The Balance between von-Willebrand Factor and its Cleaving Protease ADAMTS13: Biomarker in Systemic Inflammation and Development of Organ Failure?

Abstract

VWF is an acute phase protein and its plasma level increases in systemic inflammation. When released from endothelial cells and platelets, the native multimeric glycoprotein is mostly present in the ultralarge form (ULVWF), which may have a major clinical significance under proinflammatory conditions. ULVWF-multimers may activate endothelial cells and platelets simultaneously. The multimers undergo limited proteolysis by a specific plasma metalloprotease known as ADAMTS13 (a disintegrin and metalloprotease with thrombospondin motif), thus, in healthy individuals only marginal amounts of circulating ULVWF are detectable. Severe hereditary or acquired ADAMTS13 deficiency causes thrombotic thrombocytopenic purpura (TTP), which contributes to prothrombotic coagulation abnormalities preceding organ dysfunction systemic inflammatory response syndrome (SIRS). In proinflammatory conditions, ADAMTS13 activity decreases due to various mechanisms, (i) down regulation on a transcriptional level, (ii) proteolytic degradation, and (iii) consumption due to the high substrate level. Marked dysbalance as found in patients with severe sepsis or septic shock results in substantial amounts of plasma ULVWF. This level of dysbalance is negatively correlated with platelet count and positively correlated with the severity of inflammation and the degree of organ failure.

The ABO Histo-Blood Group and AKI in Critically Ill Patients with Trauma or Sepsis

“…Genetic polymorphisms in the ABO gene have been associated with circulating levels of glycoproteins important in endothelial function and inflammation, including soluble intercellular adhesion molecule-1 (ICAM-1), thrombomodulin, vWF, and the selectins (12,(20)(21)(22)(23). These same proteins have been implicated in the pathogenesis of AKI (24)(25)(26)(27)(28). Although non-O blood types are reported risk factors for MI, VTE, and ARDS, it is unknown if ABO blood type is associated with AKI risk (13)(14)(15)(16).…”

Preserved Expression of mRNA Coding von Willebrand Factor-Cleaving Protease ADAMTS13 by Selenite and Activated Protein C

“…This deficiency is associated with an increase in ulVWF and is postulated to cause TMA in patients (9,23,26). The impact of ADAMTS13 deficiency in thrombocytopenia and organ failure is supported by the observation that plasma exchange reversed organ dysfunction in thrombocytopenia-associated multiple organ failure in children (27) and renal deposition of thrombi enriched from activated platelets and VWF in a porcine sepsis model (28).…”

Hypochlorous Acid Generated by Neutrophils Inactivates ADAMTS13

“…Decreased ADAMTS13 activity during inflammation may be caused by inhibition of ADAMTS13 synthesis (6,38), proteolysis (9, 16), or consumption due to increased VWF secretion (39). Here, we described a new mechanism for down-regulating ADAMTS13 activity during inflammation.…”