Impaired platelet aggregation in melanoma patients treated with interferon‐α‐2b adjuvant therapy

Abstract

BACKGROUNDHigh‐dose interferon (INF)‐ α‐2b is the only Food and Drug Administration‐approved adjuvant treatment for patients with melanoma who are at high risk of recurrence. Although circumstantial evidence points to a potentially harmful effect of INF‐α‐2b on platelet function, to the authors' knowledge this has never been studied in humans.METHODSThe study group was comprised of patients who had undergone surgery for melanoma and were free of disease but at a high risk of recurrence. All patients were candidates for adjuvant INF treatment (high‐dose) and were undergoing routine evaluation to which platelet aggregation was added. Aggregation was triggered in standard fashion with adenosine diphosphate, epinephrine, collagen, thrombin, arachidonic acid, and ristocetin. Blood samples were drawn immediately before treatment, during the intravenous loading phase, during the subcutaneous maintenance phase, and 3–6 weeks after cessation of treatment. Patients receiving low‐dose, long‐standing INF‐α‐2b treatment also were tested. All results at each phase were compared with those of normal controls.RESULTSIn those patients receiving high‐dose INF‐α‐2b, ristocetin‐induced aggregation did not appear to be affected. However, the response to ≥ 1 of the other agonists was impaired in 5 of 6 samples during loading, 14 of 15 samples during the maintenance phase, and 8 of 13 samples after treatment, compared with only 1 of 8 samples before treatment (P = 0.025, P = 0.002, and P = 0.067, respectively). During treatment with low‐dose INF, platelet function was affected to a lesser extent.CONCLUSIONSINF treatment in melanoma patients appears to be associated with severe impairment of platelet aggregation, which appears to be dose‐dependent and cumulative–dose‐dependent. This is not detectable by the standard coagulation profile. This effect has significant implications in the event of accidental injury or elective surgery. The antiaggregation activity may be the mechanism by which INF delays, reduces, or prevents the formation of melanoma metastases. Cancer 2002;94:780–5. © 2002 American Cancer Society.DOI 10.1002/cncr.10261

Practical guidelines for the management of interferon‐α‐2b side effects in patients receiving adjuvant treatment for melanoma

“…Therefore, patients may be at increased risk for bleeding diathesis, and platelets should be available for transfusion should surgery be required. 56 Hypertriglyceridemia, typically without elevation of total cholesterol, may be present in patients who are treated with IFN-a. The time of onset is not clear, but hypertriglyceridemia appears to be associated with a longer duration of IFN administration.…”

Side Effects of Interferon-α Therapy

“…Another less frequent cause for thrombopenia or anemia is the induction of autoimmunity, which is addressed below. Next to thrombopenia, IFN-a also affects platelet function as indicated by the observation that IFN-a impairs platelet aggregation 16 .…”

Antiviral therapy decreases GpIIb/IIIa activation of platelets in patients with chronic hepatitis C

“…Monoclonal CD42band CD41 antibodies (both Immunotech, Instrumentation Laboratories) were used to analyseGpIb and GpIIb/ IIIa receptor densities on platelets in whole blood. Furthermore, GpIIb/IIIa activation wasanalysed in plateletrichplasma (8), in washedplatelets (14)and after in vitro incubation with the two-, five-and tenfold meanmaximum serumconcentration (Cmax: 25.6 µg/l) (15) of PegIFN-α 2a.…”

“…In brief, the systemconsistsofadisposable test cartridgewhereaplateletplug occludes amicroscopic aperturecut into amembrane coated with collagen and epinephrine or ADP. The plugformation occurs under high shearflowconditions produced by aconstant vacuumand controlled by acapillary.The timerequired forocclusion (Closure Time,CT) is indicative of global plateletfunction and primary haemostatic capacity.F or this study we used at estc artridge coated with collagenand epinephrine (CEPI), because epinephrine inducedp lateleta ggregation wast he most frequentlya ffected in the studybyGutman et al (8).…”

“…In contrast, Gutmanetal. (8) recently reported impaired plateleta ggregation in response to variousa gonistsi nm elanoma patients receiving high dose treatment with IFN-α 2b.T hese authorsspeculated that IFN-α causes this inhibition of platelet aggregation by acting on the pathway of fibrinogen receptor (GpIIb/IIIa) activation.…”