Differential Diagnosis

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 PE and arm vessels. In these instances and in subjects who are relatively young (<45 years), the differential diagnosis rests on laboratory tests aiming at the identification of congenital or other acquired thrombophilic states (Table 9.1).

Some clinical features may point toward 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 the hypereosinophilic syndrome; conditions like APS do not spare any vascular bed.

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, so these patients tend to have recognizable risk factors for atherosclerosis, which should be controlled.

Special consideration should be given to stroke where up to 18% of young (<50) patients may have aPL. Some patients present with multiple cerebral lesions on magnetic resonance imaging. These types of lesions are also seen in multiple

Table 9.1. Differential diagnosis of venous thromboembolism in APS.

  • Activated prot-C resistance/factor V Leiden (heterocygote and homozygous)
  • Heterozygous deficiencies of: o Antithrombin o Prot-C o Prot-S
  • Prothrombin 20210 heterozygous or homozygous states
  • Increased levels of factor VIII
  • Myeloproliferative disorders and Malignancies (Trousseau's syndrome)
  • Nephrotic syndrome
  • Peripartum state
  • Estrogen-containing oral contraceptives
  • Behcet's syndrome
  • Dysfibrinogenemia
  • Heparin-induced thrombosis
  • Hyperhomocysteinemia (possible risk factor)
  • Paroxymal nocturnal hemoglobinuria (very rare)

Table 9.2. Multiple cerebral lesion in brain MRI: differential diagnosis.

  • Multiple cerebral infarcts - microangiopathy
  • Multiple sclerosis (MS)
  • CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy)
  • Cerebral vasculitis sclerosis (MS), in cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL), and other conditions (Table 9.2).

CADASIL is a hereditary 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. The genetic defect has been mapped to chromosome 19 and can now be detected in the majority of major neuroscience centers.

On the other hand, it may be very difficult to differentiate APS from MS, since neurological manifestations and MRI can be indistinguishable. Both conditions can show oligoclonal bands in the CSF. Clues in those cases include a past history of venous thrombosis and pregnancy loss, suggesting APS, and the presence of atypical features of MS such as migraine or epilepsy, or other features such as livedo reticularis, sicca syndrome, Raynaud's, SLE features, or thrombocytopenia.

Evoked potential studies have been proposed as a useful tool to distinguish APS from MS, supported by the important differences described between both the groups. Abnormalities in these tests (especially in visual evoked potentials) are uncommon in APS patients, while they are quite common in MS patients.

Catastrophic APS has a number of clinical similarities to heparin-induced thrombocytopenia. In the latter, patients develop thrombosis at any site, both arterial, venous and microvascular (especially the skin). 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 thrombocy-topenia 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.

Hyperhomocysteinemia 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 homocystein result from the interplay between congenital and environmental factors (Table 9.3).

Table 9.3. Causes of hyperhomocysteinemia.

  • Homozygous deficiency of cystathionine-b-synthase (the most common; prevalence of 1 in 3,35,000)
  • Drugs (Methotrexate)
  • Folate deficiency
  • Homozygous state for the homocysteine MTHFR mutation C677T

aPL screen may also be indicated in other situations such as: thrombocytopenia, livedo reticularis, low levels of free prot-S (unknown mechanism), prot-C, and factor XII, and the presence of activated prot-C resistance.

Differential diagnosis of Pregnancy morbidity is discussed in another Chapter "Obstetric APS."

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