Low molecular weight heparin for the prevention of hepatic veno-occlusive disease (VOD) after hematopoietic stem cell transplantation: a prospective phase II study

Abstract

Summary:We evaluated 40 patients undergoing high-dose chemo/ radiotherapy (HDCT) and hematopoietic stem cell transplantation (HSCT) (allogeneic (22), autologous (18)) to determine the safety and feasibility of administering low molecular weight heparin (LMWH) as hepatic veno-occlusive disease (VOD) prophylaxis. Patients received a once daily subcutaneous injection of dalteparin 2500 anti-Xa i.u. commencing the day prior to starting HDCT, and continuing until day +30 post HSCT or hospital discharge, whichever came first. Dosage adjustments were made for patients developing renal failure. All bleeding episodes were recorded and graded and VOD was diagnosed and graded according to Seattle criteria. At 100 days of follow-up, the overall survival and probability of regimen-related mortality were 85 and 15%, respectively. Nine patients developed VOD. The probability of developing VOD post allogeneic and autologous HSCT was 28% (95% CI, 6-45) and 17% (95% CI, 0-32), respectively. VOD was graded as moderate (n ¼ 8) and severe (n ¼ 1). VOD resolved in all cases except for one patient who died secondary to severe VOD and multiorgan failure. Clinically significant bleeding episodes occurred in three patients; 24 patients developed minor bleeding not requiring specific therapy. All bleeding episodes resolved. These results suggest that LMWH for VOD prophylaxis is safe with a low incidence of serious bleeding events. Whether it is superior to unfractionated heparin, however, is unknown and should be addressed within the context of a randomized controlled trial. Bone Marrow Transplantation (2003) 31, 1143-1149. doi:10.1038/sj.bmt.1704087 Keywords: low molecular weight heparin; VOD High-dose chemo/radiotherapy (HDCT) and hematopoietic stem cell transplantation (HSCT) are widely used to treat many malignant and nonmalignant conditions. Regimen-related toxicity (RRT) remains a frequent and major complication of HSCT. 1 Hepatic veno-occlusive disease (VOD) is one of the most common life-threatening RRTs reported to occur in 5-60% of patients undergoing HSCT. [2][3][4][5][6][7][8] Clinically, VOD is characterized by jaundice, painful hepatomegaly, ascites and weight gain from fluid retention. In its most severe form, it often leads to multiorgan failure and death. 6-8 Hepatic VOD is thought to result from injury to hepatocytes surrounding the central veins in zone 3 of the liver acinus. Early pathologic changes include edema of the subendothelium of hepatic venules, followed by thrombosis of the venular lumen. 9 Risk factors for VOD have been reported to include a previous history of viral hepatitis, abnormal liver function tests at the time of HDCT and HSCT, the use of high-dose preparative regimens, mismatched or unrelated donor HSCTs, and the use of vancomycin or amphotericin B. [2][3][4][5][6][7][8][10][11][12][13] A number of prophylactic strategies have been explored in an attempt to prevent the injury and subsequent thrombosis of hepatic venules and therefore decrease the risk of VOD. They include the administration of pros...

Use of prophylactic anticoagulation and the risk of hepatic veno-occlusive disease in patients undergoing hematopoietic stem cell transplantation: a systematic review and meta-analysis

“…Figure 1 is a flow diagram of the studies identified for this review. The search resulted in identifying 17 studies, 5,[23][24][25][26][35][36][37][38][39][40][41][42][43][44][45][46] 12 of which were found to be eligible. 24,26,[35][36][37][38][39][40][41][42][43][44] Three studies were published as abstracts.…”

“…We extend our thanks to the authors of the primary studies who responded to our queries 5,[24][25][26][35][36][37][38][40][41][42]44 and we are indebted to those who provided us with additional data that were not available in their respective publications. 26,[35][36][37]42 …”

“…Despite this attention, the topic remains controversial. [23][24][25][26] Therefore, we performed a systematic review and metaanalysis of the literature to investigate the effect of anticoagulation in preventing veno-occlusive disease in pediatric and adult patients undergoing hematopoietic stem cell transplantation following the Meta-analysis of Observational Studies in Epidemiology (MOOSE) 27 and Quality of Reporting of Meta-analyses (QUOROM) 28 guidelines.…”

Coexisting or Underlying Risk Factors of Hepatic Veno-Occlusive Disease in Pediatric Hematopoietic Stem Cell Transplant Recipients Receiving Prophylaxis

“…7,[24][25][26] Bearman and associates reported that they had to stop continuous heparin infusion given for the purpose of prophylaxis because of a high ratio of moderate-to-severe bleeding (21 of 28 patients). 27 In our center, enoxaparin (0.8 mg/kg/d, once daily, sc), which was thought to be safer than classic heparin, was used as prophylaxis for VOD.…”

Safety of low-dose low-molecular-weight-heparins in thrombocytopenic stem cell transplantation patients: a case series and review of the literature

“…Dalteparin was given s.c. as 2500 U daily until day of discharge or day 30 post HSCT. 35 In total, 24 patients (60%) developed a minor bleeding. Three patients (7.5%) had a major bleed defined as bleeding episode requiring transfusions of 1-2 of packed RBCs/ episode in a 24-h period.…”