We're celebrating
40 years!
Last updated:
05/17/2023
Years published: 2019, 2023
NORD gratefully acknowledges Etienne Leveille, MD, McGill University School of Medicine, and Richard A. Larson, MD, Professor of Medicine, The University of Chicago, for assistance in the preparation of this report.
Summary
Acute promyelocytic leukemia (APL) is a blood cancer characterized by a marked increase in a type of immature white blood cells known as promyelocytes. It develops in about 600 to 800 individuals each year in the United States, most often in adults around the age of 40 but also in children. The characteristic symptom of APL is the associated bleeding disorder (coagulopathy), which can lead to excessive bleeding but also to blood clot formation (thrombosis). In APL and other types of leukemia, the bone marrow is filled by malignant cells and is unable to produce functional cells. A decreased number of platelets (thrombocytopenia) is one of the contributing factors to the bleeding often present in APL. A decreased number of red blood cells (anemia) can lead to pallor and fatigue, while a decreased number of functional white blood cells (neutropenia) predispose affected individuals to infections. Fever, chills, night sweats and weight loss, which are collectively known as constitutional or “B” symptoms, are also common in APL. The treatment of APL is centered on elimination of the malignant cells and supportive care with transfusion of blood products to minimize the risk of bleeding or thrombosis, Medications, especially all-trans retinoic acid (ATRA; tretinoin) and arsenic trioxide allow malignant promyelocytes to mature into neutrophils, which are unable to proliferate and subsequently eliminated.
Introduction
Circulating blood cells are formed in a region in the middle of large bones known as the bone marrow and are all derived from a primitive type of cell known as the hematopoietic stem cell. Hematopoiesis refers to the process of formation of blood cells from hematopoietic stem cells. The two principal lineages of blood cells are the myeloid and lymphoid cells. Cells derived from the myeloid lineage include red blood cells (erythrocytes), platelets (thrombocytes) and granulocytes and monocytes. A promyelocyte is a type of myeloid cell that normally matures to granulocytes. Eosinophils, neutrophils and basophils are the three types of mature granulocytes.
Leukemia is defined as the uncontrolled proliferation of abnormal leukocytes in the blood and bone marrow. APL is a type of leukemia caused by the uncontrolled proliferation of promyelocytes that are arrested in their normal maturation process. It is a subtype of acute myeloid leukemia (AML), but it has its own uniquely different disease mechanism, clinical manifestations and treatment. APL is a medical emergency, as treatment must be initiated as soon as the disease is suspected in order to decrease the risk of complications associated with APL coagulopathy.
The development of therapy for APL is a success story in the realm of cancer and leukemia treatment. Before modern treatments were developed, most affected individuals did not survive more than one month after diagnosis due to bleeding and/or infection. Research that elucidated the molecular mechanisms by which APL develops led to the development of ATRA, an oral medication that specifically targets the genetic defects in APL. Nowadays, with ATRA and other targeted therapies, such as arsenic trioxide (ATO), APL has shifted from an often-fatal disease to a highly curable form of leukemia.
APL most commonly occurs in middle-aged individuals. The median age at diagnosis is around 40 years, meaning that half of cases occur in people under that age and the other half in people above that age. In APL, the bone marrow is overcrowded with malignant cells and eventually fails to produce normal blood cells required for normal functioning. Depletion of red blood cells (anemia) leads to symptoms such as fatigue and pallor, while a decreased number of functional white blood cells predispose affected individuals to infections. A decreased number of platelets (thrombocytopenia) increases the risk of bleeding and bruising.
