Determination of ADAMTS13 and Its Clinical Significance for ADAMTS13 Supplementation Therapy to Improve the Survival of Patients with Decompensated Liver Cirrhosis

Abstract

<jats:p>The liver plays a central role in hemostasis by synthesizing clotting factors, coagulation inhibitors, and fibrinolytic proteins. Liver cirrhosis (LC), therefore, impacts on both primary and secondary hemostatic mechanisms. ADAMTS13 is a metalloproteinase, produced exclusively in hepatic stellate cells, and specifically cleaves unusually large von Willebrand factor multimers (UL-VWFM). Deficiency of ADAMTS13 results in accumulation of UL-VWFM, which induces platelet clumping or thrombi under high shear stress, followed by sinusoidal microcirculatory disturbances and subsequent progression of liver injuries, eventually leading to multiorgan failure. The marked imbalance between decreased ADAMTS13 activity (ADAMTS13 : AC) and increased production of UL-VWFM indicating a high-risk state of platelet microthrombi formation was closely related to functional liver capacity, hepatic encephalopathy, hepatorenal syndrome, and intractable ascites in advanced LC. Some end-stage LC patients with extremely low ADAMTS13 : AC and its IgG inhibitor may reflect conditions similar to thrombotic thrombocytopenic purpura (TTP) or may reflect “subclinical TTP.” Hence, cirrhotic patients with severe to moderate deficiency of ADAMTS13 : AC may be candidates for FFP infusion as a source of ADAMTS13 or for recombinant ADAMTS13 supplementation. Such treatments may improve the survival of patients with decompensated LC.</jats:p>

Adamts13

“…Their occurrence may be explained by a distorted balance of the ADAMTS13 -VWF ratio, in that ULVWF released by injured liver cells cannot be suffi ciently cleaved in patients with low ADAMTS13 levels, thereby inducing platelet thrombus formation locally [ 118 ]. It is therefore suggested that in patients with advanced liver cirrhosis with moderately to severely reduced (~25-<3 % of normal) ADAMTS13 levels, administration of FFP might be of benefi t as it allows replenishment of ADAMTS13 [ 135 ]. Although clinical data that support this proposal are not yet available, this subgroup appears potentially eligible for rhADAMTS13 replacement therapy.…”

Coagulation pattern in critical liver dysfunction

“…This is particularly true for the vitamin K-dependent procoagulant factors II, VII, IX, and X, as well as for factor V, but also for the vitamin K-dependent anticoagulant factors protein C and protein S, as well as for antithrombin [1 && ]. A marked imbalance between decreased ADAMTS13 activity and increased production of large vWF multimers has been shown to be closely related to functional liver capacity, hepatic encephalopathy, hepatorenal syndrome, and intractable ascites in advanced liver cirrhosis and may be useful to predict long-term survival of cirrhotic patients [3,4]. On the other hand, the activity of the vWF cleaving enzyme ADAMTS13, a metalloprotease exclusively produced in hepatic stellate cells, is reduced in liver cirrhotic patients.…”

“…Notable exceptions are the von Willebrand factor (vWF) and coagulation factor VIII, which are synthesized in the vascular endothelium and compensatorily elevated in patients with liver cirrhosis. Therefore, some end-stage liver cirrhotic patients reflect conditions similar to thrombotic thrombocytopenic purpura (TTP) [3]. Deficiency of ADAMTS13, particularly in the presence of elevated levels of large vWF multimers, increases platelet microthrombi formation and might result in sinusoidal microcirculatory disturbances and subsequent progression of liver injury, eventually leading to multiorgan failure [2,3].…”

Successful liver transplantation in a child with acute‐on‐chronic liver failure and acquired thrombotic thrombocytopenic purpura

“…In acquired TTP (aTTP), severe ADAMTS13 deficiency is due to circulating anti-ADAMTS13 autoantibodies, which act as functional inhibitors in most patients. 1-3 TTP has been described after liver transplantation (LT), [4][5][6][7][8][9] but this is, to the best of our knowledge, the first report in which aTTP is associated with pretransplant acute-on-chronic liver failure (ACLF) and no preoperative or perioperative thrombotic complications.…”

“…In the other cases reported to date, low ADAMTS13 activities were observed both before and after LT without any measurable inhibitors. [4][5][6][7][8][9] Cirrhosis is associated with impaired innate and acquired immune responses. 13,14 Although the mechanism is unclear, we hypothesize that dysimmunity due to cirrhosis, possibly exacerbated by Fusobacterium infection, might have triggered a misrouted immune response leading to the production of inhibitory anti-ADAMTS13 autoantibodies.…”