Antiphospholipid Syndrome

Doruk Erkan

Lisa R. Sammaritano

KEY POINTS

The origin of antiphospholipid (aPL) antibodies is unknown but is hypothesized to be an incidental exposure to environmental agents inducing aPL in susceptible individuals.
Concomitant prothrombotic risk factors may promote clotting in an additive manner in aPL-positive patients.
The clinical manifestations of aPL represent a spectrum [from asymptomatic to catastrophic antiphospholipid syndrome (APS)]; therefore, patients should not be evaluated and managed as having a single disease manifestation.
Stroke and transient ischemic attack are the most common presentation of arterial thrombosis; deep vein thrombosis (DVT), often accompanied by pulmonary embolism (PE), is the most common venous manifestation of APS.
The effectiveness of high-intensity anticoagulation in patients with APS and with vascular events is not supported by prospective controlled studies.
Some patients are surviving on a very tenuous balance between a nonclotting and a clotting state. These have to be watched carefully in the setting of surgery.

The antiphospholipid syndrome (APS) is defined as vascular thromboses and/or pregnancy morbidity occurring in persons with antiphospholipid antibodies (aPL) [most commonly anticardiolipin antibodies (aCL), positive results for lupus anticoagulant (LA) test, and anti-β₂glycoprotein-I (βGPI) antibodies].

The clinical manifestations of aPL represent a spectrum (Tables 31-1 and 31-2); therefore, patients should not be evaluated and managed as having a single disease manifestation.
- The presence of aPL in the absence of typical clinical complications does not indicate a diagnosis of APS, and aPL-positive patients may remain asymptomatic for a long period.
- aPL-related vascular events range from a superficial thrombosis to life-threatening multiple-organ system thromboses developing over a short period (i.e., catastrophic APS).

APS may be seen in patients with autoimmune diseases such as systemic lupus erythematosus (SLE) or in otherwise healthy persons (i.e., primary APS).

Table 31-1 Clinical Manifestations of the Antiphospholipid Syndrome

Arterial thrombosis: Extremity gangrene, stroke, myocardial infarction, aortic occlusion, and other visceral infarctions
Venous thrombosis: Peripheral venous thrombosis, pulmonary emboli, and visceral venous occlusion (e.g., Budd-Chiari syndrome, portal vein)
Renal: Arterial or venous occlusion and thrombotic microangiopathic glomerular disease
Cardiac: Valvular disorders, early myocardial infarction, and intracardiac thrombus
Cutaneous: Livedo reticularis^a, pyodermalike leg ulcerations, distal digital cyanosis, and distal gangrene
Hematologic abnormalities^a: Thrombocytopenia, Coombs’-positive hemolytic anemia, and thrombotic microangiopathic hemolytic anemia
Nonthrombotic neurologic^a: Transverse myelitis, migraine, chorea, multiple sclerosislike syndrome, and seizure
Obstetric: Fetal loss, recurrent (pre)embryonic losses, intrauterine growth retardation, and (pre)eclampsia
Catastrophic antiphospholipid syndrome: Sudden multisystem thromboses

^a Not included in the Sapporo criteria.

ETIOPATHOGENESIS

The aPL are a family of autoantibodies directed at phospholipid-binding plasma proteins, most commonly the natural anticoagulant βGPI.

Physiologic phospholipids include cardiolipin, phosphatidylserine, phosphatidylinositol, and phosphatidylethanolamine.

Phospholipid-binding plasma proteins are not limited to βGPI and include prothrombin, thrombomodulin, high- and low-molecular-weight kininogen, antithrombin III, protein C and S, and annexins I and V.

Table 31-2 Sapporo Classification Criteria for Antiphospholipid Syndrome

Clinical criteria
1. Vascular thrombosis:
  - Arterial, venous, or small vessel thrombosis, in any organ or tissue
2. Pregnancy morbidity:
  - One or more unexplained deaths of morphologically normal fetus at or beyond the tenth week of gestation or
  - One or more premature births of a morphologically normal neonate at or before the thirty-fourth week of gestation because of severe pre-eclampsia or eclampsia, or severe placental insufficiency or
  - Three or more unexplained consecutive spontaneous abortions before the tenth week of gestation
Laboratory criteria
1. Anticardiolipin antibody of IgG and/or IgM isotype in blood, present in medium or high titer, on two or more occasions, at least 6 weeks apart and/or
2. Positive lupus anticoagulant test on two or more occasions at least 6 weeks apart

Definite APS: one clinical and one laboratory criteria.

Ig, immunoglobulin.

The origin of aPL is unknown but it is hypothesized that an incidental exposure to environmental (primarily infectious) agents induces aPL in susceptible individuals (i.e., a molecular mimicry mechanism).
- Most infection-induced aPL are not truly pathogenic (βGPI-independent). Furthermore, infection-induced aPL that can occur during infections, such as syphilis, Lyme disease, and viral infections, especially HIV and hepatitis C, are usually transient and in low titers.
- The aPL can also be induced by certain drugs (such as chlorpromazine, procainamide, quinidine, and phenytoin) and malignancies (such as lymphoproliferative disorders). In these cases, aPL are usually in low titer, of the IgM isotype, and are reversible once the inducing drug is discontinued. They are rarely associated with thrombosis.
The pathogenesis of aPL-related thrombosis is unknown; any or all of the major components of the clotting system may be involved, and laboratory and clinical research suggest that more than one mechanism may be at work.
- Possible aPL mechanisms of pathogenic actions include inhibition of coagulation cascade reactions catalyzed by phospholipids (such as inhibition of activation of the protein C and S); activation of the endothelial cells or platelets; aPL-induced increase of tissue factor (a physiologic initiator of coagulation) expression on monocytes; and interaction between aPL and an annexin V anticoagulant shield in the placenta.
- Complement activation is necessary for the induction of fetal loss by aPL; in animal models, blocking certain complement components prevents fetal loss.
The strength of association between aPL and thrombosis varies considerably among studies (from none to strong), depending largely on the aPL and the clinical populations studied. There is substantial support that the presence of other thrombotic risk factors in aPL-positive individuals influences the risk of thrombosis.

In the currently accepted “second-hit hypothesis”, a second trigger event (such as cigarette smoking, oral contraceptive usage, surgical procedures, prolonged immobilization such as a long duration plane travel, or a genetic prothrombotic state), which by itself may not be sufficient to initiate thrombosis, may be necessary for an aPL-positive patient to develop a vascular event.
Familial occurrence of aPL has been reported. Suggested associations include HLA-DR4, DR7, DRw53, and C4 null allele; however, none of these data are as yet compelling for a strong genetic predisposition and these tests need not be performed routinely.

PREVALENCE

The prevalence of aPL among the general population is 2% to 5%, and its incidence increases with age (generally low-titer aCL). aPL are present in 12% to 34% of patients with SLE.

Although it is difficult to accurately estimate the risk of thrombosis annually, on the basis of the limited number of uncontrolled studies available, asymptomatic aPL-positive patients have a 0% to 3.8% risk.
Approximately 50% of patients who are younger than 50 years and affected with stroke and up to 20% of patients with idiopathic deep vein thrombosis (DVT) possess aPL. However, the true significance of the association is unknown.

CLINICAL MANIFESTATIONS