22 Antiphospholipid Syndrome: Differential Diagnosis

Diagnosis

Beverley J. Hunt and Paul R. J. Ames

Introduction

Reaching the correct diagnosis is the aim of every physician. This chapter is designed to ensure that the correct diagnosis is achieved in patients whose differen- tial diagnosis includes antiphospholipid syndrome (APS). In the past, APS was often not considered in the differential diagnosis of a thrombotic state, although this has occurred less frequently as the condition is becoming better known and understood. Lack of understanding of the assays can result in interpretation difficulties, particularly if investigators do not appreciate that both lupus anticoagu- lant (LA) and anticardiolipin antibodies (aCL) are different facets of the same problem, and that both must be performed to exclude the diagnosis.

If physicians read this particular book, then they will consider APS in the dif- ferential diagnosis of thrombotic disease, and should be highly skilled at inter- preting the antiphospholipid (aPL) assays. However, there is a possibility of

“overdiagnosis,” which is as important to avoid as non-recognition, for once a diagnosis of APS has been made, the management of thrombosis in APS is not without recognized morbidity and mortality due to bleeding. Thus, in patients with aPL, it is important to establish from the history, examination, and investi- gations that the associated clinical features are consistent with APS, that the aPL assays are reproducible, and that there is no other explanation for the throm- botic events.

In view of the diverse presentation of APS, we have planned this chapter taking into account the new international consensus statement on preliminary criteria for the classification of the APS [1].

Clinical Criteria

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 or Doppler studies or histopathology, with the exception of superficial venous thrombosis. For

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histopathological confirmation, thrombosis should be present without significant evidence of inflammation in the vessel wall.”

The Differential Diagnosis of Venous Thrombosis

Any part of the venous circulation may undergo occlusion in APS. Deep and superficial veins of the lower limbs are most frequently involved, followed by pul- monary embolism and arm vessels. In these instances, and in subjects who are rela- tively young (< 45 years), the differential diagnosis rests on laboratory tests aiming at the identification of congenital or other acquired thrombophilic states. The current venous thrombophilia screen (1999) is shown in Table 22.1. aPL seems to be a common etiological factor in venous thrombosis in unusual sites such as the abdominal circulation. APS has been described as the second most common cause of Budd-Chiari syndrome [2], after myeloproliferative disorders [3], and thrombo- sis in other abdominal veins are reported in APS. APS should be included in the differential diagnosis of cerebral vein thrombosis, because the presence of aPL in this population ranges from 8% to 55%, and affected patients tend to have younger age at onset and more extensive involvement than patients with conventional thrombophilic states [4, 5]. Consideration should be given to the prothrombin 20210 mutation, present in 2% of Caucasians, that also appears to predispose to thrombosis in the coronary and cerebral venous vessels. The differential effects of hypercoagulable states in different vascular beds is excellently reviewed by Rosenberg and Aird [6]. In the ophthalmology setting, aPL have been detected from 5% to 47% of subjects presenting with retinal vein occlusion, alongside other thrombophilic factors and vasculitis [7–9]. aPL should be included in the differen- tial diagnosis of thrombotic events causing endocrine abnormalities, such as Addison’s disease [10–12] and Sheehan’s syndrome (hypopituitarism) [13].

Although the differential diagnosis of venous occlusions often relies on detecting a thrombophilic state, some clinical features may point towards systemic disorders with a higher-than-average risk of venous thrombosis. For example, a history of oral and genital ulceration in a young person with venous thrombosis may suggest Behcet’s disease, and the presence of peripheral blood eosinophilia could suggest

Table 22.1. Differential diagnosis of venous thromboembolism in antiphospholipid syndrome.

Activated protein C resistance/factor V Leiden (heterozygote and homozygous) Heterozygous deficiencies of

Antithrombin Protein C Protein S

Prothrombin 20210 heterozygous or homozygous states Increased levels of factor VIII

Myeloproliferative disorders Dysfibrinogenemia Very rare

Paroxysmal nocturnal hemoglobinuria Possible risk factor

Hyperhomocysteinemia

the hypereosinophilic syndrome, a condition that, like APS, does not spare any vas- cular bed.

The Differential Diagnosis of Arterial Thrombosis

When compared to the potentially recognized risk factors for venous thrombotic disease, there are fewer factors to consider in arterial thrombotic disease. All the other known risk factors for arterial thrombotic disease tend to produce thrombosis on the background of arteriosclerosis, that is, these patients tend to have recogniz- able risk factors for atherosclerosis. Evidence is slowly accumulating to support accelerated atherosclerosis in APS, suggesting that management should include treatment of conventional risk factors as well as anticoagulation. The risk factors for arterial thrombosis are summarized in Table 22.2.

