Contribution of fibrinolytic tests to the differential diagnosis of veno‐occlusive disease complicating pediatric hematopoietic stem cell transplantation

Sartori, Maria Teresa; Cesaro, Simone; Peruzzo, Mattia; Messina, Chiara; Saggiorato, Graziella; Calore, Elisabetta; Pillon, Marta; Varotto, Stefania; Spiezia, Luca; Cella, Giuseppe

doi:10.1002/pbc.23213

Cited by 20 publications

(21 citation statements)

References 42 publications

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“…Accepting a threshold of ≥ 26.4 ng/mL, in agreement with a previous report, PAI‐1 Ag resulted in a sensitivity of 100% and a specificity of 93% for the identification of VOD with a positive predictive value of 67% and a negative predictive value of 100%. Reduction of protein C levels below 34.5% was observed in 33% patients with VOD with a sensitivity of 67%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 95% for the diagnosis of VOD.…”

Section: Resultssupporting

confidence: 90%

“…VOD in WT patients is characterized more by an increase of liver enzymes than bilirubin; therefore, the criteria used for HSCT patients are not completely satisfactory for WT patients. The endothelial activation and dysfunction observed in VOD is associated with a procoagulant state with a reduced fibrinolytic capacity, as highlighted by the increase in PAI‐1 levels . This alteration of coagulation and fibrinolytic cascade was initially described in HSCT patients, but we found it also in patients with VOD occurring after chemotherapy for WT and acute lymphoblastic leukemia .…”

Section: Discussionsupporting

confidence: 62%

“…During this time, the level of PAI‐1 antigen (PAI‐1 Ag) and activity (PAI‐1 Act) and protein C activity were tested at the time of clinical diagnosis and before each chemotherapy cycle. Based on our previous studies, the following plasma levels were considered abnormal: PAI‐1 Ag ≥ 26.4 ng/mL, PAI‐1 Act > 0.5 U/mL and protein C < 70%. In addition, data on the following parameters were collected: platelet count, liver function tests (LFT) (alanine aminotransferase [ALT], aspartate aminotransferase [AST], gamma‐glutamyl transpeptidase [GGT], total conjugated and unconjugated bilirubin), coagulation tests (prothrombin time [PT], activated partial thromboplastin time [aPTT], fibrinogen, antithrombin activity, factor VIII) and fibrinolytic parameters (D‐dimer).…”

Section: Methodsmentioning

confidence: 99%

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PAI‐1 and protein C as early markers of veno‐occlusive disease in patients treated for Wilms tumor

Cesaro

Mauro

Sattin

et al. 2019

Pediatric Blood & Cancer

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Background Hepatic veno‐occlusive (VOD) disease has been described in hematopoietic stem cell transplantation (HSCT), solid tumors, and acute lymphoblastic leukemia. The incidence of VOD in Wilms tumor (WT) ranges from 1.2% to 8%. The diagnosis of VOD is clinical, and there are no validated laboratory biomarkers. Procedure We prospectively evaluated the specificity and sensitivity of plasminogen‐activator inhibitor‐1 (PAI‐1) and protein C as diagnostic markers of VOD in WT patients. Fifty patients treated from 2008 to 2016 for WT were eligible. VOD was diagnosed according to modified Seattle criteria and retrospectively reclassified according to the recently published criteria for VOD in pediatric HSCT patients. Results VOD occurred in 6 of 50 patients (12%) after 20 to 97 days from starting chemotherapy. The average duration of VOD was 10 days (range, 4–13 days). PAI‐1 levels were elevated in all VOD patients, while a decrease in protein C levels was observed in 33% of patients with VOD. PAI‐1 antigen (Ag) values ≥ 26.4 ng/mL demonstrated high sensitivity and specificity for the clinical diagnosis of VOD with sensitivity 100%, specificity 93%; whereas protein C levels below 34.5% had sensitivity 67%, specificity 100%. Both PAI‐1 and protein C had an high negative predictive value: PAI‐1 Ag 100%; protein C 95%. Conclusions PAI‐1 Ag and protein C have good sensitivity and specificity for the diagnosis of VOD in WT patients. Their high negative predictive value can be used in the differential diagnosis of liver toxicity, especially in VOD episodes with absent or delayed hyperbilirubinemia.

