Page 2250 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 134 Thrombotic Thrombocytopenic Purpura and the Hemolytic Uremic Syndromes 1997

Since CFH, CFI, factor B and C3 are all soluble plasma proteins, with progressive, otherwise unexplained renal insufficiency. MAHA
deficiency or dysfunction is not corrected by renal allografting. The or thrombocytopenia is found in only half these patients and are
outcome of renal transplantation in aHUS has been poor, with a high usually mild. The glomerular capillary and arteriolar thrombotic
rate of failure because of recurrent disease. In fact, the failure rate can lesions are similar in appearance to those in primary cases of TMA.
approach 60% to 70% and failure often occurs within the first month The distinction between calcineurin-induced TMA and acute tubular
after transplantation. The underlying genetic defect is predictive of necrosis or rejection can often be made by biopsy, but not in all cases.
relapse risk, being as high as 80% with mutations in CFH, C3 and Broad alloantibody reactivity and coinfection with cytomegalovirus
factor B, but as low as 20% in patients with defects in MCP or in may predispose to cyclosporin-associated TMA.
those without genetic abnormalities. Before the introduction of The extent to which calcineurin-induced TMA responds to a
eculizumab, combined liver and kidney transplantation was recom- reduction of the dose or temporary discontinuation of medication is
mended; however, the 1-year survival for this complicated procedure uncertain. The prognosis is generally good, although some patients
was disappointing. Anecdotal reports suggest that eculizumab pro- develop permanent renal failure. In many patients, cyclosporin A can
phylaxis may prevent posttransplantation recurrence. be reintroduced at a lower dose; in others, tacrolimus has been sub-
stituted successfully, although the latter may also precipitate TMA.
Other strategies include substitution of an alternative immunomodu-
OTHER THROMBOTIC MICROANGIOPATHIC DISORDERS latory medication. The utility of plasma exchange is uncertain.
Recent evidence suggests that mTOR (mammalian target of
Posttransplantation Thrombotic Microangiopathy rapamycin) inhibitors, such as sirolimus and everolimus, can also be
associated with posttransplant TMA. It is likely that mTOR inhibi-
TMA can occur in three transplant-related settings: (1) recurrent tors impair endothelial function, but the mechanism remains to be
disease after transplantation for a TMA-related disorder, (2) in elucidated.
association with the use of immunosuppressive medications (calci-
neurin inhibitors [cyclosporine A and tacrolimus] and inhibitors of
the mammalian target of rapamycin [mTOR inhibitors sirolimus and Hematopoietic Stem Cell Transplantation
everolimus]) and (3) after hematopoietic stem cell transplantation.
TMA occurs in approximately 6% of patients who undergo allogeneic
Recurrent Disease and “De Novo Thrombotic marrow transplantation; the incidence is estimated to be 0.1% to 1%
after autologous marrow or stem cell transplantation. Though guide-
Microangiopathy” After Renal Transplantation lines have been developed, diagnosis is difficult because schistocytes
and thrombocytopenia are common after bone marrow transplanta-
As indicated previously, there is a high risk of developing recurrent tion, and because the differential diagnosis of fever, renal failure, and
aHUS after renal transplantation in patients with disorders of comple- neurologic complications is extensive. The clinical manifestations
ment regulation. However, it is important to note that the diagnosis typically begin months after transplantation and the kidneys appear
of recurrent TMA depends on the correct diagnosis of the index to be a major target organ. The pathophysiology is assumed to reflect
disorder. Patients with suspected de novo TMA that is subsequently systemic endothelial cell injury from a variety of causes. ADAMTS13
attributed to aHUS may have initially presented with hypertension, activity may fall after transplantation, but severe deficiency such as
renal failure and nephrosclerosis. In a French series of renal transplant occurs in TTP is uncommon. Risk factors include the use of an
recipients whose initial diagnosis was not aHUS, 7 of 24 of those unrelated or mismatched donor, total body irradiation as part of the
diagnosed with de novo aHUS after renal transplantation were shown pretransplant conditioning regimen, calcineurin inhibitor treatment,
to have mutations of CFH or CFI. In the majority of these individu- systemic cytomegalovirus or other infection, older age, female gender,
als, renal failure was attributed to hypertension or chronic glomeru- and graft-versus-host disease (GVHD). Systemic microangiopathy is
lonephritis. No mutations were identified in a control group of renal rare, but an intestinal biopsy may be needed to distinguish TMA
transplant recipients who did not develop TMA, suggesting that from GVHD in patients with refractory diarrhea. Evidence of termi-
underlying defects of complement should be considered when TMA nal complement deposition in the skin may suggest an aHUS-like
develops in the postrenal transplant setting. However, the most cases mechanism.
of posttransplant de novo TMA are attributable to drug toxicity, Withdrawal or substitution of another immunosuppressive agent
rejection, viral infection (such as parvovirus, cytomegalovirus and for cyclosporin A, if possible, should be considered, although at the
hepatitis C), or a combination of these processes. Antibody-mediated risk for worsening of the underlying GVHD. Alternative causes
rejection may be confirmed by demonstrating the presence of major should be sought, and aggressive treatment of infection and GVHD
histocompatibility complex antibody, or by renal biopsy evidence of should be used in all but the most overt cases. It is difficult to
peritubular capillary C4d staining. Antibody-mediated rejection determine the prognosis because of variable inclusion criteria.
associated with TMA has a poorer prognosis than antibody-mediated Although patients may appear to show an initial response to plasma
rejection alone. Plasma exchange therapy appears beneficial in this therapy, the long-term effectiveness of plasma exchange has not been
setting. established and mortality exceeds 50%, often caused by complica-
tions of GVHD or opportunistic infection. Defibrotide has been used
with reported success in a few cases, and there have been anecdotal
Immunosuppressive Medications successes with rituximab, anti-CD25 antibodies and eculizumab.

Cyclosporine A and tacrolimus are common causes of drug-induced
TMAs. The pathogenesis of calcineurin-induced TMA is uncertain. Cancer and Chemotherapy-Associated Thrombotic
Cyclosporine A causes arteriolar vasoconstriction, probably through Microangiopathy
upregulation of endothelin and thromboxane, and downregulation
of vasodilators (nitric oxide and prostacyclin). In vitro studies showed TMA may occur late in the course of some patients with disseminated
that cyclosporin A induces endothelial release of complement activat- malignant neoplasms and large tumor burdens, most commonly
ing microparticles, suggesting both a toxic effect on the cells and a adenocarcinoma of the gastrointestinal tract, breast, or lung. Patients
role for complement in the pathogenesis of renal dysfunction. Cyclo- generally present with an abrupt onset of moderate to severe MAHA
sporin A also enhances platelet aggregation and thromboxane release. and thrombocytopenia. Renal insufficiency and neurologic dysfunc-
TMA occurs in 1% to 5% of renal transplant recipients, as well tion occur less commonly than in idiopathic or chemotherapy-induced
as in occasional solid organ recipients treated with cyclosporin A or TMA and may result from concurrent metabolic disturbances, central
tacrolimus. Calcineurin-induced TMA typically develops insidiously nervous system metastases, stroke, or hemorrhage.