APL: symptoms, emergency signs and diagnosis
Acute promyelocytic leukemia (APL) is a special form of AML with two faces: in the first days it carries a serious risk of bleeding, yet with treatment started in time it is one of the leukemias with the very best results. This topic covers the signs of APL, which situations are emergencies, how the diagnosis is made quickly and what the results mean.
01Short answer
02Simple explanation
In APL, cells that have got “stuck” at one stage of maturing — promyelocytes — build up in the bone marrow. They are full of granules, and substances released from these granules upset the clotting balance: the blood starts both to clot and to dissolve clots far too quickly at the same time. As a result, the risk of bleeding rises sharply.
That is why the first signs of APL are often about bleeding: bruises for no reason, tiny red spots on the skin (petechiae), nosebleeds and bleeding gums, longer and heavier periods than usual, and bleeding that will not stop after a blood test or a tooth extraction. There may also be the tiredness, pallor, fever and infections typical of AML.
The most dangerous problem in APL is internal bleeding — in the brain, lungs or gut. Its signs are a sudden severe headache, confusion, weakness on one side of the body, coughing up blood, sudden breathlessness, black stools or vomiting blood. In these situations, not a minute should be lost.
The good news is that the cause of APL is well understood and there are very effective drugs against it: ATRA (a vitamin A derivative) and arsenic trioxide. They force the leukemia cells to “mature”, and the clotting problem usually settles within days to weeks. That is why doctors start ATRA as soon as they suspect APL, without waiting for genetic confirmation.
The first weeks are the period that needs the most attention. After that, APL treatment results are among the best of all leukemias, and most people achieve long-lasting remission with modern treatment.
03Scientific explanation
APL is driven by the translocation t(15;17)(q24;q21) and the resulting PML::RARA fusion gene; rarely, RARA fuses with other partner genes (for example ZBTB16::RARA), and some of these variants respond poorly to ATRA. In the WHO 2022 and ICC 2022 classifications, AML with PML::RARA is recognised as a distinct type regardless of the blast percentage. Under the microscope there are two forms: the hypergranular (classic) form — promyelocytes with coarse granules, often with bundles of Auer rods (“faggot cells”), usually with a low white cell count; and the microgranular variant — cells with bilobed nuclei and barely visible granules, often with a high white cell count.
The clotting disorder combines features of DIC and marked hyperfibrinolysis: platelets are low, the prothrombin time is prolonged, fibrinogen is low and D-dimer is high. According to the ELN 2019 recommendations, ATRA should be started immediately when APL is suspected, platelets should be kept above roughly 30–50×10⁹/L and fibrinogen above 100–150 mg/dL, and clotting tests should be checked once or more each day until they normalise. Invasive procedures such as central venous lines and lumbar puncture are avoided as far as possible — at least until the coagulopathy is under control.
The typical APL profile on flow cytometry is: bright CD33, heterogeneous CD13, CD117 often positive and strong MPO; HLA-DR and CD34 are usually negative, and CD11b is negative. In the microgranular variant, CD34 and CD2 may be positive. Genetic confirmation uses FISH (PML::RARA) or RT-PCR; RT-PCR also identifies the PML breakpoint isoform (bcr1, bcr2, bcr3), which is needed for later molecular MRD monitoring. Some labs offer a rapid immunofluorescence test with anti-PML antibodies that gives a preliminary answer within hours. The karyotype shows any additional chromosome changes.
The risk group is set by the white cell count at diagnosis: ≤10×10⁹/L is low/intermediate risk, >10×10⁹/L is high risk. For low-risk APL, ATRA plus arsenic trioxide without chemotherapy has become the standard: in a randomised trial (NEJM, 2013), two-year event-free survival was 97% with this combination and 86% with ATRA plus chemotherapy. Population studies, however, showed that early deaths in the first days after diagnosis are more frequent than in clinical trials: 17.3% in US SEER data (1992–2007) and 29% within 30 days in the Swedish registry (1997–2006); a large share were due to bleeding, and some patients never received ATRA. That is exactly why starting treatment at the moment of suspicion is vital. Before treatment, an ECG (QT interval, because of arsenic trioxide), potassium and magnesium, creatinine and a pregnancy test (ATRA is harmful to an unborn baby) are also checked.