The most dangerous symptom of APL is the bleeding disorder (coagulopathy) associated with the disease. Coagulopathy is common in all types of leukemia, mainly due to thrombocytopenia. However, molecules present in APL cells can lead to a severe coagulopathy characterized by the breakdown of the clotting factors known as fibrinogen and fibrin (systemic fibrinolysis), and the development of a condition called disseminated intravascular coagulation (DIC). In DIC, the coagulation system of the body is abnormally activated, and coagulation factors are excessively consumed. This leads to numerous complications, including bleeding and the formation of blood clots (thrombosis). Bleeding in the skin and mucous membranes can manifest as small red or purple spots (petechiae) or patches (purpura) or as bruises (ecchymoses). Affected individuals may also bleed excessively from their gums or from sites of minor trauma such as vascular puncture sites. Other sites of bleeding include blood in the stools (hematochezia) due to gastrointestinal bleeding, blood in the urine (hematuria) due to bleeding in the genitourinary tract, excessive menstrual blood losses (menorrhagia) and excessive or recurrent nose bleeding (epistaxis). Bleeding inside the skull (intracranial hemorrhage) and pulmonary hemorrhage are the two most common causes of hemorrhagic death in APL. Symptoms of intracranial hemorrhage depend on the region of the brain that is affected and include arms and/or leg weakness, headaches, vomiting and a decreased level of consciousness. Pulmonary hemorrhage can lead to cough, shortness of breath (dyspnea) and coughing up blood (hemoptysis). In addition to excessive bleeding, APL-associated coagulopathy increases the likelihood of forming abnormal blood clots that can dislodge and obstruct blood vessels (thromboembolism). Occlusion of blood vessels in the lungs may result from a pulmonary embolism, while obstruction of vessels in the brain and the heart can respectively lead to a stroke and heart attack (myocardial infarction). DIC can also lead to organ dysfunction, most notably of the liver and kidneys.
In addition to coagulopathy, constitutional symptoms are common at presentation. These symptoms, also called B symptoms, occur with many types of cancer and are also associated with some infections and autoimmune diseases. Although their exact cause is unknown, a probable contributing factor is the release of molecules that modulate immunity and inflammation (cytokines). These cytokines are thought to be released by the malignant cells. Constitutional symptoms include fever, fatigue, chills, weight loss, and drenching night sweats.
Differentiation syndrome is a potentially severe complication of APL treatment that occurs in up to a quarter of patients. It most often occurs within 2 to 21 days after treatment initiation and is characterized by fever, rash, swelling due to accumulation of fluid (edema), shortness of breath (dyspnea), low blood pressure (hypotension), kidney and liver dysfunction and accumulation of fluid within or around the lungs (pleural effusion) and the heart (pericardial effusion). Another rare complication of APL treatment is called idiopathic intracranial hypertension. (For more information on this condition, choose “idiopathic intracranial hypertension” as your search term in the Rare Disease Database.)
Most deaths due to APL occur early in the disease because of hemorrhage, infection or differentiation syndrome. Older age, male sex, high white blood cell count, increased creatinine levels (a marker of renal function) and abnormal fibrinogen levels (a coagulation factor) have been associated with an increased risk of early death in APL. White blood cell count is particularly important for risk stratification: APL with a white blood cell count of more than 10,000 cells per microliter is considered high-risk APL, while a white blood cell count under this value is considered standard-risk APL. Once the critical early period has passed, most patients are able to be cured. A large study carried on in the United States that included APL patients that had survived more than 48 hours after diagnosis found that 88% of individuals were alive after 5 years of follow-up.
APL is caused by the uncontrolled proliferation of promyelocytes, a type of immature cell from the myeloid lineage of blood cells. The hallmark of APL is genetic alterations involving the retinoic acid receptor alpha (RARA) gene. Retinoic acid (a derivative of vitamin A) is critical in the process of cellular maturation and specialization (differentiation) of many cells, including myeloid precursors. In normal cells, the RARA protein is bound to proteins and forms a complex that prevents genes involved in cellular differentiation from being read; this is called transcriptional repression. When retinoic acid binds to this protein complex, transcriptional repression is relieved, genes involved in cellular differentiation can be read, and promyelocytes can continue their maturation and differentiation process into mature granulocytes. In most patients with APL, RARA gene alterations occur due to exchange of genetic material (translocation) between chromosomes 15 and 17, where the RARA and PML genes are located, respectively. This translocation results in a fusion gene termed PML/RARA, which leads to an abnormal retinoic acid receptor that blocks the differentiation process that is normally induced by retinoic acid. The myeloid precursors are therefore “stuck” in the promyelocyte stage and accumulate in the bone marrow, and eventually the blood. The fusion gene PML/RARA that leads to APL is an acquired mutation and is not inherited. When patients enter a remission, cells containing the PML/RARA fusion gene are no longer detectable.
