Pathophysiology of VOD

VOD CAN RAPIDLY PROGRESS FROM ENDOTHELIAL DAMAGE TO DEATH1,2

PROGRESSIVE CASCADE OF VOD

Hepatocyte
Endothelial cell
Red blood cell
White blood cell
Platelets
Extracellular matrix
Healthy sinusoid
Healthy sinusoid
Sinusoidal endothelial cells provide a barrier between the blood and hepatocytes and regulate hemostasis, permeability, vascular tone, and immune and inflammatory responses.3

Based on experimental models, buildup of toxic metabolites from conditioning regimens may trigger damage to sinusoidal endothelium.4-6

Endothelial damage
Endothelial damage

Activation of endothelial cells triggers expression of cytokines and adhesion molecules, activating inflammatory pathways that cause additional endothelial damage.4-6

In addition, release of the enzyme heparanase contributes to degradation of the extracellular matrix, loss of cytoskeletal structure, and gap formation between sinusoidal endothelial cells.4-6

Sinusoidal narrowing
Sinusoidal narrowing

This disruption of the endothelium allows red blood cells, leukocytes, and cellular debris to move into the space of Disse. This can lead to sinusoidal narrowing and dissection of endothelial cells, which may embolize downstream and contribute to sinusoidal blockage.5,6

Sinusoidal blockage
Sinusoidal blockage

Sinusoidal endothelial cell damage also triggers the expression of multiple factors that regulate coagulation and fibrinolysis (table A).6-8

All of these events can lead to a procoagulant and hypofibrinolytic state, where fibrin deposition, clot formation, and sinusoidal narrowing can cause further blockage. This sinusoidal disruption may be associated with hepatocyte cell death.1,3,5,6

A. FACTORS THAT REGULATE COAGULATION AND FIBRINOLYSIS6-8
Factor Function
von Willebrand factor stimulates platelet aggregation
Tissue factor promotes activation of factor X
Plasminogen activator inhibitor-1 reduces fibrinolysis

The cascade of events appears to start BEFORE clear clinical and
pathological manifestations are evident.5,6

Reduction in hepatic venous outflow
Post-sinusoidal hypertension4-6

Clinical manifestation of signs and symptoms may include4:

  • Bilirubin (>2 mg/dL), hepatomegaly and/or upper right quadrant pain, weight gain, fluid retention, ascites

Multi-organ dysfunction1,5,9

  • Progressing damage may lead to renal or pulmonary dysfunction

Death1,5

  • Often due to multi-organ failure

84%overall mortality in VOD with multi-organ dysfunction1,a

aBased on 19 studies (235 patients) that specifically determined mortality from severe VOD, as reported within a meta-analysis of 135 studies performed between 1979 and 2007.

Indication

Defitelio® (defibrotide sodium) is indicated for the treatment of adult and pediatric patients with hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation (HSCT).

Important Safety Information

Contraindications

Defitelio is contraindicated in the following conditions:
  • Concomitant administration with systemic anticoagulant or fibrinolytic therapy
  • Known hypersensitivity to Defitelio or to any of its excipients

Warnings and Precautions

Hemorrhage

Defitelio may increase the risk of bleeding in patients with VOD after HSCT. Do not initiate Defitelio in patients with active bleeding. Monitor patients on Defitelio for signs of bleeding. If bleeding occurs, withhold or discontinue Defitelio.

Concomitant systemic anticoagulant or fibrinolytic therapy may increase the risk of bleeding and should be discontinued prior to Defitelio treatment. Consider delaying Defitelio administration until the effects of the anticoagulant have abated.

Hypersensitivity Reactions

Hypersensitivity reactions including rash, urticaria, and angioedema have occurred in less than 2% of patients treated with Defitelio. One case of an anaphylactic reaction was reported in a patient who had previously received Defitelio. Monitor patients for hypersensitivity reactions, especially if there is a history of previous exposure. If a severe hypersensitivity reaction occurs, discontinue Defitelio, treat according to the standard of care, and monitor until symptoms resolve.

Most Common Adverse Reactions

The most common adverse reactions (incidence ≥10% and independent of causality) with Defitelio treatment were hypotension, diarrhea, vomiting, nausea, and epistaxis.

Please see full Prescribing Information.

References:
  1. Coppell JA, Richardson PG, Soiffer R, et al. Hepatic veno-occlusive disease following stem cell transplantation: incidence, clinical course, and outcome. Biol Blood Marrow Transplant. 2010;16(2):157-168.
  2. Carreras E. How I manage sinusoidal obstruction syndrome after haematopoietic cell transplantation. Brit J Haematol. 2015;168(4):481-491.
  3. Vion AC, Rautou PE, Durand F, et al. Interplay of inflammation and endothelial dysfunction in bone marrow transplantation: focus on hepatic veno-occlusive disease. Semin Thromb Hemost. 2015;41(6):629-643.
  4. Carreras E. Early complications after HSCT. In: Apperley J, Carreras E, Gluckman E, et al, eds. The EBMT Handbook. 6th ed. Paris, France: European School of Haematology; 2012:176-195.
  5. Richardson PG, Ho VT, Cutler C, et al. Hepatic veno-occlusive disease after hematopoietic stem cell transplantation: novel insights to pathogenesis, current status of treatment, and future directions. Biol Blood Marrow Transplant. 2013;19(suppl 1):S88-S90.
  6. Richardson PG, Corbacioglu S, Ho VT, et al. Drug safety evaluation of defibrotide. Exper Opin Drug Saf. 2013;12(1):123-136.
  7. Coppell JA, Brown SA, Perry DJ. Veno-occlusive disease: cytokines, genetics, and haemostasis. Blood Rev. 2003;17(2):63-70.
  8. Bearman SI. The syndrome of hepatic veno-occlusive disease after marrow transplantation. Blood. 1995;85(11):3005-3020.
  9. McDonald GB, Hinds MS, Fisher LD, et al. Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients. Ann Intern Med. 1993;118(4):255-267.