Veno-Occlusive Disease (VOD)
Veno-occlusive disease (VOD) can be a life threatening complication affects approximately half of individuals undergoing TBI/BMT (Grundy, 2000). VOD occur anytime between Day –7 to Day +35 of bone marrow transplantation (BMT). The reported incidence of VOD is 5-40% in children (Brugieres et al., 1988; Reiss et al., 2002) and similar or higher rates have been reported in adults ( Jones et al., 1987; Carreras et al., 1988; Hasegawa et al., 1988; Reiss et al., 2002). VOD can be resolved in most of the cases but the mortality rate can be over 90% in severe cases. Radiation therapy used in bone marrow transplantation, and Stem cell transplantation can produce a blockage of the small veins, such blockage causes a backup of blood in the liver, reducing the amount of blood flowing into the liver. The insufficient blood supply, in turn, damages the liver cells causing Hepatic veno-occlusive disease (HVOD). The disease varies between mild to severe and results in failure of the liver and death.
VOD lasts until the damaged hepatic tissue heals & resumes normal function – generally 10 to 14 days after onset.
Clinical manifestations of VOD are jaundice, painful liver enlargement, and fluid-sodium retention. Hepatic venular occlusion, hepatic venular eccentric luminal narrowing, phlebosclerosis, sinusoidal fibrosis, and hepatocyte necrosis are the most common histologic features of this damage. (Shulman, 1994) and it is characterized by hyperbilirubinemia, fluid retention, and painful hepatomegaly appearing soon after BMT
Symptoms of veno-occlusive disease may begin suddenly. Blockage of the small veins causes the liver to swell with blood, making it tender when a doctor presses on the abdomen. Fluid may leak from the surface of the swollen liver and accumulate in the abdomen, producing a condition called ascites. The backup of blood in the liver also raises the pressure in the portal vein (a condition called portal hypertension) and in the veins that empty into it. This higher pressure may cause dilated, twisted (varicose) veins in the esophagus (esophageal varices), which may rupture and bleed, sometimes massively. The bleeding results in vomiting of blood and the passage of blood through the digestive tract, resulting in black stools (melena) and even shock if the bleeding is severe
Risk Factors:
Two categories of factors associated to the development of VOD (Rozman et al., 1996; Bearman, 1995; Shulman et al., 1994; Jones et al 1987; Carrera et al., 1983) were analyzed: (1) patient-related factors, ie, age greater than 20 years, previous radiation therapy of the abdomen, second BMT, previous liver disease, increased serum aspartate aminotransferase (AST) before cytoreductive therapy, Karnofsky performance score less than 90%, and presence of fungal infection 1 week before BMT; and (2) transplant-related factors, i.e., type of transplant, type of donor, pre-transplant acyclovir therapy, vancomycin administration during cytoreductive therapy, and dose of cytoreductive therapy. The kind of preparative regimen used is related to VOD, too. Higher doses of cyclophosphamide and higher exposure to its active metabolite 4-hydroxycyclophosphamide, total body irradiation (TBI), as well as the use and higher serum levels of busulphan (Bu) are all related to higher risk for VOD (Meletis, 1985; Vilmer et al., 1987; Rozman et al., 1996; Ringden et al., 1996; Dix et al., 1996; Huitema et al., 2002; Pihusch et al., 2002. Careful measurement of Bu levels and the use of iv busulphan can decrease the incidence of VOD (Kashyap et al., 2002). There is evidence that TBI based regimens cause less VOD than the Bu containing preparative regimens (Ringden et al., 1996; Hartman et al., 1998; Litzow et al., 2002). Patient cohorts receiving autologous HSCT, matched sibling donor, matched unrelated donor and partially matched unrelated donor HSCT develop increasingly higher incidence of VOD (Baglin, 1994). Recently, lower serum cholinesterase levels and high N-terminal propeptide for type III procollagen (P-III-P) pre-transplant were associated with higher incidence of VOD (Kami et al., 1997; Tanikawa et al., 2000). Younger patients have better outcome and survival once they develop VOD (Reiss et al., 2002). Recently, it has been shown that impaired activity of plasma von Willebrand factor-cleaving protease may predict the occurrence of hepatic veno-occlusive disease after stem cell transplantation (Park et al., 2002).
