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2003 101: 2446 doi:10.1182/blood-2002-12-3757

No effect of fasting plasma total homocysteine on protein C activity in vitro GianMarco Podda, Elena M. Faioni, Maddalena L. Zighetti and Marco Cattaneo

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Correspondence

To the editor: Severe skin reaction to imatinib in a case of Philadelphia-positive acute lymphoblastic leukemia STI571 (imatinib) is increasingly being used in the treatment of different phases of chronic myeloid leukemia and metastatic gastrointestinal stromal tumors.1,2 Philadelphia-positive acute lymphoblastic leukemia (Ph⫹ALL) has a poor prognosis with the current treatment options.3 Allogenic stem cell transplantation is the only curative management option available to date, the long-term survival being 35% to 65%4 in first complete remission, and poorer in second and third remissions. In a phase 2 trial with relapsed or refractory Ph⫹ALL, imatinib induced hematologic responses in 60% of cases.5 In this journal, Rule et al6 recently reported that imatinib treatment can be continued in patients with skin eruptions by using concomitant short-term steroid therapy or by reintroducing imatinib with gradual dose escalation. The present study describes a case of Ph⫹ALL with a severe adverse cutaneous reaction to imatinib, and its course upon reintroducing imatinib. A 72-year-old white woman with Ph⫹ALL showed hematologic response with induction therapy (vincristine, daunorrubicine, cyclophosphamide, and prednisolone). Maintenance therapy was started with mercaptopurine, after which imatinib was continued at a dose of 400 mg/d. After 17 days of treatment, the patient developed an erythematous maculopapular and mildly pruritic rash, with erosive ulcers on the mouth. The rash affected the back, abdomen, and upper and lower limbs. Some papules had a vesiculated center whereas others were target lesions. A papule biopsy diagnosed drug-induced erythema multiforme with folliculitis. Imatinib was discontinued and prednisolone was introduced. The patient refused to restart imatinib and continued with mercaptopurine alone. ALL relapsed 3 months later, followed by second complete remission with reinduction chemotherapy. At this point the patient agreed to restart treatment with imatinib. We decided to start with a low imatinib dose (100 mg/d) associated to prednisolone (30 mg/d). There were no further recurrences in skin eruption and presently, 30 days later, the dose is well tolerated. As a result, the imatinib dosage has been increased to 400 mg/d, with continuation of prednisolone at 10 mg/d.

Erythema multiforme is a severe adverse cutaneous reaction producing important morbidity.7,8 In patients treated with imatinib, 7% to 21% suffer adverse cutaneous reactions.9 This incidence appears to be dose-dependent, and 5% of such reactions are severe or life-threatening.9 In coincidence with Rule et al,1 the present case shows that imatinib can be reintroduced when it is associated to steroids over the short-term, even in patients with severe adverse cutaneous reactions. Blanca Sanchez-Gonzalez, Jose C. Pascual-Ramirez, Pascual Fernandez-Abellan, Isabel Belinchon-Romero, Concepcion Rivas, and Gloria Vegara-Aguilera Correspondence: Blanca Sanchez-Gonzalez, Hospital General Universitario, Hematology, Alicante, Spain; e-mail: [email protected]

References 1.

Savage DG, Antman KH. Imatinib mesylate: a new oral targeted therapy. N Engl J Med. 2002;346:683-693.

2.

Demetri GD, Von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 2002; 347:472-480.

3.

Faderl S, Kantarjian HM, Thomas DA, et al. Outcome of Philadelphia chromosome-positive adult acute lymphoblastic leukemia. Leuk Lymphoma. 2000;36: 263-273.

4.

Snyder DS, Nademanee AP, O’Donnell MR, et al. Long-term follow-up of 23 patients with Philadelphia chromosome-positive acute lymphoblastic leukemia treated with allogenic bone marrow transplant in first complete remission. Leukemia. 1999;13:2053-2058.

5.

Ottman O, Druker B, Sawyers C, et al. A phase II study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. Blood. 2002;100:1965-1971.

6.

Rule SA, O’Brien SG, Crossman LC. Managing cutaneous reactions to imatinib therapy. Blood. 2002;100:3434-3435.

7.

Forman R, Koren G, Shear NH. Erythema multiforme, Steven-Johnson syndrome and toxic epidermal necrolysis in children: a review of 10 years experience. Drug Saf. 2002;25:965-972.

8.

Hsiao LT, Chung HM, Lin JT, et al. Stevens-Johnson syndrome after treatment with STI571: a case report. Br J Haematol. 2002;117:620-622.

9.

Brouard MV, Saurat JH. Cutaneous reactions to STI571. N Eng J Med. 2001;345:618-619.

