A cohort study on blood coagulation in childhood cancer survivors.

Cancer survivors are at an increased risk of thromboembolism compared to the general pediatric population. Anticoagulant therapy decreases the risk of thromboembolism in cancer patients. We hypothesized that pediatric cancer survivors are in a chronically hypercoagulable state compared to healthy controls. Children who survived for more than five years from cancer diagnosis at the UT Health Science Center at San Antonio Cancer Survivorship Clinic were compared to healthy controls. The exclusion criteria were recent NSAID use or a history of coagulopathy. Coagulation analysis included platelet count, thrombin-antithrombin complexes (TAT), plasminogen activator inhibitor (PAI), routine coagulation assays, and thrombin generation with and without thrombomodulin. We enrolled 47 pediatric cancer survivors and 37 healthy controls. Platelet count was significantly lower in cancer survivors at a mean of 254 × 109/L (95%CI: 234-273 × 109/L) compared at 307 × 109/L (283-331 × 109/L) in healthy controls (p < 0.001), although not outside the normal range. Routine coagulation assays showed no differences, except for a significantly lower prothrombin time (PT) in cancer survivors (p < 0.004). Cancer survivors has significantly elevated biomarkers of the procoagulant state, such as TAT and PAI, compared to healthy controls (p < 0.001). A multiple logistic regression model controlling for age, BMI, gender, and race/ethnicity documented that a low platelet count, short prothrombin clot time, and higher procoagulant biomarkers (TAT and PAI) were significantly associated with past cancer therapy. Survivors of childhood cancer have a persistent procoagulant imbalance for more than five years after diagnosis. Further studies are needed to establish whether procoagulant imbalance increases the risk of thromboembolism in childhood cancer survivors.

Effect of blood flow on platelets, leukocytes, and extracellular vesicles in thrombosis of simulated neonatal extracorporeal circulation.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) has frequent and sometimes lethal thrombotic complications. The role that activated platelets, leukocytes, and small (0.3-micron to 1-micron) extracellular vesicles (EVs) play in ECMO thrombosis is not well understood. OBJECTIVES: To test the effect of blood flow rate on the generation of activated platelets, leukocytes, and EVs in a simulated neonatal ECMO circuit using heparinized human whole blood. METHODS: Simulated neonatal roller pump circuits circulated whole blood at low, nominal, and high flow rates (0.3, 0.5, and 0.7 L/min) for 6 h. Coagulopathy was defined by thromboelastography (TEG), STA® -procoagulant phospholipid clot time (STA®- Procoag-PPL), and calibrated automated thrombogram. High-resolution flow cytometry measured the cellular expression of prothrombotic phospholipids and proteins on platelets, leukocytes, and EV. RESULTS: Despite heparinization, occlusive thrombosis halted flow in two of five circuits at 0.3 L/min and three of five circuits at 0.7 L/min. None of the five circuits at 0.5 L/min exhibited occlusive thrombosis. Phosphatidylserine (PS)-positive platelets and EVs increased at all flow rates more than blood under static conditions (P < .0002). Tissue factor (TF)-positive leukocytes and EVs increased only in low-flow and high-flow circuits (P < .0001). Tissue factor pathway inhibitor (TFPI), at 50 times more than the concentration in healthy adults, failed to suppress thrombin initiation in low-flow and high-flow circuits. CONCLUSIONS: This in vitro study informs ECMO specialists to avoid low and high blood flow that increases TF expression on leukocytes and EVs, which likely initiate clot formation. Interventions to decrease TF generated by ECMO may be an effective approach to decrease thrombosis.