Bone marrow failure

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Bone marrow failure occurs in individuals who produce an insufficient amount of red blood cells, white blood cells or platelets. Red blood cells transport oxygen to be distributed throughout the body's tissue. White blood cells fight off infections that enter the body. Bone marrow progenitor cells known as megakaryocytes produce platelets, which trigger clotting, and thus help stop the blood flow when a wound occurs. [1]

Contents

Signs and symptoms

The two most common signs and symptoms of bone marrow failure are bleeding and bruising. Blood may be seen throughout the gums, nose or the skin, and bleeding tends to last longer than normal. Children have a greater chance of seeing blood in their urine or stools, which results in digestive problems with an unpleasant scent. Individuals with this condition may also encounter tooth loss or tooth decay. Chronic fatigue, shortness of breath, and recurrent infections can also be symptoms of bone marrow failure. [2]

Causes

Bone marrow failure in both children and adults can be either inherited or acquired. Inherited bone marrow failure is often the cause in young children, while older children and adults may acquire the disease later in life. [3] Acquired bone marrow failure may be due to aplastic anemia [4] or myelodysplastic syndrome.

Inherited Bone marrow failure syndromes

Inherited marrow failure syndromes include:

Fanconi anemia is an inherited blood disorder due to abnormal breakages in DNA genes. It is linked to hyperpigmentation, which is the darkening of an area of skin or nails caused by increased melanin, though in about 30% of FA patients no physical abnormalities are found. [6]

Dyskeratosis congenita often affects multiple parts of the body. Individuals with this disorder usually show changes in skin pigmentations, unusual fingernail growth, and mucosa leukoplakia; the inner part of the mouth is encased with white patches. [6]

Inherited bone marrow failure syndromes represent a kind of premature aging of the bone marrow. In patients with these syndromes, as in elderly patients, mutations associated with clonal hematopoiesis may arise as an adaptive response to a progressively deteriorating hematopoietic niche, i.e., a depleting pool of Hematopoietic stem cells. The mutated stem cells then acquire a self-renewal advantage. [7]

Acquired bone marrow failure

Aplastic anemia is an acquired autoimmune disease in which T cells attack and destroy bone marrow precursor cells. [8]

Myelodysplastic syndrome (MDS) is a form of blood cancer in which the bone marrow no longer produces enough healthy, normal blood cells. [9] MDS are a frequently unrecognized and rare group of bone marrow failure disorders, yet the incidence rate has rose from 143 reported cases in 1973 to approximately 15,000 cases in the United States each year. MDS is likely under-diagnosed, with the believed actual incidence rate estimated at 35,000 to 55,000 new cases annually. [10] One in three people with MDS progress to acute myeloid leukemia. [9] For lower risk patients, those who do not undergo a bone marrow transplant have an average survival rate of up to six years. [9] However, high-risk patients have a survival rate of approximately five months. [9]

Diagnosis

Cytopenias may be noted in the peripheral blood. Bone marrow examination is required to assess erythroid, myeloid and megakaryocytic precursors, identify genetic abnormalities, and rule out other entities such as leukemia. [11] B-cell lymphopenia has been observed in some patients with MECOM deficiency but is not a definitive indicator. [12]

Epidemiology

For those with severe bone marrow failure, the cumulative incidence of resulting stem cell transplantation or death was greater than 70% by individuals 60 years of age. [13] The incidence of bone marrow failure is triphasic: one peak at two to five years during childhood (due to inherited causes), and two peaks in adulthood, between 20 and 25 years old and after 60 years old (from acquired causes). [14]

One in ten individuals with bone marrow failure have unsuspected Fanconi anemia (FA). [14] FA is the most common inherited bone marrow failure with an incidence of one to five episodes per million individuals. [14] The carrier frequency for FA is 1 in 200 to 300, however this differs by ethnicity. [14] In Europe and North America, the incidence of acquired aplastic anemia is rare with two episodes per million people each year, yet in Asia rises with 3.9 to 7.4 episodes per million people each year. [15] While acquired aplastic anemia with an unknown cause is rare, it is commonly permanent and life-threatening as half of those with this condition die within the first six months. [10]

