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

Home , Factor VIII, Protein C deficiency, Von Willebrand factor

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 following 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 protein 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 cyclophosphamide 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 venules 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). Mortality rates at day Results 100 post-transplant were 5.0, 7.7 and 25.0%, respectively for patients with no VOD, mild VOD and moderate to = Patient characteristics severe VOD (P 0.116). Fifty patients, 30 males and 20 females, were enrolled in Natural anticoagulants (protein C, protein S and AT III) the study. The median age of the patients was 32.5 years (range, 16–49). The indication for BMT was acute myelo- As shown in Table 3, none of the parameters were signifi- cytic leukemia (AML) in 22 patients, acute lymphoblastic cantly different at the baseline or on day 0 of BMT between leukemia (ALL) in five, chronic myelocytic leukemia patients with and without subsequent VOD. On day 7, the (CML) in nine, severe aplastic anemia (SAA) in nine, mye- mean plasma levels of protein C and AT III were signifi- lodysplastic syndrome (MDS) in four, and neuroblastoma cantly lower in patients with moderate to severe VOD when Coagulation parameters in VOD after allogeneic BMT J-H Lee et al 885 Table 1 Patient characteristics which were putative risk factors for the development of VOD

Patient characteristics Patients with VOD Patients without VOD P value (n = 26) (n = 24)

Sex Male 19 11 0.049 Female 7 13 Age (years) р30 12 9 0.536 Ͼ30 14 15 Diagnosis Acute leukemia/MDS 20 11 0.069 CML 2 7 SAA 4 5 Neuroblastoma 1 Disease status at BMT Standard risk 20 17 0.624 High risk 6 7 Donor–recipient ABO incompatibility No 12 10 0.749 Yes 14 14 Donor–recipient sex mismatch No 15 11 0.402 Yes 11 13 Time to BMT from diagnosis (day) р120 13 12 1.000 Ͼ120 13 12 Amount of transfusion prior to BMT Red blood cells р10 units 6 12 0.048 Ͼ10 units 20 12 Platelets р40 units 11 15 0.153 Ͼ40 units 15 9 History of liver disease prior to BMT No 21 19 0.887 Yes 5 5 Liver function tests Alanine aminotransferase Ͻ40 IU/l 14 16 0.355 у40 IU/l 12 8 Aspartate aminotransferase Ͻ40 IU/l 21 20 0.814 у40 IU/l 5 4 Positivity of hepatitis B virus antigen Negative 22 21 0.769 Positive 4 3 Infection within a week prior to BMT No 22 22 0.443 Yes 4 2 Use of heparin prophylaxis No 5 5 0.887 Yes 21 19 Preparative regimen BUCY based 22 19 0.616 CY-ATG 4 5

compared to patients with no/mild VOD (P = 0.007 for VOD and with moderate to severe VOD, except for the day protein C, P = 0.034 for AT III). These differences were 14 level of total protein S in mild VOD patients. also significant on day 14 (P Ͻ 0.000 for protein C, P = When compared with the baseline, a significant decrease 0.030 for AT III) and day 21 (P = 0.001 for protein C, P in mean plasma level of natural anticoagulants was Ͻ 0.000 for AT III). Mean plasma levels of protein C and observed in patients with moderate to severe VOD. Protein AT III decreased with time between day 7 and day 21 in C level decreased significantly from the baseline on day 14 the patients with moderate to severe VOD, and was vir- (91 vs 53%, P = 0.038) and day 21 (91 vs 49%, P = 0.041) tually parallel without significant change in patients with in patients with moderate to severe VOD (Figure 1). no/mild VOD (Figures 1 and 2). The mean plasma levels Changes in AT III were similar to those in protein C of total and free protein S showed no significant difference (Figure 2). The mean plasma level of AT III on day 21 fell at five different time points between patients with no/mild significantly when compared to the baseline level in Coagulation parameters in VOD after allogeneic BMT J-H Lee et al 886 Table 2 Clinical outcomes of patients according to the occurrence and severity of VOD

Clinical outcomes No VOD Mild VOD Moderate to P value (n = 24) (n = 13) severe VOD (n = 13)

Time to engraftment Neutrophils (у500/␮l) Day 12–22 Day 14–25 Day 11–26 0.527b (median 16) (median 17) (median 16) Platelets (у20 000/␮l) Day 16–60 Day 19–90 Day 23–88 0.005b (median 26) (median 33) (median 40) Transfusion requirements Red blood cells 0–16 units 4–30 units 4–52 units 0.174c (mean 7.5) (mean 10.8) (mean 12.7) Plateletsa 30–191 units 54–218 units 54–763 units 0.011c (mean 82.2) (mean 129.3) (mean 193.5) Mortality at day 100 post-transplant 5.0% 7.7% 25.0% 0.116b

aOne unit of single donor pheresis was calculated as 6 units of random donor platelet concentrates. bLog-rank test. cOne-way ANOVA test.

