Organogenesis 7:1, 28-31; January/February/March 2011; © 2011 Landes Bioscience
Plasma exchange therapy
for thrombotic microangiopathies
28 Organogenesis volume 7 issue 1
During the times of Hippocrates and Galen, ancient physicians
embraced the concept that human illness and disease emerged
from an imbalance of four bodily components, or “humors”—
blood, phlegm, black bile and yellow bile. Interventions such as
phlebotomy or leech therapy were frequently performed in an
effort to “remove evil humors” and restore humoral balance.1
Although such beliefs and practices might now seem rather prim-
itive and archaic as viewed through the lens of modern scientific
and medical principles, in one, somewhat ironic sense, perhaps
our physician predecessors were not entirely incorrect with their
notion of humoral balance. In fact, if we were to direct this con-
cept to the hematologic and endothelial systems and utilize con-
temporary tools of investigation, we find that many aspects of
thrombotic microangiopathy (TMA) can be better understood
through this “old view with a modern twist.”
In this regard, there are four major components in whole
blood: red blood cells, white blood cells, platelets and plasma.
The normal homeostatic maintenance and functioning of these
four components are essential for the host’s survival. However,
under pathological conditions, these four blood components
interact with themselves and/or others to the detriment of the
host. In this review, we will discuss the hypotheses of (1) how
the failing plasma contributes to coagulopathy in TMA and
*Correspondence to: Trung C. Nguyen;
Submitted: 08/01/10; Accepted: 10/21/10
Thrombotic microangiopathies (TMAs) are syndromes
associated with thrombocytopenia and multiple organ failure.
Plasma exchange is a proven therapy for primary TMA, such as
thrombotic thrombocytopenic purpura (TTP). There is growing
evidence that plasma exchange therapy might also facilitate
resolution of organ dysfunction and improve outcomes
for secondary TMAs, such as disseminated intravascular
coagulation (DiC) and systemic inflammation-induced TTP.
in this review, we survey the current available evidence and
practice of plasma exchange therapy for TMAs.
Trung C. Nguyen1,* and Yong Y. Han2
1Section of Critical Care; Department of Pediatrics; Texas Children’s Hospital; Baylor College of Medicine; Houston, TX USA; 2Division of Critical Care Medicine;
Department of Pediatrics and Communicable Diseases; University of Michigan Medical School; Ann Arbor, Mi USA
Key words: VWF, ADAMTS-13, thrombocytopenia-associated multiple organ failure (TAMOF), plasma exchange,
TTP, DIC, thrombotic microangiopathy
(2) whether removing and/or replenishing plasma constituents
could reverse the coagulopathy in TMA.
“Classic” Thrombotic Microangiopathies—
Thrombotic Thrombocytopenic Purpura (TTP)
and Disseminated Intravascular Coagulation (DIC)
The thrombotic microangiopathies (TMA) are considered a fam-
ily of related syndromes recognized clinically by the development
of new onset thrombocytopenia and multiple organ failure (MOF)
and are characterized pathologically by widespread microvascular
thromboses in multiple vascular beds and organs.2,3 Classically,
two distinct pathogenic and histological forms of TMA have
been described. The first classic form, thrombotic thrombocyto-
penic purpura (TTP), is categorized as a primary TMA since its
development has historically been regarded as being idiopathic in
nature, while the second classic form, disseminated intravascu-
lar coagulation (DIC), is considered a secondary TMA because
its development can often be attributed to an underlying trigger,
such as sepsis, cancer, trauma or other insult.3 Histologic exami-
nation of tissue specimens obtained from patients with TTP
typically reveals platelet-rich and von Willebrand factor (VWF)-
rich microthrombi in all organs,4-8 whereas, in contrast, fibrin-
rich microthrombi predominate in patients with DIC. Other
non-classic forms of TMA have been more difficult to delineate
because they share pathological similarities and overlap with both
TTP and DIC. However, it is through our evolving mechanistic
knowledge of these two classic forms of TMA that we can better
understand other non-classic TMA forms. Namely, we can begin
to appreciate that the pathogenesis of all forms of TMA emanates
from a perturbation of homeostatic processes that regulate the
complex interactions among the soluble plasma molecules, white
blood cells, platelets and endothelium.