The prevalence of bone marrow failure is over three times higher in Japan and East Asia than in the United States and Europe. [10] When one's body fails to produce blood cell lines, the morbidity and mortality rate increases. [10]

Treatment

Supportive care with blood transfusions including platelets should be provided for symptoms of anemia and bleeding. Inherited bone marrow failure syndromes may require hematopoietic stem cell transplantation. Depending on severity, aplastic anemia may be treated with T-cell suppression in the form of cyclosporine and anti-thymocyte globulin, or may require hematopoietic stem cell transplantation.

Related Research Articles

<span class="mw-page-title-main">Myelodysplastic syndrome</span> Diverse collection of blood-related cancers

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.

Aplastic anemia (AA) is a severe hematologic condition in which the body fails to make blood cells in sufficient numbers. Blood cells are produced in the bone marrow by stem cells that reside there. Aplastic anemia causes a deficiency of all blood cell types: red blood cells, white blood cells, and platelets.

<span class="mw-page-title-main">Fanconi anemia</span> Medical condition

Fanconi anemia (FA) is a rare, autosomal recessive, genetic disease resulting in impaired response to DNA damage in the FA/BRCA pathway. Although it is a very rare disorder, study of this and other bone marrow failure syndromes has improved scientific understanding of the mechanisms of normal bone marrow function and development of cancer. Among those affected, the majority develop cancer, most often acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), and liver tumors. 90% develop aplastic anemia by age 40. About 60–75% have congenital defects, commonly short stature, abnormalities of the skin, arms, head, eyes, kidneys, and ears, and developmental disabilities. Around 75% have some form of endocrine problem, with varying degrees of severity. 60% of FA is FANC-A, 16q24.3, which has later onset bone marrow failure.

<span class="mw-page-title-main">Paroxysmal nocturnal hemoglobinuria</span> Blood disease in which red blood cells are attacked by the immune system

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, life-threatening disease of the blood characterized by destruction of red blood cells by the complement system, a part of the body's innate immune system. This destructive process occurs due to deficiency of the red blood cell surface protein DAF, which normally inhibits such immune reactions. Since the complement cascade attacks the red blood cells within the blood vessels of the circulatory system, the red blood cell destruction (hemolysis) is considered an intravascular hemolytic anemia. There is ongoing research into other key features of the disease, such as the high incidence of venous blood clot formation. Research suggests that PNH thrombosis is caused by both the absence of GPI-anchored complement regulatory proteins on PNH platelets and the excessive consumption of nitric oxide (NO).

<span class="mw-page-title-main">Hematopoietic stem cell transplantation</span> Medical procedure to replace blood or immune stem cells

Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood, in order to replicate inside a patient and produce additional normal blood cells. HSCT may be autologous, syngeneic, or allogeneic.

Pancytopenia is a medical condition in which there is significant reduction in the number of almost all blood cells.

<span class="mw-page-title-main">Macrocytosis</span> Medical condition

Macrocytosis is a condition where red blood cells are larger than normal. These enlarged cells, also known as macrocytes, are defined by a mean corpuscular volume (MCV) that exceeds the upper reference range established by the laboratory and hematology analyzer. Upon examination of a peripheral blood smear under microscope, these macrocytes appear larger than standard erythrocytes. It’s noteworthy that macrocytosis is a common morphological feature in neonatal peripheral blood. The presence of macrocytosis can indicate a range of conditions, from benign, treatable illnesses to more serious underlying disorders.