High busulfan area under the plasma concentration verses time curve (AUC) values (>1,500 m M/min) may be associated with an increased risk of developing hepatic veno-occlusive disease (HVOD). Excessively high busulfan AUC or CSS is associated with an increase in hepatic veno-occlusive disease, low levels are associated with graft rejection in allogeneic transplantation (Grochow et al., 1989; Slattery et al., 1995). Patients who have received prior radiation therapy, greater than or equal to three cycles of chemotherapy, or a prior progenitor cell transplant may be at an increased risk of developing HVOD with the recommended BUSULFEX dose and regimen.
Usually, an unexplained weight gain is the first symptom of VOD. This weight gain, attributable to water and sodium retention by the kidney, appears within 6 to 8 days following the transplant in 95% of patients that develop VOD. Two to three days later, hyperbilirubinemia of varying degrees is observed in 98% of the cases (Carreras et al., 1993). An increase in aspartate aminotransferase and alkaline phosphatase may occur simultaneously or a few days later. Most patients develop ascites and pain in the upper right quadrant of abdomen, and clinical examination usually reveals a firm and painful hepatomegaly. Many patients become refractory to platelet transfusions ( Shulman and Hinterberger , 1992; Bearman , 1995; Carreras et al., 1993). Renal insufficiency is also present in 50% of patients developing VOD (mainly patients with severe VOD) and 25% of them will require hemodialysis.( Carreras, et al, 1993, Zager et al., 1989). Finally, patients with severe VOD can display severe encephalopathy or even become comatose. In 50 to 80% of the cases, a gradual improvement of the clinical condition is noted at 2 to 4 weeks after the onset of the disease (McDonald et al, 1991; Carreras, et al, 1993). In the remaining 20 to 50% of the cases, patients die because of or with severe VOD. The majority of them die of multiple organ failure (MOF) with hepatic failure, but also of renal failure, congestive heart failure, extravascular fluid effusions, and pulmonary failure requiring oxygen support and mechanical ventilation (McDonald et al, 1991). The reasons for lung failure may include pulmonary VOD, pleural effusions and interstitial pneumonitis of infectious or non-infectious origin (Zager et al., 1989;. Wingard et al., 1989). Bleeding at gastrointestinal sites or at other sites is a significant cause of death as well.
Differential diagnosis:
Acute liver GVHD (graft-versus-host disease) causes jaundice with increased serum alkaline phosphatase and aminotransferase levels. AGVHD usually develops between days 20 and 40 post-transplant together with skin and/or gut GVHD (Wolford and McDonald, 1988). However, the differential diagnosis with VOD can be difficult when GVHD develops earlier (hyperacute GVHD) or when the onset of VOD is later than day 10. Moreover, both diseases are common after allogeneic BMT and may thus coexist. In this case, measurement of the hepatic venous pressure and/or a histologic evaluation of the liver may be helpful in determining which disease is dominant.
Fungi, mainly Candida species invade blood vessels, causing hepatic infarctions or venous obstructions that produce tender hepatomegaly, ascites and signs of portal hypertension mimicking VOD. Viral infections of the liver are unusual in the early posttransplant period because of the systematic use of acyclovir and because B and C hepatitis viruses can produce liver injury only in the presence of an intact immune system (Bearman, 1995).
Medications used in the transplant can induce liver dysfunction. Cyclosporine, in a dose-dependent fashion, may cause cholestasis and hepatocyte necrosis and lead to gallstones. Some antimicrobial drugs (such as trimethoprim-sulfamethoxazole, some third-generation penicillins, fluconazole and itraconazole) and methotrexate can produce both cholestasis as well as hepatocellular injury as well. Constrictive pericarditis and right congestive heart failure can cause pain in the upper right quadrant, hepatomegaly, ascites, peripheral edema and pleural effusions, as well as renal failure and an increase in the concentration of serum hepatic enzymes. In addition to this hyperbilirubinemia and fluid retention is observed.