In 1924, Dr. Moschowitz described the first case of TTP in a
girl who abruptly succumbed with petechiae, paralysis and coma.
On autopsy her terminal arterioles and capillaries were found to
be occluded with hyaline thrombi. Dr. Moschowitz postulated
that a “powerful poison which had both agglutinative and hemo-
lytic properties” had existed in the bloodstream of this girl.9 In
1982, Dr. Moake proposed that this “powerful poison” with the
www.landesbioscience.com Organogenesis 29
pathologic consumption and exhaustion of coagulation proteins
and platelets, caused by excessive, systemic release of tissue factor.3
Tissue factor is a transmembrane glycoprotein that is expressed
in numerous tissues, including the vascular endothelium and leu-
kocytes, and plays a pivotal role in the initiation and propagation
of the coagulation cascade. Local tissue injury or inflammation
induces the release of tissue factor into the bloodstream,27 which
complexes with factor VIIa to enhances its procoagulant property.
The tissue factor-factor VIIa complex activates factors IX and X,
eventually leading to thrombin generation and, finally, fibrin clot
formation. Local clot formation during a focal infection lends a
teleological survival advantage to the host by immobilizing bac-
teria and limiting their spread. Hence, with limited local release,
tissue factor activation is thought to be beneficial. However,
under the conditions of vigorous systemic injury and inflamma-
tion, excessive release of tissue factor can cause deleterious hyper-
activation of the coagulation system, leading to disseminated
microvascular thrombosis as well as simultaneous consumption
and depletion of coagulation proteins, often leading to increased
bleeding. To further aggravate the prothrombotic state in DIC,
the level of anti-fibrinolytic plasminogen activator inhibitor type-1
(PAI-1) is elevated, and the levels of anticoagulants antithrombin
III and protein C are diminished. In contrast to TTP, histologi-
cal studies in DIC have shown that there are extensive fibrin-rich
microthrombi in small and mid-size vessels of all organs.4,6,8
Biologic Plausibility Supporting the Role
of Plasma Exchange Therapy in TMA
Through our ever expanding understanding of TTP and DIC,
we have begun to recognize that a potential common pathogenic
mechanism for the development of TMA points to the abnormal
interactions among the soluble plasma molecules, platelets, white
cells and endothelium. While many soluble proteins and cellu-
lar components are elevated and activated in the blood, others
are deficient or depleted as a result of consumptive coagulopathy.
This provides us with the biological plausibility supporting the
role of plasma exchange therapy for TMA. The goals of plasma
exchange in TMA are to remove excessively thrombogenic and
anti-fibrinolytic molecules and to replenish the deficient anti-
coagulants and profibrinolytic molecules in order to regain a
normal homeostatic milieu. In TTP, plasma exchange is hypoth-
esized to replenish ADAMTS-13 and to remove the ULVWF
and ADAMTS-13 inhibitors/proteolytic inactivators, such as
ADAMTS-13 autoantibodies, IL-6, plasma-free hemoglobin,
plasmin, thrombin and granulocyte elastase.25 In DIC, plasma
exchange is hypothesized to remove tissue factors, PAI-1 and
replenish antithrombin III, protein C and S and tissue plasmino-
gen activator inhibitor.28-32 In essence, plasma exchange attempts
to bring the patient’s plasma from dysregulated prothrombotic
and antifibrinolytic states back to its homeostatic milieu.
Different Techniques of Plasma Exchange Therapy
Plasmapheresis is the process of separating plasma component
from whole blood. It can be done by two different techniques—
hyper-adhesive property in the blood was ultra-large von-Will-
ebrand factor (ULVWF), a multimeric, high molecular weight
form of von-Willebrand factor (VWF) that is not typically seen
under normal conditions.10 VWF is the largest multimeric glyco-
protein in human plasma, with molecular masses ranging from
500–20,000 kD.11 The intrinsic role of VWF itself is to assist
platelets in clot formation in order to minimize blood loss and
regain hemostasis caused by blood vessel disruption or damage.