<span class="mw-page-title-main">Sideroblastic anemia</span> Medical condition

Sideroblastic anemia, or sideroachrestic anemia, is a form of anemia in which the bone marrow produces ringed sideroblasts rather than healthy red blood cells (erythrocytes). In sideroblastic anemia, the body has iron available but cannot incorporate it into hemoglobin, which red blood cells need in order to transport oxygen efficiently. The disorder may be caused either by a genetic disorder or indirectly as part of myelodysplastic syndrome, which can develop into hematological malignancies.

<span class="mw-page-title-main">Dyskeratosis congenita</span> Medical condition

Dyskeratosis congenita (DKC), also known as Zinsser-Engman-Cole syndrome, is a rare progressive congenital disorder with a highly variable phenotype. The entity was classically defined by the triad of abnormal skin pigmentation, nail dystrophy, and leukoplakia of the oral mucosa, and myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), but these components do not always occur. DKC is characterized by short telomeres. The disease initially can affect the skin, but a major consequence is progressive bone marrow failure which occurs in over 80%, causing early mortality.

Reticulocytopenia is the medical term for an abnormal decrease in circulating red blood cell precursors (reticulocytes) that can lead to anemia due to resulting low red blood cell (erythrocyte) production. Reticulocytopenia may be an isolated finding or it may not be associated with abnormalities in other hematopoietic cell lineages such as those that produce white blood cells (leukocytes) or platelets (thrombocytes), a decrease in all three of these lineages is referred to as pancytopenia.

<span class="mw-page-title-main">Promyelocyte</span> Granulocyte precursor cell

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.

<span class="mw-page-title-main">Chronic myelomonocytic leukemia</span> Medical condition

Chronic myelomonocytic leukemia (CMML) is a type of leukemia, which are cancers of the blood-forming cells of the bone marrow. In adults, blood cells are formed in the bone marrow, by a process that is known as haematopoiesis. In CMML, there are increased numbers of monocytes and immature blood cells (blasts) in the peripheral blood and bone marrow, as well as abnormal looking cells (dysplasia) in at least one type of blood cell.

Juvenile myelomonocytic leukemia (JMML) is a rare form of chronic leukemia that affects children, commonly those aged four and younger. The name JMML now encompasses all diagnoses formerly referred to as juvenile chronic myeloid leukemia (JCML), chronic myelomonocytic leukemia of infancy, and infantile monosomy 7 syndrome. The average age of patients at diagnosis is two (2) years old. The World Health Organization has included JMML as a subcategory of myelodysplastic and myeloproliferative disorders.

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.

<span class="mw-page-title-main">Congenital amegakaryocytic thrombocytopenia</span> Medical condition

Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare autosomal recessive bone marrow failure syndrome characterized by severe thrombocytopenia, which can progress to aplastic anemia and leukemia. CAMT usually manifests as thrombocytopenia in the initial month of life or in the fetal phase. Typically CAMPT presents with petechiae, cerebral bleeds, recurrent rectal bleeding, or pulmonary hemorrhage.

Congenital hypoplastic anemia is a congenital disorder that occasionally also includes leukopenia and thrombocytopenia and is characterized by deficiencies of red cell precursors.

Guo Mei is a hematologist and associate director of 307th Hospital of Chinese People’s Liberation Army and deputy director of Radiation Research Institute.

Refractory cytopenia of childhood is a subgroup of myelodysplastic syndrome (MDS), having been added to the World Health Organization classification in 2008. Before then, RCC cases were classified as childhood aplastic anemia. RCC is the most common form of MDS in children and adolescents, accounting for approximately half of all MDS cases.

