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CORRESPONDENCE Bianchi et al1 report that a severe deficiency of
the von Willebrand factor (VWF)-cleaving protease ADAMTS13 is
specific for thrombotic thrombocytopenic purpura (TTP). This
is in agreement with the results of our studies, demonstrating that a
severe deficiency of ADAMTS13 is detected only in patients with either
the acquired2 or congenital form of TTP3 but
not in patients with other pathologic conditions.2,4,5 On
the other hand, Remuzzi et al6 report contradictory
results. Discrepancy in the case criteria clearly contributes to the
variant results observed by Remuzzi et al. The syndrome of
thrombocytopenia and microangiopathic hemolysis consists of a
heterogeneous group of disorders with overlapping clinical
manifestations but different pathogenesis. In the study by Remuzzi et
al,6 criteria for distinguishing TTP from hemolytic uremic
syndrome (HUS), based on the presence of neurologic or renal
abnormalities, are unfortunately arbitrary. The use of a decreased
high-molecular-weight (HMW) multimers to low-molecular-weight (LMW)
multimers ratio (HMW/LMW) as an indicator of increased
cleavage of VWF is particularly misleading because VWF multimer size
distribution is determined by a kinetic balance among secretion,
proteolysis, and VWF-platelet binding. At the advanced stage of TTP,
VWF-platelet binding predominates, resulting in a depletion of the
ultralarge and large multimers; hence, a normal or even
decreased HMW/LMW-multimer ratio is common, as observed by
Remuzzi et al. Now that the molecular mechanism of TTP is
elucidated,3 it would be of little value and
counterproductive to apply the diagnosis of TTP to patients who do not
have severe ADAMTS13 deficiency. A deficiency of ADAMTS13 as the cause
of the manifestations of TTP offers an explanation of why plasma
infusion or exchange is effective. The role of plasma therapy in
patients without deficiency of ADAMTS13 is questionable. Since plasma
exchange is costly and associated with potentially serious
complications, efforts should be directed toward delineating the role,
if any, of plasma therapy in patients without TTP. Bianchi et al also report that ADAMTS13 activity is very low in some
cases with heparin-induced thrombocytopenia or severe sepsis, and they
raise doubt that all cases of TTP are associated with a severe
deficiency of ADAMTS13 activity. First, in patients with
heparin-induced thrombocytopenia, the ADAMTS13 activity is not as low
as the authors report.2 Previously, we investigated the
level of ADAMTS13 activity in 18 patients with heparin-induced thrombocytopenia.2 Table
1
compares the result of that study with that described by Bianchi et
al.1 While 4 of our cases had ADAMTS13 activity
below the normal range, none had a level below 30%. The discrepancy is
obviously due to the difference in the normal ranges of the assays.
Notably, the narrow normal range of our assay is critical for correctly
identifying the members in kindreds with genetic deficiency of the
protease, leading to the positional cloning of the ADAMTS13
gene.3
Furthermore, the low levels of ADAMTS13 detected by Bianchi et al in patients without TTP are not accompanied by evidence that cleavage of VWF is diminished. Since ADAMTS13 regulates the size of VWF in the circulation, a low ADAMTS13 level that is not associated with evidence of diminished VWF cleavage raises doubt on the validity of the test result. Alternative explanations of low laboratory values, such as plasma factors interfering the assays or instability of ADAMTS13 activity in vitro, have not been explored. Hence, unless the result is supported by evidence of diminished VWF proteolysis or the presence of inhibitors, we urge caution before inferring that a low laboratory value indicates that the ADAMTS13 activity is decreased in the patient. On the other hand, clinical observations and laboratory studies suggest that in conditions with severe ADAMTS13 deficiency, the propensity of VWF to bind platelets is likely to be affected by the genetic composition of the individuals and by environmental factors such as fever, infection, surgery, or pregnancy. Just as patients with von Willebrand disease have variable severity of bleeding manifestations, in patients with severe ADAMTS13 deficiency, the absence of apparent thrombocytopenia or microangiopathic hemolysis is not evidence against the diagnosis of TTP, provided the low level of ADAMTS13 is supported by evidence of decreased VWF proteolysis.
Han-Mou Tsai
References
1.
Bianchi V, Robles R, Alberio L, Furlan M, Lammle B.
Von Willebrand factor-cleaving protease (ADAMTS13) in thrombocytopenic disorders: a severely deficient activity is specific for thrombotic thrombocytopenic purpura.
Blood.
2002;100:710-713
2.
