L-asparaginase treatment reduces the anticoagulant potential of the protein C system without affecting vitamin K-dependent carboxylation.
The changes in plasma levels of the vitamin K-dependent natural anticoagulants protein C (PC) and protein S (PS) and procoagulant factors II, IX and X were evaluated in 8 adult patients during treatment with L-asparaginase (L-ase i.v. 120,000 U/m2 over 10 days). PC anticoagulant activity and factor IX, X and II coagulant activity decreased proportionally to their half-lives to a nadir of 50-60% of pretreatment values after 2-5 L-ase infusions, suggesting that inhibition of protein synthesis rather than consumption is the main mechanism responsible for the observed changes. Free PS antigen levels declined at a rate similar to total PS antigen, reaching a nadir of 56% of pretreatment values after 3 L-ase infusions; however due to C4b-binding protein levels higher than total PS levels (p less than 0.05), they were constantly lower than the corresponding total PS antigen levels (0.05 less than p less than 0.001). This implicates that total PS antigen levels cannot be taken as an indicator of PS activity. No differences between the antigenic levels and the anticoagulant activities of PC and free PS could be observed suggesting that L-ase does not affect the mechanisms of vitamin K-dependent carboxylation of Gla-residues. The faster rate of decline of PC and PS activities relative to that of factor II may be responsible for the onset of an hypercoagulable state during the early phase of L-ase treatment.
Vigano'D'Angelo
S
S
Servizio di Coagulazione, IRCCS H.S.Raffaele, Milano, Italy.
Gugliotta
L
L
Mattioli Belmonte
M
M
Cascione
M L
ML
Pattarini
E
E
D'Angelo
A
A
D000328:Adult; D000577:Amides / Q000378:metabolism; D001215:Asparaginase / Q000627:therapeutic use*; D001777:Blood Coagulation / Q000187:drug effects*; D001779:Blood Coagulation Factors / Q000187:drug effects; D001798:Blood Proteins / Q000187:drug effects; D019735:Carbon-Carbon Ligases; D002352:Carrier Proteins / Q000187:drug effects; D003169:Complement Inactivator Proteins; D005260:Female; D006023:Glycoproteins / Q000187:drug effects; D006801:Humans; D008025:Ligases / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy; D011486:Protein C / Q000037:antagonists & inhibitors*; D017293:Protein S
D000577:Amides; D001779:Blood Coagulation Factors; D001798:Blood Proteins; D002352:Carrier Proteins; D003169:Complement Inactivator Proteins; D006023:Glycoproteins; D011486:Protein C; D017293:Protein S; D001215:Asparaginase; D008025:Ligases; D019735:Carbon-Carbon Ligases; C020660:glutamyl carboxylase