Update on thrombotic microangiopathies: part 2

In my update on thrombotic thrombocytopenia purpura published in [May 10 issue, page 4], I discussed new insights and possible new therapies for this most life-threatening form of thrombotic microangiopathy.

In addition to TTP, the pathophysiology of several other types of microangiopathies has also become clearer in recent years. These include hemolytic uremic syndrome (HUS), thrombotic microangiopathies associated with transplantation-immunosuppression or antiangiogenesis therapy, and the preeclampsia/hemolysis-elevated liver enzymes and low platelets, also known as HELLP syndrome.

Microvascular platelet clumping (fibrin polymer formation) that is either systemic or predominantly renal, thrombocytopenia, erythrocyte fragmentation, and increased serum levels of LDH are also characteristic of the other thrombotic microangiopathies discussed below. Unlike ADAMTS-13-deficient types of TTP, which I discussed in my previous column, the entities to be summarized here are not usually associated with absent or severely reduced plasma ADAMTS-13 activity. This latter finding may explain the poor response of these patients to plasma infusion or exchange.

Hemolytic uremic syndrome

HUS is frequently preceded by hemorrhagic enterocolitis that is usually caused by cytotoxin-producing serotypes of Escherichia coli (eg, 0157:H7). Shiga toxin (Stx)-1 and Stx-2 are cytotoxins produced by enterohemorrhagic E. coli, the bacteria most frequently associated with diarrhea-associated HUS. This relatively common disorder is the result of obstruction of the glomerular microvasculature by platelet-fibrin thrombi. Stx-1 and Stx-2 are transported by white cells to specific globotriaosylceramide (Gb₃) receptors on glomerular endothelial cells where the toxins stimulate the rapid and profuse secretion of long Von Willebrand factor (VWF) multimeric strings.

Platelets immediately adhere to the secreted long VWF strings, and the rate of platelet-VWF string cleavage by ADAMTS-13 is delayed in the presence of Stx-1 or Stx-2 (which may interfere with ADAMTS-13 binding to the VWF strings).

Joel Moake

The initial and progressive platelet adhesion to long VWF strings atop Stx-stimulated glomerular endothelial cells in diarrhea-associated HUS may explain the glomerular microvascular occlusion and acute renal failure.

The “cytokine storm” that accompanies diarrhea-associated HUS augments these processes: tumor necrosis factor (TNF)-alpha, interleukin (IL)-8 and IL-6 (bound to its soluble receptor) stimulate endothelial cell secretion of long VWF strings; IL-6 also interacts with the long VWF strings to inhibit the rate of VWF string cleavage. The inflammatory cytokines, therefore, potentiate the similar effects of Shiga toxins described above. The incorporation of Shiga toxins into glomerular endothelial cells, and the resultant interference with peptide synthesis over the course of hours to days, may cause additional renal endothelial cell injury and subendothelial exposure. Therapy for diarrhea-associated HUS is thus far limited to supportive care for the renal and hematologic complications.

HUS usually occurs as a single episode, except in rare individuals who have a familial, recurrent type of the disease. In these latter patients (often children) with “atypical” HUS, there is inadequately controlled complement attack on renal cells. This can be caused by deficient quantity or defective function of the plasma alternative complement pathway regulatory protein, Factor H. The result is over-activation of complement component 3 (C3) whenever the alternative complement component pathway is activated.

A similar clinical syndrome results from deficiency in another alternative complement pathway control substance, membrane cofactor protein (MCP; CD46), or in deficiency of C3b-cleaving protease (Factor I). It is not yet known whether eculizumab (Soliris, Alexion), the monoclonal antibody to C5 that prevents the formation of the C5b6789 membrane attack complex, may be useful therapy in atypical HUS.

A thrombotic microangiopathy that clinically more often resembles HUS than TTP sometimes occurs weeks to months after exposure to one of the following: cyclosporin or tacrolimus [FK 506], inhibitors of the protein phosphasae 2B (calcineurin) that are often used as immunosuppressants with allogeneic bone marrow or solid organ transplantation; mitomycin; gemcitabine; bevacizumab (Avastin, Genentech), combinations of chemotherapeutic agents; and/or total-body irradiation. Clues to the cause of several of these entities have emerged recently.

Cyclosporin, a cyclic nonapeptide, and tacrolimus, a macrolide, inhibit protein phosphatase 2B (calcineurin) in immune and endothelial cells. The biochemical effect is to maintain some proteins in a phosphorylated state for a prolonged time. Cyclosporin- or tacrolimus-treated endothelial cells profusely secrete long VWF multimeric strings. The latter process may slowly overwhelm the capacity of ADAMTS-13 to defend the microvasculature against platelet thrombotic occlusion and thrombotic microangiopathy.

There may be some analogies with the pathophysiology both of diarrhea-associated HUS (discussed above) and of sepsis/DIC/renal failure. In sepsis/DIC/renal failure, there is cytokine-stimulated VWF string secretion from stimulated endothelial cells associated with the consumption of plasma ADAMTS-13). Treatment for transplantation-immunosuppression-induced or chemotherapy-radiotherapy-associated thrombotic microangiopathy is to date limited to discontinuation of any putative offending drug combined with supportive care.

Bevacizumab is a humanized monoclonal antibody that binds/inactivates vascular endothelial growth factor and has been used as adjunctive antiangiogenesis therapy for various malignant solid tumors. The toxicity of the antibody is that it may bind the VEGF produced by renal epithelial podocytes, cause glomerular endothelial cell dysfunction, and induce a disorder clinically similar to HUS.

Inhibition of VEGF receptor/tyrosine kinase signaling by the antineoplastic agent, sunitinib (Sutent, Pfizer), may also cause thrombotic microangiopathy in occasional recipients of the drug. Discontinuation of bevacizumab or sunitinib is the therapy for this type of thrombotic microangiopathy.

The bevacizumab effect has pathophysiologic analogies to the preeclampsia/HELLP syndrome, a serious microangiopathic complication of pregnancy. In preeclampsia/HELLP, the hypoxic placenta releases soluble extravascular domains of at least two receptors for angiogenic factors: soluble VEGF receptor, which binds/inactivates VEGF; and soluble endoglin (Eng), which binds/inactivates another proangiogenic factor, transforming growth factor beta (TGF-beta). These circulating soluble portions of receptors impede the normal action of VEGF and TGF-beta and contribute to the progressive renal dysfunction/hypertension and hepatic necrosis in preeclampsia/HELLP syndrome.

Delivery of the fetus and placenta is usually effective therapy in preeclampsia/HELLP. It is not yet known if some VEGF formulation may be useful adjunctive treatment for these entities (or for bevacizumab/sunitinib-toxicity).

It is also unknown if an analogous excessive release of one or more soluble antiangiogenic receptors from neoplastic cells during chemotherapy/radiotherapy might cause thrombotic microangiopathy in a subgroup of patients under treatment for malignant disorders.

Considerable progress in elucidating the pathogenesis of several types of thrombotic microangiopathies has been made in recent years. It is likely that the emerging clues will help unravel the causes of the still-mysterious types of thrombotic microangiopathies and lead to overdue therapeutic breakthroughs.

Joel Moake, MD, is a Senior Research Scientist at Rice University and is a member of the HemOnc Today Editorial Board.

For more information:

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• Moake JL. Hematol Oncol Clinics North America. 1996;10:485.
• Mutter WP. Microvasc Res. 2008;75:1.
• Nolasco L. Blood. 2005;106:4199.
• Nolasco LH. J Thromb Haemost. 2009;in press.
• Ono T. Blood. 2006;107:528.