Blood Product Transfusions Key in Acute Promyelocytic Leukemia

Blood transfusions play a key role in managing complications of acute promyelocytic leukemia (APL), involving unique blood product strategies, reported an expert at the Oncology Nursing Society (ONS) 41^st Annual Congress in San Antonio, Texas.

Patients diagnosed with APL are likely to need many transfusions, reported Nicole Draper, MD, associate medical director, transfusion services, at the University of Colorado Hospital in Aurora. These patients are likely to have disseminated intravascular coagulation (DIC) and hyperfibrinolysis.

APL is a distinct subtype of acute myelogenous leukemia (AML) that accounts for about 5% to 20% of all AML cases. Transfusion of blood products for APL follows guidelines that differ from other forms of AML. It is clinically distinguished from other AML subtypes by life-threatening bleeding disorders.

Its rapidly increasing propensity for bleeding means that APL needs to be recognized and treated quickly. “APL is a medical emergency,” Dr. Draper said. Studies have found that between 17% to 29% of APL patients die within 30 days of diagnosis. The disease has the potential for severe intracranial or pulmonary hemorrhage and infection.

APL is also demographically distinct from other AMLs, showing up more frequently in younger patients, with a median age at diagnosis of 47 years. Patients can present with sudden onset of fatigue, petechiae, ecchymosis, or mucosal or retinal hemorrhage.

Pancytopenia is a typical lab test result at presentation.

APL is treated with all-trans retinoic acid (ATRA) with or without arsenic trioxide. Treatment should begin if there is suspicion of APL, even before diagnosis is confirmed with cytogenetic test results.

There are two different pathways for clotting in APL, Dr. Draper said: an “intrinsic” pathway involving damage to the endothelium that exposes underlying cellular structures, measured as partial thromboplastin time (PTT), and an “extrinsic” pathway tested with prothrombin time (PT) and international normalized ratio (INR) values.

Patients with APL have a “propensity for DIC” associated with increased expression of procoagulants and enhanced fibrinolysis, Dr. Draper said.

Thrombosis and hemorrhage can occur simultaneously, she noted.

“In DIC, for some reason, activators spread through the entire bloodstream, and you start getting clotting everywhere,” she explained. “The body gets confused because it sees tissue factors everywhere-APL patients have an extra-high level of tissue factor-causing a lot of clotting.”

The PML/RARA fusion protein in APL patients can induce a promoter of the tissue-factor gene, causing cells to produce a lot of tissue factor “for no good reason,” Dr. Draper said, rather than in response to tissue damage. “So these cells have a lot of tissue factor, and when you get apoptosis, cells break apart and give off tissue factors into circulation.” APL cells also produce too much annexin II, which is involved in clot breakdown, she added. (Annexin II levels are higher in APL than other types of leukemia.)

“We measure this with D-dimer,” she noted. “Patients with APL have very high D-dimer because they turned on their clot-breakdown mechanism.”

A major cause of death in APL patients is differentiation syndrome. Previously called retinoic acid syndrome, differentiation syndrome is a frequent and often severe complication of APL treatment with retinoic acid or arsenic, and is associated in severe cases with fever, dyspnea, hypotension, and renal failure.

Transfusions play a key role in the management of APL complications.

National Comprehensive Cancer Network (NCCN) goals for supportive measures include hemoglobin (Hgb) > 8 g/dL, platelet counts > 50 × 10⁹/L, fibrinogen > 150 mg/dL, and PT (sec) and PTT (sec) values “close to normal,” Dr. Draper reported. Lab values should be monitored at least daily. “Where I work, we monitor lab values every 4 to 6 hours,” she said.

Indications for transfusion include decreased oxygen-carrying capacity. Anemia symptoms or Hgb < 7 g/dl (or Hgb < 10 g/dl for patients with cardiopulmonary disease) are a transfusion trigger, she said. One unit of red blood cells (or 5 mL/kg for children) are administered at a time.

Platelet transfusions are administered prophylactically, in nonbleeding patients when platelet counts fall below 10 × 10⁹/L. Platelet transfusion is also indicated by bleeding in a surgical patient when platelet counts fall below 50 × 10⁹/L, or when there’s platelet dysfunction associated with antiplatelet drugs or urea, she noted.

Plasma transfusion indications include deficiency of multiple coagulation factors, such as is seen in DIC, liver disease, or warfarin therapy. INR > 1.5 is also considered to be an indication for plasma transfusion.

“If you think they’re missing multiple coagulation factors, you give plasma,” Dr. Draper said. “We don’t know exactly what the dose is because of all the [coagulation] factors. RBCs are pretty predictable but plasma annoys me as a physician, because I don’t know what the dose is. There’s no quality control. There’s a ton of stuff in plasma, a whole lot of factors.”

The usual plasma-transfusion dose for control of bleeding is 10–20 mL/kg, she said. For a 70-kg patient, that is typically approximately four units, she said.  

“A lot of people I work with like to give two units [of plasma] at a time,” adding more at two units at a time. But it is easy to fluid-overload a patient quickly “by chasing an INR,” Dr. Draper cautioned.

Cryoprecipitated antihemophilic factor, or “cryo,” is indicated when fibrinogen drops below 100 mg/dL, or with uremic platelet dysfunction. “Your spontaneous bleeding risk increases with fibrinogen less than 100 mg/dL,” she noted.

Five to ten bags are pooled for adults, or one bag per 10 kg in children, she said.

Blood product special needs in APL include recommended leukocyte reduction to reduce febrile non-hemolytic transfusion reactions and to reduce the risk of cytomegalovirus (CMV) transmission and HLA alloimmunization, she said. CMV screening should be considered for candidates for hematopoietic stem cell transplant.

Washing blood products to remove plasma factors that can cause adverse reactions “is something we almost never do,” cautioned Dr. Draper. “Only wash if there’s a significant allergic response.”

Transfusion reactions

Identifying, treating, and reporting possible transfusion reactions is crucial. Transfusion reactions can be serious and can be misdiagnosed. “When a patient has fever, respiratory distress, rash-we want to always consider that it could be related to the transfusion,” said Dr. Draper.

Acute hemolytic reactions. These reactions are particularly worrisome. “They’re not common because we do a lot to try to prevent them. Most commonly, they’re caused by ABO-incompatible red blood cells delivered due to clerical error, causing immediate intravascular hemolysis.”

Acute hemolytic transfusion reactions can cause shock and, in 36% of APL patients, renal failure, Dr. Draper said.

“We treat the symptom,” she advised. “If they are going into shock, we treat the shock. If they have renal failure, we treat renal failure.”

Delayed hemolytic reactions. These are usually not a reaction to ABO mismatch, and are often misdiagnosed. In these cases the patient might have a low-grade fever, which is mistaken for infection. Ten percent of patients with delayed hemolytic reactions will have jaundice and 55% will have fever and chills.

Bacterial sepsis. Among the very worst transfusion-related adverse events are cases of bacterial sepsis-typically involving contaminated platelets that have to be kept at room temperature. “They’re a perfect ‘petri dish’ for bacteria,” explained Dr. Draper. Culprits frequently involve gram-positive skin flora or endotoxin-releasing gram-negative strains that “get into the bag” before transfusion.

The US Food and Drug Administration advises that bags be administered within 4 hours once it’s spiked, to avoid bacterial growth, she noted.