Acute Promyelocytic Leukaemia: Spotting a Bleeding Emergency

Acute promyelocytic leukaemia (APL) is a medical emergency: a patient can die of bleeding within the first day or the first week, yet of patients who come through that first week, 95% are cured. Dr. Niti Raizada, Principal Director Medical Oncology, Fortis Hospital, Bannerghatta Road, Bengaluru, India, used one case to show how a basic blood count and a peripheral smear make the diagnosis.

APL is a subtype of acute myeloid leukaemia, classified as AML M3. Dr. Raizada described it as rare but very curable. The danger lies in how ordinary its first symptoms look, and treatment has to start before the final report arrives.

Symptoms of APL: a case that looked like nothing serious

A schoolteacher in her early thirties, with one child, came with a short history. For two weeks she had noticed easy bruising on her arms, with purple patches. Her gums bled when she brushed her teeth in the morning. She felt tired and had mild breathlessness, which she had noticed only recently, and occasional headaches. The fatigue had been getting worse over the previous ten days.

Just as important were the negatives:

• No nosebleeds, blood in the urine or bleeding from the gut
• No fever and no recent infection
• No painkillers, antiplatelet drugs or anticoagulants
• No family history of a bleeding disorder
• A non-smoker who had never drunk alcohol, vegetarian, with no recent travel

On examination she was pale and looked fatigued, without fever. There were multiple ecchymotic patches (bruises) on her arms and legs, bleeding from the gums and a purpuric patch (small bleeds into the skin) on the cheek. There were no enlarged lymph nodes and no enlargement of the liver or spleen. Her pulse was mildly raised; everything else was normal.

Why APL is easy to miss

A patient who feels tired and low, and who puts bleeding gums down to brushing too hard, may not seek attention until a crisis. The moderator raised exactly this concern during the session. Dr. Raizada's answer was to lower the threshold for basic blood tests. A young woman presenting for the first time fatigued, pale and with multiple bleeding spots is a red flag, and the next step is simply a complete blood count.

Differential diagnosis of bleeding with low blood counts

In a bleeding patient, low blood counts together with abnormal clotting should raise the alarm for APL, while isolated prolonged clotting times point towards a clotting factor disorder.

Dr. Raizada asked the doctors on the session for their diagnoses and welcomed the range of answers. A bleeding patient like this can have a platelet disorder such as immune thrombocytopenic purpura (ITP), a clotting factor problem, heparin-induced thrombocytopenia or a leukaemia. Her approach to narrowing the list rests on one distinction.

• Isolated prolonged clotting times (a high PTT or APTT on its own) raise the possibility of a clotting factor disorder such as haemophilia or von Willebrand disease.
• Cytopenias, low counts of red cells, white cells and platelets, point away from a pure clotting factor abnormality.
• Cytopenias together with coagulopathy is the combination that should raise the alarm for APL.

The blood tests that diagnose APL

The complete blood count, clotting screen and peripheral smear gave the answer:

The low fibrinogen and markedly raised D-dimer, together with the prolonged clotting times, indicate disseminated intravascular coagulation (DIC), a state in which clotting factors are consumed faster than the body can replace them, so the patient bleeds.

The peripheral smear was the single most informative test. Promyelocytes are immature white cells, and Auer rods are needle-shaped inclusions very characteristic of acute myeloid leukaemia. When the smear shows promyelocytes in a patient like this, Dr. Raizada treats the case as APL unless proven otherwise.

The diagnosis was AML M3 with DIC.

Acute promyelocytic leukaemia: why the first week decides survival

Because the bleeding time, clotting time, prothrombin time and PTT are prolonged, fibrinogen is low and the patient already has a bleeding tendency, a bleed into the gut or the brain can occur at any moment. Dr. Raizada described the first day, the first 48 hours and the first week as crucial. If the patient survives the first seven days, 95% are cured of the disease and go on to very good survival.

Emergency management of APL

Dr. Raizada's management was immediate and did not wait for confirmation.

1. Transfuse urgently. Cryoprecipitate and fresh frozen plasma replace the clotting factors and correct the fibrinogen.
2. Keep the platelet count above 50,000. She described this threshold as the mandate in APL.
3. Start ATRA straight away. All-trans retinoic acid (ATRA), taken by mouth, is started even without the final report, before the patient is lost.
4. Confirm the diagnosis. A bone marrow examination and a molecular test confirmed the PML-RARA fusion that defines APL.

In this patient, ATRA was started and the coagulopathy was corrected with fresh frozen plasma, cryoprecipitate and platelets before the bone marrow and molecular confirmation. Dr. Raizada's treatment for APL is ATRA or arsenic trioxide. Current standard regimens combine ATRA with arsenic trioxide, with chemotherapy added in high-risk disease. Costs for chemotherapy are on the chemotherapy cost page.

Classifying leukaemia: a practical framework

Asked in the masterclass Live Discussion to recap how leukaemia is managed, Dr. Raizada set out the framework she uses. The first step is always to confirm the type.

Acute or chronic

• Acute leukaemias have a short history, with low haemoglobin and platelets and a white cell count that may be low or high. They usually present with fever and bleeding.
• Chronic leukaemias generally occur in older age groups and are often managed with tablets alone.

The four main types

Every patient needs immediate management, but in the longer term, genetic testing subcategorises each leukaemia, and treatment follows the subcategory.

The basic blood panel: a first line of defence

The APL case carries a lesson well beyond leukaemia. Dr. Raizada's advice to general practitioners and every clinician is to order basic blood tests whenever there is doubt. When a patient comes with persistent symptoms that have not been explained, she asks for:

• A complete blood count (CBC): haemoglobin, white cell count and platelets
• Liver function tests (LFT)
• Kidney function tests (RFT)
• A clotting profile (PT, PTT and INR), if there is any bleeding tendency

These three core tests give quite a few clues. If they are abnormal, something significant is happening, and the clinician becomes more alert. A low haemoglobin needs attention. So does a high bilirubin, deranged kidney function or abnormal sodium or potassium. Her instruction is to start with a basic blood panel rather than jumping to scans, and to take it from there. Doing just this, she said, can prevent many tragedies. Dr. Nithin S.G.'s guide to how cancer is diagnosed covers blood tests, imaging and biopsy in more detail.

The same panel caught the colon cancer in her series: a haemoglobin of 9 in a young man was the first clue. That case and the others are in the article on lung, colon, liver and oral cancer.

Where this fits

Dr. Raizada's masterclass concentrated on common cancers, with APL as its one blood disorder. Participants asked for a future session dedicated to blood disorders. The full set of eight cases is in the complete guide to diagnosing common cancers and blood disorders, and more on blood cancers and other blood conditions is on the haematology hub.