VWF augments platelet adhesiveness by bridging the platelet
receptor glycoprotein Ib-IX-V complex to exposed subendothe-
lial collagen of damaged vessels, helping to form a platelet plug.
VWF is initially synthesized by the endothelial cells and mega-
karyocytes in monomeric form, which then multimerizes before
being released into the bloodstream.12,13 Upon synthesis, VWF
is secreted by either the constitutive pathway of lower molecular
mass (~500 kDa) dimers or the inducible pathway of the larger
and ULVWF multimers. The inducible pathway is primarily trig-
gered by inflammatory processes.14-17 The “adhesiveness” of VWF
is proportional to the size of VWF multimers, with the larger
multimers having the ability to cause spontaneous platelet aggre-
gation. The normal host counter-regulates this hyper-adhesive-
ness of ULVWF by cleaving them into smaller sizes that remain
hemostatically active but are considerably less prothrombogenic.
In 1998 Furlan et al. and Tsai et al. independently identified a
VWF-cleaving protease that is now known as ADAMTS-13,
an acronym for A Disintegrin And Metalloprotease with
ThromboSpondin motifs-13.18-20 Discovery of ADAMTS-13 was
critical in delineating the pathophysiologic mechanism of TTP,
as it is now known to be caused by an underlying deficiency in
ADAMTS-13 activity. In the chronic relapsing form of TTP, a
genetic abnormality in the ADAMTS-13 gene leads to a congeni-
tal deficiency of ADAMTS-13 activity,19 while in the acquired
idiopathic form of TTP, there is the presence of inhibitors or
proteolytic inactivators of ADAMTS-13, such as autoantibod-
ies, IL-6, plasma-free hemoglobin, VWF proteolytic fragments,
thrombin, plasmin and granulocyte elastase.14,20-24 With either
form of TTP, the absent or reduced activity of ADAMTS-13
impairs the removal of ULVWF, the “powerful poison” origi-
nally postulated by Dr. Moschowitz and Moake, leading to spon-
taneous formation and dissemination of microthrombi and the
classic clinical “pentad” of TTP that includes thrombocytope-
nia, hemolytic anemia, fever, central nervous system abnormality
and renal dysfunction.25 New onset thrombocytopenia in TTP
heralds the progression of MOF and death if left untreated. On
autopsy, patients who died with TTP have VWF-rich and plate-
let-rich microthrombi in all organs.4-8
In 2001, the Scientific Subcommittee on DIC of the International
Society of Thrombosis and Haemostasis proposed the consensus
definition of DIC as “an acquired syndrome characterized by the
intravascular activation of coagulation with loss of localization
arising from different causes. It can originate from and cause dam-
age to the microvasculature, which if sufficiently severe, can pro-
duce organ dysfunction.”26 In DIC, investigators have observed
30 Organogenesis volume 7 issue 1
days 3 to 9 and improved outcome.47 Despite such studies report-
ing positive benefits of plasma exchange therapy for certain sec-
ondary TMA, unlike for primary TMA, the strength of these
data has been more limited. Still, this has not negated a grow-
ing interest in attempting to alter plasma components in patients
with systemic inflammation, especially in patients with sepsis-
In our own single-center study, we identified a subset of criti-
cally ill pediatric patients with Thrombocytopenia-Associated
Multiple Organ Failure (TAMOF) (defined clinically as plate-
let counts <100,000/mm3 and ≥3 failing organs) and found that
they had similar pathophysiologic process to those with TTP.22
These patients had the presence of ULVWF, were deficient in
ADAMTS-13 activity and inhibitors to ADAMTS-13. Autopsies
in TAMOF patients had microvascular thrombosis in the lungs,
kidneys and brain. We randomized patients with TAMOF to
either receive plasma exchange or standard therapy. Patients
randomized to plasma exchange received a 1.5x plasma volume
exchange on day 1 followed by 1x volume exchange for 14 days
or until the resolution to less than 3 failing organs for 48 hours.
