Bone marrow disease anemia

Aplastic Anemia & Myelodysplastic Syndromes

What are aplastic anemia and myelodysplastic syndromes (MDS)?

Aplastic anemia and myelodysplastic syndromes (MDS) are rare and serious disorders that affect the bone marrow and blood. Bone marrow is the soft, spongelike tissue inside the bones. Bone marrow makes stem cells that develop into one of the three types of blood cells—red blood cells, white blood cells, or platelets. Red blood cells contain hemoglobin, an iron-rich protein that gives blood its red color and carries oxygen from the lungs to all parts of the body. White blood cells help the body fight infections. Platelets are blood cell fragments that stick together to seal small cuts or breaks on blood vessel walls and stop bleeding.

In both disorders, bone marrow does not produce enough healthy red or white blood cells or platelets. Too few functioning red and white blood cells can lead to fatigue and infection. Too few platelets can lead to spontaneous or uncontrolled bleeding.

Anemia most often describes a condition in which the number of red blood cells is less than normal, resulting in less oxygen carried to the body’s cells. In aplastic anemia, however, normal production of all blood cells slows or stops. Blood cell production declines because bone marrow stem cells are damaged. The number of stem cells also declines because they are unable to replicate themselves. Although production of mature blood cells is seriously impaired in aplastic anemia, the few blood cells that mature and enter the bloodstream are normal.

In MDS, a shortage of bone marrow stem cells usually does not occur, as it does in aplastic anemia. However, the stem cells are defective and do not mature normally. Progenitor cells and immature blood cells are deformed and fail to develop into healthy, mature red or white blood cells or platelets. These cells often die in the bone marrow. Many of the blood cells that do enter the bloodstream do not survive or function normally. Some forms of MDS are prone to develop into leukemia, an aggressive blood cancer.

Blood Cell Production

All three types of blood cells begin as unspecialized stem cells. Stem cells divide and produce more stem cells or can evolve through a series of stages into mature, specialized blood cells of any type. Early in the maturation process, progenitor cells emerge from stem cells. Unlike stem cells, progenitor cells are committed to develop into only one blood cell type and evolve into mature red or white blood cells or platelets.

Who has aplastic anemia and MDS?

Young adults ages 20 to 25 years and people older than 60 years are most likely to have aplastic anemia.1 Men and women are equally affected. Most new cases in children are due to inherited bone marrow failure syndromes, caused by abnormal chromosomes. About four out of every 1 million people in the United States get aplastic anemia each year.2

MDS affect more than 15,000 people in the United States each year.3 Researchers consider this number an underestimation resulting from challenges in classifying and reporting the syndromes. MDS are typically diagnosed between the ages of 70 and 80 years.3

What causes aplastic anemia and MDS?

Although a cause is not found in most cases of aplastic anemia and MDS, the diseases may be triggered by exposure to

  • chemotherapy
  • radiation therapy
  • high levels of ionizing radiation—the type produced by high-power x-ray machines and in nuclear power plants
  • benzene, a chemical used in some manufacturing processes
  • toxic chemicals found in some pesticides
  • certain viral infections

In most cases of aplastic anemia, these triggers, or other unknown causes, provoke the body’s own immune system to destroy the bone marrow stem cells. Certain rare, inherited bone marrow failure syndromes can also lead to aplastic anemia and MDS.

What are the symptoms of aplastic anemia and MDS?

Symptoms may include

  • fatigue
  • weakness
  • excessive bleeding, such as from external injuries or operations
  • pinpoint red spots on the skin caused by bleeding from small blood vessels
  • easy bruising
  • frequent infections
  • fevers
  • pale skin
  • shortness of breath

Symptoms vary depending on the person and the severity and type of disease. MDS often do not cause symptoms at first. Many of these symptoms also resemble those of other illnesses, making diagnosis difficult.

How are aplastic anemia and MDS diagnosed?

In addition to a medical history and physical exam, health care providers use blood tests, a bone marrow biopsy, and cytogenic analysis to diagnose aplastic anemia or MDS. A health care provider may refer a person to a hematologist—a doctor who treats diseases or disorders of the blood. A person also may be referred to an oncologist—a doctor who treats cancer—because aplastic anemia and MDS may be related to bone marrow cancers.

Blood tests. A blood test involves drawing a person’s blood at a health care provider’s office or a commercial facility and sending the sample to a lab for analysis. A complete blood count is usually the first test a health care provider uses to detect aplastic anemia or MDS. The test includes measurement of a person’s hematocrit, the percentage of the blood that consists of red blood cells. A complete blood count also measures

  • the amount of hemoglobin in the blood
  • whether a person has a lower-than-normal number of red blood cells
  • whether a person has enough iron
  • the number of white blood cells and platelets in the blood

Lower-than-normal numbers of one or more blood cell types may suggest aplastic anemia or MDS.

In another test called a peripheral blood smear, the health care provider examines a sample of blood with a microscope for unusual changes in the size, shape, and appearance of the blood cells. These cells usually appear normal in aplastic anemia; however, they may be abnormal in MDS.

A health care provider also may order blood tests to check for a shortage of folate, vitamin B12, and erythropoietin—a hormone made in the kidneys that stimulates the production of red blood cells.

Bone marrow biopsy. A health care provider needs results from a bone marrow biopsy to confirm the diagnosis of aplastic anemia or MDS. A biopsy is a procedure that involves taking a small piece of bone marrow, blood, and a small piece of bone for examination with a microscope. A health care provider performs the biopsy during an office visit or in a hospital and uses light sedation and local anesthetic. During the biopsy, the health care provider inserts a needle into the hip bone or breastbone. A pathologist—a doctor who specializes in diagnosing diseases—analyzes the bone marrow samples in a lab. The test can show abnormal cells, the number and type of blood progenitor cells, and levels of iron in the bone marrow.

