VENO-OCCLUSIVE

DISEASE

Fatma VARAL

Director of Nurse of BMT Hospital

Erciyes University - Kayseri

Goals and Objectives • Epidemiology

• Risk Faktors for VOD

• Pathophysiology of VOD

• Prevention of VOD

• Treatment of VOD

• Prognosis

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Veno-Occlusive Disease (VOD)

• Sinusoidal obstructive syndrome (SOS), also called hepatic veno-occlusive disease (VOD), is part of a spectrum of organ injury syndromes that occur after HSCT.

• SOS usually affects 10% to 30% of patients after allogeneic stem cell transplantation (Sousa, 2012).

• The incidence of SOS is lower after autologous HSCT and with RIC (Reduced Intensity Conditioning) regimens.

• SOS occurs as a result of tissue injury to sinusoidal endothelial cells and hepatocytes caused by TBI or high-dose alkylating chemotherapy agents.

• Endothelial injury to the liver activates cytokine and tumor necrosis factor, which stimulates coagulation and thrombosis in the hepatic sinusoids and eventually in the venules.

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Veno-Occlusive Disease (VOD)

• The resulting impairment of blood flow leads to SOS (Anderson-Reitz & Clancy, 2013).

• Clinical manifestations of SOS usually begin within the first 2 weeks after transplantation and include hyperbilirubinemia, rapid weight gain, ascites, right upper quadrant pain, hepatomegaly, splenomegaly, jaundice, coagulopathy, and increased platelet consumption.

• Effective treatment options for VOD/SOS are absent.

• Due to this, much focus has been placed on prevention of VOD/SOS.

• Progression of SOS can lead to fatal.

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Epidemiology

• Mean incidence of VOD is 14 % (0-62.3 %) in patients undergoing SCT.

• Incidence of VOD is highest in children.

• VOD occurs withen the first 30 days after SCT.

Cesaro et al. 2015 and Coppell et al. 2010

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Risk Faktors for VOD

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The following criteria are associated with a significantly increased risk for developing veno-occlusive disease (VOD) and should be identified prior to bone marrow transplantation (BMT):

Pre-existing liver disease (eg liver fibrosis, hepatitis, abdominal irradiation)

Allogeneic SCT

Autologous SCT

Second myeloablative hematopoietic stem cell transplantation (HSCT)

Allogeneic HSCT for leukemia beyond the second relapse

History of treatment with gemtuzumab ozogamicin (Mylotarg, Pfizer); withdrawn from US market June, 2010

Conditioning with busulfan, melphalan, or both

Risk Faktors for VOD cont’d

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CONTINUED...

Use of HLA –mismatched donors

Osteopetrosis and Macrophage-activating syndromes (eg, hemophagocytic lymphohistiocytosis, Griscelli syndrome)

High dose radiation to the liver

Radio-embolization of liver tumors and after liver transplant

Pyrolizidine alkaloids from herbal sources (eg, bush tea)

Physical

• .

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The clinical symptoms of veno-occlusive disease include :

• Rapid weight gain

• Elevated total and direct bilirubin levels

• An increase in abdominal circumference

• Right upper quadrant pain

• Hepatomegaly • Mid-epigastric abdominal pain

• Peripheral edema • Jaundice

• Liver tenderness • Ascites

• The onset of transfusion-refractory thrombocytopenia with no detectable cause is frequently noted as an early and suggestive sign. *****

• The onset of veno-occlusive disease usually occurs prior to 20 days after HSCT, with a peak 12 day post transplantation. However, the onset of veno-occlusive disease has been reported even later.*****

Clinical Signs of VOD

Laboratory Evidence

• Elevated aminotransferases

• Hyperbilirubinemia (conjugated)

• Prolonged PT

• Signs of decreased synthetic function (low albumin)

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Clinical Signs of VOD Typical early symptoms include weight gain and tender hepatomegaly, followed by

edema and ascites, which are reflected in the clinical criteria developed by the Seattle

and Baltimore groups. These criteria predict veno-occlusive disease with an accuracy

of more than 90% but have a relatively low sensitivity of 56%.