Plasma exchange was initiated within 30 hours of the diagnosis
of TAMOF. Plasma exchange reversed the coagulopathy, facili-
tated organ failure resolution and improved outcome in patients
with TAMOF. Currently, there is an ongoing collaborative study
composed of a network of twelve pediatric intensive care units in
the US enrolling children meeting criteria for TAMOF. The net-
work is comparing biochemical markers and outcome in patients
receiving standard therapy versus plasma exchange (NCT
There are currently no consensus recommendations regard-
ing indication, patient selection, method, timing and duration
of plasma exchange therapy for secondary TMA. Some clinical
applications of plasma exchange therapy for patients with sec-
ondary TMA have included (1) overt DIC, (2) TAMOF (throm-
bocytopenia and ≥3 failing organs), (3) persistent TMA with
progressive of MOF or (3) significant coagulopathy with progres-
sive MOF. Patient selection is probably the most important cri-
terion in determining the success of the therapy. Because plasma
exchange has been shown to significantly reduce mortality in
patients with TTP, it would be reasonable to hypothesize that
patients with secondary TMA, who share similar pathophysio-
logic biochemical markers to TTP, would respond to the plasma
exchange. However, the laboratory tests for ADAMTS-13 activ-
ity, VWF activity and detection of ULVWF are still difficult
to obtain in a timely manner to make clinical decisions. We are
still relying on simple lab tests to suggest the presence of TMA
such as (1) blood smear to detect the presence of schistocytes
and (2) elevation of lactate dehydrogenase (LDH) and clinical
data such coagulopathy and MOF to make decision for plasma
There is growing evidence that plasma exchange therapy may
improve outcome in patients with secondary TMA. With fur-
ther understanding of the pathophysiologic mechanism of TMA,
centrifugation or membrane filtration. The pros and cons of these
techniques have been vigorously debated.33-36 Centrifugation has
the advantage of (1) removing all sizes of soluble plasma compo-
nents and (2) no interaction of blood components to a membrane
filter. The centrifugation machine spins the blood, separates
the blood components by gravity and density and removes the
desired component according to its sedimentation characteristic
during the spin. This technique is commonly utilized by blood
banks and hematologists. The filtration technique has the advan-
tage of being easily accessible by intensivists and nephrologists,
as a membrane filter can be added to a continuous extracorpo-
real veno-venous circuit. However, compared to centrifugation,
the filtration technique can potentially activate platelets and the
complement cascade.37,38 Furthermore, the pore size rating of the
filter can potentially limit the size of the soluble molecules being
removed. For example, it might not be expected that a membrane
filter with a pore size rating of 1,000 kDa can remove ULVWF
that approaches 20,000 kD in size. Despite this theoretical limi-
tation and somewhat unexpectedly, experimental data have actu-
ally shown that ULVWF can still be removed by current existing
plasmapheresis membrane filters,39 postulated, perhaps, through
protein adsorption rather than actual filtration. With the help
of modern technology, filters with larger membrane pores
and less contact activation properties are continuously being
Current Practices with Plasma
Exchange Therapy for TMA
Patients with TMA have a high risk of mortality if the coagu-
lopathy is not addressed. For primary TMA, plasma exchange
is recommended as soon as the diagnosis of TTP is suspected.
This recommendation is supported by Rock et al. who in 1991
reported in a randomized control trial that plasma exchange ther-
apy significantly reduced mortality compared to plasma infusion
alone for patients with acute TTP.43 In this study, the plasma
exchange therapy group experienced a mortality rate of 3.9%
compared to 15.7% for the plasma infusion group by the end of
the first treatment cycle (day 9). This beneficial effect on mortal-
ity remained statistically significant six months after the trial, as
21.6% of the patients treated with plasma exchange therapy had
died compared to 37.3% of the patients who had received plasma
infusion. Plasma exchange therapy has since become a standard
therapy for documented TTP.
