defined and the complex heparin-platelet factor 4 (PF4) identified as the major immunological target of antibody response. During the early phase heparin binds to PF4, generating the heparin-PF4 complex toward which IgG antibodies are produced. In HIT the heparin-PF4-IgG complex is also able to activate platelets via FcγRIIa receptor, causing microthrombosis and thrombocytopenia. The resulting platelet activation is also associated with serotonin release and thrombin generation. HIT laboratory diagnosis, based on detection of antibodies to heparin-PF4 complex, can be made mainly using the following two methods: a serotonin release assay (SRA), characterized by low sensitivity but very specific for HIT, or alternatively an ELISA test, more sensitive than the previous one, but less specific for HIT; neither of the above cited tests anyways represents the gold standard and the diagnosis is currently based on probability according to a compatible clinical scenario [22].

Finally HIT management is very problematic and consists of both the immediate discontinuation of heparin and the beginning of an alternative anticoagulation strategy with (a) direct thrombin inhibitors, (b) heparinoids, and (c) pentasaccharides. The differential diagnosis with APS can be difficult because both can be associated with low platelet count and thrombosis, even if thrombocytopenia is generally more severe in HIT than in APS. Obviously previous heparin exposure, the precise timing of thrombocytopenia insorgence, and the absence of circulating aPL are all points to make a correct diagnosis.

14.2.6 Disseminated Intravascular Coagulation

Disseminated intravascular coagulation (DIC) is a serious disorder, secondary to infections, surgery, chronic inflammatory diseases, different obstetrical diseases, and solid and hematological malignancies. It is characterized by disseminated microvascular thrombosis, consumptive coagulopathy, and hemorrhagic diathesis, which can eventually lead to multiple organ failure. Laboratory features of DIC are thrombocytopenia, prolonged clotting times, reduced plasma fibrinogen, and increased levels of fibrin degradation products. Interestingly, DIC could both mimic and complicate APS, especially in its catastrophic form; indeed, CAPS is a condition with widespread intravascular thrombosis resulting in multiorgan failure. More frequently DIC presents thrombotic and hemorrhagic complications at the same time [23]

For differential diagnosis between microangiopathies, HIT, and DIC, see Fig. 14.3.


Fig. 14.3

Main causes of recurrent miscarriage

14.2.7 Hyperviscosity Syndromes

Patients with hyperviscosity syndrome (e.g., in multiple myeloma or Waldenstrom’s macroglobulinemia) may present cerebral ischemia and transitory ocular problems, such as amaurosis fugax, and sometimes a differential diagnosis with APS may be needed.

14.2.8 Other Clinical Clues

The malignant atrophic papulosis (MAP), also known as Köhlmeier-Degos disease, needs to be differentiated from APS. It exists in two variants: the “benign” type with only cutaneous involvement and the “malignant” type with internal organ involvement in addition to the typical cutaneous lesions. These latter systemic type can indeed involve not only the skin but also the gastrointestinal tract or other critical anatomical districts such as eye, heart, liver, kidneys, and CNS. The differential diagnosis is especially with neuro-APS or CAPS. Typical skin lesions are erythematous papules that evolve into atrophic scars with a porcelain white center, histopathologically indistinguishable from certain cutaneous lesions of SLE. Gastrointestinal involvement is present in approximately 60 % of patients and is the most common cause of death, while the CNS involvement is characterized by single or multiple infarcts in the brain and spinal cord. The differential diagnosis is based on (a) the presence of typical skin lesions, (b) gastrointestinal symptoms, and (c) the absence of aPL [24].

Susac’s syndrome (SS) is a noteworthy autoimmune disease caused by microangiopathy damage affecting the precapillary arterioles of the brain, retina, and inner ear. It is clinically characterized by the following triad: encephalopathy with typical radiological features on MR, branch retinal artery occlusions on fluorescein angiography, and neurosensorial hearing loss. Even if brain MR showing corpus callosum is very suggestive of SS, symptoms and clinical signs can also mimic vascular neurological presentations of APS. However, in this case the research of aPL is usually negative; moreover, SS requires treatment with immunosuppressive drugs [25].

Sneddon’s syndrome, a disorder characterized by the occurrence of cerebrovascular disease associated with livedo reticularis, is another condition that sometimes can give some problems of differential diagnosis with APS. For more detail about this entity, see the paragraph “non-criteria clinical clues.”

