Leukostasis (also called symptomatic hyperleukocytosis) is a medical emergency most commonly seen in patients with acute myeloid leukemia. It is characterized by an extremely elevated blast cell count and symptoms of decreased tissue perfusion. The pathophysiology of leukostasis is not well understood, but inadequate delivery of oxygen to the body's cells is the result. Leukostasis is diagnosed when white cell plugs are seen in the microvasculature. The most common symptoms are dyspnea and hypoxia, usually accompanied by visual changes, headaches, dizziness, confusion, somnolence, and coma. Prompt treatment is required since, if left untreated, it has a very high mortality rate. Treatments aim to rapidly reduce white blood cell counts while also treating the underlying disorder.
Asymptomatic hyperleukocytosis and symptomatic hyperleukocytosis (leukostasis)
Leukocytes
Symptomatic Hyperleukocytosis (Leukostasis) is defined by a tremendously high blast cell count along with symptoms of decreased tissue perfusion. Leukostasis is associated with people who have bone and blood disorders and is very common among people with acute myeloid leukemia or chronic myeloid leukemia. Leukostasis is a pathologic diagnosis that inhibits efficient flow to the microvasculature of the body. Continued and untreated leukostasis presents respiratory and neurological distress simultaneously and is a medical emergency, with untreated patient mortality rates reaching a minimum of 20 and a maximum of 40 percent. A leukemia blood cell count greater than 50 x 10^9/ L (50,000 / microL) or 100 x 10^9 L / (100,000/ microL) signifies hyperleukocytosis. Symptoms of leukostasis start when blood levels of leukocytes reach over 100 x 10^9 / L (100,000 / microL). As stated before, these counts are critical and associated with Leukemias.[1]
Symptoms and signs
When a patient has symptomatic leukocytosis, specifically caused by a form of leukemia, it is common to find leukostasis in all their organs. The majority of the time a patient dies from neurological complications (40% of patients die due to neurological conditions) as opposed to particular organ damage. The lungs alone account for approximately 30 percent of leukostasis fatalities. All other organs combined attribute to 30 percent of deaths, with the major outliers being neurological and respiratory failure equating to 70 percent of all death rates. Damage to the microvasculature of the body is the primary cause of death by leukostasis. Microvasculature damage to the lungs is only second to neurological damage because the body is already experiencing hypoxic conditions, which lead to lung tissue damage as the second leading cause of fatalities.[2]
Pulmonary signs - Dyspnea and hypoxia with or without diffuse interstitial or alveolar infiltrates on imaging studies.
Hyperleukocytosis is very common in acutely ill patients. It occurs in response to a wide variety of conditions, including viral, bacterial, fungal, or parasitic infection, cancer, hemorrhage, and exposure to certain medications.
For lung diseases such as pneumonia and tuberculosis, white blood cell count is crucial for the diagnosis of the disease, as leukocytosis is usually present.
The mechanism in which hyperleukocytosis or leukostasis manifests and disrupts homeostasis is greatly associated with leukemia's but multiple other factors may cause leukocytosis. Major types of leukocytosis and their mechanisms depend on the types of leukemia that cause them. White blood cell levels either rise in distinct white blood levels or in unison with others, a patient may have neutrophilia, lymphocytosis, monocytosis, eosinophilia, basophilia or a rise in immature blast cells.[2]
Acute myeloid leukemia - 10 to 20 percent of patients newly diagnosed with this type leukemia have hyperleukocytosis.
Acute lymphoblastic leukemia - 20 to 30 percent of patients newly diagnosed with this type of leukemia have hyperleukocytosis.
Chronic lymphocytic leukemia - Exact percentage of people diagnosed with chronic lymphocytic leukemia is unknown but a significant number also have hyperleukocytosis.
Chronic myeloid leukemia - The majority of patients with chronic myeloid leukemia usually have hyperleukocytosis.
The primary pathophysiology of leukostasis is not completely understood, but there are two possible theories.