There have been many studies appraising the potential
role of plasma exchange therapy for patients with secondary
TMA.22,28,29,31,32,44-51 For example, Stegmayr et al. reported in a
large case series that adults with DIC and MOF who received
plasma exchange had an 82% survival compared to <20%
observed survival in historical controls.31 Pene et al. reported that
plasma exchange in adults with TMA triggered by infections
was independently associated with lower mortality, regardless
of disease severity [Hazard Ratio = 0.234 (Confidence Interval
95%: 0.095–0.573), p = 0.001].49 And Darmon et al. reported
that plasma exchange for adult patients with secondary TMA
is associated with significantly lower organ failure scores from
www.landesbioscience.com Organogenesis 31
using plasma exchange for patients with TMA. Studies of plasma
exchange comparing the different methods, timing, duration and
patient population are needed.
we should have a better understanding regarding how plasma
exchange therapy might beneficially alter course of TMA outcome
in these patients. There are still many unanswered questions in
35. House AA, Ronco C. Extracorporeal blood purification
in sepsis and sepsis-related acute kidney injury. Blood
Purif 2008; 26:30-5.
36. Stegmayr BG. A survey of blood purification tech-
niques. Transfus Apher Sci 2005; 32:209-20.
37. Stegmayr B, Tarnvik A. Complement activation in
plasma exchange by single filtration and centrifugation
and in cascade filtration. Blood Purif 1989; 7:10-5.
38. Stegmayr B. Apheresis of plasma compounds as a
therapeutic principle in severe sepsis and multiorgan
dysfunction syndrome. Clin Chem Lab Med 1999;
39. Peng ZY, Kiss JE, Cortese-Hasset A, Carcillo JA,
Nguyen TC, Kellum JA. Plasma filtration on mediators
of thrombotic microangiopathy: an in vitro study. Int J
Artif Organs 2007; 30:401-6.
40. Burnouf T, Eber M, Kientz D, Cazenave JP, Burkhardt
T. Assessment of complement activation during mem-
brane-based plasmapheresis procedures. J Clin Apher
41. House AA, Ronco C. Extracorporeal blood purification
in sepsis and sepsis-related acute kidney injury. Blood
Purif 2008; 26:30-5.
42. Matson J, Zydney A, Honore PM. Blood filtration:
new opportunities and the implications of systems biol-
ogy. Crit Care Resusc 2004; 6:209-17.
43. Rock GA, Shumak KH, Buskard NA, Blanchette VS,
Kelton JG, Nair RC, 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; 325:393-7.
44. Bueno D Jr, Sevigny J, Kaplan AA. Extracorporeal
treatment of thrombotic microangiopathy: a ten year
experience. Ther Apher 1999; 3:294-7.
45. Busund R, Koukline V, Utrobin U, Nedashkovsky E.
Plasmapheresis in severe sepsis and septic shock: a pro-
spective, randomised, controlled trial. Intensive Care
Med 2002; 28:1434-9.
46. Caggiano V, Fernando LP, Schneider JM, Haesslein
HC, Watson-Williams EJ. Thrombotic thrombocyto-
penic purpura: report of fourteen cases—occurrence
during pregnancy and response to plasma exchange. J
Clin Apher 1983; 1:71-85.
47. Darmon M, Azoulay E, Thiery G, Ciroldi M, Galicier
L, Parquet N, et al. Time course of organ dysfunc-
tion in thrombotic microangiopathy patients receiving
either plasma perfusion or plasma exchange. Crit Care
Med 2006; 34:2127-33.
48. Niewold TB, Bundrick JB. Disseminated intravas-
cular coagulation due to cytomegalovirus infection
in an immunocompetent adult treated with plasma
exchange. Am J Hematol 2006; 81:454-7.