14.3 Definite APS with Unusual Clinical Manifestations

As mentioned above, APS must be also taken into consideration when arterial or venous thrombosis is present in atypical sites or recurs during appropriate anticoagulant treatment.

14.3.1 Kidney Manifestations

Kidney manifestations – renal involvement is definitely less frequent and less recognized in APS than in SLE. From a pathological point of view, it differs mainly for its primary vascular involvement with only secondary glomerular damage [2627]. The most well-known renal complications are renal vein thrombosis, clinically characterized by nephrotic syndrome (nephrotic syndrome, however, can in turn be complicated by renal vein thrombosis), renal infarction, and kidney microangiopathy. The latter mainly involve the afferent arterioles and it is histologically characterized by thrombotic microangiopathy with fibrin deposition and microthrombi causing secondary glomerular dysfunction, interstitial fibrosis, and tubular atrophy; it clinically manifests itself with hypertension and laboratory signs of renal failure. The criteria for the diagnosis of APS-associated nephropathy include the presence of aPL and typical histopathologic finding of thrombotic microangiopathy, involving both arterioles and glomerular capillaries [28]. In patients with SLE and aPL, a biopsy procedure is strongly recommended to differentiate inflammatory from thrombotic lesions, since the two conditions require different therapeutic approaches. Noteworthy, the presence of damage secondary to APS on kidney histology severely affects the prognosis of patients with lupus nephritis. Long-term warfarin therapy has been recommended for such patients [29].

14.3.2 Gastrointestinal Manifestations

Gastrointestinal manifestations – these manifestations are mainly represented by arterial thrombosis or alternatively to venous involvement in different anatomical sites such as sovraepatic (Budd-Chiari syndrome), portal, mesenteric (with risk of intestinal ischemia), and more rarely of the splenic veins [30] (see also Fig. 14.4). Vasculitis with prevalent involvement of gastrointestinal tract, in particular Schonlein-Henoch and polyarteritis nodosa, should be differentiated from APS. However, differently from vasculitides, APS is not usually associated with increased inflammatory markers. The involvement of the intra-abdominal district is even more frequent during CAPS course and this entity should be always suspected in patients who present with severe and multiorgan ischemic dysfunction rapidly developing, often in less than 1 week [31].


Fig. 14.4

Different causes of Budd-Chiari syndrome

14.3.3 Neurological Manifestations

Neurological manifestations – cerebral venous thrombosis, as opposed to cerebral ischemic events, are rare manifestations of APS, but must always be considered [32].

14.3.4 Endocrinological Manifestations

Endocrinological manifestations – adrenal insufficiency secondary to acute vascular infarction is a rare but well-known manifestation of APS [33].

14.4 Non-criteria Clinical Clues

The differential diagnosis becomes rather complex for the so called “non-criteria,” the clinical clues that do not allow a diagnosis of definite APS according to Myakis criteria; however, these clinical signs strongly suggest the suspicion of underlying APS or the possibility of evolution over time toward it. These patients represent a significant proportion of subjects to be evaluated prospectively in order to detect early symptoms of definite disease.

14.4.1 Nonthrombotic Cardiac and Pulmonary Manifestations

Nonthrombotic cardiac and pulmonary manifestations – echocardiographic studies demonstrated a spectrum of heart valves abnormalities, especially of the mitral valve, ranging from mild valve thickening to the typical nonbacterial thrombotic lesions (Libman-Sacks endocarditis) [34]. Isolated case reports of cardiomyopathy in APS patients have also been published; however, a convincing pathogenetic relationship with circulating aPL has not been clearly demonstrated [35]. Pulmonary nonthrombotic manifestations are quite rare in APS patients and are mainly represented by intra-alveolar hemorrhage, acute respiratory distress syndrome (ARDS), and fibrosing alveolitis [3637].

