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Relevance of Proteins C and S, Antithrombin III, Von Willebrand

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Bone Marrow Transplantation, (1998) 22, 883–888 1998 Stockton Press All rights reserved 0268–3369/98 $12.00 http://www.stockton-press.co.uk/bmt Relevance of proteins C and S, antithrombin III, von Willebrand factor, and factor VIII for the development of hepatic veno-occlusive disease in patients undergoing allogeneic bone marrow transplantation: a prospective study J-H Lee1, K-H Lee1, S Kim1, J-S Lee1, W-K Kim1, C-J Park2, H-S Chi2 and S-H Kim1 Division of Oncology-Hematology, Departments of 1Medicine and 2Clinical Pathology, Asan Medical Center, University of Ulsan, Seoul, Korea Summary: ted venules. Factors that enhance hypercoagulability fol- lowing BMT may have a pathogenetic role in the Factors that enhance hypercoagulability following BMT development of VOD.4 In fact, a decrease in the natural may have a pathogenetic role in VOD. To investigate anticoagulants such as protein C,5,6 protein S5 and the relevance of hemostatic parameters for the develop- antithrombin III (AT III)6 as well as an increase in plasma ment of VOD, we prospectively measured protein C, fibrinogen4 and von Willebrand factor (vWF)7 have been protein S, antithrombin III (AT III), von Willebrand observed after BMT. Several investigators have reported factor, and factor VIII in 50 consecutive patients that these hemostatic derangements may have pathogenetic undergoing allogeneic BMT. Each parameter was relevance for the occurrence of VOD.8–10 determined before conditioning, on day 0 of BMT and In this study, we prospectively measured the levels of weekly for 3 weeks, and patients were monitored pro- protein C, protein S (total and free), AT III, vWF and factor spectively for the occurrence of VOD. VOD occurred in VIII in 50 consecutive patients undergoing allogeneic -patients at median post-BMT day 8.5 (range, day ؊2 BMT. We investigated the predictive value of these hemo 26 to 17). Thirteen patients had mild, 10 had moderate and static parameters for the development of VOD after allo- three had severe VOD. No coagulation parameters were geneic BMT. Changes in the hemostatic parameters were significantly different at the baseline or on day 0 of correlated with subsequent clinical course particularly with BMT between patients with no/mild VOD and moderate regard to the development and severity of VOD. to severe VOD. On day 7 and thereafter, levels of pro- tein C and AT III were significantly lower in patients with moderate to severe VOD when compared to Patients and methods patients with no/mild VOD. Levels of protein C and AT III decreased before the clinical onset of VOD in Patients patients with moderate to severe VOD. Early post-BMT reduction of these parameters may indicate the develop- All patients who underwent allogeneic BMT in the Asan ment of moderate to severe VOD. Medical Center from October 1995 to February 1998 were Keywords: BMT; VOD; coagulation parameters enrolled into the study. The following preparative regimens were used: BUCY (busulfan 16 mg/kg and cyclophospham- ide 120 mg/kg) for leukemia/MDS, BUCY plus etoposide for CML in blastic phase, BUCY plus melphalan for neuro- Veno-occlusive disease (VOD) of the liver is a major early blastoma, and CY-ATG (cyclophosphamide 200 mg/kg and complication of bone marrow transplantation (BMT).1,2 antithymocyte globulin 90 mg/kg) for SAA. All patients Typical clinical features of VOD include hyperbilirubin- received cyclosporine and methotrexate for prophylaxis of emia, painful hepatomegaly and fluid retention. Histologi- graft-versus-host disease (GVHD). For the prevention of cally, VOD is characterized by deposition of factor VIII VOD, heparin was administered to those patients who and fibrinogen in the subenthothelial zones of affected ven- received the BUCY-based regimen, at a rate of 100 ules and by necrosis of hepatocytes in zone 3 of the liver units/kg/day from day Ϫ7 to day 30. Heparin was discon- acinus.3 Endothelial damage induced by high-dose chemo- tinued if there was clinically significant bleeding or the PTT radiation therapy is believed to be the key event in the exceeded 1.2 times the upper limit of control. pathogenesis of VOD. This endothelial injury triggers the coagulation cascade, induces thrombosis of the hepatic ven- ules and eventually leads to fibrous obliteration of the affec- Diagnosis of hepatic VOD All enrolled patients were monitored prospectively for the Correspondence: J-H Lee, Department of Medicine, Asan Medical Center, occurrence of VOD. A diagnosis of VOD was made accord- 11 388-1 Poongnap-dong, Songpa-ku, Seoul 138-040, Korea ing to clinical criteria, as having two of the following Received 3 April 1998; accepted 20 June 1998 before day 20 post-transplant: (1) hyperbilirubinemia Coagulation parameters in VOD after allogeneic BMT J-H Lee et al 884 (bilirubin у2.0 mg/dl