49. Pene F, Vigneau C, Auburtin M, Moreau D, Zahar
JR, Coste J, et al. Outcome of severe adult thrombotic
microangiopathies in the intensive care unit. Int Care
Med 2005; 31:71-8.
50. Stricker RB, Main EK, Kronfield J, Kallas GS, Gerson
LB, Autry AM, et al. Severe post-partum eclampsia:
response to plasma exchange. J Clin Apher 1992; 7:1-3.
51. von BH. Plasmapheresis in thrombotic microangiop-
athy-associated syndromes: Review of outcome data
derived from clinical trials and open studies. Ther
Apher 2002; 6:320-8.
19. 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 thrombocyto-
penic purpura. Nature 2001; 413:488-94.
20. Tsai HM, Lian EC. Antibodies to von Willebrand
factor-cleaving protease in acute thrombotic thrombo-
cytopenic purpura. N Engl J Med 1998; 339:1585-94.
21. Crawley JT, Lam JK, Rance JB, Mollica LR, O’Donnell
JS, Lane DA. Proteolytic inactivation of ADAMTS13
by thrombin and plasmin. Blood 2005; 105:1085-93.
22. Nguyen TC, Han YY, Kiss JE, Hall MW, Hassett AC,
Jaffe R, et al. Intensive plasma exchange increases a
disintegrin and metalloprotease with thrombospondin
motifs-13 activity and reverses organ dysfunction in
children with thrombocytopenia-associated multiple
organ failure. Crit Care Med 2008; 36:2878-87.
23. Ono T, Mimuro J, Madoiwa S, Soejima K, Kashiwakura
Y, Ishiwata A, et al. Severe secondary deficiency of von
Willebrand factor-cleaving protease (ADAMTS13) in
patients with sepsis-induced disseminated intravascular
coagulation: its correlation with development of renal
failure. Blood 2006; 107:528-34.
24. Studt JD, Hovinga JA, Antoine G, Hermann M, Rieger
M, Scheiflinger F, et al. Fatal congenital thrombotic
thrombocytopenic purpura with apparent ADAMTS13
inhibitor: in vitro inhibition of ADAMTS13 activity by
hemoglobin. Blood 2005; 105:542-4.
25. Moake JL. Thrombotic microangiopathies. N Engl J
Med 2002; 347:589-600.
26. Taylor FB Jr, Toh CH, Hoots WK, Wada H, Levi M.
Towards definition, clinical and laboratory criteria and
a scoring system for disseminated intravascular coagula-
tion. Thromb Haemost 2001; 86:1327-30.
27. Chou J, Mackman N, Merrill-Skoloff G, Pedersen B,
Furie BC, Furie B. Hematopoietic cell-derived micropar-
ticle tissue factor contributes to fibrin formation during
thrombus propagation. Blood 2004; 104:3190-7.
28. Churchwell KB, McManus ML, Kent P, Gorlin J,
Galacki D, Humphreys D, et al. Intensive blood and
plasma exchange for treatment of coagulopathy in
meningococcemia. J Clin Apheresis 1995; 10:171-7.
29. Gardlund B, Sjolin J, Nilsson A, Roll M, Wickerts CJ,
Wretlind B. Plasma levels of cytokines in primary septic
shock in humans: correlation with disease severity. J
Infect Dis 1995; 172:296-301.
30. Hodgson A, Ryan T, Moriarty J, Mellotte G, Murphy
C, Smith OP. Plasma exchange as a source of protein
C for acute onset protein C pathway failure. Br J
Haematol 2002; 116:905-8.
31. Stegmayr BG, Banga R, Berggren L, Norda R, Rydvall
A, Vikerfors T. Plasma exchange as rescue therapy in
multiple organ failure including acute renal failure. Crit
Care Med 2003; 31:1730-6.
32. van Deuren M, Santman FW, van Dalen R, Sauerwein
RW, Span LF, van der Meer JW. Plasma and whole
blood exchange in meningococcal sepsis. Clin Infect
Dis 1992; 15:424-30.