Early diagnosis of VOD is important to initiate antithrombotic therapy before serious organ failure. But at the sever stage of disease liver biopsy remains the hallmark for diagnosis. It is extremely difficult in thrombopenic and possibly septic patients and it does not appear to be mandatory. In percutaneous liver biopsy specimens non-diagnostic or falsely negative specimens can be noted (Shulman and Hinterberger, 1992). Transvenous liver biopsies are advantageous, as possible hemorrhage drain intravascularly and it is possible to measure hepatic venous pressure gradients (HVPGs). HVPGs higher than 10 mmHg are associated with the histological diagnosis of VOD and there is evidence that higher gradients indicate a more severe disease (Shulman et al., 1994; Carreras et al., 1993). However, is not necessary to obtain liver biopsy in order to diagnose and treat VOD, early and rapid total serum bilirubin elevation, together with weight gain, indicating onset of severe VOD (Bearman et al., 1993), are enough indications to initiate appropriate treatment.
Other than the liver biopsy, ultrasound of abdomen studies may help in diagnosis by showing ascites, hepatomegaly or thickening of the gallbladder wall, which are, in any case, all non-specific or unreliable findings. Pulsed Doppler ultrasound may show a decreased or inverted portal blood flow but this is a relatively late finding in patients with established VOD (Hommeyer et al., 1992).
Prophylaxis:
The prophylaxis of VOD changed over the years. Prophylaxis with Ursodeoxycholic acid (UDCA), an artificial bile acid, may be helpful in reducing the incidence of severe VOD. It protects hepatocytes from damage caused by cholestasis. A dose of 12 mg/kg/d , twice a day , administered on the day preceding the first dose of conditioning and continued until day 90 after transplantation resulted in clinically relevant beneficial effects, particularly in the reduction of the incidence of severe GVHD and in improved survival (Tapani Ruutu et al., 2002).
Treatment:
Defibrotide, a novel polydeoxyribonucleotide, has several properties of potential interest for the treatment of VOD. Defibrotide promotes the synthesis of thrombomodulin, increases endogenous t-PA (tissue plasminogen activator) and decreases PAI-1(plasminogen activator inhibitor type 1), without having anticoagulant activity by itself (Bearman et al., 1997). Defibrotide’s effects are predominately local within the vascular bed, and there is no significant effect on systemic coagulation. Its beneficial pharmacological effects are due to its anti-thrombotic, anti-inflammatory and antiischemic properties. Defibrotide acts by decreasing the procoagulant activity and increasing the fibrinolytic potential of endothelial cells, favoring an anticoagulant phenotype of the endothelium, which may protect from fibrin deposition and vascular occlusion. It also significantly increments t-PA antigen in resting endothelial cells (Falanga et al., 2003). Corbaciqlu et al., (2004) evaluated the efficacy of defibrotide in pediatric patients developing hepatic VOD after HSCT in a retrospective analysis. A total of 45 patients between 0.2 and 20 years (median age: 8.2 years) with hepatic VOD were treated with defibrotide: 22 patients (49%) met risk criteria for severe or progressive disease and 23 (51%) for moderately severe and mild disease. The median duration of DF treatment was 17 days. In all, 34 patients (76%) achieved complete response (CR) with a survival rate of 64% at day 100. CR rate in patients with severe disease was 50% with long-term survival of 36%. The average defibrotide dose in the CR group was 45 mg/kg/day and in the no responder (NR) group 27 mg/kg/day. The use of additional drugs besides defibrotide to treat VOD made no difference in the outcome compared to defibrotide alone.
Nursing management:
HVOD has been increasingly recognized as a complication of conventional chemotherapy with or without abdominal irradiation, which most frequently occurs in children. There are major challenges in managing pediatric patients with veno-occlusive syndrome, especially when they have severe disease. When VOD is diagnosed, the medical team will take steps to prevent the more serious complications from developing.