• According to the modified Seattle criteria, 2 or more of the following must be

present prior to 20 days after stem cell transplantation for a diagnosis of veno-

occlusive disease:

o Bilirubin level of more than 2 mg/dL (34 µmol/L)

o Hepatomegaly and upper right quadrant pain of liver origin

o Ascites and/or unexplained weight gain of more than 2% above the reference

range

• According to the Baltimore criteria, hyperbilirubinemia (≥2 mg/dL) and 2 or

more of the following must be present prior to 21 days after stem cell

transplantation:

o Hepatomegaly (usually painful)

o Ascites

o Weight gain of more than 5% above the reference range

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Clinical Signs of VOD

• Criteria established for diagnosis of VOD w/o need for

liver biopsy.

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Original Seatle Criteria Baltimore Criteria

Presence before day 30 post-SCT of

2+ of the following:

Bilirubin ≥ 2 mg/dl before day 21

post-SCT and at least 2 of the

following:

1. Bilirubin ≥ 2 mg/dl 1. Hepatomegaly

2. Hepatomegaly, right upper

quatrant pain

2. Ascites

3. Ascites with or without

unexplained weight gain of > 2%

over baseline

3. Weight gain > 5% over baseline

Coppell et all 2010

Clinical Gradation of VOD

• MİLD: Patients requiring no medications for pain control or diuresis for fluid overload. Eventually patients have resolution of all signs and symptoms and complete normalization of lab abnormalities.

• MODERATE: Patient reguiring sodium restriction and diuresis to minimize fluid overload and/or medication to alletive pain. Eventually patients have complete resolution of all signs and symptoms of hepatic disease.

• SEVERE: 15-27% of VOD cases. Patients demonstrate adverse effects from liver disease including severe pain, fluid overload leading to respiratory compromise, hepato-renal syndrome etc. In these patients all abnormal symptoms , signs and laboratory values do not resolve before day 100 post HSCT.

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Pathophysiology

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• VOD, also known as sinusoidal obstruction syndrome, is a potentially life-threatening complication of HSCT

• Conditioning regimens given before HSCT cause toxic metabolites to be produced by hepatic hepatocytes in liver

• These metabolites trigger the activation, damage and inflammation of endothelial cells that line the sinusoids

• Sinusoids are small capillary vessels found in the liver

• This ultimately leads to VOD, and

• This VOD,

• Increased thrombosis and decreased fibrinolysis

• Sinusoidal damage and constriction

• Watching with inflammation.

Pathophysiology

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Histological section of the liver viewed through a microscope. Blood vessels shown in

red, cell nuclei in blue, cytoplasm in pink

Pathophysiology

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• The chemotherapy agents used as conditioning regimens for haematopoietic stem cell transplantation (HSCT) are metabolized in the liver.

• Toxic metabolites are released by the hepatocytes, causing the damage and activation of the sinusoidal endothelial cells (SECs), which line the sinusoids.

• These events can be triggered as soon as the conditioning regimen is administered.

Pathophysiology

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Pathophysiology

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• The activated sinusoidal epithelial cells release inflammatory cytokines, adhesions molecules and heparanase.

• Heparanase digests the extracellular matrix that supports the structure of the sinusoids.

• The action of these factors causes the endothelial cells to round up and to form gaps between the cells.

• Carreras E et al. Biol Blood Marrow Transplant 2011;17:1713–1720

• Richardson PG et al. Expert Opin Drug Saf 2013;12:123–136

Pathophysiology

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• Red blood cells, white blood cells and other cellular debris exits through these gaps into the space of Disse the peri-sinusoidal space that is located between the endothelium and the hepatocytes.

• The accumulation of cells and debris in this space causes narrowing of the sinusoids.

• Endothelial cells can get loose and may embolise further downstream.