Cytogenic analysis. This test involves sending the person’s bone marrow samples from the biopsy to a lab where a pathologist examines them with a microscope to look for abnormal changes in the person’s chromosomes.

How is aplastic anemia treated?

People with mild or moderate aplastic anemia may not need treatment at first. However, people with severe aplastic anemia need immediate medical treatment to prevent or reverse complications from having low blood cell levels. Treatment options, which a health care provider may use alone or in combination, include

  • blood and bone marrow stem cell transplants, which require chemotherapy and radiation therapy
  • medications
  • blood transfusions

Treatment options depend on the age and general health of the person and the severity of the disease.

Blood and bone marrow stem cell transplants. Blood and bone marrow stem cell transplants, also called stem cell transplants, replace damaged stem cells in bone marrow with healthy stem cells from a donor’s blood or bone marrow and can cure aplastic anemia. Treatment guidelines state that stem cell transplant is the best treatment for people younger than 40 who have an available donor whose blood and bone marrow cells have been tested and found to “match” those of the patient.4 Stem cell transplants in people older than 40 are possible; however, long-term survival rates are lower.4 Older adults are generally less able to tolerate the treatments used to prepare the body for transplant and are more likely to develop severe posttransplant complications.

A health care provider confirms a matching donor by using a blood test called human leukocyte antigen tissue typing. Human leukocyte antigens are proteins found on the surface of white blood cells.

If health care providers do not find a matching donor in a person’s family, they will search the National Marrow Donor Program to look for other sources of stem cells for a transplant. Millions of volunteer donors are registered to provide a potential match. Health care providers look for

  • donors who are a match and not family members
  • family members who are close matches, although not exact
  • unrelated donors who are close matches, although not exact
  • umbilical cord blood that is a match

Umbilical cord blood collected from an umbilical cord and a placenta after a baby is born is frozen and stored at a cord blood bank for future use. Some people donate umbilical cord blood to a public cord blood bank, while others pay to store it at a private bank.

Before the transplant, a health care provider uses chemotherapy and sometimes radiation therapy to destroy a person’s own damaged bone marrow cells. These therapies also suppress a person’s immune system to prevent it from attacking the new stem cells after the transplant.

Chemotherapy and Radiation Therapy

Chemotherapy. Chemotherapy is a treatment that uses medications to stop the growth of immature blood cells, either by killing the cells or stopping them from dividing. A person can take chemotherapy medications by mouth or have them injected into cerebrospinal fluid or a vein, a muscle, an organ, or a body cavity, such as the abdomen. High doses can cause side effects such as nausea, vomiting, diarrhea, and fatigue. Treatment takes place in a hospital or chemotherapy treatment center. People may take oral chemotherapy medications at home. A team of health care providers, such as an oncologist and an oncology nurse, cares for people undergoing chemotherapy. A patient does not need anesthesia.

Radiation therapy. Radiation therapy is a treatment that uses external beams of either small doses of radiation over a period of time or a single, precise, high dose of radiation. Treatment takes place in a hospital or radiation treatment center. A team of health care providers, including a radiation oncologist—a doctor who specializes in treating tumors or cancer with radiation—cares for people receiving radiation therapy. Most people cannot feel radiation and do not require anesthesia. Side effects may include fatigue and skin sensitivity around the area being treated.

In a hospital, health care providers remove stem cells from the donor and freeze them for storage. If the donor stem cells are coming from the blood, the blood is removed from a large vein in the donor’s arm or through a central venous catheter, a flexible tube that is placed in a large vein in the neck, chest, or groin area. The blood goes through a machine that removes the stem cells. The blood is then returned to the donor and the health care provider stores the collected cells. If the donor stem cells are coming from the bone marrow, the health care provider will insert a hollow needle into the donor’s pelvis to withdraw the marrow. This procedure occurs in a hospital with local or general anesthesia and is less common.

After receiving chemotherapy or radiation therapy, a person receives the thawed donor stem cells through an intravenous (IV) line, a needle in a vein, or a central venous catheter. The stem cells then travel to the bone marrow where they re-establish and maintain normal blood cell production. The person may be given medication to relax. The transplant will take an hour or longer to complete. The catheter will stay in place for at least 6 months after the transplant, and the person will stay in the hospital from several weeks to months to ensure the transplant is successful. During this time, a person may easily develop an infection due to a weak immune system.

Stem cell transplants carry risks. A person’s immune system may attack the donated stem cells, called graft failure. Donated stem cells can attack the recipient’s body, called graft-versus-host disease. Both of these complications can be life threatening.

Read more in Bone Marrow Transplantation and Peripheral Blood Stem Cell Transplantation at www.cancer.gov.

Medications. Health care providers often prescribe one or more immunosuppressive medications, which suppress the immune system and reduce damage to bone marrow cells. Medications such as antithymocyte globulin may let the marrow start making blood cells again and reduce or eliminate the need for transfusions. In some people, blood counts return to normal. These medications are the preferred form of treatment for adults with severe aplastic anemia older than 40, younger patients who do not have a matched stem cell donor, and people with aplastic anemia who depend on blood transfusions.5 Taking these medications alone usually does not result in a cure. Health care providers often prescribe corticosteroid medications to limit the side effects of immunosuppressants such as antithymocyte globulin and cyclosporine.

A person also may be given a man-made version of erythropoietin or a growth factor therapy that stimulates white blood cell production.

