10. Thrombotic Microangiopathies
Thrombotic microangiopathies (TMAs) present with thrombocytopenia, microangiopathic hemolytic anemia, and symptoms of microvascular occlusion. They arise from excess platelet aggregation. TMA has often been associated with low levels of metalloprotease ADAMTS13, which induces cleavage of von Willebrand factor (vWF). Thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS) are the main thrombotic microangiopathies. TMA can be familial, idiopathic or acquired secondary to toxins, pregnancy, infections (e.g., HIV, certain Shigella and E. coli), and drugs.
Although drug-induced TMA is well-documented, its mechanism is not well-determined [41–44]. Immune-mediated or direct toxicity factors are most often proposed. In some patients with drug-induced TMA, autoantibodies to the ADAMTS13 protease are present, in some patients TMA incidence seems to be dose-dependent, and in many cases, there are no “hints” of mechanism at all.
One drug commonly implicated in inducing TMA is the immunosuppressant cyclosporine A (CyA). CyA-induced TMA is seen often in transplant patients (solid or liquid), but also in patients treated for rheumatoid arthritis and uveitis. The mechanism is believed to be a dose-related toxicity. TMA generally resolves once CyA treatment is reduced or discontinued.
Other drugs associated with TMA include chemotherapeutic agents mitomycin-C, gemcitabine, and cisplatin, as well as α-interferon and tacrolimus [41–43]. In patients with metastatic adenocarcinoma, it may be difficult to distinguish drug-induced TMA from anemia, thrombocytopenia, and microangiopathy related to carcinomatosis. Mitomycin-C is a known nephrotoxin, and there is evidence that its mechanism for inducing TMA is a dose-dependent, direct toxic effect on endothelium.
The thienopyridines, antiaggregating agents ticlopidine, and less commonly clopidogrel, have also been implicated in inducing TMA [44]. Ticlopidine-related TPA is more likely to occur after at least two weeks of therapy, to be associated with low ADAMTS13 levels with demonstrable auto-antibodies, and to benefit from plasma exchange therapy. Clopidogrel-induced TMA tends to occur within the first two weeks of treatment, is less likely to be associated with low ADAMTS13 levels and auto-antibodies, and is less likely to benefit from plasma exchange.
Quinine may also induce TMA. The mechanism is immune-mediated. Patients with quinine-induced TMA have been found with antibodies against endothelial cells, lymphocytes, and granulocytes as well as quinine-dependent antibodies including IgG or IgM reactive with platelet glycoprotein Ib/IX or IIb/IIIa. TMA generally resolves with withdrawal of quinine along with plasma exchange [45].