• Carreras E et al. Biol Blood Marrow Transplant 2011;17:1713–1720

• Richardson PG et al. Expert Opin Drug Saf 2013;12:123–136

Pathophysiology

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Pathophysiology

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The accumulation of cells and debris in the space of Disse, the perisinusoidal space located between the endothelium and the hepatocyte, lead to narrowing of the sinusoids

Pathophysiology

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• An increase in the expression of tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1) causes an increase in clot formation and a decrease in the breakdown on clots. This contributes to the deposition of fibrin, clot formation, and the narrowing of the sinusoids. This may ultimately lead to obstruction of the sinusoids.

• This image shows the pathophysiology of VOD. • The endothelial cells have rounded up, leading to gap formation, and some have dissected off into the bloodstream. • The sinusoid has narrowed due to the accumulation of cells in the space of Disse. • Clots forming at the sites of endothelial damage have caused the obstruction of the sinusoids.

Richardson PG et al. Expert Opin Drug Saf 2013;12:123–136

Pathophysiology

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Pathophysiology

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• Activation and damage due to

conditioning regimen-mediated

injury. Damage is both directed

and mediated by cytokines such as:

- TNF-α, IL-1b, IL-6

• Increased expression of

adhesion molecules ICAM-1 and

VCAM-1 of endothelial cell

surface

• Activation of leukocytes that

release additional inflammatory cytokines

• Digestion of extracellular matrix

• Portal vein hypotension

• Hepatic venous outflow obstruction

1. Richardson PG et al. Expert Opin Drug Saf 2013;12:123–136 2. Bearman SI. Blood 1995;85:3005–3020 3. Coppell JA et al. Blood Rev 2003;17:63–70

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Prevention of VOD

Careful screening for pre-existing risk factors:

• Obesity

• Younger age at SCT

• Elevated LFT’s

• h/o viral hepatitis

• h/o previous VOD

• h/o abdominal irradiation

Johnson and Savani 2012

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Laboratory Studies

• Early diagnosis and subsequent timely treatment significantly affect the risks of morbidity and mortality.

• The laboratory workup of a patient with possible veno-occlusive disease has several objectives.

• The first goal, of course, is to confirm the diagnosis,

• The second goal is to look for a detectable discrete cause,

• The third goal is to establish the function of the liver and other end organs.

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Laboratory Studies Relevant laboratory findings include :

Hyperbilirubinemia

Parameters of cholestasis (alkaline phosphatase and γ-

glutamyltransferase [GGT])

Thrombocytopenia and abnormal coagulation parameters (especially

elevated plasminogen activator inhibitor-1 [PAI-1] levels)

Decreased antithrombin III (ATIII), protein C, and protein S levels

İncreased total and direct bilirubin levels

CBC count

Fibrinogen levels, fibrin split product levels, D-dimer levels, ATIII levels

Sedimentation rates

Baseline chemistries, including BUN, creatinine, and serum albumin and

total protein levels

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• Documentation of increased total and direct bilirubin levels assists in the identification of cholestatic disease.

• GGT, alkaline phosphatase, and transaminase levels should be measured to rule out other causes of hepatic inflammation.

• A CBC count and differential should be obtained to assess engraftment total lymphocyte count, as well as transfusion-refractory thrombocytopenia.

• Coagulation parameters should include prothrombin and activated partial thromboplastin times, fibrinogen levels, fibrin split product levels, D-dimer levels, ATIII levels, protein C levels, and protein S levels to rule out disseminated intravascular coagulation (DIC) and to assess specific veno-occlusive disease–related coagulation factors.

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Laboratory Studies Cont’d

Laboratory Studies Cont’d

• PAI-1 levels are often abnormally elevated, and ATIII levels are decreased in patients with hepatic veno-occlusive disease; thus, measurement of these factors may be helpful as sensitive markers of veno-occlusive disease

• Parameters of infection and/or inflammation (eg, C-reactive protein levels) should be obtained to help assess the infectious risk and rule out sepsis.