If infections due to low white blood cell counts occur, a health care provider may give the patient medications to kill bacteria, fungi, or viruses.

Health care providers often treat people with mild, inherited forms of aplastic anemia with man-made forms of androgens—male sex hormones that stimulate blood production. Androgens can help improve blood counts; however, they are not a cure.

Blood transfusions. A blood transfusion is a procedure in which a person receives healthy blood cells from a donor with the same blood type through an IV line. A health care provider performs the procedure during an office visit or in a hospital. The procedure lasts 1 to 4 hours, depending on how much blood the patient needs. Transfusions of red blood cells or platelets can raise blood cell counts and relieve symptoms. Transfusions are not a cure.

Most people with aplastic anemia need repeated transfusions, which can lead to complications. Over time, the body may develop antibodies that damage or destroy donor blood cells. Iron from transfused red blood cells can build up in the body and damage organs unless the health care provider prescribes medications called iron chelators to remove extra iron. Health care providers avoid giving a transfusion before a blood and bone marrow stem cell transplant because it increases the chances that the transplant will fail.

How are MDS treated?

Treatment options for MDS, which a health care provider may use alone or in combination, include supportive care, medications, chemotherapy, and blood and bone marrow stem cell transplants. Treatment options depend on the following:

  • age and general health of the person
  • whether the health care provider classifies MDS as a lower-risk or higher-risk disease
  • whether the MDS occurred after chemotherapy or radiation therapy for another disease
  • whether the MDS has worsened after being treated.

Supportive care. Traditionally the first line of treatment, supportive care aims to manage the symptoms of the disease. This approach may include blood transfusions to help problems caused by low blood cells counts, such as fatigue and infections, and may also include growth factor therapy.

Medications. A health care provider may give immunosuppressive medications such as lenalidomide (Revlimid) and antithymocyte globulin with or without cyclosporine to help the bone marrow function more normally. A person may need an iron chelator to treat too much iron in the blood. Some people also may benefit from erythropoietin. A health care provider may also give medications to fight infections with bacteria, fungi, or viruses.

Chemotherapy. A health care provider may give chemotherapy in an effort to destroy defective blood progenitor cells in severe MDS and let the few remaining normal blood stem cells re-establish normal blood cell production. Chemotherapy medications may include azacitidine (Vidaza), decitabine (Dacogen), or other anticancer medications. This approach is often not effective over the long term. A health care provider may also use chemotherapy prior to stem cell transplants.

Blood and bone marrow stem cell transplants. In the past, only a stem cell transplant with a matched sibling donor offered a cure for MDS. However, experts have made much progress with transplants from unrelated matched donors, including unrelated umbilical cord blood transplantation. In the past, health care providers did not routinely perform blood and bone marrow stem cell transplants for older adults with MDS. However, health care providers who are using newer techniques that use a less toxic pre-transplant regimen are performing successful blood and bone marrow stem cell transplants in this age group.

Eating, Diet, and Nutrition

Eating, diet, and nutrition have not been shown to play a role in preventing or treating aplastic anemia and MDS. However, people with either disorder who receive a stem cell transplant need to eat a healthy diet to help with their recovery. A person also may need to avoid some foods to lower the chances of infection while the immune system is still weak. A health care provider will advise a person on which specific foods to eat or avoid and when it is safe to eat in a restaurant. When dining out, stem cell transplant recipients should avoid foods that may be spoiled or not cleaned thoroughly, such as those at buffets or salad bars, to prevent infection.

Some people may not feel hungry, or medication side effects may make eating difficult or painful. Many people also may have nausea, diarrhea, or vomiting. People may need to eat or drink a nutritional supplement in the form of a shake or pudding. Eating foods high in potassium and magnesium will help replace these minerals if they are lost from diarrhea and vomiting. A health care provider also may suggest a person eat a diet high in phosphorus and calcium to strengthen and maintain bone health. Eating smaller, more frequent meals can help with nausea. Drinking enough water and other fluids daily is also important.

Stem cell transplant recipients may need to avoid alcohol to prevent reduced liver function. They may also need to avoid sodium, often from salt, to prevent high blood pressure and swelling.

Clinical Trials

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and other components of the National Institutes of Health (NIH) conduct and support research into many diseases and conditions.

What are clinical trials, and are they right for you?

Clinical trials are part of clinical research and at the heart of all medical advances. Clinical trials look at new ways to prevent, detect, or treat disease. Researchers also use clinical trials to look at other aspects of care, such as improving the quality of life for people with chronic illnesses. Find out if clinical trials are right for you.

What clinical trials are open?

Clinical trials that are currently open and are recruiting can be viewed at www.ClinicalTrials.gov.

What Is Multiple Myeloma?

Myeloma develops and grows in the bone marrow. The disease can suppress the bone marrow’s ability to make new blood cells (myelosuppression, or bone marrow suppression). Many of the drugs used to treat multiple myeloma can cause myelosuppression as well.

What Is Myelosuppression?

It is a decrease in bone marrow activity that results in

  • fewer red blood cells (anemia)
  • fewer white blood cells (neutropenia)
  • fewer platelets (thrombocytopenia)

The risk of myelosuppression varies with each medication. Managing side effects can

  • reduce your discomfort
  • prevent serious complications
  • allow you to receive the best treatment for your disease

To manage symptoms of myelosuppression, your healthcare provider may change your medication dose or schedule. Do not stop or adjust medications without discussing it with your healthcare provider.

Learn more about anemia, low red blood cell or low hemoglobin count.