<span class="mw-page-title-main">Emberger syndrome</span> Medical condition

The Emberger syndrome is a rare, autosomal dominant, genetic disorder caused by familial or sporadic inactivating mutations in one of the two parental GATA2 genes. The mutation results in a haploinsufficiency in the levels of the gene's product, the GATA2 transcription factor. This transcription factor is critical for the embryonic development, maintenance, and functionality of blood-forming, lympathic-forming, and other tissues. The syndrome includes as its primary symptoms: serious abnormalities of the blood such as the myelodysplastic syndrome and acute myeloid leukemia; lymphedema of the lower limbs, and sensorineural hearing loss. However, the anomalies caused by GATA2 mutations are highly variable with some individuals showing little or no such symptoms even in old age while others exhibit non-malignant types of hematological anomalies; lymphedema in areas besides the lower limbs, little or no hearing loss; or anomalies in other tissues. The syndrome may present with relatively benign signs and/or symptoms and then progress rapidly or slowly to the myelodysplastic syndrome and/or acute myeloid leukemia. Alternatively, it may present with one of the latter two life-threatening disorders.

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.

References

  1. ↑ "Bone Marrow Failure In Children - What You Need to Know". www.drugs.com. Archived from the original on 2018-06-25. Retrieved 2017-01-31.
  2. ↑ Peslak SA, Olson T, Babushok DV. Diagnosis and Treatment of Aplastic Anemia. Curr Treat Options Oncol. 2017 Nov 16;18(12):70. doi: 10.1007/s11864-017-0511-z. PMID: 29143887; PMCID: PMC5804354.
  3. ↑ "Bone Marrow Failure In Children". Thomson Reuters (2011): 1-5. Archived from the original on 25 June 2018. Retrieved 7 Nov 2011.
  4. ↑ Ciangola G, Santinelli E, McLornan DP, Pagliuca S, Gurnari C. Diagnostic evaluation in bone marrow failure disorders: what have we learnt to help inform the transplant decision in 2024 and beyond? Bone Marrow Transplant. 2024 Apr;59(4):444-450. doi: 10.1038/s41409-024-02213-6. Epub 2024 Jan 30. PMID: 38291125.
  5. ↑ Narumi S. Discovery of MIRAGE syndrome. Pediatr Int. 2022 Jan;64(1):e15283. doi: 10.1111/ped.15283. PMID: 35972063.
  6. 1 2 Leguit, Roos J; Jan G. van den Tweel (2010). "The pathology of bone marrow failure" (PDF). Histopathology. 57 (5): 655–670. doi:10.1111/j.1365-2559.2010.03612.x. PMID   20727024. S2CID   1807526.
  7. ↑ Hall T, Gurbuxani S, Crispino JD. Malignant progression of preleukemic disorders. Blood. 2024 May 30;143(22):2245-2255. doi: 10.1182/blood.2023020817. PMID: 38498034; PMCID: PMC11181356.
  8. ↑ "Aplastic Anemia". Health and Wellness Magazine. 12 December 2010.
  9. 1 2 3 4 MDS Foundation. "What is MDS?". Myelodysplastic Syndromes Foundation.
  10. 1 2 3 4 Nagalla, Srikanth (19 July 2021). "Bone Marrow Failure". Medscape.
  11. ↑ Nakao, Shinji (7 January 2023). "Diagnosis of immune pathophysiology in patients with bone marrow failure". International Journal of Hematology. doi:10.1007/s12185-022-03519-1.
  12. ↑ Voit, R.A., Sankaran, V.G. MECOM Deficiency: from Bone Marrow Failure to Impaired B-Cell Development. J Clin Immunol 43, 1052–1066 (2023). https://doi.org/10.1007/s10875-023-01545-0
  13. ↑ Blanche, Alter (January 2018). "Cancer in the National Cancer Institute Inherited Bone Marrow Failure Syndrome Cohort After Fifteen Years of Follow-Up". Hemaematologica - Via MEDLINE (EBSCO).
  14. 1 2 3 4 Moore, Christine (January 2019). "Bone Marrow Failure". StatPearls.
  15. ↑ Ashraf, Malouf (May 2018). "Comparison of a therapeutic-only versus prophylactic platelet transfusion policy for people with congenital or acquired bone marrow failure disorders (Review)". Cochrane Database of Systematic Reviews.
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