04What happens in the body?
Symptoms that need urgent help
Call emergency services at once if: there is a sudden severe headache, confusion, drowsiness, trouble speaking or seeing, or weakness on one side of the body; you cough up blood or suddenly become breathless; bleeding from the nose, gums or elsewhere does not stop after 10–15 minutes of pressure; you vomit blood, pass black or bloody stools, or see blood in your urine; bruises and petechiae are spreading quickly; you have a temperature of 38 °C or higher. During treatment, fever, breathlessness, rapid weight gain, swollen legs or dizziness can be signs of differentiation syndrome — tell your team immediately.
How is the diagnosis made so quickly?
Usually: history and examination → complete blood count → blood smear (abnormal promyelocytes) → urgent clotting tests (PT, aPTT, fibrinogen, D-dimer) → ATRA and transfusions as soon as APL is suspected → FISH or RT-PCR for PML::RARA (often from peripheral blood) → bone marrow and flow cytometry (when your condition allows) → karyotype. Treatment starts before genetic confirmation; if confirmation does not come, the plan is reviewed.
What do the results roughly mean?
Finding PML::RARA confirms the diagnosis of APL. The white cell count at diagnosis sets the risk group: 10×10⁹/L or lower is low risk, higher is high risk; this affects whether chemotherapy is added. Clotting tests are used to follow the bleeding risk during the first days of treatment, and their return to normal is a good sign.
Why does treatment start on suspicion?
The biggest danger in APL is bleeding in the first days, while genetic confirmation can take a day or more. Starting ATRA early rapidly reduces the clotting disorder. If APL is later not confirmed, ATRA is stopped. This approach is the cornerstone of international recommendations and saves lives.
Questions you can ask your doctor
Has the APL diagnosis been confirmed genetically (PML::RARA)? What is my risk group — what is my white cell count? What are my clotting results and how often will they be checked? Which bleeding signs should I report immediately? Can my treatment be chemotherapy-free? Which signs of differentiation syndrome should I watch for? How will my ECG be monitored? What do I need to know about pregnancy and contraception?
Fear and hope side by side
Reading about APL, words like “emergency” and “bleeding” can sound frightening. But this close attention is there to protect you: in the first weeks your team watches you very carefully. After this period, APL treatment is among the most successful in all of leukemia care, and most people achieve long-lasting remission and return to normal life.
05APL: from suspicion to confirmation — the fast track
In APL, diagnosis and treatment run in parallel.
06Key tests in APL and typical findings
| Test | What does it check? | What is often seen in APL? |
|---|---|---|
| Complete blood count | Red cells, white cells, platelets | Thrombocytopenia, anemia; white cells often low (high in the microgranular variant) |
| Blood smear | How the cells look | Abnormal promyelocytes with coarse granules, bundles of Auer rods |
| Clotting tests | PT, aPTT, fibrinogen, D-dimer | Prolonged PT, low fibrinogen, high D-dimer — DIC/hyperfibrinolysis |
| Flow cytometry | Cell markers | Bright CD33, CD13, CD117, MPO; HLA-DR and CD34 usually negative |
| FISH / RT-PCR | PML::RARA fusion gene | Positive — confirms the diagnosis; RT-PCR shows the isoform |
| Bone marrow and karyotype | Blasts/promyelocytes, t(15;17) | Marrow filled with abnormal promyelocytes; t(15;17) |
| ECG and electrolytes | QT interval, potassium, magnesium | Baseline values before arsenic trioxide |
* This table is general information. When APL is suspected, treatment starts without waiting for all of these results. Discuss your own results with your hematologist.
07Key terms
- APL
- Acute promyelocytic leukemia — a form of AML defined by PML::RARA.
- Promyelocyte
- The granule-rich maturation stage of a myeloid cell that follows the blast.
- PML::RARA
- The fusion gene created by the t(15;17) translocation.
- ATRA
- All-trans retinoic acid — a drug that forces APL cells to mature.
- Arsenic trioxide
- A drug that breaks down the PML::RARA protein; very effective in APL.
- DIC
- Disseminated intravascular coagulation: clotting and bleeding problems at the same time.
