Transcript veno-occlusive disease and other acute complications of hsct

VENO-OCCLUSIVE DISEASE AND OTHER
ACUTE COMPLICATIONS OF HSCT
Dr Sunday Ocheni
Consultant Haematologist,
Department of Haematology & Immunology
University of Nigeria, Enugu Campus,
Mobile Nos: +234-7039222313, +234-8185766742
E-mails: [email protected], [email protected]
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
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
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.
ACUTE COMPLICATIONS OF HSCT
INTRODUCTION
The high doses of RT and/or CT included in conditioning
regimens affect all the pt’s 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
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
morbidity
to
considerable
mortality
&
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
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
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.
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
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
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
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 patient’s discharge
CHRONIC VOD
Occurs outside of the HSCT setting eg following
chronic assumption of pyrrolizidine alkaloids
contained in Senecio tea (South Africa).
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
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 (> 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
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
Percentage with peripheral edema
23
7.9 ± 6.6
70
26.6 ± 15.2
85
Percentage with ascites
5
16
48
Day 100 mortality (all causes) (%)
3
20
98
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
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.
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 < 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.
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 4760% 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
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%.
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.
VENO-OCCLUSIVE DISEASE: Conclusion
Hepatic VOD is a formidable challenge both for patients
undergoing HSCT and for their physicians.
Hepatic
VOD
contributes
considerably
transplantation-related morbidity and mortality.
to
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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