Theory 1
Increased blood viscosity due to large leukemic blast populations which are less deformable than mature leukocytes may lead to leukostasis. The accumulation of less malleable blast products in the bloodstream accumulate within the microcirculation causing an accumulation of blockages leading to leukostasis.[citation needed]
Theory 2
Hypoxic events in body regions may increase the high metabolic activity of dividing blast cells and lead to an increase in cytokine production. The increasing levels of cytokines within tissues may result in endothelial damage and subsequent hemorrhage. Therefore, hypoxia, in addition to various cytokine accumulations, act in unison to further damage tissue and attract leukemic blast cells to form a triad of damage.[citation needed]
The combination of these theories, in addition to other events, may lead to hyperleukocytosis.
Diagnosis
White blood counts exceeding 100 x 10^9 / L (100,000 / microL) present symptoms of tissue hypoxia and may signal possible neurological and respiratory distress. Ongoing research has shown that patients have experienced hypoxia at leukocyte levels below 100 x 10^9 / L (100,000 / microL), therefore patients with leukemia need regular neurological and respiratory monitoring when leukocyte counts are approaching 100 x 10^9 / L (100,000 / microL) to decrease chances of tissue hypoxia.
Acquired biopsies are examined for damage to microvasculature, which serves as evidence of hypoxia through the identification of leukocyte blockage within the tissue. Due to the biopsy's invasive nature and the risks associated with the procedure, it is only used when deemed necessary.[2]
Measurements for arterial pO2 have shown to be falsely decreased in patients with hyperleukocytosis because of white blood cells ability to utilize oxygen. Pulse oximetry should be used to more accurately assess pO2 levels of a patient suspected to have leukocytosis. Automated blood cell counters may be inaccurate due to fragments of blast cells being labeled on blood smears as platelets. The most accurate form of confirming platelet counts is by using a manual platelet count and a review of a peripheral smear. Serum potassium levels may also be artificially elevated by a release from leukemic blasts during in vitro clotting process, therefore serum potassium levels should be monitored by heparinized (the addition of heparin prevents coagulation) plasma samples in order to obtain accurate results of potassium levels. Disseminated intravascular coagulation may occur in a significant number of patients with presentation of various degrees of thrombin generation, followed by decreased fibrinogen and increased fibrinolysis.[citation needed]
Spontaneous tumor lysis syndrome is present in approximately 10 percent of patients with leukostasis. Lab tests are used to measure the potential of elevated serum concentrations such as uric acid, potassium, phosphate, and hypocalcemia.
Disseminated intravascular coagulation and spontaneous tumor lysis syndrome can develop before and after chemotherapy treatment. Patients undergoing this type of therapy need to be closely monitored before and after, in addition to undergoing prophylactic measures to prevent possible complications.
Prevention
Since leukostasis and hyperleukostasis are associated with leukemia, preventive treatments are taken upon diagnosis.[2]
Patients with hyperleukocytosis associated with leukemia are always considered candidates for tumor lysis syndrome prophylaxis in addition to aggressive intravenous hydration with allopurinol or rasburicase to decrease serum uric acid levels.