Tsai HM, Lian EC.
Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura.
N Engl J Med.
1998;339:1585-1594 3. Levy GG, Nichols WC, Lian EC, et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature. 2001;413:488-494[CrossRef][Medline] [Order article via Infotrieve]. 4. Tsai HM, Chandler WL, Sarode R, et al. von Willebrand factor and von Willebrand factor-cleaving metalloprotease activity in Escherichia coli O157:H7- associated hemolytic uremic syndrome. Pediatr Res. 2001;49:653-659[Medline] [Order article via Infotrieve]. 5. Arai S, Allan C, Streiff M, Hutchins GM, Vogelsang GB, Tsai HM. Von Willebrand factor-cleaving protease activity and proteolysis of von Willebrand factor in bone marrow transplant-associated thrombotic microangiopathy. Hematol J. 2001;2:292-299[CrossRef][Medline] [Order article via Infotrieve].
6.
Remuzzi G, Galbusera M, Noris M, et al.
von Willebrand factor cleaving protease (ADAMTS13) is deficient in recurrent and familial thrombotic thrombocytopenic purpura and hemolytic uremic syndrome.
Blood.
2002;100:778-785
Response:ADAMTS13 and thrombotic thrombocytopenic purpuraWe thank Dr Tsai for his letter commenting on our studies1 and Remuzzi et al's2 studies. The criticisms concerning our paper are addressed as follows. 1. Tsai states that our main conclusion (a severe deficiency of ADAMTS13 activity is a specific finding for a thrombotic microangiopathy commonly labeled thrombotic thrombocytopenic purpura [TTP]) is in agreement with his own findings. In fact, during the past 6 years there were several instances when Tsai's and our groups independently and almost simultaneously published articles on similar topics. These topics included the isolation and partial characterization of von Willebrand factor (VWF)-cleaving protease,3,4 the discovery of its severe acquired deficiency in patients with acute TTP,5,6 as well as the finding of always,7 or most often,8 normal protease levels in children with enterohemorrhagic Escherichia coli-associated hemolytic uremic syndrome (HUS). Thus, our and Tsai's data largely confirmed and sometimes complemented each other, increasing the likelihood that these findings are true. 2. Tsai correctly mentions that the syndrome of thrombocytopenia and microangiopathic hemolysis consists of a heterogeneous group of disorders with overlapping clinical manifestations but different pathogenesis, and he believes that TTP should no longer be diagnosed in patients without severe ADAMTS13 deficiency. It is exactly because of the overlapping clinical manifestations between TTP and HUS that no clear-cut clinical criteria for distinction can be provided. Thus, some experts in the field refrain from clinically distinguishing, at least in adults, between TTP and HUS as 2 separate entities.9 Rather surprisingly, in our multicenter study on patients with TTP-HUS,5 21 of 23 patients diagnosed with HUS at the respective participating centers had normal VWF-cleaving protease activity, whereas 26 of 30 diagnosed with TTP had a severe VWF-cleaving protease deficiency. Similarly, Veyradier et al10 found a severe protease deficiency in all 25 patients diagnosed with idiopathic TTP, whereas all 17 with idiopathic HUS had normal levels. Among the 69 patients with secondary thrombotic microangiopathy, the distinction was somewhat less clear-cut; 7 of 41 patients with secondary TTP had normal ADAMTS13 activity, whereas 6 of the 28 patients with secondary HUS had partial or complete protease deficiency. Therefore, the laboratory finding of severe ADAMTS13 deficiency delineates a group of patients more likely to be clinically diagnosed with TTP than with HUS, and the finding of normal or moderately decreased ADAMTS13 activity delineates a group more likely to be diagnosed with HUS than with TTP. The sensitivity of severe ADAMTS13 deficiency for the clinical diagnosis of TTP varied between 66% and 100% in 3 retrospective studies5,6,11 and 1 prospective study.10 This suggests that many but not all patients with a clinical diagnosis of TTP have severe protease deficiency, but that in some patients other pathogenetic factors may lead to a clinical picture indistinguishable from TTP. A new classification scheme of the thrombotic microangiopathies, based on their pathophysiology, might be needed with severe hereditary and acquired ADAMTS13 deficiency as 2 distinct entities.12 3. Tsai suggests that the role of plasmatherapy in patients without ADAMTS13 deficiency is questionable. We agree with Tsai that the therapeutic and prophylactic effectiveness of fresh frozen plasma (FFP) infusion in patients with Upshaw-Schulman syndrome13 (constitutional TTP) associated with severe hereditary ADAMTS13 deficiency is likely to be explained by