The coagulopathy associated with APL is multifactorial. In addition to thrombocytopenia, which can lead to bleeding in many types of leukemia, other molecules present in promyelocytes contribute to the severity of the coagulopathy encountered in APL. Notably, tissue factor (TF), a molecule found on the surface of APL cells, activates the coagulation cascade. Annexin II is also present on the surface of APL cells and facilitates the activation of plasmin, a molecule that breaks down blood clots. Overall, the action of tissue factor and annexin II, in combination with other molecules, leads to excessive clotting (thrombosis), and excessive bleeding due to consumption of coagulation factors and excessive breakdown of clots.
APL comprises 5 to 10% of all cases of adult acute myeloid leukemia. Each year in the United States, it develops in around 2.2 people per million, for a total of 600 to 800 individuals. Although APL can occur at any age, middle-aged adults are most commonly affected; the median age at diagnosis is around 40. Epidemiological studies have shown that APL is slightly more common in Hispanics and slightly less common in African Americans compared to other ethnic groups. In very rare cases, APL can occur after chemotherapy or radiation therapy for other cancers, especially when therapy involves a class of medication known as topoisomerase II inhibitors; this is called therapy-related APL.
The diagnosis of APL is based on a combination of patient history, physical examination and numerous laboratory tests. In cases where patients present with symptoms such as fever, fatigue and bruising or bleeding, a complete blood count (CBC) is usually performed to evaluate the number of red blood cells (erythrocytes), white blood cells (leukocytes) and platelets (thrombocytes). In APL, platelets and red blood cells are often low, and white blood cells might be low, normal or elevated (however, the number of functional white blood cells is usually decreased). The combination of low platelets (thrombocytopenia), red blood cells (anemia) and white blood cells (leukopenia) is known as pancytopenia and is a warning sign that requires further speedy investigation. The cells taken from a blood sample can also be evaluated by a physician specialized in disorders related to the blood (hematologist) to see if they are abnormal and potentially leukemic. Further evaluation usually requires bone marrow examination to assess for the presence of abnormal cells. Bone marrow samples are obtained by bone marrow aspiration and biopsy, which are respectively used to collect the liquid and solid portions of the bone marrow. The location of choice for bone marrow aspiration and biopsy is the hip bone (pelvic bone).
Once cells are obtained, they can be evaluated in numerous ways to confirm the diagnosis of APL and characterize the affected cells. Flow cytometry is a laboratory method where cells are suspended in fluid and processed into an instrument known as a flow cytometer. The cells flow one at a time through a laser, and the pattern of light scattering and cell fluorescence allows identification of cells based on their size, shape and the presence or absence of specific markers on the cell surface (immunophenotyping). The genes and chromosomes of the affected cells can also be evaluated. Karyotyping is a method where chromosomes are stained and visualized under a microscope during cell division. Fluorescence in situ hybridization (FISH) is a technique where selected chromosomal regions are stained to identify large genetic insertions, deletions, or translocations. Polymerase chain reaction (PCR) is a DNA sequencing technique that allows the detection of mutations and smaller insertions and deletions. Next generation sequencing (NGS) is a method of evaluating multiple genes simultaneously for mutations.
In addition to tests used to diagnose and characterize APL, numerous ancillary tests are performed to evaluate the health of the patient and to assess for complications related to the disease. Especially in the case of APL, evaluation of coagulation parameters is crucial. Coagulations tests typically performed in the diagnostic evaluation of APL include prothrombin time (PT), activated partial thromboplastin time (aPTT), D-dimer (a product of clot breakdown) and fibrinogen levels. Other routine tests include measurement of levels of electrolytes, renal function tests, such as creatinine levels, cardiac function tests and liver function tests.
Treatment & Management
The treatment of APL is centered on all-trans retinoic acid (ATRA; tretinoin). The goal of this targeted therapy is to allow the differentiation of promyelocytes, which have been blocked by the PML/RARA fusion gene, into mature neutrophils. The treatment course is constituted of three phases: induction, consolidation, and maintenance. APL is a medical emergency, as treatment must be initiated as soon as the disease is suspected to decrease the risk of bleeding complications associated with APL coagulopathy.