Neutropenia

Neutrophils are a type of white blood cell. They make up about 60% of the immune system’s cells. Neutrophils provide defense against fungal and bacterial illnesses.

Neutropenia is a decrease in the number of these neutrophils. Thus, the greatest concern with neutropenia is infection.

If you experience symptoms of infection, contact your healthcare provider immediately. Infection in a multiple myeloma patient can be lethal. Do not ignore any of the following possible symptoms:

  • Fever of 100.5°F (38°C) or higher
  • Shaking chills
  • Dizziness
  • Fainting
  • Redness at a wound site
  • Difficulty breathing
  • Cough
  • Sinus congestion
  • Sore throat
  • Mouth sores

Your physician will check your blood counts. She or he may prescribe antibiotics to prevent infections as well as growth factors to stimulate white blood cell growth.

Some Tips on How to Reduce Your Risk of Infection

While these tips may be obvious, here is a quick reminder:

  • Wash your hands often.
  • Avoid crowds.
  • Take antibiotics as prescribed by your healthcare provider.

Thrombocytopenia

Thrombocytes are platelets, or the blood cells that help to clot the blood after an injury. Thrombocytopenia is a decrease in these platelets. It is often a side effect of treatment with proteasome inhibitors such as Velcade® (bortezomib), Kyprolis® (carfilzomib), and Ninlaro® (ixazomib). If you experience signs of thrombocytopenia, contact your healthcare provider immediately.

Symptoms include:

  • Bruising
  • Pink urine
  • Nosebleeds
  • Small red or purple spots on the body (petechiae)
  • Bleeding that does not stop with pressure

Your physician will monitor blood counts. She or he may make changes in the choice, dosing, or scheduling of your medications or other treatments. If necessary, your doctor may prescribe a platelet transfusion.

How to Reduce Your Risk of Bruising or Bleeding

  • Do not take aspirin, ibuprofen, or naproxen.
  • Avoid activities that can cause bruising or bleeding.

Discussion

The results of this study indicate that, in elderly subjects, SF tests have a different diagnostic ability according to the cutoff levels. In the present study, the optimal SF with a cutoff point of 100 ng/mL yielded the highest sensitivity and specificity for the diagnosis of IDA in subjects aged 60 years and older. Based on this study, SF of less than 100 ng/mL identified 51% of patients who had transferrin saturation <15%, whereas SF >100 ng/mL identified 74% of subjects without IDA indicating a higher negative predictive value compared to the positive predictive value. This suggests that in elderly subjects SF levels >100 ng/mL compared with <100 ng/mL yield greater ability to exclude rather than confirm IDA.

This study found different diagnostic properties across various SF levels. Compared to the cutoff level of 100 ng/mL, cutoffs of 18 ng/mL, 45 ng/mL and 60 ng/mL yielded greater positive predictive values as well as positive likelihood ratios but lower sensitivity for the diagnosis of IDA (Table 3).

O ff levels of 45 and 60 ng/mL yielded comparable diagnostic properties, levels ≤18 ng/mL compared with other cutoff points exhibited higher specificity and likelihood ratio but lower sensitivity.

Overall, by increasing SF cutoff levels, the sensitivity and the negative predictive value of this test in the diagnosis of IDA increases at the expense of decreasing specificity and the positive predictive value.

In the present study, the mean SF in patients with IDA was higher than 100 ng/mL, whereas in a study of apparently healthy 80-year-old Danish men and women, the median SF value was 100 ng/mL in men and 78 ng/mL in women. In 9% of these subjects, the SF levels were >300 ng/mL.23 In a study of 73 patients with anemia and chronic diseases by Coenen et al., SF concentrations of less than 70 ng/mL were always indicative of IDA.24 In patients with inflammatory disease such as rheumatoid arthritis, iron deficiency anemia may develop at higher levels of SF and so the cutoff point is expected to be higher.25 The results of a systematic review suggest that further investigations are needed on the diagnosis of IDA in conditions with SF concentrations lower than 100 ng/mL.26

The results of another study of anemic veterans with a wide variety of general medical comorbidities were partly similar to this study. The study found a sensitivity of 64.9% with SF ≤100 ng/mL and a specificity of 96.1% to detect patients with IDA.27

The cutoff points for SF in patients with IDA in previous studies vary from 12 to 100 ng/mL.7,23,24,27 In a randomly selected sample of 38-year-old women, SF <16 ng/mL was the best cutoff level to differentiate patients with and without iron deficiency with a sensitivity of 75% and specificity of 98%; the iron stores began to disappear at SF levels from 25 to 40 ng/mL.7 However, compared to the current study the age of patients was lower.

In another study of elderly patients, SF measurement was the best diagnostic test to discriminate patients with and without IDA. In this study, the likelihood of diagnosis of IDA in cases with SF from 18 to 45 ng/mL was 3.12 and in those with less than 18 ng/mL, it was 41.47, with a negative predictive value of 72%.22

This study indicates that, in elderly people, SF has less diagnostic ability compared to percent of transferrin saturation. In a study of 49 consecutive subjects aged 80 years or more with IDA as confirmed by bone marrow aspiration, correct diagnosis by SF, serum iron and percent of transferrin saturation was possible in only 16.3%.28

Variations in the diagnostic ability of SF to diagnose IDA across various studies may be attributed to factors such as the diagnostic criteria applied for IDA, characteristics of the study patients, and the prevalence of comorbidities in the study patients.6,7,22,24-32 The presence of comorbidities in the study population, particularly in older subjects, is associated with elevated levels of acute phase proteins including ferritin and thus may affect the cutoff level and change the results.