Table 3 Plasma levels of coagulation parameters at ﬁve different times in the patients with no, mild and moderate to severe VOD

VOD Baseline Day 0 Day 7 Day 14 Day 21

Protein C (%) No 82 Ϯ 27 83 Ϯ 20 89 Ϯ 22 77 Ϯ 21 75 Ϯ 19 Mild 84 Ϯ 16 98 Ϯ 36 94 Ϯ 31 82 Ϯ 19 76 Ϯ 29 Moderate/severe 91 Ϯ 53 91 Ϯ 29 63 Ϯ 31 53 Ϯ 14 49 Ϯ 15 P value 0.724 0.308 0.007 Ͻ0.001 0.001 Protein S, total (%) No 79 Ϯ 28 76 Ϯ 23 88 Ϯ 24 78 Ϯ 21 77 Ϯ 28 Mild 90 Ϯ 38 102 Ϯ 56 91 Ϯ 32 99 Ϯ 30 88 Ϯ 26 Moderate/severe 92 Ϯ 24 89 Ϯ 19 77 Ϯ 21 73 Ϯ 18 74 Ϯ 23 P value 0.490 0.139 0.395 0.023 0.399 Protein S, free (%) No 72 Ϯ 24 59 Ϯ 19 70 Ϯ 21 69 Ϯ 19 66 Ϯ 20 Mild 73 Ϯ 22 61 Ϯ 22 76 Ϯ 25 74 Ϯ 13 74 Ϯ 16 Moderate/severe 88 Ϯ 34 73 Ϯ 16 78 Ϯ 41 75 Ϯ 49 66 Ϯ 24 P value 0.229 0.098 0.689 0.796 0.471 AT III (%) No 92 Ϯ 25 94 Ϯ 17 93 Ϯ 12 91 Ϯ 19 97 Ϯ 13 Mild 87 Ϯ 894Ϯ 15 89 Ϯ 11 88 Ϯ 15 96 Ϯ 8 Moderate/severe 85 Ϯ 15 92 Ϯ 18 80 Ϯ 20 73 Ϯ 22 68 Ϯ 15 P value 0.543 0.919 0.034 0.030 Ͻ0.001 vWF (%) No 102 Ϯ 30 126 Ϯ 25 134 Ϯ 29 134 Ϯ 29 137 Ϯ 28 Mild 109 Ϯ 30 135 Ϯ 40 146 Ϯ 88 134 Ϯ 24 143 Ϯ 31 Moderate/severe 109 Ϯ 36 113 Ϯ 31 113 Ϯ 30 117 Ϯ 24 122 Ϯ 35 P value 0.758 0.206 0.266 0.139 0.240 Factor VIII (%) No 107 Ϯ 50 124 Ϯ 65 123 Ϯ 78 126 Ϯ 64 137 Ϯ 60 Mild 114 Ϯ 56 110 Ϯ 52 109 Ϯ 52 129 Ϯ 74 146 Ϯ 88 Moderate/severe 114 Ϯ 48 127 Ϯ 42 98 Ϯ 42 109 Ϯ 48 129 Ϯ 66 P value 0.917 0.747 0.559 0.668 0.832

patients with moderate to severe VOD (85 vs 68%, P Ͻ In patients with no/mild VOD, mean plasma levels of natu- 0.001). On day 14 and day 21, total protein S levels sig- ral anticoagulants did not change significantly from the nificantly decreased from baseline levels in patients with baseline throughout the monitoring period. moderate to severe VOD (92 vs 73%, P = 0.048 for day Although the administration of heparin may decrease the 14, 92 vs 74%, P = 0.046 for day 21). Free protein S levels level of AT III, there was no difference in AT III levels also fell compared to the baseline levels in patients with whether patients received heparin prophylaxis or not. moderate to severe VOD on day 21 (88 vs 66%, P = 0.002). Coagulation parameters in VOD after allogeneic BMT J-H Lee et al 887 110 natural anticoagulants5,6 (protein C, protein S and AT III), 4,7 100 a increase of procoagulants (factor VIII, fibrinogen and 90 von Willebrand factor), or changes in fibrinolytic para- 12–14 80 meters (tissue plasminogen activator, plasminogen activator inhibitor-1). Gordon et al15 found that deficiencies in 70 protein C persisted for at least 100 days after BMT in 60