The first phase, induction, aims to put the patient in a state called complete remission (CR), where most malignant cells from the blood and bone marrow will be eliminated and production of normal blood cells (hematopoiesis) will be restored. Molecular complete remission is a more durable state of remission where the PML/RARA fusion gene is not detectable by polymerase chain reaction (PCR) testing. In the induction phase, oral ATRA is combined with different medications for as long as 60 days or until complete remission is achieved. Depending on the treatment regimen used, ATRA can be combined with idarubicin, daunorubicin and cytarabine, or arsenic trioxide (ATO) with or without gemtuzumab ozogamicin (GO). Idarubicin and daunorubicin are chemotherapy agents that induce DNA damage and therefore kill malignant cells, while cytarabine prevents the synthesis of DNA in cells. As is the case for ATRA, ATO promotes the differentiation of promyelocytes into mature neutrophils, although it acts via a slightly different mechanism. GO is a medication that specifically targets CD33, a marker that is present on APL cells. ATRA and ATO are most often used together for treating APL, and GO is added for patients with high-risk APL due to elevated WBC counts.
After complete remission is achieved, patients move to the consolidation phase, which aims to prevent relapse. In the United States, the most prescribed consolidation regimen includes 4 monthly cycles of daily ATO together with daily ATRA.
A third phase, maintenance, has been used to prevent relapse and usually involves less intensive therapy. Research now indicates that patients who have previously achieved complete molecular remission with ATRA and ATO do not require maintenance therapy. In other patients, ATRA alone is often used for maintenance, although it might be combined with chemotherapy agents such as 6-mercaptopurine or methotrexate. During maintenance and follow up, patients must be monitored for possible disease relapse. Monitoring should be more frequent in the first year after remission is achieved since most relapses occur during that time period. PCR can be performed on blood samples to see if there is sustained molecular complete remission. If this is not the case, a bone marrow biopsy should be performed for confirmation of relapse and treatment for relapsed disease can be initiated. In cases of relapse or treatment resistance, a possible treatment option is a prolonged infusion of intravenous ATO followed by allogeneic hematopoietic stem cell (HSC) transplantation. The rationale behind HSC transplantation is that it makes possible the pre-transplantation administration (preparative regimen) of very high doses of chemotherapy medications that are very effective to control cancer but also damage healthy hematopoietic stem cells. The patient’s HSCs are then replaced with healthy HSCs via the transplantation. The stem cells can be obtained from the blood or bone marrow from a healthy donor (allogeneic transplantation) or from the patient’s own body (autologous transplantation) before the preparative regimen is initiated if a molecular remission was achieved. Another goal of the preparative regiment is to suppress the immune system to decrease the risk of graft rejection. Although effective, HSC transplantation is a high-risk procedure and is associated with numerous short- and long-term side effects. Patients therefore must be chosen and followed carefully throughout the entire process.
In addition to therapy used to treat the leukemia itself, other essential considerations specific to the management of APL include control of the associated coagulopathy and prevention or treatment of differentiation syndrome. Close monitoring of coagulation parameters with transfusion of blood products is necessary to minimize the risk of bleeding and thrombosis. Blood has four main components: plasma, which is the fluid that contains proteins and coagulation factors, red blood cells, white blood cells and platelets. Commonly used blood products for the management of coagulopathies include platelets, fresh frozen plasma, and cryoprecipitate (a derivative of plasma proteins). Differentiation syndrome is treated with corticosteroids such as dexamethasone or prednisone. However, corticosteroids are sometimes given in advance with induction regimens in a preventive manner (prophylactically) to decrease the risk of differentiation syndrome.