33. Carcillo JA. Multiple organ system extracorporeal sup-
port in critically ill children. Pediatr Clin North Am
34. Fortenberry JD, Paden ML. Extracorporeal therapies in
the treatment of sepsis: experience and promise. Semin
Pediatr Infect Dis 2006; 17:72-9.
1. Parapia LA. History of bloodletting by phlebotomy. Br
J Haematol 2008; 143:490-5.
Kwaan HC. Miscellaneous secondary thrombotic
microangiopathy. Semin Hematol 1987; 24:141-7.
Levi M, ten Cate H. Disseminated intravascular coagu-
lation. N Engl J Med 1999; 341:586-92.
Asada Y, Sumiyoshi A, Hayashi T, Suzumiya J,
Kaketani K. Immunohistochemistry of vascular lesion
in thrombotic thrombocytopenic purpura, with special
reference to factor VIII related antigen. Thromb Res
Asada Y, Sumiyoshi A. [Histopathology of thrombotic
thrombocytopenic purpura]. Nippon Rinsho 1993;
Burke AP, Mont E, Kolodgie F, Virmani R. Thrombotic
thrombocytopenic purpura causing rapid unexpected
death: value of CD61 immunohistochemical staining
in diagnosis. Cardiovasc Pathol 2005; 14:150-5.
Hosler GA, Cusumano AM, Hutchins GM.
Thrombotic thrombocytopenic purpura and hemolytic
uremic syndrome are distinct pathologic entities. A
review of 56 autopsy cases. Arch Pathol Lab Med 2003;
Tsai HM, Chandler WL, Sarode R, Hoffman R, Jelacic
S, Habeeb RL, et al. von Willebrand factor and von
Willebrand factor-cleaving metalloprotease activity in
Escherichia coli O157:H7-associated hemolytic uremic
syndrome. Pediatr Res 2001; 49:653-9.
Moschcowitz E. Hyaline thrombosis of the terminal
arterioles and capillaries: A hitherto undescribed dis-
ease. Proc NY Pathol Soc 1924; 24:21-4.
10. Moake JL, Rudy CK, Troll JH, Weinstein MJ,
Colannino NM, Azocar J, et al. Unusually large plasma
factor VIII: von Willebrand factor multimers in chron-
ic relapsing thrombotic thrombocytopenic purpura. N
Engl J Med 1982; 307:1432-5.
11. Fowler WE, Fretto LJ, Hamilton KK, Erickson HP,
McKee PA. Substructure of human von Willebrand
factor. J Clin Invest 1985; 76:1491-500.
12. Vischer UM, Wagner DD. von Willebrand factor
proteolytic processing and multimerization precede
the formation of Weibel-Palade bodies. Blood 1994;
13. Wagner DD, Lawrence SO, Ohlsson-Wilhelm BM,
Fay PJ, Marder VJ. Topology and order of formation
of interchain disulfide bonds in von Willebrand factor.
Blood 1987; 69:27-32.
14. Bernardo A, Ball C, Nolasco L, Moake JF, Dong JF.
Effects of inflammatory cytokines on the release and
cleavage of the endothelial cell-derived ultralarge von
Willebrand factor multimers under flow. Blood 2004;
15. Sadler JE. Biochemistry and genetics of von Willebrand
factor. Annu Rev Biochem 1998; 67:395-424.
16. Sporn LA, Marder VJ, Wagner DD. Inducible secre-
tion of large, biologically potent von Willebrand factor
multimers. Cell 1986; 46:185-90.
17. Wagner DD. Cell biology of von Willebrand factor.
Annu Rev Cell Biol 1990; 6:217-46.
18. Furlan M, Robles R, Galbusera M, Remuzzi G, Kyrle
PA, Brenner B, et al. von Willebrand factor-cleaving
protease in thrombotic thrombocytopenic purpura and
the hemolytic-uremic syndrome. N Engl J Med 1998;