14.4.2 Cutaneous Manifestations

Cutaneous manifestations – these are mainly represented by livedo, acrocyanosis, and peripheral ulcers [3839]. Livedo in particular represents one of the most commonly reported cutaneous manifestation in patients with APS. Histologically livedo is characterized by partial or complete lumen occlusion of small or medium caliber arteries located in the dermo-hypodermis level, with no evidence of perivascular inflammatory infiltrates. The skin inspection reveals reticulated, purple, red, or bluish lesions which are persistent and more evident with cold exposure but usually not reversible by heating. Lower limbs are more frequently involved than upper limbs and trunk. The lesion is defined as livedo reticularis when its borders are circular and continuous, while on the other hand, livedo racemosa is characterized by irregular and interrupted borders. Interestingly only livedo racemosa is associated with pathological conditions and in particular with APS, while livedo reticularis is considered a benign condition and is more commonly encountered during clinical practice. For this reason the term livedo reticularis, currently included also into the APS non-criteria features, could be indeed considered a misnomer and should be ideally changed with the more accurate dermatologic definition of livedo racemosa [40]. Some diagnostic difficulties arise in the differential diagnosis between APS and Sneddon’s syndrome, since both can be marked by the presence of livedo and cerebrovascular accidents. Sneddon’s syndrome patients usually present also with high blood pressure; moreover, circulating aPL are rarely detected in such condition. The extent of livedo, usually very pronounced, and the absence of circulating aPL represent important clues for diagnosing Sneddon’s syndrome. In selected circumstances a skin biopsy can show the typical histological findings of endothelial cells proliferation and occlusion of the small cutaneous vessels [41]. For the main cutaneous manifestation, see Table 14.2.

Table 14.2

Main cutaneous manifestations in APS patients

Livedo racemosa

Digital necrosis

Splinter hemorrhages

Postphlebitic ulcers

Pseudo-vasculitic lesions

Primary anetoderma

14.4.3 Ocular Manifestations

Ocular manifestations – Amaurosis fugax is certainly the most frequent ophthalmologic sign, usually not associated with any pathological fundoscopic findings, and it may represent a manifestation of cerebrovascular disease (in particular transient ischemic attack). On the other hand, APS may be responsible for severe ocular events, such as artery or vein thrombosis, retinal vascular occlusive retinopathy, and ischemic optic neuropathy, the latter also occurring in other autoimmune diseases such as giant cell arteritis (GCA). However, unlike other inflammatory or immune-rheumatological condition, APS is not usually associated with an elevation of inflammatory markers and this is particularly important in differentiating the diseases from GCA in patients with rapidly progressive and severe visual impairment. Moreover, consider APS in the differential diagnosis workup is critical, for example, in the correct diagnosis of young patients presenting with ocular vaso-occlusive disease without any traditional thromboembolic risk factors or obvious causes [4243].

14.4.4 Hematological Manifestations

Hematological manifestations – these may be present in APS patients with thrombocytopenia, autoimmune hemolytic anemia, and Evans syndrome. It is noteworthy that thrombocytopenia was previously included into the APS classification criteria, while currently is considered a non-criterial APS complication. When SLE and APS coexist in the same patient, it is challenging to distinguish which one of the two conditions determines low circulating platelets. However, APS-associated thrombocytopenia is generally considered less severe and rarely requires aggressive treatment, and it is not usually associated with the developing of hemorrhagic complications. The current criteria of APS-associated thrombocytopenia consist of coexistence of aPL positivity with thrombocytopenia <100,000/mm3 confirmed in two different samples. Mild thrombocytopenia is indeed found in 30–40 % of patients and this close relation justifies why aPL screening is strongly recommended in every patients with idiopathic thrombocytopenia [44]. Clinical conditions to be excluded in the differential diagnosis are in particular pseudo-thrombocytopenia, TTP, DIC, and HIT. Finally, Evans syndrome, a hematological condition characterized by the association of thrombocytopenia and hemolytic anemia, was also reported to be associated with APS [45].

14.4.5 Musculoskeletal Manifestations

Musculoskeletal manifestations – APS patients may rarely suffer from arthralgia and arthritis, which, if present, could be the first symptoms of an associated connective tissue disease. Aseptic bone necrosis, especially of the femoral head, is rare but it has been reported in patients with APS in both its classical and catastrophic variant [46]. If a patient with APS at any time reports pain of the lower limbs worsened under load and improved at rest, it is mandatory to perform an MR scan in order to rule out this complication. The pathogenesis of osteonecrosis is not yet completely understood; however, it is believed that microthrombosis or vasculopathy is involved more than classical ischemia from medium arterial vessel occlusion [47].