Treatment
Treatment includes utilization of prophylactic methods if the patient has been diagnosed with hyperleukocytosis. This is usually in combination with other treatments, which are dependent on the type of leukemia. Specific treatments include lysis syndrome treatment in addition to aggressive intravenous hydration with allopurinol or rasburicase to decrease serum uric acid levels.[2]
Hematopoietic cell transplants are critical to correct leukostasis and leukemia. Cytoreduction is also a critical course of treatment in order to rapidly decrease white blood cell counts. Twenty to forty percent of patients diagnosed with hyperleukocytosis die within the first week of symptom presentation. Patients with the best outcome have none or limited symptoms of respiratory or neurological distress. An accumulation of these symptoms lead to decreased levels of statistical survival compared to patients diagnosed with asymptomatic hyperleukocytosis alone. Cytoreduction methods include chemotherapy, utilizing the drug hydroxyurea (Hydroxyurea is usually used in asymptomatic hyperleukocytosis), and the less common leukapheresis procedure. This procedure is often utilized for asymptomatic hyperleukocytosis patients who have induction chemotherapy postponed for patient-specific factors.[citation needed]
Prognosis of patients with hyperleukocytosis is dependent on the cause and type of leukemia the patient has. Patients diagnosed with asymptomatic hyperleukocytosis have significantly better survival rates than symptomatic hyperleukocytosis (leukostasis). Preventative measures and contentious monitoring of patients diagnosed with leukemia is critical in receiving treatment as early as possible to prevent and treat hyperleukocytosis.[citation needed]
Recent research
Recent and continuing research has shown that patients have had hypoxia at leukocyte levels below 100 x 10^9 / L (100,000 / microL), therefore patients with leukemia need regular neurological and respiratory monitoring when leukocyte counts are approaching 100 x 10^9 / L (100,000 / microL) to decrease chances of hypoxia.[2]
Leukemia and population types are also believed to be associated with possible symptoms and may require a change in treatment.[2]
Results of Tumor lysis/ consumption of coagulopathy in patients with acute leukemia is much more often than in patients with chronic malignant hematological diseases.[5]
Data retrieved for reference is 2017
Leukostasis, also known as symptomatic hyperleukocytosis, is a life-threatening complication of various leukemias characterized by an excess of white blood cells in the bloodstream. Hyperleukocytosis is arbitrarily defined as greater than 100,000 white blood cells per microliter of blood. The condition is characterized by abnormal aggregation and clumping of white blood cells in the blood vessels resulting in impaired blood flow and delivery of oxygen to the body's cells. The brain and lungs are the two most commonly affected organs.[6] Leukostasis most commonly occurs with acute myeloid leukemia.
Hyperleukocytosis/leukostasis occurs more commonly, and at lower white blood cell (WBC) counts, in acute myeloid leukemia than in acute lymphocytic leukemia, because the cells of acute myeloid leukemia have a larger corpuscular (cell) volume than those of acute lymphocytic leukemia, and the cells of acute myeloid leukemia have more surface adhesion molecules than those of acute lymphocytic leukemia (i.e., the cancer cells in AML are "stickier").
The pathophysiology of leukostasis is not well understood. Inadequate delivery of oxygen to the body's cells is thought to be the main abnormal result of leukostasis.[7] Proposed mechanisms for this include increased blood viscosity due to the high number of white blood cells circulating in the blood and a higher proportion of cells with a greater mean corpuscular volume (larger cells) with decreased deformability occupying the blood vessels.[6] However, certain studies have demonstrated that the blood viscosity of affected individuals is not increased due to a compensatory decrease in the number of red blood cells sometimes resulting in anemia and a decreased hematocrit.[7]
Diagnosis
The clinical signs and symptoms of leukostasis are non-specific but should be suspected in susceptible individuals with leukemia, a high white blood cell count (e.g., over 100,000), and new-onset neurologic or respiratory signs or symptoms. Rales may be heard when listening to the lungs with a stethoscope.[6]
Laboratory abnormalities seen in those with leukostasis include a markedly elevated white blood cell count (hyperleukocytosis) and electrolyte abnormalities seen with tumor lysis syndrome such as high concentrations of potassium, phosphorus, and uric acid in the blood and a low level of calcium in the blood (due to being bound by high amounts of circulating phosphorus).[7]
Leukostasis is different from leukemic infiltration, which is a neoplastic process where leukemic cells invade organs.[8]
Prognosis
Leukostasis is a high-risk condition and can lead to significant complications resulting from occlusion of blood vessels, including transient ischemic attacks and strokes.
Epidemiology
The incidence and prevalence of hyperleukocytosis and leukostasis vary depending on the form of leukemia.[7] Hyperleukocytosis is common in chronic myelogenous leukemia and chronic lymphocytic leukemia, but leukostasis rarely occurs.[7] Similarly, the incidence of hyperleukocytosis in people with acute lymphoblastic leukemia is between 10 and 30% but rarely does this progress to symptomatic leukostasis.[7] The incidence of hyperleukocytosis in acute myeloid leukemia (AML) ranges between 5-20% but leukostasis is less common than hyperleukocytosis in this population; leukostasis tends to occur more often in people with AML with monocytic features.[7]
Related Research Articles
Leukemia is a group of blood cancers that usually begin in the bone marrow and produce high numbers of abnormal blood cells. These blood cells are not fully developed and are called blasts or leukemia cells. Symptoms may include bleeding and bruising, bone pain, fatigue, fever, and an increased risk of infections. These symptoms occur due to a lack of normal blood cells. Diagnosis is typically made by blood tests or bone marrow biopsy.