the replacement of the missing protease.12,14-16 The effectiveness of plasma exchange and replacement of FFP in acquired TTP17,18 can nowadays be explained by removal of autoantibodies inhibiting ADAMTS13 activity and replacement of the enzyme. Mori et al11 observed that patients diagnosed with TTP having acquired severe ADAMTS13 deficiency showed a better response to plasma exchange and higher survival than those diagnosed with TTP without severe deficiency. This may, as suggested by Tsai, indicate that plasma exchange and FFP replacement may not be the optimal therapy for these patients. Still, in the absence of knowledge on the underlying pathogenesis of the thrombotic microangiopathy in these patients, it is probably not justified to withhold plasma exchange until better pathophysiology-based therapeutic measures become available. 4. Tsai then criticizes the fact that in our report1 several patients with heparin-induced thrombocytopenia type 2 or sepsis had "very low levels" of ADAMTS13 activity. He found fewer patients with heparin-induced thrombocytopenia showing decreased protease activity and the extent of the decrease of ADAMTS13 activity was less pronounced6 than in our patients.1 Tsai believes that this is related to the narrower normal range of ADAMTS13 activity as assessed by his method4,6 compared with our method.1,3,5 Different assay techniques for ADAMTS13 may show some discrepancies in the measured activity levels. This is the very reason why we initiated a multisite study in June 2002. We invited several researchers (including Dr Tsai), having reported different methods for assaying ADAMTS13 activity, to measure the VWF-cleaving protease activity in some 30 plasma samples that vary in ADAMTS13 activity. The results of this study are expected later this year. Tsai's method was helpful in identifying clinically healthy heterozygous carriers of hereditary TTP and thereby allowed Levy et al19 to identify, using a genome-wide positional cloning approach, the ADAMTS13 gene as the gene responsible for hereditary TTP in 4 families. Nevertheless, as of July 2002, using our method,1 we too were able to identify 30 patients with hereditary TTP having ADAMTS13 activity lower than 3% and more than 100 patients with acquired TTP lacking protease activity due to inhibiting autoantibodies (Furlan and Lämmle12 and B.L. et al, unpublished observations, July 2002). The healthy parents of patients with constitutional TTP most often had values around 50%,14 but they were normal (> 50%) in one family.15 Kinoshita et al,16 using a modification of our assay, also identified 3 children with hereditary TTP and VWF-cleaving protease activity lower than 3%, their 6 parents having values between 5.6% and 60%. This broad range of ADAMTS13 activity levels in the presumably heterozygous parents of the 3 patients16 should not be taken as evidence of imprecision of the assay used. Instead, different genetic mutations of the ADAMTS13 gene might account for differing activity levels in these heterozygous carriers.20 Thus, in our opinion, there is no good reason to believe that Tsai's assay is superior or inferior to our method. 5. Tsai further states that the low levels of VWF-cleaving protease in some of our thrombocytopenic patients1 are not accompanied by evidence that cleavage of VWF is diminished, and he argues that this raises doubt on the validity of the test results. It is true that we did not show VWF multimer analyses in our 68 patients with various thrombocytopenic disorders other than TTP.1 Twelve of the 68 patients had moderately decreased ADAMTS13 activity between 10% and 30%. In 1997, following earlier observations21 of unusually large (UL) VWF multimers in patients with chronic relapsing TTP in remission, we reported 4 such patients showing ULVWF multimers in their plasma.22 It was exactly this finding of ULVWF multimers that led to the identification of a severe VWF-cleaving protease deficiency in these patients.22 Nevertheless, patients with congenital TTP rapidly become symptom-free and their platelet count normalizes after infusion of only small amounts of FFP that will arithmetically lead to an increase of ADAMTS13 activity to just about 10% to 15% of normal human plasma (NHP).12,14-16 Therefore, ADAMTS13 activity levels as low as 10% are sufficient to degrade the ULVWF multimers leading to in vivo platelet clumping, and we strongly oppose Tsai's reasoning that a protease activity level of 10% to 30% is invalid if no evidence of diminished VWF cleavage is provided. Whether plasma factors may interfere with our and/or Tsai's ADAMTS13
activity assays remains to be tested (eg, by using recombinant ADAMTS1323 tested with and without addition of plasma).