Special Arterial Situations

Special consideration should be given to stroke, where up to 18% of young strokes may have aPL [15]. The neurological manifestations of APS are protean (see Chapter 7). Some patients present with multiple cerebral lesions on magnetic resonance imaging, consistent with multiple cerebral infarcts. These types of lesions are also seen in multiple sclerosis and a cerebral autosomal dominant arteriopathy with sub- cortical infarcts and leucoencephalopathy (CADASIL) [16, 17]. CADASIL is a heredi- tary cause of stroke, migraine with aura, mood disturbances, and dementia. Thus, if a patient does present with multiple cerebral lesions, a family history of stroke and dementia should be sought. Post-mortem studies of affected patients show multiple small deep infarcts in the brain and a diffuse leukoencephalopathy. The vasculopa- thy leads to median thickening by an eosinophilic, granular, and electron-dense material of unknown origin. The genetic defect has been mapped to chromosome 19 and can now be detected in the majority of major neuroscience centers.

It may be very difficult to differentiate APS from multiple sclerosis. Clues include a past history of venous thrombosis and pregnancy loss, suggesting APS, while the presence of cerebellar lesions on MRI are more suggestive of multiple sclerosis [18].

Both states can produce oligoclonal bands in the cerebrospinal fluid (CSF). Another differential diagnosis of multiple cerebral lesions can be cerebral vasculitis, and in such cases the diagnosis may only become apparent on cerebral biopsy.

Catastrophic APS

This syndrome has a number of clinical similarities to heparin-induced thrombocy- topenia. In heparin-induced thrombocytopenia patients develop thrombosis at any

Table 22.2. Risk factors for arterial thrombosis.

Hypertension

Smoking

Fibrinogen levels

Hyperhomocysteinemia

Hyperlipidemia

Diabetes mellitus

Lipoprotein (a)

site, both arterial, venous, and microvascular (especially the skin). This is due to the presence of an antibody that binds to the complex of platelet factor 4/heparin [19].

It usually develops within 10–14 days after starting heparin and the first sign is a falling platelet count. It should be differentiated from a transient thrombocytopae- nia that occurs in the first few days of heparin therapy, which is probably due to heparin causing platelet activation and is not associated with any clinically harmful effects.

The differentiation of aPL related thrombocytopenia from heparin induced thrombocytopenia would appear almost straightforward, especially from the history, although the differential diagnosis could be tricky on the laboratory side when both conditions coexist [20, 21].

Pregnancy Morbidity

(A) One or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation, with normal fetal morphology documented by ultrasound or by direct examination of the fetus, or

(B) One or more premature births of a morphologically normal neonate at or before the 34th week of gestation because of severe pre-eclampsia or eclampsia or severe placental insufficiency, or

(C) Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation, with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes excluded.

In studies of populations of patients who have more than 1 type of pregnancy morbidity, investigators are strongly encouraged to stratify groups of subjects according to A, B, or C above.

In the United Kingdom, pulmonary thrombo-embolism is the leading cause of maternal death. Deep vein thrombosis underlies this disorder and is frequently unrecognized. The risk factors for thrombo-embolism in pregnancy remain the same as those outside of pregnancy: congenital and acquired thrombophilias.

APS has also been identified as a cause of first, second, and third trimester losses as well as intra-uterine growth restriction and pre-eclampsia. One of the major advances in the field of thrombophilia in the last few years has been the recognition that other thrombophilic states also predispose to second and third trimester losses, as well as intra-uterine growth restriction and pre-eclampsia. A case-control study revealed that factor V Leiden, the prothrombin 20210 mutation, and homozygous state for the homocysteine MTHFR mutation C677T were strongly associated with late pregnancy complications of placental abruption, pre-eclampsia and eclampsia, and intra-uterine growth restriction in women [22]. Moreover, a recent study has shown that if women with a previous second or third trimester loss and an inherited thrombophilia show a marked improvement in fetal outcome in the next pregnancy if they receive low-molecular-weight heparin throughout the pregnancy [23].

Interestingly, a cohort study following a group of women with factor V Leiden during pregnancy found its presence was unrelated to adverse pregnancy outcome apart from an 8-fold increased risk of venous thromboembolism [24]. It is now clear that aPL are also associated with first trimester losses. It is not clear at the time of writing whether congenital thrombophilia are associated with first trimester losses.

The answers should be available in the next few years.

It is important when considering the late pregnancy morbidity associated with aPL to check that the history concurs with that of placental insufficiency, for in the Lupus Pregnancy clinic at St Thomas’ Hospital (London) we have a number of women referred with APS on the basis of pregnancy loss and aPL is an incidental finding. These women have proved to have pregnancy loss due to other causes such as premature labor secondary to an incompetent cervix (in these cases the waters break first, labor supervenes, and the fetus may be born alive of a normal birth weight). Thus, history taking and obtaining the post-mortem findings in previous pregnancy losses are very important. In considering the etiology of first trimester losses it is also important that a gynecologist excludes other relevant causes. It thus seems imperative to run a joint clinic with an obstetrician and/or obstetric physi- cian before aPL can be attributed to be the cause of the pregnancy loss.