or 34.2 ␮mol/l), (2) painful hepato- in one. At the time of BMT 13 patients had high-risk fea- megaly, and (3) unexplained weight gain (Ͼ2% from tures: AML in second remission (two patients), CML in baseline), no other explanation for these signs and symp- blastic phase (one patient), refractory anemia of excess toms being present at the time of diagnosis. Severity of blasts (RAEB) (two patients), RAEB in transformation (one VOD was classified into mild, moderate or severe.1 Patients patient), chemotherapy-resistant neuroblastoma (one who met the criteria for VOD, but who were not treated patient), and heavily transfused SAA (six patients). Forty- and whose illness was self-limited, were considered to have seven patients received allogeneic marrow grafts from mild VOD. Those whose VOD resolved but who received HLA-identical siblings, one patient from an HLA-mis- treatment such as diuretics for fluid retention or narcotic matched sibling, and two from HLA-phenotypically ident- analgesics for painful hepatomegaly, were considered to ical unrelated donors. Heparin was administered for have moderate VOD. Patients who died of VOD or whose prophylaxis of VOD in 40 patients. In 24 patients, heparin VOD did not resolve by 100 days post-transplant were con- was discontinued before day 10 post-transplant because of sidered to have severe VOD. Onset of VOD was defined PTT prolongation and/or evidence of bleeding. as the day on which total serum bilirubin exceeded 2.0 Of the 50 patients enrolled, 26 developed VOD (52.0%). mg/dl (34.2 ␮mol/l) or body weight increased more than Table 1 illustrates the patient characteristics which were 2% above the baseline. putative risk factors for the development of VOD. In univa- riate analysis, male sex (P = 0.049) and a larger amount of red cell transfusion prior to BMT (P = 0.048) were signifi- Assays of hemostatic parameters cant risk factors for VOD. However, these factors lost their Changes in protein C, protein S (total and free), AT III, significance after multivariate analysis using a multiple vWF antigen and factor VIII were monitored in all enrolled logistic regression model (P = 0.054 for male sex, P = patients. Each hemostatic parameter was determined before 0.390 for red cell transfusion). preparative chemotherapy, on the day of marrow infusion (day 0), and on days 7, 14 and 21. Protein C was measured Clinical features of the patients with VOD by a commercially available enzyme-linked immunosorbent assay (ELISA) using monoclonal antibodies (Asserachrom- Of 26 patients with VOD, 13 (50.0%) had mild, 10 (38.0%) Protein C; Stago, Asnie`res, France). Protein S (total and had moderate and three (12.0%) had severe VOD. Seven- free) and vWF antigen were also determined by a commer- teen patients (65.4%) satisfied all three clinical criteria for cially available ELISA using monoclonal antibodies VOD. The frequencies of clinical features associated with (Asserachrom-Total Protein S, Asserachrom-Free Protein VOD were as follows: unexplained weight gain in 25 S, Asserachrom-vWF; Stago). Antithrombin III was meas- (96.2%), hyperbilirubinemia in 23 (88.5%), painful hepato- ured by chromogenic assay (Stachrome-AT III; Stago). megaly in 21 (80.8%), ascites in 13 (50%), peripheral Factor VIII was measured using Stago-Deficient VIII edema in four (15.4%) and azotemia in four (15.4%). The (Stago). median onset of VOD was day 8.5 (range, day Ϫ2today 17) in all patients with VOD, day 11 (range, day 1 to day 17) in patients with mild VOD, and day 8 (range, day Ϫ2 Statistical analysis to day 13) in patients with moderate to severe VOD. The Individual characteristics were analyzed using the ␹2 test median duration of VOD was 27 days (range, 10 to 103 for association with development of VOD. The multiple days). All patients with VOD received supportive care only, logistic regression model was used for subsequent multi- without specific treatment such as recombinant tissue plas- variate analysis. The one-way ANOVA test was used to minogen activator. Clinical outcomes according to the analyze differences in the values of each hemostatic para- occurrence and severity of VOD were analyzed in terms meter at different times between patients with no VOD, of engraftment probabilities, transfusion requirements, and mild VOD and moderate to severe VOD. Changes of each mortality at day 100 post-transplant (Table 2). Platelet hemostatic parameter from the baseline values were ana- engraftment, which was defined as a platelet count of over lyzed using the paired t-test. Probabilities of engraftment 20 × 106/l without platelet transfusions, was significantly and survival were calculated using the Kaplan–Meier slower in patients with VOD and severity of VOD corre- method and compared by log-rank analysis. lated with degree of delay in platelet engraftment (P = 0.005). Patients with VOD also required a larger amount of platelet transfusion (P = 0.011).
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