• Despite the vasculitic basis for this disease, obtaining sedimentation rates is not particularly helpful because they may be nonspecifically elevated in any patient who has undergone transplantation.

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Laboratory Studies Cont’d • A decrease in the anticoagulant protein levels after

transplantation may be a harbinger of early end-organ damage, particularly in patients with preexisting conditions (eg, low anticoagulant protein levels prior to transplantation).

• Weekly measurements of these anticoagulants during the first 2 weeks after transplantation may allow for early detection of veno-occlusive disease.

• Baseline chemistries, including BUN, creatinine, and serum albumin and total protein levels, may reveal other end-organ dysfunction and may delineate the severity of the capillary leak syndrome (CLS) in the patient.

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Imaging Studies

• The diagnostic imaging study of choice is abdominal Doppler ultrasonography. Ultrasonography of the liver reveals engorgement, and the Doppler reveals direction of flow in the veins.

• Other hepatic pathology may be detected (eg, gallbladder thickening, gallstones, lymphadenopathy).

• Ultrasonography is a powerful tool for confirming diagnosis, but typical findings often manifest late in the course or are not always apparent.

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Imaging Studies

• The diagnostic ultrasonography finding is a reversal of flow in the portal and hepatic veins. Other findings include ascites and hepatomegaly.

• Imaging studies should be used to assess the following:

Size of liver and spleen

Free abdominal fluid

Thickening of the gallbladder wall

Diameter of the portal vein and liver veins

Portal venous flow

Hepatic venous flow

Loss of the respiration dependent flow modulation

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Medical Care

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• No specific treatment modality for veno-occlusive disease (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.

• Low-dose tissue plasminogen activator (t-PA) has been used to increase fibrin degradation.

Supportive Care

• Minimize exposure to potential hepatotoxic (ie, cyclosporine) and nephrotoxic agents (ie, aminoglycosides).

• Manage the sodium and water balance.

• Diuretic medication is indicated when symptoms associated with excess extravascular volume are observed.

• Opiate analgesia should be copiously administered, if indicated (ie, right upper quadrant pain).

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Supportive Care cont’d

• When ascites cause respiratory compromise, paracentesis is appropriate. However, it should be performed with caution, and careful attention should be paid to coagulation parameters.

• Renal and pulmonary failure are managed with hemodialysis, ultrafiltration, and mechanical ventilation, as indicated.

• Patients with severe veno-occlusive disease and multi-organ failure are at increased risk for infection.

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Supportive Care cont’d

• Total parenteral nutrition, almost always used during hematopoietic stem cell transplantation (HSCT), is a potential source of additional liver damage and should be modified according to the guidelines in consideration of the hepatic injury.

• Coagulopathy should be corrected.

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Further Inpatient Care

• A Cochrane Review concluded that there is low or very

low quality evidence that ursodeoxycholic acid may

reduce the incidence of hepatic VOD, all-cause mortality

and mortality due to VOD in haematopoietic stem cell

transplantation recipients. The authors also added that

there is insufficient evidence to support the use of

heparin, low molecular weight heparin, defibrotide,

glutamine, fresh frozen plasma, antithrombin III, and

prostaglandin E1.

Cheuk DK, Chiang AK, Ha SY, Chan GC. Interventions for prophylaxis of hepatic veno-occlusive disease in people undergoing haematopoietic

stem cell transplantation. Cochrane Database Syst Rev. 2015 May 27. 5:CD009311. [Medline]

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Complications

• Hepatic failure: Some degree of hepatic dysfunction is observed in all cases of post-BMT hepatic veno-occlusive disease; however, in rare severe cases, overt liver failure may be observed.

• Renal failure: This may be secondary to hepatorenal syndrome, as well as direct injury by the vasculopathy. In patients who have undergone transplantation, numerous frequently used nephrotoxic drugs (eg, vancomycin, amphotericin B, cyclosporine) can result in preexisting renal dysfunction and loss of renal function reserve. Separating the effects of the drugs from the effects of veno-occlusive disease may be difficult.