Intravenous formulations of retinoid medications and oral forms of arsenic trioxide are currently in experimental clinical trials. Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and most supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
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Email: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/
For information about clinical trials sponsored by private sources, in the main, contact: www.centerwatch.com
For more information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Arber DA, Orazi A, Hasserjian RP, et al. International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data. Blood. 2022;140(11):1200-1228. doi:10.1182/blood.2022015850
Iland HJ, Russell NH, Dillon R, et al. Characteristics and outcomes of patients with acute promyelocytic leukemia and extreme hyperleukocytosis at presentation [published online ahead of print, 2022 Sep 8]. Blood Adv. 2022;bloodadvances.2022007126. doi:10.1182/bloodadvances.2022007126
Kutny MA, Alonzo TA, Abla O, et al. Assessment of Arsenic Trioxide and All-trans Retinoic Acid for the Treatment of Pediatric Acute Promyelocytic Leukemia: A Report From the Children’s Oncology Group AAML1331 Trial. JAMA Oncol. 2022;8(1):79-87. doi:10.1001/jamaoncol.2021.5206
Efficace F, Platzbecker U, Breccia M, et al. Long-term quality of life of patients with acute promyelocytic leukemia treated with arsenic trioxide vs chemotherapy. Blood Adv. 2021;5(21):4370-4379. doi:10.1182/bloodadvances.2021004649
Cicconi L, Platzbecker U, Avvisati G, et al. Long-term results of all-trans retinoic acid and arsenic trioxide in non-high-risk acute promyelocytic leukemia: update of the APL0406 Italian-German randomized trial. Leukemia. 2020;34(3):914-918. doi:10.1038/s41375-019-0589-3
Lancet JE, Moseley AB, Coutre SE, et al. A phase 2 study of ATRA, arsenic trioxide, and gemtuzumab ozogamicin in patients with high-risk APL (SWOG 0535). Blood Adv. 2020;4(8):1683-1689. doi:10.1182/bloodadvances.2019001278
Hong-Hu Zhu, Jiong Hu, Francesco Lo-Coco, and Jie Jin. The simpler, the better: oral arsenic for acute promyelocytic leukemia. Blood 2019; 134(7):597-605.
Sanz MA, Fenaux P, Tallman MS, et al. Management of acute promyelocytic leukemia: updated recommendations from an expert panel of the European LeukemiaNet. Blood. 2019;133(15):1630-1643. doi:10.1182/blood-2019-01-894980
Kayser S, Schlenk RF, Platzbecker U. Management of patients with acute promyelocytic leukemia. Leukemia 2018;32:1277-94.
Osman AEG, Anderson J, Churpek JE, Christ TN, Curran E, Godley LA, Liu H, Thirman MJ, Odenike T, Stock W, Larson RA. Treatment of acute promyelocytic leukemia in adults. J Oncol Pract 2018 Nov; 14(11): 649-657. doi: 10.1200/JOP.18.00328. PMID: 30423270.
Abaza Y, Kantarjian H, Garcia-Manero G, et al. Long-term outcome of acute promyelocytic leukemia treated with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab. Blood 2017;129:1275-83.
de The H, Pandolfi PP, Chen Z. Acute Promyelocytic leukemia: a paradigm for oncoprotein-targeted cure. Cancer Cell 2017;32:552-60.
Platzbecker U, Avvisati G, Cicconi L, et al. Improved Outcomes With Retinoic Acid and Arsenic Trioxide Compared With Retinoic Acid and Chemotherapy in Non-High-Risk Acute Promyelocytic Leukemia: Final Results of the Randomized Italian-German APL0406 Trial. J Clin Oncol 2017;35:605-12.
Cicconi L, Lo-Coco F. Current management of newly diagnosed acute promyelocytic leukemia. Ann Oncol 2016;27:1474-81.
Lo-Coco F, Cicconi L, Breccia M. Current standard treatment of adult acute promyelocytic leukaemia. Br J Haematol 2016;172:841-54.
Mantha S, Tallman MS, Soff GA. What’s new in the pathogenesis of the coagulopathy in acute promyelocytic leukemia? Curr Opin Hematol 2016;23:121-6.
Testa U, Lo-Coco F. Prognostic factors in acute promyelocytic leukemia: strategies to define high-risk patients. Ann Hematol 2016;95:673-80.
Adams J, Nassiri M. Acute Promyelocytic Leukemia: A Review and Discussion of Variant Translocations. Arch Pathol Lab Med 2015;139:1308-13.
Burnett AK, Russell NH, Hills RK, et al. Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a randomised, controlled, phase 3 trial. Lancet Oncol 2015;16:1295-305.
Coombs CC, Tavakkoli M, Tallman MS. Acute promyelocytic leukemia: where did we start, where are we now, and the future. Blood Cancer J 2015;5:e304.
Mitrovic M, Suvajdzic N, Elezovic I, et al. Thrombotic events in acute promyelocytic leukemia. Thromb Res 2015;135:588-93.
Breccia M, Lo Coco F. Thrombo-hemorrhagic deaths in acute promyelocytic leukemia. Thromb Res 2014;133 Suppl 2:S112-6.
Lehmann-Che J, Bally C, de The H. Resistance to therapy in acute promyelocytic leukemia. N Engl J Med 2014;371:1170-2.