A myelodysplastic syndrome (MDS) is one of a group of cancers in which immature blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may include fatigue, shortness of breath, bleeding disorders, anemia, or frequent infections. Some types may develop into acute myeloid leukemia.
Chronic lymphocytic leukemia (CLL) is a type of cancer in which the bone marrow makes too many lymphocytes. Early on, there are typically no symptoms. Later, non-painful lymph node swelling, feeling tired, fever, night sweats, or weight loss for no clear reason may occur. Enlargement of the spleen and low red blood cells (anemia) may also occur. It typically worsens gradually over years.
Chronic myelogenous leukemia (CML), also known as chronic myeloid leukemia, is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of myeloid cells in the bone marrow and the accumulation of these cells in the blood. CML is a clonal bone marrow stem cell disorder in which a proliferation of mature granulocytes and their precursors is found; characteristic increase in basophils is clinically relevant. It is a type of myeloproliferative neoplasm associated with a characteristic chromosomal translocation called the Philadelphia chromosome.
Tumors of the hematopoietic and lymphoid tissues or tumours of the haematopoietic and lymphoid tissues are tumors that affect the blood, bone marrow, lymph, and lymphatic system. Because these tissues are all intimately connected through both the circulatory system and the immune system, a disease affecting one will often affect the others as well, making aplasia, myeloproliferation and lymphoproliferation closely related and often overlapping problems. While uncommon in solid tumors, chromosomal translocations are a common cause of these diseases. This commonly leads to a different approach in diagnosis and treatment of hematological malignancies. Hematological malignancies are malignant neoplasms ("cancer"), and they are generally treated by specialists in hematology and/or oncology. In some centers "hematology/oncology" is a single subspecialty of internal medicine while in others they are considered separate divisions. Not all hematological disorders are malignant ("cancerous"); these other blood conditions may also be managed by a hematologist.
Leukocytosis is a condition in which the white cell (leukocyte) count is above the normal range in the blood. It is frequently a sign of an inflammatory response, most commonly the result of infection, but may also occur following certain parasitic infections or bone tumors as well as leukemia. It may also occur after strenuous exercise, convulsions such as epilepsy, emotional stress, pregnancy and labor, anesthesia, as a side effect of medication, and epinephrine administration. There are five principal types of leukocytosis:
Neutrophilia
Lymphocytosis
Monocytosis
Eosinophilia
Basophilia
Hypereosinophilic syndrome is a disease characterized by a persistently elevated eosinophil count in the blood for at least six months without any recognizable cause, with involvement of either the heart, nervous system, or bone marrow.
A myeloid sarcoma is a solid tumor composed of immature white blood cells called myeloblasts. A chloroma is an extramedullary manifestation of acute myeloid leukemia; in other words, it is a solid collection of leukemic cells occurring outside of the bone marrow.
Myeloproliferative neoplasms (MPNs) are a group of rare blood cancers in which excess red blood cells, white blood cells or platelets are produced in the bone marrow. Myelo refers to the bone marrow, proliferative describes the rapid growth of blood cells and neoplasm describes that growth as abnormal and uncontrolled.
Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with normal blood cell production. Symptoms may include feeling tired, shortness of breath, easy bruising and bleeding, and increased risk of infection. Occasionally, spread may occur to the brain, skin, or gums. As an acute leukemia, AML progresses rapidly, and is typically fatal within weeks or months if left untreated.
A promyelocyte is a granulocyte precursor, developing from the myeloblast and developing into the myelocyte. Promyelocytes measure 12–20 microns in diameter. The nucleus of a promyelocyte is approximately the same size as a myeloblast but their cytoplasm is much more abundant. They also have less prominent nucleoli than myeloblasts and their chromatin is more coarse and clumped. The cytoplasm is basophilic and contains primary red/purple granules.