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Complications cont’d

• Pulmonary failure

• Increased risk of infectious complications due to peritoneal drainage and transfer of an immuno-deficient patient to intensive care with no laminar air flow units

• Severe consumptive coagulopathy with an increased risk for thrombosis and bleeding

Prevention of VOD Heparin

• In 1992 Attal et al. Demonstrated that continuous heparin infusion from -8 to day +30 s/p SCT resulted in reduction of VOD from 13.7% in control group to 2.5% in the study group.

• Other studies supported use of heparin and Low Molecular

Weight Heparin (LMWH) for VOD ppx, although not all outcomes have been as robuts as the initial studies

• In 2002 Park et al. Demonstrated that heparin ppx was not improved with addition of ursodiol

• No study has yet to look at ursodiol vs. ursodiol+heparin

Rosenthal et al, Or et al and Imran et al.

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Prevention of VOD Ursedeoxycholic Acid (UA)

It is natural component of bile (<5%)

It is hydrophilic bile acid which, by changing the total composition of bile, reduces retained bile acid within the hepatic biliary tree, thereby reducing its hepato-toxicity.

Also attenuates the pro-inflammatory environment by reducing expression of pro inflamatory cytokines.

UA ppx did not change overall survival in patients undergoing allogeneic SCT.

UA ppx is started two weeks prior to SCT and continued through the high risk period after SCT.

Johnson and Savani 2012

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Prevention of VOD Prostoglandin E1(PGE1)

• PGE1 induces vasodialtion inhibits platelet aggregation

and activates the fibrinolytic system.

• Conflicting evidence exist for the use of PGE1 which is

also shown to be highly toxic.

• New preparations using lipid microspheres containing

PGE1 are being studied and appear to have some efficacy

for VOD ppx in pediatric SCT.

Lee et al. 2010

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Prevention of VOD Defibrotide

• Defibrotide is a porcine derived mixture of single

stranded oligonucleotide swith anti-inflammatory, pro-

fibrinolytic and antiothrombotic action without significant

systemic anticoagulation effects.

• Defibrotide has protective effects on activated endothelial

cells.

• Defibrotide is suggested at a dose of 6.25 milligrams/kg

intravenously 4 times daily for the prevention of VOD

(sinusoidal obstruction syndrome) in adults undergoing

allogeneic stem cell transplantation.

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Prevention of VOD Defibrotide

• In 2012 Çorbacıoğlu et al. Published a phase III

clinical trial examining the use of defibrotide

profphylaxis in pediatric patients at risk for VOD

• Patients were randomized to prophylaxis with defibrotide

or no VOD prophylaxis.

• Patients began prophylaxis w/their pre-conditioning

regimen and completed prophylaxis 30 days s/p SCT.

• All patients who developed VOD were treated with

defibrotide until complete recovery or death.

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Prevention of VOD Defibrotide

As a result of this clinical trial;

• Defibrotide reduced VOD rate from 20% in control group

to 12% in treatment group (p=0.0488)

• In patients undergoing allogeneic SCT the severity of

VOD was reduced with defibrotide ppx (p=0.0062 at 30

days and p=0.0034 at 100 days)

• Defibrotide therapy did not improve morbidity or

mortality in patients who did develop VOD.

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Treatment of VOD

• MILD DISEASE: No specific treatment required

• MODERATE DISEASE: Sodium restriction, diuresis and

pain control

• SEVERE DISEASE: Above + supportive care managing

symptoms including ascites, renal insufficiency, cardiac

failure, bleeding and confusion.

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Prognosis

• Overall VOD mortality : 6.9% of all VOD patients

• Severe Disease mortality : > 50%

• Mortality highest in patients who patients who develop multi-organ failure.