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Section: Resultssupporting

confidence: 90%

Section: Discussionsupporting

confidence: 62%

Section: Methodsmentioning

confidence: 99%

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PAI‐1 and protein C as early markers of veno‐occlusive disease in patients treated for Wilms tumor

Cesaro

Mauro

Sattin

et al. 2019

Pediatric Blood & Cancer

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“…There are currently no validated blood tests for SOS and the diagnosis is mainly based on clinical and laboratory criteria that are nonspecific and/or late events in the development of the disease (12). SOS-associated endothelial injury triggers a hypercoagulable state and several studies have evaluated in human patients the diagnostic value of proteins involved in coagulation, such as PAI-1 and protein C (22,38), with inconsistent results. PAI-1 is an inhibitor of fibrinolysis that is synthetized and released by endothelial cells and protein C has anticoagulant activity through inactivation of factors V a and VIII a .…”

Section: Discussionmentioning

confidence: 99%

Liver Microvascular Injury and Thrombocytopenia of Antibody–Calicheamicin Conjugates in Cynomolgus Monkeys—Mechanism and Monitoring

Guffroy

Falahatpisheh

Biddle

et al. 2017

Clinical Cancer Research

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Purpose: Adverse reactions reported in patients treated with antibody-calicheamicin conjugates such as gemtuzumab ozogamicin (Mylotarg) and inotuzumab ozogamicin include thrombocytopenia and sinusoidal obstruction syndrome (SOS). The objective of this experimental work was to investigate the mechanism for thrombocytopenia, characterize the liver injury, and identify potential safety biomarkers.Experimental Design: Cynomolgus monkeys were dosed intravenously at 6 mg/m 2 /dose once every 3 weeks with a nonbinding antibody-calicheamicin conjugate (PF-0259) containing the same linker-payload as gemtuzumab ozogamicin and inotuzumab ozogamicin. Monkeys were necropsied 48 hours after the first administration (day 3) or 3 weeks after the third administration (day 63).Results: PF-0259 induced acute thrombocytopenia (up to 86% platelet reduction) with nadirs on days 3 to 4. There was no indication of effects on megakaryocytes in bone marrow or activation of platelets in peripheral blood. Microscopic evaluation of liver from animals necropsied on day 3 demonstrated midzonal degeneration and loss of sinusoidal endothelial cells (SECs) associated with marked platelet accumulation in sinusoids. Liver histopathology on day 63 showed variable endothelial recovery and progression to a combination of sinusoidal capillarization and sinusoidal dilation/hepatocellular atrophy, consistent with early SOS. Among biomarkers evaluated, there were early and sustained increases in serum hyaluronic acid (HA) that correlated well with serum aspartate aminotransferase and liver microscopic changes, suggesting that HA may be a sensitive diagnostic marker of the liver microvascular injury.Conclusions: These data support the conclusion that target-independent damage to liver SECs may be responsible for acute thrombocytopenia (through platelet sequestration in liver sinusoids) and development of SOS.

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“…These criteria allow a diagnosis of HSOS with good specificity and negative predictive value,4 but they have a relatively low sensitivity 5. Additional characteristic features that may assist in diagnosis include thrombocytopenia refractory to platelet transfusions and an increase in fibrinolytic parameters, particularly plasminogen activator inhibitor-1 antigen in combination with elevated d -dimer and bilirubin 6. Doppler-ultrasonographic findings can help to support the diagnosis of HSOS and may include hepatomegaly, splenomegaly, ascites, gallbladder wall thickening, elevation of the hepatic artery resistive index, and reversal of flow in the portal vein 7…”

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confidence: 99%

Hepatic Sinusoidal Obstruction Syndrome During Chemotherapy for Childhood Medulloblastoma

Kotecha

Buckland

Phillips

et al. 2014

Journal of Pediatric Hematology/Oncology

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Hepatic sinusoidal obstruction syndrome (HSOS), also known as veno-occlusive disease, is a well-recognized toxic complication after autologous and allogeneic hematopoietic stem cell transplant, during treatment of Wilms tumor and rhabdomyosarcoma associated with actinomycin-D, and during acute lymphoblastic leukemia therapy due to oral 6-thioguanine. However, its occurrence in the context of chemotherapy regimens for other childhood malignancies is rare. We report a 5-year-old girl with high-risk anaplastic medulloblastoma, who developed severe HSOS during her second cycle of maintenance chemotherapy, consisting of vincristine, cisplatin, and cyclophosphamide. She was treated with defibrotide with complete resolution of the HSOS. These findings and a review of the literature, highlight the occurrence of HSOS in children outside the established settings of hematopoietic stem cell transplantation, Wilms tumor, rhabdomyosarcoma, and acute lymphoblastic leukemia.

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Contribution of fibrinolytic tests to the differential diagnosis of veno‐occlusive disease complicating pediatric hematopoietic stem cell transplantation

Abstract: Our study demonstrates that fibrinolytic tests can help diagnose VOD after HSCT in the pediatric population.

Cited by 20 publications

References 42 publications

PAI‐1 and protein C as early markers of veno‐occlusive disease in patients treated for Wilms tumor

PAI‐1 and protein C as early markers of veno‐occlusive disease in patients treated for Wilms tumor

Liver Microvascular Injury and Thrombocytopenia of Antibody–Calicheamicin Conjugates in Cynomolgus Monkeys—Mechanism and Monitoring

Hepatic Sinusoidal Obstruction Syndrome During Chemotherapy for Childhood Medulloblastoma

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