Stability of ADAMTS13 activity in plasma samples stored at 6. Finally, Tsai suggests that the absence of thrombocytopenia or microangiopathic hemolysis is not evidence against the diagnosis of TTP in the presence of severe ADAMTS13 deficiency, provided that the latter is supported by decreased VWF proteolysis. At present, the diagnosis of TTP is still used to characterize a clinical condition and not a laboratory finding strongly predisposing to the disease. This may be a mere semantic problem, however, as long as the new pathophysiology-based classification scheme is not generally used.
Bernhard Lämmle, Valentina Bianchi, Lorenzo Alberio, and Miha Furlan
References
1.
Bianchi V, Robles R, Alberio L, Furlan M, Lämmle B.
Von Willebrand factor-cleaving protease (ADAMTS13) in thrombocytopenic disorders: a severely deficient activity is specific for thrombotic thrombocytopenic purpura.
Blood.
2002;100:710-713
2.
Remuzzi G, Galbusera M, Noris M, et al.
Von Willebrand factor cleaving protease (ADAMTS13) is deficient in recurrent and familial thrombotic thrombocytopenic purpura and hemolytic uremic syndrome.
Blood.
2002;100:778-785
3.
Furlan M, Robles R, Lämmle B.
Partial purification and characterization of a protease from human plasma cleaving von Willebrand factor to fragments produced by in vivo proteolysis.
Blood.
1996;87:4223-4234
4.
Tsai HM.
Physiologic cleavage of von Willebrand factor by a plasma protease is dependent on its conformation and requires calcium ion.
Blood.
1996;87:4235-4244
5.
Furlan M, Robles R, Galbusera M, et al.
Von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic uremic syndrome.
N Engl J Med.
1998;339:1578-1584
6.
Tsai HM, Lian ECY.
Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura.
N Engl J Med.
1998;339:1585-1594 7. Tsai HM, Chandler WL, Sarode R, et al. Von Willebrand factor and von Willebrand factor-cleaving metalloprotease activity in Escherichia coli O157:H7-associated hemolytic uremic syndrome. Pediatr Res. 2001;49:653-659[Medline] [Order article via Infotrieve]. 8. Hunt BJ, Lämmle B, Nevard CHF, Haycock GB, Furlan M. Von Willebrand factor-cleaving protease in childhood diarrhoea-associated haemolytic uraemic syndrome. Thromb Haemost. 2001;85:975-978[Medline] [Order article via Infotrieve].
9.
George JN.
How I treat patients with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome.
Blood.
2000;96:1223-1229
10.
Veyradier A, Obert B, Houllier A, Meyer D, Girma JP.
Specific von Willebrand factor-cleaving protease in thrombotic microangiopathies: a study of 111 cases.
Blood.
2001;98:1765-1772 11. Mori Y, Wada H, Gabazza EC, et al. Predicting response to plasma exchange in patients with thrombotic thrombocytopenic purpura with measurement of vWF-cleaving protease activity. Transfusion. 2002;42:572-580[CrossRef][Medline] [Order article via Infotrieve]. 12. Furlan M, Lämmle B. Aetiology and pathogenesis of thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome: the role of von Willebrand factor-cleaving protease. Best Pract Res Clin Haematol. 2001;14:437-454[Medline] [Order article via Infotrieve]. 13. Upshaw JD. Congenital deficiency of a factor in normal plasma that reverses microangiopathic hemolysis and thrombocytopenia. N Engl J Med. 1978;298:1350-1352[Medline] [Order article via Infotrieve]. 14. Häberle J, Kehrel B, Ritter J, Jürgens H, Lämmle B, Furlan M. New strategies in diagnosis and treatment of thrombotic thrombocytopenic purpura: case report and review. Eur J Pediatr. 1999;158:883-887[CrossRef][Medline] [Order article via Infotrieve]. 15. Barbot J, Costa E, Guerra M, et al. Ten years of prophylactic treatment with fresh-frozen plasma in a child with chronic relapsing thrombotic thrombocytopenic purpura as a result of a congenital deficiency of von Willebrand factor-cleaving protease. Br J Haematol. 2001;113:649-651[CrossRef][Medline] [Order article via Infotrieve]. 16. Kinoshita S, Yoshioka A, Park YD, et al. Upshaw-Schulman syndrome revisited: a concept of congenital thrombotic thrombocytopenic purpura. Int J Hematol. 2001;74:101-108[Medline] [Order article via Infotrieve]. 17. Rock GA, Shumak KH, Buskard NA, et al. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura: Canadian Apheresis Study Group. N Engl J Med. 1991;325:393-397[Abstract]. 18. Bell WR, Braine HG, Ness PM, Kickler TS. Improved survival in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. N Engl J Med. 1991;325:398-403[Abstract]. 19. Levy GG, Nichols WC, Lian EC, et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature. 2001;413:488-494[CrossRef][Medline] [Order article via Infotrieve].