To the editor: No effect of fasting plasma total homocysteine on protein C activity in vitro Although the association between the plasma levels of total homocysteine (tHcy) and the risk of atherosclerosis and thrombosis is well documented, the mechanism(s) by which hyperhomocysteinemia might contribute to atherogenesis and thrombogenesis are scarcely understood.1 In vitro studies showed that homocysteine, among other effects, inhibits both protein C activation and the activity of activated protein C (APC).1,2 The inhibition of APC activity in vitro apparently depends on the interaction of homocysteine with cysteine residues of factor V, which interferes with the

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proteolytic action of APC on factor Va, resulting in APC resistance, a very common and well-established risk factor for venous thromboembolism.2 However, several in vitro findings have not been confirmed in in vivo studies. For instance, in a study of healthy individuals and patients with previous thrombotic events, Cattaneo et al3 showed that neither the fasting plasma levels of tHcy nor their acute increase after an oral methionine load affects the plasma concentration of APC. These data, which suggest that hyperhomocysteinemia does not interfere with protein C activation

BLOOD, 15 MARCH 2003 䡠 VOLUME 101, NUMBER 6

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in vivo, have recently been supported by the results of the study by Lentz et al,4 which showed that hyperhomocysteinemia did not interfere with protein C activation in vivo in cynomolgus monkeys to which an intravenous injection of thrombin had been administered. In the same study, Lentz et al4 showed that hyperhomocysteinemia did not interfere with the in vitro inactivation of factor V by APC in mice deficient in cystathionine-␤-synthase nor in 10 human volunteers in whom hyperhomocysteinemia was acutely induced by an oral methionine load. Like Lentz and collaborators, we recently addressed the problem of whether or not hyperhomocysteinemia influences the anticoagulant response to APC. We studied subjects referred to our center between June 1991 and December 2001 to undergo screening for thrombophilic states, which included the measurement of fasting tHcy and the in vitro anticoagulant response to APC. The plasma levels of tHcy were measured by high-performance liquid chromatography (HPLC) and fluorometric detection5; APC resistance was measured using an activated partial thromboplastin time (APTT)–based clotting assay using undiluted patient plasma. The results were expressed as normalized ratios.6 Hyperhomocysteinemia was diagnosed when the plasma tHcy exceeded the 90th percentile of distribution of values obtained in a population of 553 healthy subjects (14.8 ␮M). We enrolled 1254 subjects (median age 43 years, range 9-83 years) who had normal APTT and absence of factor V Leiden (the most common congenital cause of APC resistance7). Of these subjects, 730 were women, of whom 108 (15%) used oral contraceptives; 434 (34.6%) had previous episodes of venous or arterial thrombosis; and 820 had a negative personal history for thrombosis. The plasma levels of tHcy ranged from 3.9 ␮M to 223 ␮M in the subjects studied. The mean APC normalized ratio of subjects with normal tHcy plasma levels (0.97 ⫾ 0.13) was not different from that of subjects with hyperhomocysteinemia (0.96 ⫾ 0.16, P ⫽ .73). There was no statistically significant correlation between the plasma levels of fasting tHcy and APC ratio (Table 1) whether considering the total number of subjects, those with hyperhomocysteinemia, or those with previous

CORRESPONDENCE

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Table 1. Correlation coefficients between APC ratio and fasting plasma tHey concentration

All subjects

N

r

P

1254

⫺0.10

.73

Subjects with hyperhomocysteinemia*

147

⫺0.02

.99

Subjects with thrombotic event

434

⫺0.04

.45

Subjects without thrombotic event

820

0.03

.39

*In subjects with hyperhomocysteinemia, 34 had plasma levels of tHcy 30 ␮M, a concentration that caused APC resistance in an in vitro study.2

thrombotic events. In conclusion, in agreement with Lentz et al,4 our findings do not support the hypothesis that hyperhomocysteinemia negatively affects the in vitro anticoagulant response to APC. GianMarco Podda, Elena M. Faioni, Maddalena L. Zighetti, and Marco Cattaneo Correspondence: Marco Cattaneo, Unita` di Ematologia e Trombosi, Ospedale San Paolo, DMCO University of Milano, Via di Rudinı`, 8 20142 Milano, Italy; e-mail: [email protected]

References 1.

Cattaneo M. Hyperhomocysteinemia and thrombosis. Lipids. 2001;36(suppl): S13-S26.

2.

Undas A, Williams EB, Butenas S, Orfeo T, Mann KG. Homocysteine inhibits inactivation of factor Va by activated protein C. J Biol Chem. 2001;276:43894397.

3.

Cattaneo M, Franchi F, Zighetti ML, Martinelli I, Asti D, Mannucci PM. Plasma levels of activated protein C in healthy subjects and patients with previous venous thromboembolism: relationships with plasma homocysteine levels. Arterioscler Thromb Vasc Biol. 1998;18:1371-1375.

4.

Lentz SR, Piegors DJ, Fernandez JA, et al. Effect of hyperhomocysteinemia on protein C activation and activity. Blood. 2002;100:2108-2112.

5.

Zighetti ML, Cattaneo M, Falcon CR, et al. Absence of hyperhomocysteinemia in ten patients with primary pulmonary hypertension. Thromb Res. 1997;85: 279-282.

6.

Faioni EM, Franchi F, Asti D, Sacchi E, Bernardi F, Mannucci PM. Resistance to activated protein C in nine thrombophilic families: interference in a protein S functional assay. Thromb Haemost. 1993;70:1067-1071.

7.

Tripodi A, Mannucci PM. Laboratory investigation of thrombophilia. Clin Chem. 2001;47:1597-1606.

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