Antiphospholipid Antibody Syndrome (APS) - Diagnosis

Robbins-based pathology exam answer

Diagnosis

1. Clinical criteria

A. Vascular thrombosis

• Must be objectively confirmed by imaging, Doppler study, or histopathology.
• Histology should show thrombosis without significant inflammatory vasculitis.

B. Pregnancy morbidity

1. One or more unexplained fetal deaths of a morphologically normal fetus at or after 10 weeks gestation.
2. One or more premature births of a morphologically normal neonate before 34 weeks, due to:
   • Eclampsia or severe pre-eclampsia, or
   • Placental insufficiency.
3. Three or more unexplained consecutive spontaneous abortions before 10 weeks gestation, after excluding:
   • Maternal anatomic abnormalities
   • Maternal hormonal abnormalities
   • Parental chromosomal abnormalities

2. Laboratory criteria

Important pathology points from Robbins

• APS is an important cause of acquired thrombophilia.
• Antibodies are called “antiphospholipid,” but their pathogenic targets are generally phospholipid-binding proteins, especially β2-glycoprotein I.
• In vivo, these antibodies promote a prothrombotic state.
• In vitro, they interfere with phospholipid-dependent clotting tests and may cause a prolonged aPTT, hence the term lupus anticoagulant.
• Paradox: despite prolonged clotting tests in vitro, the patient develops thrombosis in vivo.
• Anticardiolipin antibodies can cause a false-positive VDRL/RPR test for syphilis, because cardiolipin is used in these assays.
• Antiphospholipid antibodies alone do not establish APS, since they may occur in healthy people. Robbins notes they are found in about 5%-15% of healthy individuals. - Robbins & Kumar Basic Pathology, p. 90

Types

Primary APS

Secondary APS

One-line exam conclusion

Antiphospholipid syndrome is diagnosed by the presence of at least one thrombotic or defined obstetric clinical event together with persistent positivity for lupus anticoagulant, anticardiolipin antibody, or anti-β2-glycoprotein I antibody on two tests at least 12 weeks apart.

Antiphospholipid Antibody Syndrome (APS)

Definition

• Recurrent arterial, venous, or small-vessel thrombosis
• Pregnancy morbidity, especially recurrent fetal loss
• Persistent circulating antiphospholipid antibodies (aPL)

Etiology and types

1. Primary APS
   • Occurs without another associated autoimmune disease.
2. Secondary APS
   • Occurs with an autoimmune disease, classically systemic lupus erythematosus (SLE).

Pathogenesis

Mechanism of thrombosis

• Endothelial cell activation/injury, with increased procoagulant activity
• Platelet activation and aggregation
• Interference with natural anticoagulant mechanisms
• Activation of inflammatory and coagulation pathways

Important paradox

• In the laboratory, lupus anticoagulant interferes with phospholipid-dependent clotting assays and may cause prolonged aPTT.
• In vivo, the patient has a tendency toward thrombosis, not bleeding.

Pregnancy loss

Clinical features

1. Thrombotic manifestations

• Deep venous thrombosis
• Pulmonary embolism
• Recurrent pulmonary emboli causing pulmonary hypertension
• Arterial thrombosis, including myocardial infarction
• Cerebral ischemia, transient ischemic attacks, and stroke
• Focal cerebral or ocular ischemia
• Bowel infarction
• Renal arterial thrombosis or renal microangiopathy causing hypertension and renal failure
• Superficial thrombophlebitis

2. Obstetric manifestations

• Recurrent spontaneous abortions
• Recurrent fetal loss
• Placental insufficiency
• Pre-eclampsia/eclampsia and premature delivery may occur

3. Cardiac manifestations

• Sterile valvular vegetations, commonly affecting mitral or aortic valves
• Valve thickening or regurgitation

4. Hematologic manifestations

• Mild to moderate thrombocytopenia
• Sometimes autoimmune hemolytic anemia

5. Cutaneous manifestations

• Livedo reticularis
• Purpura
• Skin ulceration or digital ischemia due to vascular thrombosis

6. Catastrophic APS

Morphology

Vessels

• Fresh or organizing thrombi in arteries, veins, capillaries, and arterioles
• Thrombi may occur in multiple organs
• Typically, thrombotic occlusion occurs without prominent inflammatory vasculitis

Kidney

• Renal microangiopathy with thrombosis of glomerular capillaries, arterioles, and small arteries
• May lead to ischemic renal injury, hypertension, and renal failure

Placenta

• Placental vascular thrombosis and infarction may be found
• Defective placentation due to impaired trophoblast function contributes to fetal loss

Heart valves

• Small, sterile valvular vegetations with fibrosis or thickening may occur

Brain and other organs

• Thrombotic occlusion produces infarcts in the brain, bowel, kidney, lung, or other affected organs.

Diagnosis

A. Clinical criteria

Vascular thrombosis

Pregnancy morbidity

• One or more unexplained deaths of a morphologically normal fetus at or after 10 weeks gestation
• One or more premature births before 34 weeks because of severe pre-eclampsia/eclampsia or placental insufficiency
• Three or more unexplained consecutive spontaneous abortions before 10 weeks gestation

B. Laboratory criteria

1. Lupus anticoagulant
2. Anticardiolipin antibody, IgG or IgM, medium/high titre
3. Anti-β2-glycoprotein I antibody, IgG or IgM, high titre

Exam conclusion

Antiphospholipid antibody syndrome is an acquired autoimmune hypercoagulable state caused by persistent antiphospholipid antibodies. It presents with recurrent arterial or venous thrombosis, recurrent fetal loss, thrombocytopenia, and cardiac valve vegetations. Pathologically, it produces thrombotic occlusion of vessels in multiple organs, generally without vasculitis.