20.
Kokame K, Matsumoto M, Soejima K, et al.
Mutations and common polymorphisms in ADAMTS13 gene responsible for von Willebrand factor-cleaving protease activity.
Proc Natl Acad Sci USA.
2002;99:11902-11907 21. Moake JL, Rudy CK, Troll JH, et al. Unusually large plasma factor VIII: von Willebrand factor multimers in chronic relapsing thrombotic thrombocytopenic purpura. N Engl J Med. 1982;307:1432-1435[Medline] [Order article via Infotrieve].
22.
Furlan M, Robles R, Solenthaler M, Wassmer M, Sandoz P, Lämmle B.
Deficient activity of von Willebrand factor-cleaving protease in chronic relapsing thrombotic thrombocytopenic purpura.
Blood.
1997;89:3097-3103
23.
Plaimauer B, Zimmermann K, Völkel D, et al.
Cloning, expression, and functional characterization of the von Willebrand factor-cleaving protease (ADAMTS13).
Blood.
2002;100:3626-3632
24.
Gerritsen HE, Robles R, Lämmle B, Furlan M.
Partial amino acid sequence of purified von Willebrand factor-cleaving protease.
Blood.
2001;98:1654-1661
Response:ADAMTS13 in thrombotic microangiopathiesWe disagree with Dr Tsai that severe deficiency of the von Willebrand factor (VWF)-cleaving protease ADAMTS13 is found only in patients with the acquired or congenital forms of thrombotic thrombocytopenic purpura (TTP) but not in other pathologic conditions. Our argument is based on the following evidence. 1. Complete deficiency of ADAMTS13 activity was found
in children with a diagnosis of hemolytic uremic syndrome
(HUS). Three of these patients, who never had any neurologic
signs, were reported in our study1; Loirat et
al2 reported 5 patients with a diagnosis of
diarrhea-negative (D 2. Undetectable ADAMTS13 activity was also found in 2 adults with atypical HUS without neurologic signs and in 4 adults with secondary HUS.4 3. Severe deficiency of the protease activity was also found in diseases other than thrombotic microangiopathies such as immune thrombocytopenic purpura, disseminated intravascular coagulation, systemic lupus erythematosus,5 metastatic malignancies,6 liver cirrhosis, and chronic inflammation.7 Dr Tsai states that the clinical and laboratory criteria we used to distinguish TTP from HUS, based on the prevalent presence of neurologic or renal abnormalities, are arbitrary. In the current absence of other criteria, the same critical argument does apply to anybody who tries to make a differential diagnosis among thrombotic microangiopathies, including Dr Tsai. Maybe it is time to think about a new classification of thrombotic microangiopathies. A committee of experts should take in account the clinical history and the identification of genetic abnormalities and perhaps employ the term "thrombotic microangiopathy" (TMA)8 with ADAMTS13 deficiency in infants or children who have clinical features of HUS and undetectable ADAMTS13 activity. For consistency, such a term should also apply to adult patients with TTP or HUS and ADAMTS13 deficiency. Dr Tsai also criticizes the use of the high-molecular-weight (HMW) multimers-low-molecular-weight (LMW) multimers ratio (HMW/LMW) as an index of VWF proteolysis. We agree that this is an indirect index; however, Dr Tsai should consider that the increased cleavage of VWF in TMA patients during the acute phase of the disease is supported by the analysis of VWF subunit and fragments, showing a decreased native 225-kDa subunit.9,10 During the acute phase, increased levels of normal VWF fragments were also present in patients with undetectable ADAMTS13 activity.10 We agree that VWF multimer size is determined by a kinetic balance among secretion, proteolysis, and VWF-platelet binding. However, there is no direct evidence to prove that during the acute phase of the disease in vivo unusually large (UL) VWF multimers disappear from the circulation because they are bound to platelets because, as stated also by Chow et al,11 it is not possible to evaluate the size of VWF multimers bound to platelets. In this respect, in our patients with familial forms of TMA and congenital deficiency of ADAMTS13, no ULVWF multimers were found in remission at the time when platelet count was normal. Yet in these patients, there was an increased proportion of VWF fragments.10 Moreover, patients with the recurrent form of TMA had ULVWF multimers in the circulation independently of disease activity.10 Dr Tsai also raises doubts on the validity of test results when low ADAMTS13 levels are not associated with diminished VWF cleavage. There are no data supporting the views that deficient ADAMTS13 activity is associated with decreased VWF proteolysis. It has been clearly documented that VWF can be cleaved by a number of proteases (ie, calpain, elastase, plasmin) other than ADAMTS13.12-14 In addition, it has recently been shown that plasma from TMA patients with complete deficiency of ADAMTS13 activity has the same capacity as control plasma to proteolyze VWF, leading to the generation of normal fragments, and that this proteolytic activity was inhibited by a serine protease inhibitor.15 Altogether these evidences challenge the views of Dr Tsai that low ADAMTS13 levels must be associated with diminished VWF cleavage.