In a study of patients in the general practice aged 65 years and older, 23% suffered from at least one chronic disease with 15% suffering from more than one chronic disease such osteoarthritis, diabetes, chronic obstructive pulmonary disease, coronary artery disease, hypertension and diabetes.18 In another study, 82% of aged Medicare beneficiaries had one or more chronic conditions and 65% had multiple chronic conditions.17 About 82% of the participants aged 65-84 years of the 2003 National Sleep Foundation study reported one or more of 11 medical conditions and nearly 25% of respondents had four or more conditions such as obesity, arthritis, diabetes, lung disease, stroke and osteoporosis.19 In the present study hypertension, urinary incontinency, diabetes and chronic lung disease were found in significant proportions of patients in both groups. Most chronic medical conditions particularly diabetes, urinary incontinency and chronic lung disease are associated with inflammatory processes.10,11,13-16,20,21 The prevalence of both general and abdominal obesity increases with aging.13,14 Obesity is associated with inflammation and there is a positive correlation between the body mass index and SF.33

The limitations of this study should be considered. One major limitation is the lack of bone marrow aspiration for definitive diagnosis of iron deficiency anemia. Although absence of iron in the bone marrow is considered the gold standard diagnostic test for diagnosis of IDA, the lack of iron stores in the bone marrow aspirate is not necessarily predictive of IDA.34 In a retrospective study of 12 patients with depleted iron stores, iron deficiency was the cause of anemia only in 50% of the patients.34 However, Klantar-Zadeh et al. reported high sensitivity and specificity of the percent of transferrin saturation test in the diagnosis of IDA in chronic renal disease with inflammatory conditions.35 Another limitation is related to lack of data concerning the assessment of serum C-reactive protein and other measures of inflammation to show the existence of inflammatory processes. However, the high prevalence of diabetes, chronic lung disease and urinary incontinence even in the control group indicates that there were chronic comorbidities in the elderly people, and consequently inflammatory processes are common.

The strength of this study is related to the study sample which included all participants of the Almirkola Cohort Study that enrolled all the inhabitants of Amirkola, a small town in northern Iran. Another strength is related to the homogeneity of the study population in respect to demographic features, lifestyle and ethnicity.

The clinical significance of these findings is related to the incapability of the SF test as a measure to identify IDA in elderly people. These findings suggest that SF levels in many elderly subjects with IDA may be normal or higher than normal, and thus SF using conventional cutoff levels is not a reliable measure in the diagnosis of absolute IDA.

Bone-Marrow Diseases and Anemia

Anemia, a condition in which the blood is either low in total volume or is deficient in red blood cells or hemoglobin, can occur for several reasons. Among the more serious causes of anemia are bone marrow diseases.

One bone marrow disease, bone cancer, may be the result of a malignant tumor of the bone or cancer that has spread, or metastasized, from another area of the body to the bone. Bone cancer can destroy bone marrow tissue and the body’s ability to manufacture red blood cells, thereby causing anemia.

Other non-cancerous bone marrow conditions can lead to decreased ability to manufacture normal blood cells. The three most common bone marrow diseases in this category are:

  • Myelodysplastic syndromes (MDS). In myelodysplastic syndromes, something goes wrong at the stem cell level in the bone marrow, says Adetola Kassim, MD, an assistant professor of medicine and a hematologist/oncologist at Vanderbilt University Medical Center in Nashville. “This results in too many defective blood cells,” says Dr. Kassim. Those with MDS may have low counts for platelets, red blood cells, white blood cells, or all three.
  • Aplastic anemia. With this type of anemia, the body does not make enough red and white blood cells and platelets. In severe cases of aplastic anemia, the body totally stops production of these cells.
  • Paroxysmal nocturnal hemoglobinuria (PNH). In PNH, abnormal stem cells in the bone marrow produce defective red blood cells. The bone marrow then becomes prone to destruction by the immune system, which recognizes that these defective cells are not normal. “Defective bone marrow cells lead to more profound anemia,” Kassim says.

Other bone marrow diseases that result in patients becoming anemic include leukemia and myelopropliferative disorders (MPD). Leukemia is cancer of the white blood cells, and MPD causes increased production of immature bone marrow cells, which can crowd out production of new, healthy red blood cells.

Bone-Marrow Disease Anemia Risk Factors

Myelodysplastic syndromes, which affect 10,000 to 15,000 people in the United States annually, occur more frequently in older people, with an average age at diagnosis of 70. Only about 3 out of every 1 million people in the United States are diagnosed with aplastic anemia every year, as opposed to 15 out of every 1 million new cases each year in eastern Asia. Paroxysmal nocturnal hemoglobinuria is also more prevalent in Asia and Mexico than in the United States.

For most patients with a bone marrow disease, the cause of the illness is unknown. Risk factors for MDS include smoking, exposure to radiation and benzene, and past treatment with certain chemotherapy drugs. Additionally, myelodysplastic syndromes are more likely to occur in men.

“Aplastic anemia may be congenital, or develop from Franconi anemia, an inherited disorder,” says Kassim. “External radiation, viral infections such as hepatitis and HIV, and certain medications such as gold and sulfonamides may also cause aplastic anemia.”

“PNH is acquired, not inherited,” Kassim explains. About 30 percent of people with aplastic anemia also develop paroxysmal nocturnal hemoglobinuria.