Lee et al. 2010

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Summary

• VOD is a common problem post-SCT

• Results from hepatic endothelial injury > sinusoidal

congestion > venular congestion > hepato-cellular injury

• Patients present with weight gain, pain and jaundice

• Preophylaxis with heparin, ursodiol, PGE1 or defibrotide can

lead to a reduced risk of VOD post-SCT

• Severe disease requires aggressive multi-organ supportive care

and is associated with high mortality rates.

• Defibrotide is a promising new intervention that can decrease

both the morbidity and mortality associated with severe VOD.

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Pulmonary Veno-Occlusive Disease (PVOD)

• Pulmonary veno-occlusive disease (PVOD) is the primary

pulmonary vascular complication following HCT.

• This rare disease occurs 4 to 6 weeks after HCT.

• Patients present with signs of pulmonary hypertension, cough,

dyspnea, and possible right heart failure.

• Diagnosis is made by biopsy with signs of pulmonary venular

thrombosis.

• Corticosteroids are the treatment of choice, though few hard

data exist to support this choice of therapy.

• Infectious pulmonary complications remain the primary cause

of pulmonary disease following HCT. Kreit JW. Respiratory complications. In: Ball ED, Lister J, Law P, eds. Hematopoietic Stem Cell Transplantation. Philadelphia, PA: Churchill Livingstone; 2000:563–577. 84. Bryant D. Pulmonary complications. In: Atkinson K, ed. Clinical Bone Marrow and Blood Stem Cell Transplantation. New York: Cambridge University Press; 2000:943–957. 50

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Pulmonary Veno-Occlusive Disease (PVOD) cont’d

• Gram negative bacteria are most commonly the infecting agents in the first 100 days post-HCT.

• Most of these infections are from endogenous sources.

• Viral pneumonitis is most often caused by CMV and herpes viruses.

• Herpes pneumonitis usually occurs in the early post-transplant period.

• Patients present with a nonproductive cough, fever, hypoxemia, and dyspnea.

• Radiographs reveal diffuse reticulonodular or “ground glass” infiltrates.

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Pulmonary Veno-Occlusive Disease (PVOD) cont’d

• Early treatment with antiviral therapies such as ganciclovir or foscarnet and corticosteroids improves survival, although mortality rates for CMV pneumonitis remain high.

• Viral pneumonitis can also be caused by respiratory syncytial virus, adenovirus, influenza A and B, and parainfluenza.

• Fungal pneumonia caused by the Aspergillus fungi remains a serious problem for HCT patients.

• Invasive disease is difficult to treat, although extended therapy with new antifungal agents has greatly improved outcomes.

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Pulmonary Veno-Occlusive Disease (PVOD) cont’d

• Opportunistic infections such as Pneumocystis carinii pneumonia (PCP) present a risk for patients who are profoundly immunosuppressed for extended periods of time.

• Patients receiving immunosuppressive agents for GVHD should receive PCP prophylaxis until all immunosuppressive agents have been discontinued.

• Patients who experience severe VOD/SOS often develop a hepato-renal syndrome.

• Decreased intravascular volume and low cardiac output lead to renal hypoperfusion and RI/ARF in severe VOD/SOS.

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Pulmonary Veno-Occlusive Disease (PVOD) cont’d

• Nursing management includes the administration of diuretics and evaluating responses.

• Patients may require hemodialysis or continuous veno-venous hemodialysis for renal failure or fluid management.

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Pulmonary Veno-Occlusive Disease (PVOD)

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Pulmonary Veno-Occlusive Disease (PVOD)

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Pulmonary Veno-Occlusive Disease (PVOD)

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Self-Assessment Questions

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1. VOD affects which major organ?

2. What by-product of HSCT conditioning causes damage to the

sinusoidal endothelial cells and hepatocytes?

3. Which of the following is not a characteristic of

VOD pathophysiology?

a) Increased clot formation

b) Decreased clot breakdown

c) Expansion of the sinusoids

d) Inflammation

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