Protein C (%) b c nearly one-quarter of patients and those patients undergoing 50 a vs b: P = 0.038 a vs c: P = 0.041 BMT might be at prolonged risk of thrombotic compli- 40 cations. This hypercoagulability has been implicated in the Baseline Day 0 Day 7 Day 14 Day 21 development of VOD after BMT.16 Although Faioni et al8 no VOD; mild VOD; moderate/severe VOD suggested that protein C levels before the start of conditioning would indicate patients at risk for developing VOD, Figure 1 Changes in the mean plasma levels of protein C after BMT in patients with no, mild, or moderate to severe VOD. many others including our study have failed to demonstrate that pre-conditioning levels of various coagulation parameters can predict for the development of VOD in patients 110 undergoing BMT. However, decrease of natural anticoagu- 100 lants and change of ﬁbrinolytic activity following BMT 90 have been shown to be relevant to occurrence of VOD in 9,13,14,17–19 80 a several reports. Speciﬁcally, protein C and AT III 70 decreased usually at 0–14 days after marrow infusion in b 9,13,17

AT III (%) AT patients with VOD. Plasminogen activator inhibitor-1 60 has been reported to identify VOD in patients with post- a vs b: P < 0.001 50 transplant hyperbilirubinemia.19 40 In our study, we prospectively examined the levels of Baseline Day 0 Day 7 Day 14 Day 21 natural anticoagulants protein C, protein S (free and total)