Hyperhomocysteinemia

This condition deserves a special mention, for it is the only other condition related to pregnancy loss, arterial thrombosis, and possibly venous thrombosis. High plasma levels of homocysteine are the result of the interplay between congenital and environmental factors. There has been a growing interest on mild or moderate hyperhomocysteinemia as a risk factor for arterial and venous thrombosis.

The most common cause of severe homocysteinemia (fasting plasma levels > 100 µmol/L) is the homozygous deficiency of cystathionine-β-synthase, which has a prevalence of 1 in 335,000. Affected individuals present with premature vascular disease and thrombo-embolism as well as ectopic lens, skeletal abnormalities, and mental retardation [25]. Mild to moderate levels (fasting levels between 15–100 µmol/L) are encountered in phenotypically normal subjects with genetic defects in metabolism, acquired conditions, or more frequently a combination of the two.

Often, acquired hyperhomocysteinemia may follow deficiencies of folate, cobal- amin, and pyridoxine [26], essential co-factors for homocysteine metabolism and may develop in chronic renal insufficiency. Drugs are another important remedial cause. Drugs such as methotrexate interfere with the metabolism of folate, and nitrous oxide interferes with the metabolism of cobalamin and theophylline and affect vitamin B

.

A common genetic defect leading to hyperhomocysteinemia is a C-to-T substitu- tion at nucleotide 677 in the gene coding for methylenetetrahydrofolate reductase (MTHFR) [27]. The prevalence of the homozygous C677T mutation is between 5%

to 20% in subjects of Caucasian origin. These individuals tend not to have elevated

plasma levels of homocysteine unless they have an accompanying low serum con-

centration of folate [28]. Case-control and cross-sectional studies indicate that

mild-to-moderate hyperhomocysteinemia is associated with an increased risk of

thrombosis [reviewed in 25]. APS patients with homozygous C667T mutation devel-

oped thrombosis at an earlier age than heterozygous or non-mutated APS patients

[29]. Mild hyperhomocysteinemia appeared also as an independent predictor of

carotid intima-media thickness in primary APS [30]. However prospective studies

do not unequivocally show that hyperhomocysteinemia is associated with an

increased risk of venous thrombosis. Further studies are also required to fully

establish the relationship between homocysteine levels, the C677T MTHFR muta-

tion, and late pregnancy complications. Most importantly however, randomized

placebo-controlled double-blind trials of the effects of homocysteine–lowering

vitamins are urgently needed. They will help define the relationship between mild- to-moderate hyperhomocysteinemia and thrombosis and potentially have an impact on the prevention of thrombosis.

Other Clinical Features of APS

Thrombocytopenia

Thrombocytopenia is a feature in some patients with APS, present in almost 20% of aPL carriers and probably of autoimmune pathogenesis. Thrombocytopenic bleed- ing is not frequent in APS, unless there is a coexistent factor deficiency, but pro- longed bleeding times do occur [31]. Screening for aPL in subjects with thrombocytopenia of uncertain cause is useful, especially in thrombocytopenia of pregnancy, where the risks of hemorrhage from thrombocytopenia and thrombosis and pregnancy morbidity from aPL could jeopardize fetal and maternal outcome.

aPL were detected in 60% of thrombocytopenic HIV subjects addicted to parenteral drugs [32], but there does not appear to be a relationship with thrombosis: in HIV aCL have no anti– β

-glycoprotein I effect.

Skin Involvement

Livedo reticularis appears in a number of rheumatic conditions and hyperviscosity states. The detection of aPL in a subject with livedo reticularis and a stroke may suggest Sneddon’s syndrome, hence the finding of aPL positively in someone with isolated livedo reticularis could warrant closer follow up. Likewise, skin necrosis, skin ulcers, chilblains, and vasculitis have been associated with aPL [33], and may identify those patients at higher risk of vascular damage. Pyoderma gangrenosum is frequently associated with systemic diseases but there are cases where aPL was the only abnormal laboratory finding [34].

The Effect of aPL on Other Thrombophilic Assays

In the presence of aPL, some of the other assays for thrombophilia may cause false positive results. It is well recognized that functional assays for protein C and activated protein C resistance may yield falsely low values in the presence of aPL [35]. Similarly, phospholipid-dependent coagulation assays such as factor XII assays may produce reduced levels. This has been studied by Jones et al [36], who found that factor XII antibodies are present in a significant proportion of LA-positive patients and may lead to an erroneous diagnosis of factor XII deficiency.

Reduced levels of free protein S are present in some patients with aPL, and thus

could lead to an erroneous diagnosis of genetic protein S deficiency [37, 38]. The

mechanism of this reduction of free protein S is obscure, although this could be

caused by antibodies to protein S itself, or autoantibodies to β

-glycoprotein I with

C4b-binding protein [39, 40].

Conclusions

APS/Hughes syndrome is an increasingly diagnosed condition. This chapter empha- sizes the need for clinicians to consider the full range of differential diagnoses for each clinical state, so that the correct diagnosis is reached in an individual patient.

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