The patient’s weight and abdominal grith should be measured twice daily. If there is any increase in weight it could be due to the accumulation of free fluid in the peritoneal cavity (ascites). Patients with ascites usually present with increasing abdominal girth, nausea and anorexia. They may have shortness of breath due to elevation of the diaphragm or pleural effusion. Tense ascites can cause pain. The accuracy of the physical examination for detecting ascites is only 58%, with the most useful finding being flank dullness. Without this, the probability of ascites is below 10%. When these ascites are depleted intravascularly; at the same time they progress to other organ and system failures (renal, pulmonary, and cardiac).
The patients body fluids should be restricted to 75%. Dietary sodium restriction is important to achieve negative sodium balance. Two grams (88 mol) of sodium per day is appropriate for most patients, however, restriction of 1 g to 1.5 g (44 mmol to 66 mmol) per day may be necessary in patients with significant ascites or very low urine sodium output (less than 10 mEq/L) (Rita Sood, 2000). In addition, fluid restriction should be considered when significant hyponatremia occurs. The input and outputs should be recorded to help monitor the patient’s response to therapy. Diuretic therapy with lasex should be instituted to control fluid overload. Urine sodium excretion may be helpful in monitoring response to therapy. Therapeutic paracentesis is the removal of large volumes of fluid. Paracentesis does not improve survival rate, and ascites frequently recurs requiring repeat procedures.
The severity of the disease can be understood by looking at the levels of elevation in the alanine aminotransferase (ALT), aspartate aminotransferase (AST) and the bilirubin by monitoring lfts. Elevation of the alanine transaminase with or without aspartate transaminase usually indicates hepatocellular inflammation or necrosis. In contrast, increases in alkaline phosphatase, gamma glutamyl transferase or 5’nucleotidase incriminate cholestasis or obstructive jaundice. The serum-ascites fluid albumin gradient is high, with the total protein level in the ascitic fluid > 2.5 g/dL. Gupta et al, (2002) observed an increased serum transaminase (60-574 unit/dl), prothrombin time (16-21 sec) and serum alkaline phosphatase (98.5-488 KA unit/dl) and bilirubin levels (3.4 – 4.4 mg/dl), were observed in the children suffering from hepatic vein occlisive disease.
An imbalance between procoagulants and naturally occurring anticoagulants is observed in the patient with VOD. Usually reduced levels of circulating natural anticoagulants such as antithrombin-III (AT-III) and protein C (PC) are observed. Low levels of AT-III have been correlated with the development of organ dysfunction during BMT. Noriko Shin-Nakai, (2006) reported recovery of a 5yr old girl (who suffered from vod after an allogeneic BMT from a human lymphocyte antigens (HLA) – matched sibling donor) from the disease after administration of AT-III (doses of 50 – 75 U/kg per day) from the 14 th day onwards to the 55 th day (a total dose of 1625 U/kg over 32 days) together with 46 U doses of FFP.
The CBC and biochemistry provides valuable information about the blood cells and the liver function. Bleeding may occur throughout child’s post-transplant recovery until adequate engraftment has occurred. Nosebleeds, bruising, and bleeding from the gums, urinary tract, or gastrointestinal tract are all common problems. The reason for the bleeding is due to the damage of endothelium, due to conditioning regimen. Main reason for it is the low platelet count. Generally, these problems are handled with platelet transfusions. Platelet transfusions are required to keep children’s platelet counts at a safe level until bone marrow recovery has occurred. Generally speaking, platelets are the last type of blood cell to fully recover following bone marrow or peripheral blood stem cell transplant.
The patient may have discomfort in breathing because of abdominal grith, so comfort is provided by appropriate positioning. A sufficient analgesia is given so that they can be relived from the pain. In addition to all these the most important one is psychological support. The side effects high-dose chemotherapy and/or radiation and the prolonged hospitalization, medications and complications can be stressful for patients and make them weak. So the moral support provided by the nurses is often the best “medicine” for the patient.
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