Leukemia cutis is the infiltration of neoplastic leukocytes or their precursors into the skin resulting in clinically identifiable cutaneous lesions. This condition may be contrasted with leukemids, which are skin lesions that occur with leukemia, but which are not related to leukemic cell infiltration. Leukemia cutis can occur in most forms of leukemia, including chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, and prolymphocytic leukemia.
Large granular lymphocytic (LGL) leukemia is a chronic lymphoproliferative disorder that exhibits an unexplained, chronic elevation in large granular lymphocytes (LGLs) in the peripheral blood.
Acute megakaryoblastic leukemia (AMKL) is life-threatening leukemia in which malignant megakaryoblasts proliferate abnormally and injure various tissues. Megakaryoblasts are the most immature precursor cells in a platelet-forming lineage; they mature to promegakaryocytes and, ultimately, megakaryocytes which cells shed membrane-enclosed particles, i.e. platelets, into the circulation. Platelets are critical for the normal clotting of blood. While malignant megakaryoblasts usually are the predominant proliferating and tissue-damaging cells, their similarly malignant descendants, promegakaryocytes and megakaryocytes, are variable contributors to the malignancy.
Acute myelomonocytic leukemia (AMML) is a form of acute myeloid leukemia that involves a proliferation of CFU-GM myeloblasts and monoblasts. AMML occurs with a rapid increase amount in white blood cell count and is defined by more than 20% of myeloblast in the bone marrow. It is classified under "M4" in the French-American-British classification (FAB). It is classified under "AML, not otherwise classified" in the WHO classification.
Biphenotypic acute leukaemia (BAL) is an uncommon type of leukemia which arises in multipotent progenitor cells which have the ability to differentiate into both myeloid and lymphoid lineages. It is a subtype of "leukemia of ambiguous lineage".
White blood cells, also called immune cells or immunocytes, are cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. White blood cells are generally larger than red blood cells. They include three main subtypes: granulocytes, lymphocytes and monocytes.
Childhood leukemia is leukemia that occurs in a child and is a type of childhood cancer. Childhood leukemia is the most common childhood cancer, accounting for 29% of cancers in children aged 0–14 in 2018. There are multiple forms of leukemia that occur in children, the most common being acute lymphoblastic leukemia (ALL) followed by acute myeloid leukemia (AML). Survival rates vary depending on the type of leukemia, but may be as high as 90% in ALL.
Venetoclax, sold under the brand names Venclexta and Venclyxto, is a medication used to treat adults with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), or acute myeloid leukemia (AML).
GATA2 deficiency is a grouping of several disorders caused by common defect, namely, familial or sporadic inactivating mutations in one of the two parental GATA2 genes. Being the gene haploinsufficient, mutations that cause a reduction in the cellular levels of the gene's product, GATA2, are autosomal dominant. The GATA2 protein is a transcription factor critical for the embryonic development, maintenance, and functionality of blood-forming, lymphatic-forming, and other tissue-forming stem cells. In consequence of these mutations, cellular levels of GATA2 are deficient and individuals develop over time hematological, immunological, lymphatic, or other presentations that may begin as apparently benign abnormalities but commonly progress to severe organ failure, opportunistic infections, virus infection-induced cancers, the myelodysplastic syndrome, and/or leukemia. GATA2 deficiency is a life-threatening and precancerous condition.
↑ Schellongowski, P.; Staudinger, T. (September 2013). "[Leukostasis and tumor lysis: important complications of hyperleukocytosis]". Der Internist. 54 (9): 1051–1060. doi:10.1007/s00108-013-3260-5. ISSN1432-1289. PMID23943008.
1 2 3 4 5 Ganzel, C; Becker, J; Mintz, PD; Lazarus, HM; Rowe, JM (May 2012). "Hyperleukocytosis, leukostasis and leukapheresis: practice management". Blood Reviews. 26 (3): 117–22. doi:10.1016/j.blre.2012.01.003. PMID22364832.
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