Miyakis S, Lockshin MD, Atsumi T et al (2006) International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 4(2):295–306PubMedCrossRef


Petri M (2011) Use of hydroxychloroquine to prevent thrombosis in systemic lupus erythematosus and in antiphospholipid antibody-positive patients. Curr Rheumatol Rep 13(1):77–80PubMedCrossRef


Sanna G, D’Cruz D, Cuadrado MJ (2006) Cerebral manifestations in the antiphospholipid (Hughes) syndrome. Rheum Dis Clin North Am 32(3):465–490PubMedCrossRef


Fanouriakis A, Boumpas DT, Bertsias GK (2013) Pathogenesis and treatment of CNS lupus. Curr Opin Rheumatol 25(5):577–583PubMedCrossRef


Stam J (2005) Thrombosis of the cerebral veins and sinuses. N Engl J Med 352(17):1791–1798PubMedCrossRef


Al-Araji A, Kidd DP (2009) Neuro-Behçet’s disease: epidemiology, clinical characteristics, and management. Lancet Neurol 8(2):192–204PubMedCrossRef


Silvestri E, Emmi G, Prisco D (2014) Anti-TNF-α agents in vascular Behçet’s disease. Expert Rev Cardiovasc Ther 12(4):415–416PubMedCrossRef


Hatemi G, Silman A, Bang D, EULAR Expert Committee (2008) EULAR recommendations for the management of Behçet disease. Ann Rheum Dis 67(12):1656–1662PubMedCrossRef


Yazici H, Yazici Y (2014) Criteria for Behçet’s disease with reflections on all disease criteria. J Autoimmun 48–49:104–107PubMedCrossRef


Cuadrado MJ, Khamashta MA, Ballesteros A et al (2000) Can neurologic manifestations of Hughes (antiphospholipid) syndrome be distinguished from multiple sclerosis? Analysis of 27 patients and review of the literature. Medicine (Baltimore) 79(1):57–68CrossRef


Link H, Huang YM (2006) Oligoclonal bands in multiple sclerosis cerebrospinal fluid: an update on methodology and clinical usefulness. J Neuroimmunol 180(1–2):17–28PubMedCrossRef


Papadopoulos MC, Verkman AS (2012) Aquaporin 4 and neuromyelitis optica. Lancet Neurol 11(6):535–544PubMedCentralPubMedCrossRef


Squatrito D, Colagrande S, Emmi L (2010) Devic’s syndrome and primary APS: a new immunological overlap. Lupus 19(11):1337–1339PubMedCrossRef


Asherson RA, Cervera R (2008) Microvascular and microangiopathic antiphospholipid-associated syndromes (“MAPS”): semantic or antisemantic? Autoimmun Rev 7(3):164–167PubMedCrossRef


Merrill JT, Asherson RA (2006) Catastrophic antiphospholipid syndrome. Nat Clin Pract Rheumatol 2(2):81–89PubMedCrossRef


Shenkman B, Einav Y (2014) Thrombotic thrombocytopenic purpura and other thrombotic microangiopathic hemolytic anemias: diagnosis and classification. Autoimmun Rev 13(4–5):584–586PubMedCrossRef


Mele C, Remuzzi G, Noris M (2014) Hemolytic uremic syndrome. Semin Immunopathol. doi:10.​1007/​s00281-014-0416-xPubMed


Noris M, Mescia F, Remuzzi G (2012) STEC-HUS, atypical HUS and TTP are all diseases of complement activation. Nat Rev Nephrol 8(11):622–633PubMedCrossRef


Abildgaard U, Heimdal K (2013) Pathogenesis of the syndrome of hemolysis, elevated liver enzymes, and low platelet count (HELLP): a review. Eur J Obstet Gynecol Reprod Biol 166(2):117–123PubMedCrossRef


Appenzeller S, Souza FH, Wagner Silva de Souza A et al (2011) HELLP syndrome and its relationship with antiphospholipid syndrome and antiphospholipid antibodies. Semin Arthritis Rheum 41(3):517–523PubMedCrossRef


Chong BH, Isaacs A (2009) Heparin-induced thrombocytopenia: what clinicians need to know. Thromb Haemost 101(2):279–283PubMed


Prechel M, Walenga JM (2008) The laboratory diagnosis and clinical management of patients with heparin-induced thrombocytopenia: an update. Semin Thromb Hemost 34(1):86–96PubMedCrossRef


Taylor FB Jr, Toh CH et al (2001) Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost 86(5):1327–1330PubMed


Theodoridis A, Makrantonaki E, Zouboulis CC (2013) Malignant atrophic papulosis (Köhlmeier-Degos disease) – a review. Orphanet J Rare Dis 8:10PubMedCentralPubMedCrossRef


García-Carrasco M, Mendoza-Pinto C, Cervera R (2014) Diagnosis and classification of Susac syndrome. Autoimmun Rev 13(4–5):347–350PubMedCrossRef


