VENO-OCCLUSIVE DISEASE AND OTHER ACUTE COMPLICATIONS OF HSCT

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VENO-OCCLUSIVE DISEASE AND OTHER ACUTE
COMPLICATIONS OF HSCT
Dr Sunday Ocheni Consultant Haematologist, Departm
ent of Haematology Immunology University of
Nigeria, Enugu Campus, Mobile Nos
234-7039222313, 234-8185766742 E-mails
kcjsocheni_at_yahoo.com, sunday.ocheni_at_unn.edu.ng
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ACUTE COMPLICATIONS OF HSCT

• Several complications occur following HSCT
• These complications arise primarily from the
  effects of A Pre-transplant high dose
  chemotherapy ? radiotherapy conditioning
  strategies.
• Such complications include mucositis, pain,
  nausea, vomiting, haemorrhagic cystitis, hair
  loss, pancytopaenia, and those resulting from
  damage to the vascular endothelium

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ACUTE COMPLICATIONS OF HSCT

• Early complications resulting from damage to the
  vascular endothelium include
•  
• Hepatic veno-occlusive disease
• Capillary leak syndrome
• Engraftment syndrome
• Diffuse alveolar haemorrhage
• Thrombotic microangiopathy
• Indiopathic pneumonia syndrome
• Multi-organ dysfunction syndrome

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ACUTE COMPLICATIONS OF HSCT

• B Complications due to the genetic and
  immunologic disparities between the host and the
  donor.
• These include graft rejection, grant-versus-host
  disease (GvHD) and prolonged immune system
  dysfunctions.

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ACUTE COMPLICATIONS OF HSCT

• INTRODUCTION
• The high doses of RT and/or CT included in
  conditioning regimens affect all the pts organs
  and tissues??several early late secondary
  effects of variable intensity
• VOD is a potentially fatal syndrome of painful
  hepatomegaly, jaundice and fluid retention
  occurring 35-40 days post-HSCT as a result of
  conditioning regimen-related hepatic toxicity
• The term Sinusoidal obstruction syndrome is
  preferred because damaged sinusoidal endothelium
  sloughs and then obstructs the hepatic
  circulations, injuring centrilobular hepatocytes

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VENO-OCCLUSIVE DISEASE

• EPIDEMIOLOGY
• Incidence 5-70 in different reports, depending
  on the diagnostic criteria used, the population
  studied (eg, pediatric vs adult), and the
  differences in conditioning therapy used.
• Contributes to considerable mortality morbidity

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VENO-OCCLUSIVE DISEASE

• PATHOGENESIS
• After SCT the high dose cytoreductive therapy
  used in patients who have a particular
  susceptibility, produces endothelial injury in
  both sinusoids and small hepatic venules.
• This leads to activation of the coagulation
  cascade, and clot formation.
• Fibrin-related plugs, intracellular fluid
  entrapment and cellular debris progressively
  occlude sinusoids

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VENO-OCCLUSIVE DISEASE

• PATHOGENESIS 2
• This leads to intrahepatic post sinusoidal portal
  hypertension, responsible for the clinical signs
  of fluid retention (weight increase),
  hepatomegaly, ascites and jaundice.
• Usually fibrosis occurs several weeks after the
  onset of the disease.
• Post mortem studies have shown that hepatic
  venules are partially or completely obliterated
  by subendothelial collagen fibers

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VENO-OCCLUSIVE DISEASE
PATHOGENESIS 3 The pathogenesis is complex,
involving cytokine release, endothelial injury,
hemostatic activation, and hepatic drug
detoxification through the glutathione
pathway. Hepatocellular necrosis, fibrosis, and
vascular occlusion ultimately lead to liver
failure, hepatorenal syndrome, MOF, and death.
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VENO-OCCLUSIVE DISEASE

• Pretransplantation factors
• Preexisting liver dysfunction (elevated
  transaminases, fibrosis or cirrhosis, or low
  albumin level
• Presence of hepatic metastases
• Advanced age
• Prior radiation treatment of the liver17
• Use of vancomycin or acyclovir in the
  pretransplantation period17
• Previous stem cell transplantation17
• Prior therapy with gemtuzumab ozogamicin
  (Mylotarg)14
• ? Viral hepatitis C39-41
• ? Decreased protein C42
• ? Factor V Leiden mutation, prothrombin 20210
  mutation

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VENO-OCCLUSIVE DISEASE

• Transplantation-related factors
• High-dose conditioning regimens
• Allogeneic transplantation (compared with
  autologous
• transplantation)
• Busulfan for conditioning, and combined with
  cyclophosphamide
• Total body irradiation, especially combined with
  cyclophosphamide (depends on total dose and
  fractionation)
• Grafts from unrelated donors or related HLA
  mismatched transplants
• Methotrexate as part of graft-vs-host disease
  prophylaxis
• ? Cytomegalovirus infection

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VENO-OCCLUSIVE DISEASE

• CLASSICAL VOD
• Usually occurs from days 1 to 21 after SCT
  with regimens containing cyclophosphamide
• Triad of
• Weight gain with oedema and ascites caused by
  fluid retention not attributable to an excessive
  fluid administration
• Tender hepatomegaly and/or right upper quadrant
  pain
• Hyperbilirubinaemia/jaundice without any
• known cause

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VENO-OCCLUSIVE DISEASE
LATE VOD Same clinical manifestations as
Classical VOD Usually after conditioning with
agents such as busulphan, melphalan or
thiotepa May occur after patients
discharge CHRONIC VOD Occurs outside of the HSCT
setting eg following chronic assumption of
pyrrolizidine alkaloids contained in Senecio tea
(South Africa).
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VENO-OCCLUSIVE DISEASE

