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One of the causes of stroke on which there has been little focus is stroke associated with leukaemia. This year, the World Stroke Organisation‘s campaign is focussing on stroke prevention. Therefore, the more that is known about strokes in patients with leukaemia, the greater the opportunities for preventing them.
Having leukaemia is associated with an increased risk of stroke and death. Among hospital patients, patients with acute myeloid leukaemia (AML) show a 50-fold increase in the risk of stroke compared with other patients who do not have AML. Additionally, patients with AML have a 5-fold higher risk of death due to stroke compared to other stroke patients who do not have leukaemia.
In patients with leukaemia, the main reason that stroke occurs is the disruption of the blood coagulation process which is a direct result of the leukaemia. Coagulation disorders in leukaemia can result in either thrombosis (occurrence of blood clots) or haemorrhages (bleeding). In patients with leukaemia, haemorrhage is more common, although thrombosis also occurs.
Stroke as a result of leukaemia
In patients with leukaemia, the major causes of injury and death from stroke are thrombosis and haemorrhage, which can lead to ischaemic stroke or haemorrhagic stroke, respectively. In ischaemic stroke, a blood clot blocks the flow of blood and oxygen to the brain, whereas in haemorrhagic stroke, a blood vessel inside the skull bursts and bleeds into the brain.
Occasionally, coagulation disorders in patients with leukaemia can cause both types of strokes simultaneously, particularly if the patient has disseminated intravascular coagulation. This is a serious condition caused by the blood coagulation disorders. It is commonly seen in 10-50% of patients with AML and 10-20% of patients with acute lymphoblastic leukaemia. In disseminated intravascular coagulation, the proteins that control blood clotting become overactive and numerous small blood clots develop throughout the bloodstream. Because of this increased clotting, all the clotting factors needed to control bleeding are used up. Therefore, patients with disseminated intravascular coagulation are prone to excessive bleeding which can cause an haemorrhagic stroke. Disseminated intravascular coagulation should be treated as soon as possible.
In addition to the coagulation disorders that affect patients with leukaemia, another important factor, particularly in the acute leukaemias, is the effect of the increased numbers of abnormal leukaemia white blood cells. In patients with leukaemia, these high numbers of leukaemia cells in the bone marrow move into the blood of all the arteries and veins in the body. When the level of leukaemia cells is extremely high – a condition which is known as hyperleukocytosis – they can block the blood vessels and cause an ischaemic stroke. Hyperleukocytosis is said to be present when the number of the white blood cells is greater than 100,000 per microlitre of blood. The number of white blood cells in a healthy individual is between 4,000 and 11,000 per microlitre of blood.
Patients with hyperleukocytosis, as is often the case in acute myeloid leukaemia and acute promyelocytic leukaemia, do not respond well to chemotherapy, and have a higher death rate, mainly due to haemorrhagic stroke.
Stroke as a side effect of treatment for leukaemia
A number of treatments for leukaemia can increase the likelihood of a patient having a stroke. For example, in patients with acute promyelocytic leukaemia (a sub-type of AML), the combination of the drugs all‑trans retinoic acid and arsenic trioxide has proved extremely effective, but it also increases the likelihood of the patients having hyperleukocytosis, which in turn increases their risk of stroke.
The drug ibrutinib has provided a significant improvement in the treatment for chronic lymphocytic leukaemia; however, it has two side effects which could lead to patients having a stroke. Firstly, it is associated with increased bleeding risk compared with other chemotherapy drugs. Secondly, ibrutinib has been shown to increase the risk of atrial fibrillation (AF), which is an established risk factor for stroke. AF is a type of irregular heartbeat which makes the heart beat abnormally quickly. This means that the heart does not empty itself of blood fully with each beat, and a clot can form in the blood which remains in the heart. Patients with AF have a five-fold increase risk of ischaemic stroke compared with those without AF.
L-asparaginase is a drug often used in combination with other chemotherapy drugs to improve results and prevent relapse in patients with acute lymphoblastic leukaemia. However, it has been shown to cause thrombosis in approximately 10% of patients who are given it, thereby putting them at risk of ischaemic stroke.
Preventative measures
In general, a better assessment and classification of stroke risk factors in patients with leukaemia is needed.
Despite their side effects, the drugs mentioned above are very important for achieving the best results possible for patients with leukaemia. Therefore, identifying and treating hyperleukocytosis with a combination of chemotherapy which includes an anthracycline drug is vital to prevent ischaemic stroke in patients with leukaemia.
In patients treated with combined all trans retinoic acid and arsenic trioxide, the drug hydroxyurea may be given to keep the white blood cell count within normal levels (<10,000/µL).
In patients receiving ibrutinib and L-asparaginase, the use of the new anticoagulants, rather than warfarin, which is contra-indicated with ibrutinib, is an option to prevent thrombosis and ischaemic stroke. However, additional studies of the use of anticoagulants in patients with leukaemia are required to provide valuable information on prevention measures.
For a list of references used in this article, email communications@leukaemiacare.org.uk.