Lichtenberger JP, 3rd, Digumarthy SR, Abbott GF, Shepard JA, Sharma A. Diffuse pulmonary hemorrhage: clues to the diagnosis. Curr Probl Diagn Radiol 2014;43:128-39.
Lo-Coco F, Hasan SK. Understanding the molecular pathogenesis of acute promyelocytic leukemia. Best Pract Res Clin Haematol 2014;27:3-9.
Sanz MA, Montesinos P. How we prevent and treat differentiation syndrome in patients with acute promyelocytic leukemia. Blood 2014;123:2777-82.
Lo-Coco F, Avvisati G, Vignetti M, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med 2013;369:111-21.
Choudhry A, DeLoughery TG. Bleeding and thrombosis in acute promyelocytic leukemia. Am J Hematol 2012;87:596-603.
Park JH, Qiao B, Panageas KS, et al. Early death rate in acute promyelocytic leukemia remains high despite all-trans retinoic acid. Blood 2011;118:1248-54.
Ades L, Guerci A, Raffoux E, et al. Very long-term outcome of acute promyelocytic leukemia after treatment with all-trans retinoic acid and chemotherapy: the European APL Group experience. Blood 2010;115:1690-6.
Powell BL, Moser B, Stock W, et al. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood. 2010;116(19):3751-3757. doi:10.1182/blood-2010-02-269621
Wang ZY, Chen Z. Acute promyelocytic leukemia: from highly fatal to highly curable. Blood 2008;111:2505-15.
INTERNET
Larson RA, Bag R, Differentiation syndrome associated with treatment of acute leukemia, UpToDate. Last updated: June 24, 2021. https://www.uptodate.com/contents/differentiation-syndrome-associated-with-treatment-of-acute-leukemia Accessed Nov 25, 2022.
Larson RA, Gurbuxani S, Clinical Manifestations, pathologic features, and diagnosis of acute promyelocytic leukemia in adults, UpToDate. Last updated: Sep 20, 2022. https://www.uptodate.com/contents/clinical-manifestations-pathologic-features-and-diagnosis-of-acute-promyelocytic-leukemia-in-adults Accessed Nov 25, 2022
Larson RA, Initial treatment of acute promyelocytic leukemia in adults. UpToDate. Last updated:June 10, 2022. https://www.uptodate.com/contents/4498 Accessed Nov 25, 2022.
Larson RA, Treatment of relapsed or refractory acute promyelocytic leukemia in adults, UpToDate. Last updated:Mar 18 2022. https://www.uptodate.com/contents/treatment-of-relapsed-or-refractory-acute-promyelocytic-leukemia-in-adults Accessed Nov 25, 2022.
Larson RA, Remission criteria in acute myeloid leukemia and monitoring for residual disease, UpToDate. Last updated: Apr 17, 2022. https://www.uptodate.com/contents/remission-criteria-in-acute-myeloid-leukemia-and-monitoring-for-residual-disease Accessed. Nov 25, 2022
Leung LKL, Evaluation and management of disseminated intravascular coagulation in adults, UpToDate. Last updated: Dec 16, 2021. https://www.uptodate.com/contents/evaluation-and-management-of-disseminated-intravascular-coagulation-in-adults Accessed Nov 25, 2022.
Ma A, Approach to the adult with a suspected bleeding disorder, UpToDate. Last updated: May 17, 2022. https://www.uptodate.com/contents/approach-to-the-adult-with-a-suspected-bleeding-disorder Accessed Nov 25, 2022
Moake JL, Excessive Bleeding, MSD Manual – Professional Version. Last updated: Nov 2018. https://www.msdmanuals.com/professional/hematology-and-oncology/hemostasis/excessive-bleeding?query=Bruising%20and%20Bleeding Accessed Nov 12, 2019.
Schiffer CA, Gurbuxani S, Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia, UpToDate. Last updated: May 24, 2022. https://www.uptodate.com/contents/clinical-manifestations-pathologic-features-and-diagnosis-of-acute-promyelocytic-leukemia-in-adults Accessed Nov 25, 2022
Stock W, Thirman MJ, Molecular biology of acute promyelocytic leukemia, UpToDate. Last updated: Feb 4, 2022. https://www.uptodate.com/contents/molecular-biology-of-acute-promyelocytic-leukemia Accessed Nov 25, 2022
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