• VOD WITH MULTI-ORGAN FAILURE
• Same clinical manifestations plus
• Thrombocytopaenia (refractoriness to platelet
  transfusions)
• Pleural effusion
• Pulmonary infiltrates
• Progressive renal, cardiac and pulmonary failure,
  confusion, encephalopathy, and coma

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VENO-OCCLUSIVE DISEASE Diagnosis
DIAGNOSTIC CRITERIA OF VENO OCCLUSIVE DISEASE
AFTER SCT SEATTLE CRITERIA Within the first 20
days following HSCT, the presence of two or more
of the following 1 Hyperbilirubinaemia
34mmol/L ( 2 mg/dL) 2 Hepatomegaly or right
upper quadrant pain of liver origin 3 Unexplained
weight gain (gt 2 of baseline bodyweight) because
of fluid accumulation BALTIMORE CRITERIA In the
first 21 days after HSCT Elevated total serum
bilirubin at 34mmol/L ( 2 mg/dL) AND two or
more of the following three criteria 1 Tender
hepatomegaly 2 Weight gain 5 from baseline 3
Ascites
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VENO-OCCLUSIVE DISEASE Severity
Classification of severity of VOD after HSCT
according to weight increase (), bilirubin
concentration peak, presence of peripheral edema
and ascites (mean sd)
Mild
Moderate
Severe Weight gain ( increase)
7.0 3.5 10.1 5.3
15.5 9.2 Maximum bilirubin (mg/dL)
4.7 2.9 7.9 6.6
26.6 15.2 Percentage with peripheral edema
23 70
85 Percentage with ascites
5
16 48 Day 100
mortality (all causes) () 3
20
98
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VENO-OCCLUSIVE DISEASE Differential Diagnosis

• Other liver diseases are common after BMT
• However, the presence of weight gain and fluid
  retention is usually sufficient to differentiate
  VOD from other causes of early liver dysfunction.
• Differentials
• A) After allogeneic BMT
• 1. Acute liver GVHD
• 2. Cyclosporine-induced hepatotoxicity
• B) After autologous or allogeneic BMT
• 1. Fungal infiltration of the liver
• 2. Viral hepatitis
• 3. Cholangitis lenta, e.g. during sepsis
• 4. Drug (trimethoprim-sulfamethoxazole, some
  third-generation
• penicillins, fluconazole and itraconazole)
  induced liver dysfunction
• 5. Constrictive pericarditis and right congestive
  heart failure
• 6. Persistent tumor infiltration of the liver

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VENO-OCCLUSIVE DISEASE Therapy

• No specific standard treatment modality for VOD
• Studies on the use of many drugs to treat VOD are
  limited to case reports and small series.
• The primary goal of treatment is to normalize the
  flow in the sinusoidal vessels and veins by
  controlling the vasculitis and fibrin deposition.

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VENO-OCCLUSIVE DISEASE Therapy2

• Treatment Strategies so far
• Low-dose tissue plasminogen activator (t-PA) has
  been used to increase fibrin degradation.
  Response only in lt one third of pts
• Antithrombin III (ATIII) replacement
• ATIII administered in combination with
  heparin/t-PA
• Promising experimental drug is defibrotide---- a
  single-stranded polydeoxyribonucleotide derived
  from porcine tissue that possesses
  antithrombotic, thrombolytic, anti-inflammatory,
  and anti-ischemic properties.

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VENO-OCCLUSIVE DISEASE Therapy3

• Defibrotide----6.25mg/kg iv in 2 h infusion q 6 h
  x 14 days ? 50-55 CR in severe VOD with MOF
  and 47-60 of survival at day 100 with no
  secondary effects
• SYMPTOMATIC TREATMENT
• Restriction of salt and water intake diuretics
• Maintain intravascular volume and renal perfusion
  by means of albumin, plasma expanders and
  transfusions (PCV ?30)
• Analgesia
• Paracentesis/thoracocentesis
• Haemodialysis/haemofiltration
• Mechanical Ventilation
• Surgical shunt
• Liver Transplantation

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VENO-OCCLUSIVE DISEASE Prophylaxis

• Because there in no effective treatment for the
  syndrome, its prevention is critical
• Substitution of fludarabine for cyclophosphamide
• Use of RIC regimens decreases the risk of VOD
• Low-dose heparin decreases the overall incidence
  of VOD
• 100 U/ kg/d of unfractionated heparin started 1
  week before transplantation and continued until
  day 30 decreases the overall incidence of VOD by
  nearly 10.

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VENO-OCCLUSIVE DISEASE Prophylaxis2

• When possible, delay HSCT if an acute hepatitis
  exists
• Adjust Busulfan dose or use iv
• Fractionate TBI
• Minimize exposure to potential hepatotoxic (ie,
  cyclosporine) and nephrotoxic agents (ie,
  aminoglycosides).
• Judiciously manage the sodium and water balance.
• Use of LMWH Enoxaparin 40mg/day in place of
  unfractionated heparin decreases the risk of
  bleeding episodes and has the advantage of
  intermittent dosing.

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VENO-OCCLUSIVE DISEASE Conclusion

• Hepatic VOD is a formidable challenge both for
  patients undergoing HSCT and for their
  physicians.
• Hepatic VOD contributes considerably to
  transplantation-related morbidity and mortality.
• A high clinical index of suspicion is needed to
  correctly and consistently identify patients with
  VOD.
• Prophylactic interventions are very critical
• Therapeutic agents such as defibrotide still
  under trial

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