Treatments for Bone-Marrow Disease Anemia

Supportive care is usually the first line of treatment for bone marrow disease anemia, and this care relieves symptoms but does not cure the disease. Supportive care includes the following:

  • Blood transfusions to relieve anemia symptoms
  • Platelet transfusions to lower the risk of bleeding and bruising
  • Iron and folic acid supplements
  • Growth factor drugs such as epoetin alfa (Procrit) to stimulate production of blood cells
  • Following strict infection prevention procedures, (avoiding crowds and regular hand washing)

Specific disease treatment is as follows:

  • Myelodysplastic syndromes: The medications available for treating MDS are Vidaza (azacitidine), Dacogen (decitabine), Revlimid (lenalidomide), Kassim says, although overall responses to these drugs have not been great. “Once MDS progresses to leukemia, only a stem cell transplant will work,” he says.
  • Aplastic anemia: Immunosuppressive therapy to suppress or weaken the immune system is used to treat aplastic anemia. A bone marrow transplant may also benefit people with aplastic anemia. “Immunosuppressants are a less risky treatment,” says Kassim. “They help restore bone marrow and minimize risks if the patient does have a bone marrow transplant.”
  • Paroxysmal nocturnal hemoglobinuria: Immunosuppressants are also used to treat PNH, but other types of medications are becoming available. “The breakthrough drug is Soliris (eculizumab), which helps control PNH, but it is not curative,” says Kassim. A recent study showed that hemoglobin levels stabilized in almost 50 percent of people with PNH who received treatment with Soliris, compared with none of the patients who did not receive Soliris. Patients who received Soliris also did not need as many red blood cell transfusions as those who didn’t take the drug. While the results are promising, Kassim says researchers have not yet found a cure for PNH. “Without a bone marrow transplant, the PNH patient will eventually die from complications.”

Leukemia can be treated with chemotherapy or radiation. If leukemia is unresponsive to such treatment, a bone marrow transplant may also be an option.

Bone-Marrow Disease Anemia and the Link to Blood Cancer

The prognosis for bone marrow disease is not encouraging — myelodysplastic syndromes, aplastic anemia, and paroxysmal nocturnal hemoglobinuriacan each progress to blood cancer. “The rate of progression depends on the type of defect in the bone marrow,” says Kassim. “About 50 percent of MDS cases lead to leukemia.”

Additionally, aplastic anemia patients are at risk for bleeding or serious and even deadly infections. For pregnant women with PNH and their fetuses, there is a high rate of mortality during pregnancy and immediately after delivery.

Researchers continue to focus on new drugs to treat bone marrow diseases and the related anemia. Kassim says there are many promising drugs in the pipeline, which may bring a brighter future to those with bone marrow disease.

Medically reviewed by Akiko Shimamura, MD, PhD

Bone marrow failure occurs when the bone marrow – the soft, spongy center of the bones – fails to produce enough healthy blood cells to keep up with the body’s needs. Bone marrow is the site where all blood cells are produced. These include red blood cells, which carry oxygen throughout the body via the protein hemoglobin, white blood cells, which fight infection, and platelets, which help blood to clot.

Scanning electron micrograph of human red blood cells, monocyte white blood cells (orange), activated platelets (teal), and fibrin thread (bright blue) against a background of serum proteins.

Depending on the types of blood cells that are comprised, bone marrow failure manifests in different ways. Many conditions may cause bone marrow failure, but in about 30 percent of cases, no specific cause is identified. Bone marrow failure can be inherited or acquired after birth.

The most common cause of acquired bone marrow failure in children and adults is acquired aplastic anemia. When the bone marrow’s hematopoietic stem cells are damaged, the body cannot make enough red, white, or platelet blood cells. Acquired aplastic anemia differs from another disorder similar to bone marrow failure, called myelodysplastic syndromes (MDS), because even though the marrow fails to make enough blood cells, the few that are produced appear normal. With MDS, the bone marrow manufactures abnormal (dysplastic) cells that often have acquired chromosomal abnormalities. Both disorders are rare.

Some of the common inherited bone marrow failure syndromes are:

  • Fanconi anemia
  • Dyskeratosis congenital
  • Diamond Blackfan anemia
  • Shwachman Diamond syndrome
  • GATA2-related disorders
  • SAMD9/SAMD9L-related disorders

It is particularly important to think about inherited bone marrow failure in younger patients, as the major complications of these tend to develop with age. For example, it has been shown that Fanconi anemia can lead to aplastic anemia. Additionally, these disorders are associated with an increased risk of cancer, such as leukemia and solid tumor cancers.

How is bone marrow failure treated?

Depending on the type, there are many ways to treat bone marrow failure. Doctors sometimes provide supportive care, with treatments such as blood transfusions , to temporarily relieve symptoms. For example, a patient with thrombocytopenia, a condition characterized by abnormally low levels of platelets, can receive injections of platelets intravenously to control bleeding.

Bone marrow failure can also be treated with stem cell transplant. Otherwise known as a bone marrow transplant, a stem cell transplant involves is the infusion of healthy blood stem cells into the body to stimulate new bone marrow growth and restore production of healthy blood cells. In one type of transplant, an allogeneic transplant, cells are collected from a tissue-matched donor, usually a brother or sister or an unrelated donor, whose human leukocyte antigens (HLA) are a compatible match.

Stem cells for transplant can come from the bone marrow or blood.

Before receiving the transplant, patients undergo conditioning therapy, which includes chemotherapy and/or radiation, to prepare the body for the transplant. The goal of the conditioning therapy is to remove the diseased bone marrow cells to make space for the new healthy ones to grow. The conditioning therapy also suppresses the immune system so that the body doesn’t reject the donor’s foreign stem cells. The transplant stem cells are infused into the blood through an IV.

