VWF, Platelets and the Antiphospholipid Syndrome

Abstract

The antiphospholipid syndrome (APS) is characterized by thrombosis and/or pregnancy morbidity with the persistent presence of antiphospholipid antibodies (aPLs). Laboratory criteria for the classification of APS include the detection of lupus anticoagulant (LAC), anti-cardiolipin (aCL) antibodies and anti-β2glycoprotein I (aβ2GPI) antibodies. Clinical criteria for the classification of thrombotic APS include venous and arterial thrombosis, along with microvascular thrombosis. Several aPLs, including LAC, aβ2GPI and anti-phosphatidylserine/prothrombin antibodies (aPS/PT) have been associated with arterial thrombosis. The Von Willebrand Factor (VWF) plays an important role in arterial thrombosis by mediating platelet adhesion and aggregation. Studies have shown that aPLs antibodies present in APS patients are able to increase the risk of arterial thrombosis by upregulating the plasma levels of active VWF and by promoting platelet activation. Inflammatory reactions induced by APS may also provide a suitable condition for arterial thrombosis, mostly ischemic stroke and myocardial infarction. The presence of other cardiovascular risk factors can enhance the effect of aPLs and increase the risk for thrombosis even more. These factors should therefore be taken into account when investigating APS-related arterial thrombosis. Nevertheless, the exact mechanism by which aPLs can cause thrombosis remains to be elucidated.

Keywords: antiphospholipid antibody; antiphospholipid syndrome; arterial thrombosis; platelet; von Willebrand factor.

Figure 1

Thrombus formation under high shear and aPL related platelet activation. (A) Platelets bind to endothelial cells and collagen via VWF under high shear force, followed by platelets rolling over collagen and thrombus formation. (B) Under normal conditions, a variety of agonists and ligands bind their corresponding receptors, inducing platelet adhesion, activation and aggregation. aβ2GPI and aCL antibodies induce platelet activation in APS patients.

Figure 2

Platelet Signaling pathways. The signaling pathways induced by receptors on the surface of platelets including GPCR, GPVI, FcγIIa, GPIbα, integrin receptors and LDL-R share MAPK pathway, which leads to TXA2 production and granule secretion. In general, PIP₂ can be hydrolyzed by PLCβ and PLCγ, leading to the generation of DAG and IP₃. Both DAG and IP₃ trigger Cal-DAG-GEFI generation and only DAG can induce numbers of isoforms of PKC activation, both of which activate the MAPK pathway. GPVI, FcγIIa, GPIbα and integrin (αIIbβ3, α2β1) can induce the activation of the PI3K/Akt pathway which triggers the MAPK pathway, Ca²⁺ mobilization upregulation and granule secretion. LDL-R, including TLR2, TLR4, TLR8 and Apo-ER2′, also activate the PI3K/Akt pathway and downstream MAPK pathway. PIP₂, phosphatidylinositol 4,5-bisphosphate; PLCβ, phospholipase Cβ; PLCγ, phospholipase Cγ; DAG, diacylglycerol; IP₃, 1,4,5-inositol trisphosphate; Cal-DAG-GEFI, diacylglycerol regulated guanine nucleotide exchange factor I; PKC, protein kinase C; LDL-R, Low-density lipoprotein receptors.