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1 Division of Transfusion Medicine and Hemostasis, Department of Address for correspondence Ravi Sarode, MD, Department of
Pathology, UT Southwestern Medical Center, Dallas, Texas Pathology, University of Texas Southwestern Medical Center, 5909
Harry Hines Boulevard, HA2.179, Dallas, TX 75390-9234
Semin Thromb Hemost 2015;41:556562. (e-mail: ravi.sarode@utsouthwestern.edu).
Thrombotic microangiopathy (TMA) represents a nal com- cular clusters of cancer cells, a manifestation of metastatic
mon pathway of a diverse group of disorders characterized by tumor spread. TTP is the most important cause of TMA that
microvascular occlusive thrombosis and vasculopathy. It continues to have high morbidity and mortality. Other
manifests as microangiopathic hemolytic anemia (MAHA) important causes of TMA include classic HUS (Shiga toxin
and thrombocytopenia. The severity of clinical manifestations associated) or atypical HUS (aHUS), secondary to complement
depends on the degree of tissue ischemia and damage to pathway dysregulation. Table 1 shows broad classication
target organs. Despite the similarity of clinical manifestations, of TMAs.
the etiopathogenic factors are diverse. Recently, there have been advances in understanding of
There are four types of lesions that have been described in the role of the neutrophils in inammation and possibly
TMA1: (1) von Willebrand factor (VWF)platelet thrombi thrombosis through the formation of neutrophil extracellular
with no or minimal microangiopathythis mechanism is traps (NETs). The process of NETs formation is called netosis,
seen in thrombotic thrombocytopenic purpura (TTP); (2) which is a specic type of cell death different from necrosis
brinplatelet thrombi, as seen in disseminated intravascular and apoptosis.2 The NETs consist of neutrophil nuclear DNA
coagulation (DIC); (3) inammatory or proliferative micro- bers in extracellular space and are formed in response to
angiopathy accompanied with variable brin thrombi, as seen infection, acute and chronic inammation, and activated
in hemolytic uremic syndrome (HUS), systemic lupus eryth- platelets. The NETs have been shown to be elevated in stroke,
ematosus (SLE), or scleroderma renal crisis; and (4) intravas- myocardial infarction, and TTP.3 The organisms are trapped in
published online Issue Theme Inammation, Endothelial Copyright 2015 by Thieme Medical DOI http://dx.doi.org/
August 15, 2015 Dysfunction, and Thromboembolism; Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0035-1556587.
Guest Editors: Bashir A. Lwaleed, PhD, New York, NY 10001, USA. ISSN 0094-6176.
FRCPath, Rashid S. Kazmi, MRCP, Tel: +1(212) 584-4662.
FRCPath, and Alan J. Cooper, PhD.
Thrombosis, Microangiopathies, and Inflammation Matevosyan, Sarode 557
Abbreviations: aHUS, atypical hemolytic uremic syndrome; TTP, thrombotic thrombocytopenic purpura.
activation of the alternative complement pathway.18 This demonstrated to be of prognostic value in guiding therapy
nding may have an implication for the use of eculizumab because of poor correlation between ADAMTS-13 results and
(described later) in refractory or relapsing TTP. clinical-hematologic progression of TTP course.20
to a month after discontinuation of TPE. Patients treated with variable responses; however, once severe ADAMTS-13 de-
caplacizumab in conjunction with the standard of care ciency is ruled out, TPE should be discontinued and a diag-
achieved normalization of platelet counts in half the time nosis of aHUS should be entertained. Eculizumab was
compared with placebo group (p 0.013). A complete remis- recently approved for the treatment of aHUS. Eculizumab is
sion was achieved in 81% in the caplacizumab group com- a chimeric humanized monoclonal IgG2/4 antibody that
pared with 46% in the placebo group. Also, patients treated binds to complement factor 5, inhibiting the conversion of
with caplacizumab had 73% fewer exacerbations compared C5 to C5a and C5b by C5 convertase. This prevents the
with the placebo group.39 formation of C5b-9, the membrane attack complex.42 The
Aptamers are nucleic acid macromolecules that bind with patients generally need a long-term therapy to prevent
high afnity and specicity to specic molecular protein permanent end organ damage. Close monitoring of renal
targets. A pilot study assessed safety, pharmacokinetics and function, platelet counts, and hemolysis markers is recom-
pharmacodynamics of ARC1779, a pegylated anti-VWF DNA/ mended following discontinuation of eculizumab.