Pons-Estel GJ, Cervera R (2014) Renal involvement in antiphospholipid syndrome. Curr Rheumatol Rep 16(2):397PubMedCrossRef


Sciascia S, Cuadrado MJ, Khamashta M et al (2014) Renal involvement in antiphospholipid syndrome. Nat Rev Nephrol 10(5):279–289PubMedCrossRef


Tektonidou MG (2009) Renal involvement in the antiphospholipid syndrome (APS)-APS nephropathy. Clin Rev Allergy Immunol 36(2–3):131–140PubMedCrossRef


Tektonidou MG, Sotsiou F, Nakopoulou L et al (2004) Antiphospholipid syndrome nephropathy in patients with systemic lupus erythematosus and antiphospholipid antibodies: prevalence, clinical associations, and long-term outcome. Arthritis Rheum 50(8):2569–2579PubMedCrossRef


Uthman I, Khamashta M (2007) The abdominal manifestations of the antiphospholipid syndrome. Rheumatology (Oxford) 46(11):1641–1647CrossRef


Cervera R, Bucciarelli S, Plasín MA et al (2009) Catastrophic antiphospholipid syndrome (CAPS): descriptive analysis of a series of 280 patients from the “CAPS Registry”. J Autoimmun 32(3–4):240PubMedCrossRef


Gillis D, Wong RC (2012) Rarer clinical associations of antiphospholipid antibodies. Semin Thromb Hemost 38(4):328–332PubMedCrossRef


Mehdi AA, Salti I, Uthman I (2011) Antiphospholipid syndrome: endocrinologic manifestations and organ involvement. Semin Thromb Hemost 37(1):49–57PubMedCrossRef


Tenedios F, Erkan D, Lockshin MD (2005) Cardiac involvement in the antiphospholipid syndrome. Lupus 14(9):691–696PubMedCrossRef


Vaccaro F, Caccavo D, Roumpedaki E et al (2008) Dilated cardiomyopathy due to thrombotic microangiopathy as the only manifestation of antiphospholipid syndrome: a case report. Int J Immunopathol Pharmacol 21(1):237–241PubMed


Kanakis MA, Kapsimali V, Vaiopoulos AG et al (2013) The lung in the spectrum of antiphospholipid syndrome. Clin Exp Rheumatol 31(3):452–457PubMed


Barnini T, Silvestri E, Emmi G et al (2012) Pulmonary fibrosis and lymphocytic alveolitis associated with triple antiphospholipid antibody positivity: a diagnostic puzzle. Clin Exp Rheumatol 30(5):806PubMed


Frances C (2010) Dermatological manifestations of Hughes’ antiphospholipid antibody syndrome. Lupus 19(9):1071–1077PubMedCrossRef


Asherson RA, Francès C, Iaccarino L et al (2006) The antiphospholipid antibody syndrome: diagnosis, skin manifestations and current therapy. Clin Exp Rheumatol 24(1 Suppl 40):S46–S51PubMed


Dean SM (2011) Livedo reticularis and related disorders. Curr Treat Options Cardiovasc Med 13(2):179–191PubMedCrossRef


El Benaye J, Hsaini Y, Zoobo T et al (2013) Sneddon’s syndrome. Presse Med 42(2):138–144PubMedCrossRef


Suvajac G, Stojanovich L, Milenkovich S (2007) Ocular manifestations in antiphospholipid syndrome. Autoimmun Rev 6(6):409–414


Utz VM, Tang J (2011) Ocular manifestations of the antiphospholipid syndrome. Br J Ophthalmol 95(4):454–459PubMedCrossRef


Provan D, Stasi R, Newland AC et al (2010) International consensus report on the investigation and management of primary immune thrombocytopenia. Blood 115(2):168–186PubMedCrossRef


Rückert A, Glimm H, Lübbert M et al (2008) Successful treatment of life-threatening Evans syndrome due to antiphospholipid antibody syndrome by rituximab-based regimen: a case with long-term follow-up. Lupus 17(8):757–760PubMedCrossRef


Rueda JC, Duque MA, Mantilla RD et al (2009) Osteonecrosis and antiphospholipid syndrome. J Clin Rheumatol 15(3):130–132PubMedCrossRef


Asherson RA, Cervera R, Shepshelovich D et al (2006) Nonthrombotic manifestations of the antiphospholipid syndrome: away from thrombosis? J Rheumatol 33(6):1038–1044PubMed