Page 2240 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 134 Thrombotic Thrombocytopenic Purpura and the Hemolytic Uremic Syndromes 1987

Q448E
Q449X
Q456H
P457L
P475S P671L R1206X
179M S203P R507Q T673F C1213G
A690T
V88L D217H C508Y R692C A900V C1213Y
V88M ∗ G227R G525D Q723K S903L W1016X I1217T
A95P L232Q R528G A732V C908Y C1024G R1219W
H96D C265S/S266C Y304C G550R C908S C1024R C1239V
R102C R268P C311Y R910X A1033T W1245X
R102H H234Q R312C G385E A596V Q929X R1034X K1256F
S119F H234R C322G W390C A606P C951G R1060W K1256S
I143T D235H T323R W390X P618A
S150P D235Y F324L R398H R625H W1081X
I178T G236C R328G R398C A631V C1084Y
R193Q A250V C347S R409W Y658C R1095Q
∗
R193W S263C R349C Q436H P671L C754R R1095W
R7W T196I S263F P353L E444G I673F C758R H960D R1096X Q1302X
C365X ∗ C977F Q1105X R1336W
Q44X E812X C977W R1123C D1362V

Metalloprotease Disint. TSP Cys Spacer TSP TSP TSP TSP TSP TSP TSP CUB1 CUB2
1 2 3 4 5 6 7 8

82dupT 825_832 del8bp
106−1 G C 987 11 C T 1584 5 G A 2861 3769ins T
987 69 C T 1584 106 C G 2455 delG 55 C T
1584 236 T C 2549 delAT 2930_2935
291_319 del29bp del6bp
330 1 G A 1783−1784 T T del
414 1 G A 1244−2 T G 1786+1 G A
686 1>A 686 1 T G 1245−32 C G 1787−26 G A 3190 delCT
718−724 del G C 1309_? G A 1885 delT 3220 deIT ACC
768_774 del17bp 3254_3255 del
2259 delA
2279 G A 4077 32 T C
2279 delG 4119 del G
2376 del26 4143 dupA
Fig. 134.3 ADAMTS13 STRUCTURE AND LOCATION OF THE MUTATIONS FOUND IN
PATIENTS WITH CONGENITAL THROMBOTIC THROMBOCYTOPENIC PURPURA. ADAMTS13
is a multiple domain protein consisting of a metalloprotease domain followed by a disintegrin-like motif, a
first thrombospondin-1 (TSP-1) repeat, Cys-rich and spacer domains, seven additional TSP-2 repeats, and
two complement components C1r/C1s, urinary epidermal growth factor, and bone morphogenic protein-a
domains. About 150 candidate mutations in ADAMTS13 spread throughout the gene have been reported in
the inherited form of thrombotic thrombocytopenic purpura (Upshaw-Schülman syndrome). Most mutations
are located within the N-terminal region of the protease comprising the metalloprotease domain to the Cys-
rich-spacer domain of the protease. The N-terminal part of ADAMTS13 is the active part of the protein in
vitro; the C-terminal part is not crucial for ADAMTS13 activity in vitro, but is essential for the normal
function of ADAMTS13 in vivo. Mutations leading to amino acid substitutions (missense mutations) are
found in about two-thirds of cases and truncating mutations (nonsense mutations inducing stop codon or
splice/frameshift mutations) are also described. Missense and nonsense mutations are represented at the top
of the figure, whereas splice/frameshift mutations are represented at the bottom of the figure. (Reproduced from
Loriat C, Coppo P, Veyradier A: TTP in children. Curr Opin Pediatr 25:216, 2013.)

Acquired ADAMTS13 Deficiency ADAMTS13 levels below 5% were found in 17 of 109 patients with
sepsis-induced disseminated intravascular coagulation (DIC). More
Almost all patients with nonfamilial, idiopathic TTP have an acquired modest decreases (typically >40%) occur in newborns and among
severe reduction or absence of ADAMTS13 activity (<5%–10%), adults with cirrhosis, chronic renal insufficiency, pregnancy, connec-
usually associated with autoantibody immunoglobulin (Ig) G inhibi- tive tissue diseases, and various inflammatory conditions; none had
tors. Some of the reported variation in ADAMTS13 activity levels levels below 6%. Therefore severe ADAMTS13 deficiency appears to
may reflect inclusion or exclusion of patients with acute renal failure be specific for TTP in the appropriate clinical setting.
or other preexisting conditions. For example, severe ADAMTS13 ADAMTS13 levels appear normal in some cases of idiopathic
deficiency was found in 18 of 48 adults with idiopathic TMAs TTP. This was highlighted by the unusual case reported by Froelich-
unselected for renal function, but it was seen in 22 of 22 patients Zahnd and colleagues of a patient with multiple relapses of HIV-
without acute anuric renal failure. Acquired severe ADAMTS13 associated TTP. With the earlier relapses, the patient had detectable
deficiency (<5%–10%) is rare in other settings, with the possible ADAMTS13 activity by multiple assays and responded to plasma
exception of severe hepatic insufficiency or sepsis. For example, exchange. In contrast, with later relapses ADAMTS13 levels were