RNA aptamer. ARC1779 inhibits VWFplatelet interaction by
binding to the A1 domain of VWF.40,41 These are some
Drug-Induced Thrombotic Microangiopathy
promising alternate therapies desperately needed for relaps-
ing and refractory patients. Drugs may cause TMA by immunologic or nonimmune (toxic)
Availability of these rapid-acting drugs to prevent ongoing mechanisms.
microthromboses may be a very important treatment strate- Autoimmune mechanism is implicated in quinine-induced
gy to possibly prevent late neurocognitive complications TMA, whereas the nonimmune mechanism is responsible for
observed in many TTP patients. the TMA caused by clopidogrel, calcineurin inhibitors (cyclo-
and mortality. HELLP complicates 0.2 to 0.8% of pregnan- nolytic systems by bacterial toxins induces a proinamma-
cies.51 Its pathogenesis is not completely understood, but tory and prothrombotic state.57 This cytokine storm leads to
thought to be related to inadequate placentation secondary to consumptive coagulopathy with TMA and multisystem organ
maternal immune response to invading trophoblast. Direct failure syndrome associated with high mortality (70%).58
liver damage by various placental factors released into the Patients with severe sepsis demonstrate elevated plasma
maternal circulation leads to release of TNF- causing wide- levels of various proinammatory cytokines, such as TNF-,
spread inammation with endothelial cell damage and dys- IL-1, and IL-6. Acquired moderate ADAMTS-13 functional
function.52 The complement system, a key mediator of deciency is seen in certain patients with severe sepsis and is
systemic inammatory response, is also excessively activated associated with poor outcomes.59,60 Its mechanism is poten-
in HELLP syndrome.53 Endothelial activation leads to the tially related to IL-6mediated inhibition. ADAMTS-13 func-
release of large multimers of VWF in a GPIb binding tional deciency was suggested as a prognostic factor for
conformation. Moderate deciency of ADAMTS-13 activity mortality in patients with septic shock, independent of DIC.61
(2050% of normal) due to liver dysfunction may explain There is a signicant reduction in antithrombin and protein C
thrombocytopenia and platelet-rich thrombi in HELLP levels secondary to consumption, severe inammation, im-
syndrome.54 paired synthesis, and degradation by neutrophil elastase.62
The denitive treatment of HELLP syndrome is urgent Therapy is aimed at the eradication of infection and
delivery when possible. Intravenous steroids (dexametha- supportive care. Early initiation of TPE benets these patients
sone), magnesium sulfate, and prevention of sustained severe possibly by removing cytokines, NETs, activated clotting
systolic hypertension to arrest disease progression are the factors and complement components, brin-split products,
mainstay of therapy.51 TPE may have a role if the clinical and by supplementation of normal plasma factors.57
compared with currently marketed antiplatelet drugs. Blood 2011; 52 Johal T, Lees CC, Everett TR, Wilkinson IB. The nitric oxide pathway
118(3):757765 and possible therapeutic options in pre-eclampsia. Br J Clin
39 Results of the TITAN study for Caplacizumab. In Ablynx. Webcast Pharmacol 2014;78(2):244257
presentation. June 17, 2014. Available at: http://www.ablynx.com/ 53 Derzsy Z, Prohszka Z, Rig J Jr, Fst G, Molvarec A. Activation of
uploads/data/les/webcast-titan-_17-june-2014.pdf. Accessed the complement system in normal pregnancy and preeclampsia.
June 17, 2014 Mol Immunol 2010;47(7-8):15001506
40 Jilma-Stohlawetz P, Gorczyca ME, Jilma B, Siller-Matula J, Gilbert 54 Pourrat O, Coudroy R, Pierre F. ADAMTS13 deciency in severe
JC, Knbl P. Inhibition of von Willebrand factor by ARC1779 in postpartum HELLP syndrome. Br J Haematol 2013;163(3):
patients with acute thrombotic thrombocytopenic purpura. 409410
Thromb Haemost 2011;105(3):545552 55 Burwick RM, Feinberg BB. Eculizumab for the treatment of
41 Jilma-Stohlawetz P, Gilbert JC, Gorczyca ME, Knbl P, Jilma B. A preeclampsia/HELLP syndrome. Placenta 2013;34(2):
dose ranging phase I/II trial of the von Willebrand factor inhibiting 201203
aptamer ARC1779 in patients with congenital thrombotic throm- 56 Espinosa G, Rodrguez-Pint I, Gomez-Puerta JA, Pons-Estel G,
bocytopenic purpura. Thromb Haemost 2011;106(3):539547 Cervera R; Catastrophic Antiphospholipid Syndrome (CAPS) Reg-
42 George JN, Nester CM. Syndromes of thrombotic microangiopathy. istry Project Group (European Forum on Antiphospholipid Anti-
N Engl J Med 2014;371(7):654666 bodies). Relapsing catastrophic antiphospholipid syndrome
43 Dragon-Durey MA, Blanc C, Marliot F, et al. The high frequency of potential role of microangiopathic hemolytic anemia in disease
complement factor H related CFHR1 gene deletion is restricted to relapses. Semin Arthritis Rheum 2013;42(4):417423
specic subgroups of patients with atypical haemolytic uraemic 57 De Simone N, Racsa L, Bevan S, et al. Therapeutic plasma exchange
syndrome. J Med Genet 2009;46(7):447450 in the management of sepsis and multiple organ dysfunction
44 Bienaime F, Dragon-Durey MA, Regnier CH, et al. Mutations in syndrome: a report of three cases. J Clin Apher 2014;29(2):
components of complement inuence the outcome of Factor I- 127131
associated atypical hemolytic uremic syndrome. Kidney Int 2010; 58 Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of