no VOD; mild VOD; moderate/severe VOD and AT III as well as von Willebrand factor antigen and functional activity of factor VIII in 50 consecutive patients Figure 2 Changes in the mean plasma levels of antithrombin III (AT undergoing allogeneic BMT. Each parameter was measured III) after BMT in patients with no, mild, or moderate to severe VOD. before conditioning, on day 0 of BMT, and weekly thereafter for 3 weeks. The levels of protein C and AT III fell von Willebrand factor and factor VIII significantly on day 7 and decreased over time in patients with moderate to severe VOD when compared to the The mean plasma levels of vWF and factor VIII showed patients with no/mild VOD. In addition, there were signifi- no significant difference at each time point between patients cant reductions in natural anticoagulants (protein C, total with no/mild VOD and moderate to severe VOD. There and free protein S and AT III) after BMT from baseline was a significant rise in the mean plasma levels of vWF levels in patients with moderate to severe VOD. These fin- from baseline levels in patients with no/mild VOD, but, dings may simply have resulted from the decrease of hep- these changes of vWF were not significant in patients with atic synthetic function associated with VOD, although the moderate to severe VOD (Figure 3). changes in coagulation parameters may indicate that the natural anticoagulants have some pathogenetic role in the development of VOD. Regardless of whether decreased Discussion levels of natural anticoagulants are a cause or result of VOD, they are likely to aggravate its clinical effects. A hypercoagulable state, which has been observed in many Because the median onset of VOD in patients with moder- patients after BMT, may occur in the face of decrease of ate to severe VOD was day 8 post-transplant, levels of protein C and AT III decreased before clinical onset of the 150 disease. Thus, early post-BMT reduction in protein C and h AT III may predict for the occurrence of moderate to severe 140 g VOD. In patients with moderate to severe VOD, the time 130 c d e to platelets of over 20 × 106/l without platelet support was 120 b significantly delayed and platelet requirements were sig- f nificantly larger when compared to the patients with 110 vWF (%) no/mild VOD. Mortality rate of day 100 post-transplant was a 100 a vs c, d: P < 0.001 also higher, although not statistically significant. Thus, the a vs e, f vs h:P = 0.001 90 a vs b: P = 0.003 predictive value of protein C and AT III for the develop- f vs g: P = 0.010 80 ment of moderate to severe VOD may have clinical impli- Baseline Day 0 Day 7 Day 14 Day 21 cations. Morris et al20 administered AT III to 10 patients with AT III levels less than 88% and life-threatening single no VOD; mild VOD; moderate/severe VOD or multiorgan dysfunction, and they observed that the prob- Figure 3 Changes in the mean plasma levels of von Willebrand factor ability of death due to organ dysfunction was significantly (vWF) after BMT in patients with no, mild, or moderate to severe VOD. less when compared to an historical control group. In Coagulation parameters in VOD after allogeneic BMT J-H Lee et al 888 patients with decreased levels of protein C or AT III after 6 Gordon B, Haire W, Kessinger A et al. High frequency of BMT, early therapeutic intervention such as protein C and antithrombin 3 and protein C deficiency following autologous AT III concentrate may prevent the development of moder- bone marrow transplantation for lymphoma. Bone Marrow ate to severe VOD and improve clinical outcome. Also, the Transplant 1991; 8: 497–502. role of hemostatic abnormalities in VOD may be under- 7 Collins PW, Gutteridge CN, O’Driscoll A et al. von Wille- brand factor as a marker of endothelial cell activation follow- scored by reports of successful treatment with thrombolytic 21 ing BMT. Bone Marrow Transplant 1992; 10: 499–506. agenst such as tissue plasminogen activator. 8 Faioni EM, Krachmalnicoff A, Bearman SI et al. Naturally Endothelial cell activation may play a role in VOD after occurring anticoagulants and bone marrow transplantation: BMT and vWF antigen levels have been used as a marker plasma protein C predicts development of venocclusive dis- of endothelial cell activation. Collins et al7 measured vWF ease of the liver. Blood 1993; 81: 3458–3462. antigen levels in 72 patients during the first 6 weeks post- 9 Haire WD. Antithrombin deficiency in special clinical syn- transplant. There was a significant rise in vWF antigen in dromes – part II: hematologic malignancies and bone marrow uncomplicated patients, but the changes in vWF antigen in transplantation. Semin Hematol 1995; 32: 56–60. three patients with VOD did not show a consistent pattern. 10 Collins P, Roderick A, O’Brien D et al. Factor VIIa and other In our study, vWF increased significantly after BMT from haemostatic variables following bone marrow transplantation. the baseline level in patients with no/mild VOD, but Thromb Haemost 1994; 72: 28–32. 11 McDonald GB, Hinds MS, Fisher LD et al. Veno-occlusive changes of vWF after BMT were not significant in patients diesease of the liver and multiorgan failure after bone marrow with moderate to severe patients. Furthermore, there was transplantation: a cohort study of 355 patients. Ann Intern Med no significant difference in vWF levels between patients 1993; 118: 255–267. with no, mild and moderate to severe VOD. When taken 12 Salat C, Holler E, Reinhardt B et al. Parameters of the together these results suggest that severity of VOD does fibrinolytic system in patients undergoing BMT: elevation of not correlate with the degree of disruption of endothelial PAI-1 in veno-occlusive disease. Bone Marrow Transplant cells, and vWF cannot be used to predict for the develop- 1994; 14: 747–750. ment of VOD. 13 Park YD, Yasui M, Yoshimoto T et al. Changes in hemostatic Shulman et al3 showed that factor VIII and fibrinogen parameters in hepatic veno-occlusive disease following bone within the subendothelial zones of affected terminal hepatic marrow transplantation. Bone Marrow Transplant 1997; 19: venules seem to be a major component in the obstruction 915–920. 14 Salat C, Holler E, Wolf C et al. Laboratory markers of veno- of sinusoidal blood flow in patients with VOD. We meas- occlusive disease in the course of bone marrow and sub- ured the levels of factor VIII activity in plasma, but there sequent liver transplantation. Bone Marrow Transplant 1997; was no significant change in levels of factor VIII before 19: 487–490. and after BMT in either patients with or without VOD. 15 Gordon B, Haire W, Ruby E et al. Prolonged deficiency of In summary, levels of protein C and AT III decreased protein C following hematopoietic stem cell transplantation. before clinical onset of moderate to severe VOD. Early Bone Marrow Transplant 1996; 17: 415–419. post-BMT reduction of these parameters may indicate those 16 Faioni EM, Mannucci PM. Venocclusive disease of the liver likely to develop moderate to severe VOD. 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