It takes about two to four weeks for the new blood cells to grow – during this period, the immune system is still weak and the patient is highly susceptible to viral, bacterial, and fungal infections. Bone marrow failure disorders are often complicated to transplant, so patients, both old and young, benefit from care at a center highly experienced treating these disorders.

Learn more about treatment for bone marrow failure at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center.

Learn more about the Stem Cell Transplantation Program at Dana-Farber Cancer Institute.

Anemia

How is anemia diagnosed and evaluated?

Common symptoms of anemia include fatigue, irritability, headaches and difficulty concentrating. Your doctor may detect a heart murmur or a sudden drop in blood pressure when you stand.

A blood test will provide counts of your white blood cells, red blood cells and platelets. If you have anemia, more tests may determine its type and whether it has a serious cause. These tests may include:

  • A reticulocyte count to see if your bone marrow is making red blood cells at an accelerated rate (this is a sign of prior blood loss)
  • Serum iron and ferritin tests to check the amount of iron in your blood and body
  • A peripheral blood smear to see if your red blood cells are an abnormal shape
  • Hemoglobin electrophoresis to evaluate for abnormal hemoglobin, which is present in thalassemia and sickle cell disease
  • An osmotic fragility test to see if your red blood cells are more fragile than usual

Your doctor may use more tests to search for the cause of your anemia. If blood loss is a concern, your doctor may use endoscopy to examine your upper digestive system for signs of bleeding. You also may undergo colonoscopy to look for bleeding tumors, and other problems in the large intestine. Cell and bone marrow samples can supply clues to abnormal or lower red blood cell production.

You may undergo imaging exams to further evaluate certain causes of anemia. These may include:

  • Chest x-ray: Chest x-rays may rule out infection in anemia patients See the Radiation Dose in X-Ray and CT Exams Safety page for more information about x-rays.
  • General ultrasound: Ultrasound can find anemia-related problems without using radiation. These problems may include an enlarged spleen or uterine fibroids. Doppler ultrasound can also detect circulatory problems that suggest anemia in unborn babies.
  • Computed tomography (CT) – Abdomen and Pelvis: CT uses x-rays to image bones, internal organs, and lymph nodes. It can show an enlarged spleen or certain types of lymph node anemia-related problems. It also finds causes of bleeding, such as gastrointestinal malignancies. See the Radiation Dose in X-Ray and CT Exams Safety page for more information about CT.
  • Body magnetic resonance imaging (MRI): MRI finds bone and bone marrow disorders. It also can help assess iron concentration in the heart, liver, and other organs. This is particularly useful in patients with multiple blood transfusions and concern for iron overload. See the Magnetic Resonance Imaging (MRI) Safety page for more information about MRI.

All you need to know about bone marrow

A bone marrow transplant can be used for various reasons.

  • It can replace diseased, nonfunctioning bone marrow with healthy functioning bone marrow. This is used for conditions such as leukemia, aplastic anemia, and sickle cell anemia.
  • It can regenerate a new immune system that will fight existing or residual leukemia or other cancers not killed by chemotherapy or radiation.
  • It can replace bone marrow and restore its normal function after high doses of chemotherapy or radiation are given to treat a malignancy.
  • It can replace bone marrow with genetically healthy, functioning bone marrow to prevent further damage from a genetic disease process, such as Hurler’s syndrome and adrenoleukodystrophy.

Stem cells are primarily located in four places:

  • an embryo
  • bone marrow
  • peripheral blood, found in blood vessels throughout the body
  • cord blood, found in the umbilical cord and collected after birth9

Stem cells for transplantation are obtained from any of these except the fetus.

Hematopoietic stem cell transplantation involves the intravenous infusion of stem cells collected from bone marrow, peripheral blood, or umbilical cord blood.

This is used to re-establish hematopoietic function in patients whose bone marrow or immune system is damaged or defective.17

More than 50,000 first hematopoietic stem cell transplantation procedures, 28,000 autologous transplantation procedures, and 21,000 allogeneic transplantation procedures are performed every year worldwide, according to the first report of the Worldwide Network for Blood and Marrow Transplantation.

This number continues to increase by 10 to 20 percent annually. Reductions in organ damage, infection, and severe, acute graft versus host disease (GVHD) seem to be contributing to improved outcomes.

In a study of 854 patients who had survived at least 2 years after autologous hematopoietic stem cell transplantation (HSCT) for hematologic malignancy, 68.8 percent were still alive 10 years after transplantation.17

Bone marrow transplant is the leading treatment for conditions that threaten bone marrow’s ability to function, such as leukemia.

A transplant can help rebuild the body’s capacity to produce blood cells and bring their numbers to normal levels. Illnesses that may be treated with a bone marrow transplant include both cancerous and noncancerous diseases.

Cancerous diseases may or may not specifically involve blood cells, but cancer treatment can destroy the body’s ability to manufacture new blood cells.

A person with cancer will normally undergo chemotherapy before transplantation. This will eliminate the compromised marrow.

A matching donor, in most cases a close family member, then has their bone marrow harvested and readied for transplant

Types of bone marrow transplant

Types of bone marrow transplant include:

  • Autologous transplant: patients receive their own stem cells taken from their peripheral or cord blood to replenish bone marrow
  • Syngeneic transplant: patients receive stem cells from their identical twin
  • Allogeneic transplant: patients receive matching stem cells from their sibling, parent or an unrelated donor
  • Haploidentical transplantation: a treatment option for the approximately 70% of patients who do not have an HLA-identical matching donor
  • Umbilical cord blood: a type of allogeneic transplant. Stem cells are removed from a newborn baby’s umbilical cord right after birth. The stem cells are frozen and stored until they are needed for a transplant. Umbilical cord blood cells are very immature so there is less of a need for matching, but blood counts take much longer to recover.