- Fibrinogen
- A protein needed to form a clot; often low in APL.
- Hyperfibrinolysis
- Clots being dissolved far too quickly.
- Differentiation syndrome
- A complication of ATRA or arsenic trioxide that must be recognised early.
- QT interval
- An ECG measure of the heart’s electrical recovery; arsenic trioxide can prolong it.
08Key points
- APL is a special form of AML and is treated as a medical emergency.
- The main signs relate to bleeding: bruising, petechiae, nosebleeds and bleeding gums.
- Severe headache, confusion, coughing up blood or bleeding that will not stop — call emergency services.
- When APL is suspected, ATRA starts without waiting for genetic confirmation.
- Clotting tests (fibrinogen, D-dimer) are checked often in the first days.
- The diagnosis is confirmed with a PML::RARA (t(15;17)) test.
- The risk group is set by the white cell count at diagnosis.
- After the first weeks, APL is one of the leukemias with the best results.
09Frequently asked questions
Why is APL treated as so urgent?
Because APL cells disrupt the clotting system and create a serious risk of bleeding in the first days. When treatment starts early, this risk falls quickly. That is why anyone suspected of having APL should be referred straight away to a centre experienced in treating leukemia.
Why is a drug started before the genetic test is ready?
ATRA quickly corrects the clotting disorder in APL, while confirmation tests can take a day or more. Waiting is risky, so ATRA is started at once; if APL is not confirmed, it is stopped.
Will I need chemotherapy?
In low-risk APL, ATRA and arsenic trioxide alone are often enough, and classic chemotherapy is not needed. In high-risk APL (with a high white cell count), a small amount of chemotherapy or other drugs is usually added. Your hematologist makes this decision.
What is differentiation syndrome?
It is a complication that can occur during treatment with ATRA or arsenic trioxide: fever, breathlessness, weight gain, swelling and low blood pressure. When recognised early, it responds well to steroids. Report such signs to your team immediately.
My periods are very heavy. Could that be a sign of APL?
Most causes of heavy periods have nothing to do with leukemia. But if they come with bruising, petechiae, tiredness or other bleeding, a blood count and clotting tests are needed. During treatment, medicines to reduce menstrual bleeding may be offered.
Is a normal life possible after APL?
Yes. With modern treatment, most people achieve long-lasting remission and return to work, study and family life. Molecular monitoring (PML::RARA) may continue for a while after treatment.
10Questions for your doctor
Take these questions to your appointment. The ones you save are collected on the “My questions” page and stay on this device only.
Which bleeding signs mean I should call emergency services at once?
How often will you check my clotting tests?
What should I do if I become short of breath or gain weight quickly?
How long might this critical period last?
12Sources
- American Cancer Society. Treatment of Acute Promyelocytic (M3) Leukemia
- American Cancer Society. Signs and Symptoms of Acute Myeloid Leukemia (AML)
- American Cancer Society. Tests for Acute Myeloid Leukemia (AML)
- National Cancer Institute (NCI). Adult Acute Myeloid Leukemia Treatment (PDQ®) — Patient Version
- National Cancer Institute (NCI). Adult Acute Myeloid Leukemia Treatment (PDQ®) — Health Professional Version
- Blood Cancer United (formerly The Leukemia & Lymphoma Society). Acute promyelocytic leukemia (APL)
- National Comprehensive Cancer Network (NCCN). NCCN Guidelines for Patients: Acute Myeloid Leukemia (includes APL)
- Blood (American Society of Hematology), 2019. Management of acute promyelocytic leukemia: updated recommendations from an expert panel of the European LeukemiaNet
- Blood (American Society of Hematology), 2011. Early death rate in acute promyelocytic leukemia remains high despite all-trans retinoic acid
- Leukemia (Nature), 2011. Continuing high early death rate in acute promyelocytic leukemia: a population-based report from the Swedish Adult Acute Leukemia Registry
- Annals of Oncology (ESMO), 2020. Acute myeloid leukaemia in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
- Cleveland Clinic. Differentiation Syndrome
- Leukemia (Nature) — WHO 5th edition. WHO Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms
- Blood (American Society of Hematology), 2022. International Consensus Classification of Myeloid Neoplasms and Acute Leukemias