Giuseppe Remuzzi, Miriam Galbusera, and Pier Mannuccio Mannucci
References
1.
Remuzzi G, Galbusera M, Noris M, et al.
von Willebrand factor cleaving protease (ADAMTS13) is deficient in recurrent and familial thrombotic thrombocytopenic purpura and hemolytic uremic syndrome.
Blood.
2002;100:778-785 2. Loirat C, Veyradier A, Foulard M, et al. von Willebrand factor (vWF)-cleaving protease activity in pediatric hemolytic uremic syndrome (HUS). Paper presented at: Twelfth Congress of the International Pediatric Nephrology Association; September 1-5, 2001; Seattle, WA. 3. Hunt BJ, Lammle B, Nevard CH, Haycock GB, Furlan M. von Willebrand factor-cleaving protease in childhood diarrhoea-associated haemolytic uraemic syndrome. Thromb Haemost. 2001;85:975-978[Medline] [Order article via Infotrieve].
4.
Veyradier A, Obert B, Houllier A, Meyer D, Girma JP.
Specific von Willebrand factor-cleaving protease in thrombotic microangiopathies: a study of 111 cases.
Blood.
2001;98:1765-1772
5.
Moore JC, Hayward CPM, Warkentin TE, Kelton JG.
Decreased von Willebrand factor protease activity associated with thrombocytopenic disorders.
Blood.
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Deficient activity of von Willebrand's factor-cleaving protease in patients with disseminated malignancies.
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Changes in health and disease of the metalloprotease that cleaves von Willebrand factor.
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10.
Galbusera M, Noris M, Rossi C, et al.
Increased fragmentation of von Willebrand factor, due to abnormal cleavage of the subunit, parallels disease activity in recurrent hemolytic uremic syndrome and thrombotic thrombocytopenic purpura and discloses predisposition in families. The Italian Registry of Familial and Recurrent HUS/TTP.
Blood.
1999;94:610-620 11. Chow TW, Turner NA, Chintagumpala M, et al. Increased von Willebrand factor binding to platelets in single episode and recurrent types of thrombotic thrombocytopenic purpura. Am J Hematol. 1998;57:293-302[CrossRef][Medline] [Order article via Infotrieve]. 12. Moore JC, Murphy WJ, Kelton JG. Calpain proteolysis of von Willebrand factor enhances its binding to platelet membrane glycoprotein IIb/IIIa: an explanation for platelet aggregation in thrombotic thrombocytopenic purpura. Br J Haematol. 1990;74:457-464[Medline] [Order article via Infotrieve].
13.
Thompson EA, Howard MA.
Proteolytic cleavage of human von Willebrand factor induced by enzyme(s) released by polymorphonuclear cells.
Blood.
1986;67:1281-1285 14. Hamilton KK, Fretto LJ, Grierson DS, McKee PA. Effects of plasmin on von Willebrand factor multimers: degradation in vitro and stimulation of release in vivo. J Clin Invest. 1985;76:261-270[Medline] [Order article via Infotrieve]. 15. Contaretti S, Noris M, Benigni A, et al. Plasma from patients with HUS and TTP proteolyzes vWF subunit independently from the presence or absence of the Ba2+-dependent-cleaving protease activity (vWF-cpa) [abstract]. J Am Soc Nephrol. 2001;12:98a.   CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
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20°C for
several months is excellent and the in vitro half-life of its activity in plasma or serum incubated at 37°C is more than 1 week.
) atypical HUS and 1 patient with
D+ typical HUS related to Escherichia coli
0157:H7; and another case of D+ HUS related to
E. coli 0157 infection was reported by Hunt et al.
