By Author
  By Title
  By Keywords

February 2012, Volume 62, Issue 2


Thrombotic Microangiopathies: Role of ADAMTS-13

Salman Naseem Adil  ( Section of Haematology, Department of Pathology, Aga Khan University, Karachi. )
Farheen Karim  ( Section of Haematology, Department of Pathology, Aga Khan University, Karachi. )

Thrombotic microangiopathy (TMA) refers to conditions that cause microvascular thrombosis and result in microangiopathic haemolytic anaemia with presence of fragmented red cells on peripheral blood, thrombocytopenia and end organ damage. Syndromes most commonly associated with thrombotic microangiopathy are thrombotic thrombocytopenic purpura (TTP) and haemolytic uraemic syndrome (HUS).1 TMA may occur in other disorders, such as malignant hypertension, scleroderma, systemic lupus erythematosus, preeclampsia, radiation nephropathy, renal allograft rejection, HIV infection, disseminated malignancies and disseminated intravascular coagulation (DIC). TTP is a fatal thrombotic microangiopathy if not treated appropriately. Using a variety of approaches and case definitions the incidence of TTP has been estimated to be 2-7 per million person-years. The pentad of signs and symptoms of TTP include thrombocytopenia, microangiopathic haemolytic anaemia, neurological abnormalities, renal failure and fever.2
TTP is caused by deficiency of a von Willebrand factor cleaving protease that was identified in 1996 and as the thirteenth member of the ADAMTS family of enzymes was named as ADAMTS-13 (A disintegrin and metalloprotease with thrombospondin type-1 motives).3
ADAMTS-13 is released from the liver and is required for cleavage of the ultra large von Willebrand factor multimers. Von Willebrand factor is released from the storage granules known as weibel-palade bodies of the endothelial cells in the form of ultra large multimers. The ultra large von Willebrand factor (ULvWF) is the hyperactive form of vWF. It is not only very large in size, but it also binds platelets with greater affinity that results in spontaneous platelets aggregation.4 After release, these ULvWF undergo rapid proteolysis by ADAMTS-13 that converts these highly thrombotic forms to smaller less adhesive forms which are haemostatically critical.5
Deficiency of ADAMTS-13 results in failure of cleavage of ULvWF multimers. These ULvWF multimers due to their thrombotic potential cause excessive platelet aggregation, resulting in widespread platelet rich thrombi which in turn results in the development of thrombotic microangiopathy.6
Acquired TTP occurs due to autoantibodies to ADAMTS-13 resulting in severe ADAMTS13 deficiency, whereas, hereditary TTP previously known as Schulman-Upshaw syndrome or chronic relapsing TTP is a result of mutations in the ADAMTS-13 gene. ADAMTS13 activity levels are <10% (or <5%, depending on the assays used) of normal control in patients with acute TTP.7 A severe deficiency of ADAMTS-13 activity is a specific finding for most patients with a diagnosis of thrombotic thrombocytopenic purpura (TTP) but is not present in those with a diagnosis of haemolytic uraemic syndrome. This finding is important because distinguishing between TTP and HUS is often not possible due to the frequently overlapping clinical and laboratory features of the two disorders.
While looking into the role of ADAMTS13 in common diseases associated with thrombotic microangiopathies, it has been found that apart from classical TTP, mild to moderate ADAMTS-13 deficiency is also present in liver cirrhosis,8 malignancies,9 sepsis,10 connective tissue diseases like systemic lupus erythematosus (SLE)11 and disseminated intravascular coagulation.12 Low ADAMTS-13 levels have been associated with poor survival rate and higher in-hospital mortality in severe sepsis and DIC.13,14
The precise analysis of ADAMTS13 antigen and activity levels in disease states offers insight into the roles of ADAMTS13 in thromboembolic diseases. Severe ADAMTS-13 deficiency with activity of <5% of the normal is a specific finding for acute classical TTP. However, it does not have a solo diagnostic value for TTP. ADAMTS-13 activity can also be used as a diagnostic and prognostic marker in patients with sepsis and DIC.


1.Zipfel PF, Heinen S, Skerka C. Thrombotic microangiopathies: new insights and new challenges. Curr Opin Nephrol Hypertens 2010; 19: 372-8.
2.Nangaku M, Nishi H, Fujita T. Pathogenesis and prognosis of thrombotic microangiopathy. Clin Exp Nephrol 2007; 11: 107-14.
3.Levy GG, Nichols WC, Lian EC, Foroud T, McClintick JN, McGee BM, et al: Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature 2001; 413: 488-94.
4.Plaimauer B, Zimmermann K, Volkel D, Antoine G, Kerschbaumer R, Jenab P, et al. Cloning, expression, and functional characterization of the von Willebrand factor-cleaving protease (ADAMTS13). Blood 2002; 100: 3626-32.
5.Dong JF, Moake JL, Nolasco L, Bernardo A, Arceneaux W, Shrimpton CN, et al. ADAMTS- 13 rapidly cleaves newly secreted ultralarge von Willebrand factor multimers on the endothelial surface under flowing conditions. Blood 2002; 100: 4033-9.
6.Kremer Hovinga JA, Studt JD, Alberio L, Lämmle B. von Willebrand factor-cleaving protease (ADAMTS-13) activity determination in the diagnosis of thrombotic microangiopathies: the Swiss experience. Semin Hematol 2004; 41: 75-82.
7.Mannucci PM, Peyvandi F. TTP and ADAMTS13: When Is Testing Appropriate? Hematology Am Soc Hematol Educ Program 2007; 2007: 121-6.
8.Loof AH, van Vliet HH, Kappers-Klunne MC: Low activity of von Willebrand factor-cleaving protease is not restricted to patients suffering from thrombotic thrombocytopenic purpura. Br J Haematol 2001; 112: 1087-8.
9.Mannucci PM, Karimi M, Mosalaei A, Canciani MT, Peyvandi F. Patients with localized and disseminated tumors have reduced but measurable levels of ADAMTS-13 (von Willebrand factor cleaving protease). Haematologica 2003; 88: 454-8.
10.Nguyen TC, Liu A, Liu L, Ball C, Choi H, May WS, et al. Acquired ADAMTS-13 deficiency in pediatric patients with severe sepsis. Haematologica 2007; 92: 121-4.
11.Mannucci PM, Vanoli M, Forza I, Canciani MT, Scorza R. Von Willebrand factor cleaving protease (ADAMTS-13) in 123 patients with connective tissue diseases (systemic lupus erythematosus and systemic sclerosis). Haematologica 2003; 88: 914-8.
12.Kim YK, Lee J, Lee KA, Kwon HU. Clinical Significance of von Willebrand Factor-Cleaving Protease (ADAMTS13) Deficiency in Patients with Sepsis-Induced Disseminated Intravascular Coagulation. Infect Chemother 2009; 41: 78-81.
13.Hyun J, Kim HK, Kim JE, Lim MG, Jung JS, Park S, et al. Correlation between plasma activity of ADAMTS-13 and coagulopathy, and prognosis in disseminated intravascular coagulation. Thromb Res 2009; 124: 75-9.
14.Martin K, Borgel D, Lerolle N, Feys HB, Trinquart T, Vanhoorelbeke K, et al. Decreased ADAMTS-13(A disintegrin and metalloprotease with thrombospondin type 1 repeats) is associated with a poor prognosis in sepsis-induced organ failure. Crit Care Med 2007; 35: 2375-82.

Journal of the Pakistan Medical Association has agreed to receive and publish manuscripts in accordance with the principles of the following committees: