Changes in Hemostatic Parameters in Hepatic Veno-Occlusive Disease Following Bone Marrow Transplantation

Changes in hemostatic parameters in hepatic veno-occlusive disease following bone marrow transplantation

Y-D Park, M Yasui, T Yoshimoto, K Chayama, T Shimono, T Okamura, M Inoue, K Yumura-Yagi and K Kawa-Ha

Department of Pediatrics, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan

Summary: or Baltimore groups.7–9 Thus, in this study, examination was made of changes in hemostatic parameters in children Hepatic veno-occlusive disease (VOD) is a major com- with VOD after BMT. Some parameters appeared appli- plication after bone marrow transplantation (BMT). Its cable as markers for VOD and the coagulation-fibrinolysis prediction, diagnosis and treatment remain unclear. system was shown to possibly contribute to VOD. Examination was made of changes in hemostatic parameters in patients with or without VOD after BMT. Twenty-seven children were studied following BMT. Patients and methods Eight of them developed VOD. Tissue plasminogen acti- Patients vator (t-PA), plasminogen activator inhibitor 1 (PAI-1), thrombomodulin (TM), von Willebrand factor (vWF), From October 1993 to November 1995, 99 patients factor VII, fibrinogen (FBG), FDP, D-dimer (D-D), plas- underwent marrow grafts (65 allografts and 34 autografts), minogen (PLG), thrombin-antithrombin III (TAT), ␣2- 27 patients, 20 males and seven females, were examined. plasmin inhibitor/plasmin complex (PIC), antithrombin Median age was 7 years (range 1–15 years). The patients III (AT-III), protein C, N-terminal propeptide for type were diagnosed as ALL (n = 11), AML (n = 3), CML III procollagen (P-III-P), were measured weekly from (n = 3), severe aplastic anemia (SAA) (n = 3), neuroblas- pre-BMT to day 28 after BMT. In VOD patients, t-PA toma (NBL) (n = 2), non-Hodgkin’s lymphoma (NHL) and PAI-1 significantly increased (P Ͻ0.05) and FBG (n = 1), juvenile chronic myelogenous leukemia (JCML) significantly fell during the post-transplant period (n = 1), severe combined immunodeficiency (SCID) (P Ͻ0.05). Significantly low AT-III and PLG were also (n = 1), rhabdomyosarcoma (RMS) (n = 1) and peripheral noted before VOD (P Ͻ0.05). There were no changes in neuroectodermal tumor (PNET) (n = 1) (Table 1). other hemostatic parameters. t-PA, PAI-1 and FBG Seven patients received autologous marrow grafts and would thus appear useful markers for the diagnosis of 20, allogeneic marrow grafts (10 HLA-identical siblings, VOD, and AT-III and PLG, predictive markers for eight HLA-matched unrelated donors, two HLA-mis- VOD. The coagulation-fibrinolysis system following matched families). endothelial cell damage may contribute to the onset of For the conditioning regimen, total body irradiation VOD. (TBI) of 12 Gy + thiotepa (TEPA) 600 mg/m2 + melphalan Keywords: BMT; VOD; hemostatic parameters (LPAM) 140 mg/m2 was used for 14 patients. Busulphan (BU) 16 mg/kg + cyclophosphamide (CY) 200 mg/kg was administered to five patients, ifosfamide (IFO) 7.5 g/m2 + LPAM 210 mg/m2 to four patients, antithymo- Hepatic veno-occlusive disease (VOD) is a major compli- globulin (ATG) 10 mg/kg + CY 200 mg/kg to two patients, cation of bone marrow transplantation (BMT). Its fre- BU 16 mg/kg + CY 200 mg/kg + TEPA 300 mg/m2 to one 1,2 quency varies greatly from 1 to 54%, and its high mor- patient and BU 16 mg/kg + LPAM 210 mg/m2 to one 3–6 tality (30–50%) has not improved. VOD is characterized patient. by hyperbilirubinemia, painful hepatomegaly and ascites Ten patients who had undergone BMT from HLA- after BMT, following chemo-radiotherapy conditioning. matched siblings received cyclosporin A (CsA) alone VOD may possibly arise from injury or disruption of the and/or methotrexate (MTX) as prophylaxis for acute endothelium lining the sinusoids and pores connected to the GVHD, and 10 patients marrow grafts from HLA-matched hepatic venular lumen. Endothelial injury causes activation unrelated donors or HLA-mismatched families received of the coagulation system and post-sinusoidal obstruction, FK506. but the pathogenesis is not clear and the diagnosis of VOD To prevent VOD, heparin (100 U/kg/day) was continu- is based only on clinical criteria developed by the Seattle ously infused from days −8 to 30 after BMT. Diagnosis of VOD was based on the Baltimore group criteria: hyperbilirubinemia greater than or equal to 2 mg/dl Correspondence: Dr K Kawa-Ha, Department of Pediatrics, Osaka Medi- cal Center and Research Institute for Maternal and Child Health, 840, before day 21 after transplant and at least two of the follow- Murodo, Izumi City, Osaka, Japan ing: hepatomegaly (usually painful), ascites, and weight Received 22 April 1996; accepted 2 January 1997 gain of greater than 5% from baseline.8 Hemostatic parameters in hepatic VOD Y-D Park et al 916 Table 1 Patient characteristics Japan). ␣2-plasmin inhibitor/plasmin complex (PIC) was assayed by enzyme immunoassay (EIA) (PIC test; Teijin). VOD (−) VOD (+) Anticoagulants: Antithrombin III (AT-III) and protein C No. (Male/Female) 19 (13/6) 8 (7/1) (PC) activity were determined with the COBAS MIRA S Median age (range, years) 7 (1–15) 5 (2–3) Diagnosis coagulometer, (AT-III:Testzym AT-III auto; Daiichika- ALL 7 4 gaku, Tokyo, Japan. PC:Berichrom Protein C; Hoechst, AML 1 2 Marburg, Germany). CML 2 1 SAA 3 — Fibrogenesis marker: N-terminal propeptide for type III JCML — 1 SCID 1 — procollagen (P-III-P) was measured by radioimmunoassay Solid tumors 5 — (RIA gnost P-III-P; Behringwerke, Marburg, Germany). Conditioning regimen TBI + TEPA + LPAM 7 7 BU + CY 4 1 Statistical analysis BU + LPAM 1 — BU + CY + TEPA 1 — Statistical significance between means of hemostatic para- IFO + LPAM 4 — meters for patients with and without VOD was determined + ATG CY 2 — by the Student’s t-test, paired or unpaired, as appropriate. Autologous transplants 6 1 Allogeneic transplants P Ͻ0.05 was considered significant. HLA-matched sibling 9 1 HLA-matched unrelated donor 2 6 HLA-mismatched family 2 — Acute GVHD Results Grade 0–1 5 2 Grade II–IV 8 5 Of the 27 patients, eight developed VOD, (ALL:4, AML:2, CML:1, JCML:1). Seven had received allogeneic marrow SAA = severe aplastic anemia; JCML = juvenile chronic myelogenous leu- grafts, six of which were unrelated; one had received an kemia; SCID = severe combined immunodeficiency; TBI = total body autologous marrow graft. Seven of the eight patients irradiation; TEPA = thiotepa; LPAM = melphalan; BU = busulphan; CY = cyclophosphamide; IFO = ifosfamide; ATG = antithymoglobulin. underwent conditioning with total body irradiation (TBI) 12 Gy + thiotepa (TEPA) (600 mg/m2) + melphalan (LPAM) (140 mg/m2). Although patients with VOD Blood sampling received the recombinant tissue plasminogen activator (rt- PA) and prostaglandin E1 (PGE1), five of the eight died of Venous blood was collected in 1/10th vol of 3.8% sodium multiorgan failure (Table 2). pre-mortum liver biopsies citrate. Plasma samples were separated by centrifugation at were not done. Post-mortum liver biopsies were performed 2000 g for 10 min, 4°C and stored at −80°C until use. in two patients; one was proven VOD, but the other failed Samples were collected before the conditioning regimen to show typical histological VOD findings. and on days 0, 7, 14, 21 and 28 after BMT.

Laboratory methods Endothelial markers Endothelial markers: The tissue plasminogen activator (t- In the VOD patients, t-PA and PAI-1 significantly increased PA), plasminogen activator inhibitor 1 (PAI-1), thrombo- during the post-transplant period (Figures 1 and 2). Sig- modulin (TM) and von Willebrand factor (vWF) were mea- nificantly high t-PA and PAI-1 were observed on days 21 sured by enzyme immunoassay (EIA) using commercial and 28 after BMT (P Ͻ0.05). vWF activity increased after kits (t-PA:TintElize t-PA and PAI-1 1:TintElize PAI-1 1; BMT, but not significantly, and TM showed no significant Bio-pool, Umea, Sweden. TM:TM test; Teijin, Tokyo, change (Table 3). Japan. vWF:Asserachromm vWF; Boeringer, Mannheim, Germany). Coagulation-fibrinolysis markers Coagulation-fibrinolysis markers: Factor VII activity Patients with VOD had significantly lower FBG on days (F.VII) was determined by a one-stage clotting assay using 21 and 28 after BMT (P Ͻ0.05) (Figure 3). Their PLG deficient plasma (George King BioMedical, Kansas, USA). activity was low on days 0 and 14 after BMT, before VOD Fibrinogen (FBG), fibrin and fibrinogen degradation pro- occurred (P Ͻ0.05) (Figure 4). FDP and d-D increased dur- ducts (FDP), d-dimer (d-D) and plasminogen activity ing the post-transplant period, but not significantly. F.VII, (PLG) were assessed using a COBAS MIRA S coagulo- TAT and PIC were essentially the same in the VOD and meter and commercial kits (FBG:Fibrinoquik; Organontek- non-VOD groups (Table 3). nika, Durham, NC, USA. FDP:Seratestam FDP; Hitachi d d Kasei, Tokyo, Japan. -D:Coagsol -dimer; Medicallink, Anticoagulants Yokohama, Japan. PLG:Testzym PLG auto; Daiichikagaku, Tokyo, Japan). Thrombin-antithrombin III (TAT) was mea- AT-III activity fell significantly before VOD developed, sured by EIA with the same kits (TAT test; Teijin, Tokyo, significantly low AT-III was evident on days 0 and 7 after Hemostatic parameters in hepatic VOD Y-D Park et al 917 Table 2 Clinical features of patients with VOD

UPN Age Sex Diagnosis BMT VOD GVHD Complications Outcome acute/chronic (months) Prophylaxis Onset Treatment post-BMT (days) rt-PA PGE1 Plasma (×106U) (ng/kg/min) exchange

56 2 M ALL/2nd CR Related Heparin 21 3.6 × 4 days 6.6 × 2 days — grade III/– IP Dead 2nd 60 4 M ALL/1st CR Unrelated Heparin 2 — — ×3 IV/– Pulmonary Dead hemorrhage 77 2 M JCML/refractory Unrelated Heparin 11 5 × 75×14 — 0/– DFS (19) 80 13 F AML/2nd Autologous Heparin 19 12 × 55×24 × 7 – Fungal Dead relapse infection 93 9 M ALL/2nd CR Unrelated Heparin 17 12 × 85×12 × 1 IV/– HUS, seizure Dead 96 2 M AML/refractory Unrelated Heparin 14 6 × 55×19 — III/– HUS, Dead encephalopathy 105 6 M CML/CP Unrelated Heparin + AT- 17 6 × 57×14 — I/– DFS (8) IIIa 118 9 M ALL/2nd Unrelated Heparin + AT- 14 12 × 58×16 — II/– DFS (4) relapse IIIa aAT-III activity was kept more than 100%. CR = complete remission; JCML = juvenile chronic myelogenous leukemia; CP = chronic phase; AT-III = antithrombin III; rt-PA = recombinant tissue plasminogen activator; PGE1 = prostaglandin E1; IP = interstitial pneumonia; HUS = hemolytic uremic syndrome.

20 ∗ 150 P = 0.021

15 ∗ 100 P = 0.038

10 ∗ P = 0.032

50 PAI-1 (ng/ml) PAI-1 t-PA (ng/ml) t-PA 5

0 0 pre- 0 7 14 21 28 pre- 0 7 14 21 28 Days after BMT Days after BMT Figure 1 Change in tissue plasminogen activator (t-PA) after BMT. Figure 2 Change in plasminogen activator inhibitor 1 (PAI-1) after Among patients with VOD, t-PA increased during the post-transplant per- BMT. Among patients with VOD, PAI-1 increased gradually with VOD. .iod. Significantly high t-PA was observed on day 21 after BMT. JؠJ, Significantly high PAI-1 was observed on days 21 and 28 after BMT t-PA VOD (−); J•J, t-PA VOD (+);...,normal range. Mean PAI-1, in patients with VOD, before BMT was high but not so -significantly. JؠJ, PAI-1 VOD (−); J•J, PAI-1 VOD (+); . . . nor mal range. BMT (P Ͻ0.05) (Figure 5). Protein C activity did not change significantly (Table 3). patients with VOD after BMT have been studied. Although the numbers of patients in all reports have been small and conclusions inconsistent,10–16 significant decreases in pro- Fibrogenesis marker tein C (PC) and factor VII (F.VII), and increase in N- VOD and non-VOD patient, procollagen type III (P-III-P) terminal propeptide for type III procollagen (P-III-P) have essentially remained unchanged (Table 3). been reported. In the present study, some other parameters were found to apparently be good markers for VOD, and the coagu- Discussion lation-fibrinolysis system appeared to be a contributory factor in VOD. Of the 14 hemostatic parameters examined, Hepatic VOD may possibly be associated with coagulation, tissue plasminogen activator (t-PA), plasminogen activator but the pathogenesis is not clear. Few useful markers are inhibitor 1 (PAI-1), fibrinogen (FBG), AT-III and available for diagnosing VOD, and the diagnosis is based plasminogen (PLG) were observed to have changed in the only on clinical criteria. Hemostatic parameters VOD patients. t-PA and PAI-1 increased significantly. At (coagulation-fibrinolysis factors and endothelial markers) in the onset of VOD, a significant decrease in FBG was Hemostatic parameters in hepatic VOD Y-D Park et al 918 Table 3 Changes in hemostatic parameters after BMT

Pre- Day 0 Post-day 7 Day 14 Day 21 Day 28

Tissue plasminogen activator (t-PA) ng/ml VOD (−) 5.84 ± 1.04 9.24 ± 2.79 8.97 ± 1.72 9.46 ± 1.62 9.25 ± 1.70 7.95 ± 1.19 VOD (+) 4.13 ± 0.86 6.22 ± 1.55 7.925 ± 2.24 9.97 ± 2.14 15.8 ± 2.32 12.9 ± 3.65 P value 0.111 0.183 0.359 0.426 0.021 0.123 Plasminogen activator inhibitor 1 (PAI-1) ng/ml VOD (−) 28.8 ± 3.99 24.5 ± 5.19 25.4 ± 3.78 25.3 ± 3.04 29.1 ± 4.13 26.2 ± 3.48 VOD (+) 96.5 ± 35.8 25.4 ± 5.34 23.9 ± 4.61 37.6 ± 7.46 51.8 ± 9.82 71.2 ± 19.8 P value 0.084 0.452 0.402 0.096 0.032 0.038 Thrombomodulin (TM) U/ml VOD (−) 9.76 ± 1.15 9.82 ± 7.11 7.03 ± 0.78 8.58 ± 0.97 11.6 ± 1.23 11.36 ± 1.06 VOD (+) 6.08 ± 1.79 6.44 ± 0.96 5.57 ± 1.45 7.38 ± 1.69 15.9 ± 6.22 12.6 ± 5.30 P value 0.072 0.09 0.196 0.275 0.24 0.414 von Willebrand factor (vWF) % VOD (−) 60.7 ± 2.67 58.6 ± 3.37 60.2 ± 2.57 59.1 ± 2.86 64.4 ± 2.70 67.7 ± 3.03 VOD (+) 79.5 ± 26.3 81.7 ± 25.7 108 ± 29.6 87.8 ± 25.0 86.6 ± 25.3 100 ± 27.8 P value 0.264 0.234 0.082 0.152 0.217 0.148 Factor VII (F.VII) % VOD (−) 94.5 ± 12.4 118 ± 17.5 81.8 ± 12.3 101 ± 13.7 94.6 ± 14.5 106 ± 12.2 VOD (+) 93.5 ± 17.1 101 ± 7.02 80.2 ± 12.0 102 ± 22.6 104 ± 22.9 118 ± 42.5 P value 0.482 0.196 0.463 0.483 0.372 0.403 Fibrinogen (FBG) mg/dl VOD (−) 319 ± 32.1 316 ± 50.4 331 ± 25.4 260 ± 28.7 252 ± 29.3 219 ± 25.0 VOD (+) 250 ± 23.8 249 ± 28.6 352 ± 53.4 257 ± 56.3 164 ± 11.9 157 ± 9.12 P value 0.056 0.139 0.459 0.482 0.046 0.025 Fibrin and ﬁbrinogen degradation products (FDP) ␮g/ml VOD (−) 5.95 ± 1.58 3.70 ± 0.307 7.46 ± 2.14 4.94 ± 1.06 4.99 ± 0.452 3.72 ± 652 VOD (+) 3.88 ± 0.368 3.17 ± 0.484 4.16 ± 0.584 6.42 ± 0.887 9.44 ± 3.42 13.3 ± 5.78 P value 0.122 0.19 0.093 0.182 0.133 0.087 d-dimer (d-D) mg/dl VOD (−) 0.817 ± 0.206 0.871 ± 0.145 1.50 ± 0.518 1.27 ± 0.488 1.00 ± 0.337 0.476 ± 0.024 VOD (+) 0.715 ± 0.179 0.756 ± 0.157 0.812 ± 0.202 1.25 ± 0.421 2.49 ± 0.912 2.936 ± 1.47 P value 0.359 0.301 0.126 0.489 0.093 0.085 Plasminogen (PLG) % VOD (−) 92.0 ± 4.37 106 ± 3.10 95.8 ± 4.59 86.1 ± 5.72 89.9 ± 5.89 109 ± 11.3 VOD (+) 87.8 ± 11.3 90.8 ± 5.63 84.6 ± 4.70 64.4 ± 7.25 63.2 ± 16.8 77.6 ± 17.1 P value 0.374 0.028 0.06 0.023 0.104 0.084 Thrombin-antithrombin III (TAT) ng/ml VOD (−) 2.00 ± 0.489 1.91 ± 0.275 2.15 ± 0.558 1.74 ± 0.292 2.67 ± 0.840 3.7 ± 1.88 VOD (+) 1.88 ± 0.250 2.58 ± 0.651 2.74 ± 0.566 7.34 ± 3.87 8.68 ± 3.42 7.8 ± 4.43 P value 0.413 0.195 0.24 0.111 0.081 0.221 Alpha2-plasmin inhibitor/plasmin complex (PIC) ␮g/ml VOD (−) 0.52 ± 0.032 0.91 ± 0.052 0.655 ± 0.091 0.433 ± 0.049 0.426 ± 0.081 0.600 ± 0.147 VOD (+) 1.12 ± 0.602 0.704 ± 0.213 0.67 ± 0.089 0.712 ± 0.329 0.96 ± 0.364 0.675 ± 0.135 P value 0.198 0.201 0.454 0.225 0.112 0.36 Antithrombin III (AT-III) %a VOD (−) 101 ± 7.16 96.0 ± 3.84 90.6 ± 3.36 88.7 ± 4.02 90.3 ± 6.60 95.1 ± 5.23 VOD (+) 81.0 ± 12.1 85.0 ± 2.04 71.8 ± 6.56 83.5 ± 6.86 66.8 ± 11.2 80.3 ± 11.6 P value 0.129 0.019 0.031 0.27 0.064 0.182 Protein C (PC) % VOD (−) 73.3 ± 12.6 82.4 ± 10.3 70.2 ± 10.0 73 ± 9.62 92.3 ± 12.2 84 ± 11.7 VOD (+) 89.8 ± 18.7 87.8 ± 8.82 57.8 ± 10.5 86.2 ± 18.5 105 ± 30.8 79.0 ± 21.3 P value 0.249 0.35 0.205 0.275 0.358 0.424 N-terminal propeptide for type III procollagen (P-III-P) U/ml VOD (−) 1.39 ± 0.241 1.945 ± 0.868 1.973 ± 0.428 2.22 ± 0.426 2.09 ± 0.376 2.23 ± 0.383 VOD (+) 1.50 ± 0.00 1.95 ± 0.35 1.34 ± 0.198 1.41 ± 0.228 2.638 ± 0.878 4.07 ± 2.18 P value 0.33 0.45 0.103 0.059 0.297 0.247

aTwo patients with prophylactic use of AT-III were excluded. P values measured by Student’s t-test.

observed. Prior to that, AT-III and PLG activity was sig- by activation and/or damage to endothelial cells following nificantly low. Significant changes in protein C (PC), factor an increase in serum tissue necrosis factor ␣ (TNF␣). VII (F.VII) and P-III-P have been reported, but were not Vanhinsbergh et al18 found a significant increase in t-PA seen in this study. and PAI-1 following infusion of recombinant human The occurrence of VOD may be closely related to hyper- TNF␣. These coagulation factors significantly increased coagulability. Seeber et al17 reported endothelial coagu- with VOD in this study. lation factors such as t-PA, PAI-1 and vWF to be released Seven of the present patients who developed VOD were Hemostatic parameters in hepatic VOD Y-D Park et al 919 developed severe (grade ϾII) acute graft-versus-host dis- 400 ease (aGVHD). Endothelial cell activation and/or damage ∗ by cytokines possibly due to aGVHD, may precede VOD. P = 0.046 Following high-dose radio-chemotherapy and severe 300 ∗ P = 0.025 aGVHD, endothelial cell damage may be more profound, and many cytokines released at the onset of aGVHD may 200 activate endothelial cells. Tissue plasminogen activator (t-

FBG (%) PA) accelerates change from plasminogen (PLG) to plas- 100 min, and subsequently plasmin promotes fibrinolysis. PAI- 1 inhibits t-PA functioning. In this study, an increase in 0 PAI-1 was a major finding. Though t-PA rose among VOD pre- 0 7 14 21 28 patients, a significantly high level of t-PA disappeared by Days after BMT day 28 after BMT. PAI-1 released impedes fibrinolysis by inhibiting t-PA, and this leads to hypercoagulability which Figure 3 Change in fibrinogen (FBG) after BMT. Among patients with may result in VOD. If fibrinolysis is impeded, fibrin may VOD, FBG fell significantly on days 21 and 28 after BMT with VOD. -JؠJ, FBG VOD (−); J•J, FBG VOD (+); . . . , normal range. accumulate and FBG be consumed. AT-III is an anticoagu lant that inhibits the activity of thrombin, factor X (F.X) and factor IX (F.IX) in the coagulation system. Plasmin- 120 ∗ ogen (PLG) is activated by plasminogen activators, and P = 0.028 then stimulates fibrinolysis. It thus follows that soon after 100 ∗ P = 0.023 BMT, low AT-III and PLG cause hypercoagulability and may be risk factors of VOD. 80 The high mortality from VOD has not improved. 60 Although various drugs such as heparin, pentoxifylline, prostaglandin E1 (PGE1), ursodepxycholic acid are used to PLG (%) 40 prevent VOD, their efficacy is uncertain.19–23 There is no consistently effective therapy for VOD, although a few case 20 reports recommend recombinant tissue plasminogen acti- 24–27 0 vator (rt-PA) as treatment. Pre- 0 7 14 21 28 All VOD patients in this study received continuous Days after BMT infusions of heparin, and two received AT-III to keep the activity at more than 100%. Only three patients were cured; Figure 4 Change in plasminogen (PLG) after BMT. In patients who the others died of multiorgan failure, although they received developed VOD, significantly low PLG was noted on days 0 and 14 after BMT before VOD. JؠJ, PLG VOD (−); J•J, PLG VOD (+);..., PGE1 and rt-PA promptly and/or underwent plasma normal range. exchange. The three survivors received rt-PA and PGE1, and two received prophylactic AT-III. Treatment with rt- PA and the prophylactic use of AT-III for VOD may be 120 effective, because an increase in PAI-1 and low AT-III may ∗ P = 0.019 ∗P = 0.031 accelerate hypercoagulability leading to VOD. 100 Hypercoagulability following endothelial cell activation 80 and/or damage by cytokines may contribute to the onset of VOD, and increase in t-PA and PAI-1 and decrease in FBG 60 may be useful markers for diagnosing VOD. Low AT-III and PLG may possibly serve as predictive markers for AT-III (%) AT-III 40 VOD.

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