Tissue type

A person’s tissue type is defined as the type of human leukocyte antigen (HLA) on the surface of most of the cells of their body. HLA is a protein or marker that the body uses to help it determine if the cell belongs to the body or not.

To check if the tissue type is compatible, doctors assess how many proteins match on the surface of the donor’s and recipient’s blood cells. There are millions of different tissue types but some are more common than others.

Tissue type is inherited, and types are passed on from each parent. This means a relative will be more likely to have a matching tissue type.

However, if a suitable bone marrow donor cannot be found from family members, doctors will try to find someone with a compatible tissue type on the bone marrow donor register.

Pre-transplant tests

Several tests are performed before the bone marrow transplant, to identify any potential problems.

Tests include:

  • tissue typing and a variety of blood tests
  • chest X-ray
  • pulmonary function tests
  • CT or CAT scans
  • heart function tests including an electrocardiogram and echocardiogram (ECG)
  • bone marrow biopsy
  • skeletal survey

In addition, a complete dental exam is needed before a bone marrow transplant, to reduce the risk of infection. Other precautions will also be taken before the transplant to reduce the patient’s risk of infection.

Harvesting bone marrow

Share on PinterestThe concentration of red marrow is highest in the bones of the hips (ilium). The doctor will insert a needle into the bone and withdraw some of the bone marrow, which is then stored and frozen.

Bone marrow can be obtained for examination by bone marrow biopsy and bone marrow aspiration.

Bone marrow harvesting has become a relatively routine procedure. It is generally aspirated from the posterior iliac crests while the donor is under either regional or general anesthesia.17

It can also be taken from the sternum, and from the upper tibia in children, because it still contains a substantial amount of red bone marrow.

The doctor will insert a needle into the bone, usually in the hip, and withdraw some of the bone marrow. It is then stored and frozen.

Guidelines established by the National Marrow Donor Program (NMDP) limit the volume of bone marrow removed to 15 mL/kg of donor weight. A dose of 1 X 103 and 2 X 108 marrow mononuclear cells per kilogram are required to establish engraftment in autologous and allogeneic marrow transplants, respectively.

Complications related to bone marrow harvesting are rare. They involve problems related to anesthesia, infection and bleeding.

Another way to evaluate bone marrow function is to give certain drugs that stimulate the release of stem cells from the bone marrow into circulating blood. The blood sample is then obtained, and stem cells are isolated for microscopic examination. In newborns, stem cells may be retrieved from the umbilical cord.

How is bone marrow transplanted?

Before the transplant, chemotherapy, radiation, or both may be given. This may be done in two ways:

  • Ablative (myeloablative) treatment: High-dose chemotherapy, radiation, or both are given to kill any cancer cells. This also kills all healthy bone marrow that remains, and allows new stem cells to grow in the bone marrow
  • Reduced intensity treatment, or a mini transplant: Patients receive lower doses of chemotherapy and radiation before a transplant. This allows older patients and those with other health problems to have a transplant.

A stem cell transplant is usually done after chemotherapy and radiation are complete.

The infusion of either bone marrow or peripheral blood is a relatively simple process that is performed at the bedside. The bone marrow product is infused through a central vein through an IV tube over a period of several hours. Autologous products are almost always cryopreserved; they are thawed at the bedside and infused rapidly over a period of several minutes.17

After entering the bloodstream, the hematopoietic stem cells travel to the bone marrow. There, they begin to produce new white blood cells, red blood cells, and platelets in a process known as engraftment. Engraftment usually occurs 2 to 4 weeks after transplantation.4

Minimal toxicity has been observed in most cases. ABO-mismatched bone marrow infusions can sometimes lead to hemolytic reactions. Dimethyl sulfoxide (DMSO), which is used for the cryopreservation of stem cells, may give rise to facial flushing, a tickling sensation in the throat, and a strong taste in the mouth (the taste of garlic). Rarely, DMSO can cause bradycardia, abdominal pain, encephalopathy or seizures, and renal failure.

To avoid the risk of encephalopathy, which occurs with doses above 2 g/kg/day of DMSO, stem cell infusions exceeding 500 mL are infused over 2 days, and the rate of infusion is limited to 20 mL/min.

Doctors regularly check blood counts. Complete recovery of immune function can take several months for autologous transplant recipients and 1 to 2 years for patients receiving allogeneic or syngeneic transplants.

Blood tests will confirm that new blood cells are being produced and that any cancer has not returned. Bone marrow aspiration can also help doctors determine how well the new marrow is working.4

Risks

Complications associated with HSCT include both early and late effects.17

Early-onset problems include:

  • mucositis
  • hemorrhagic cystitis
  • prolonged, severe pancytopenia
  • infection
  • GVHD (Graft versus host disease)
  • graft failure
  • pulmonary complications
  • hepatic veno-occlusive disease
  • thrombotic microangiopathy

Late-onset problems include:

  • chronic GVHD
  • ocular effects
  • endocrine effects
  • pulmonary effects
  • musculoskeletal effects
  • neurologic effects
  • immune effects
  • infection
  • congestive heart failure
  • subsequent malignancy

Major risks include increased susceptibility to infection, anemia, graft failure, respiratory distress, and excess fluid, which can lead to pneumonia and liver dysfunction.

A mismatch between donor and recipient tissues can lead to an immune reaction between cells of the host and cells of the graft.

When graft cells attack host cells, the result is a dangerous condition called graft-versus-host disease (GVHD), which may be acute or chronic and may manifest as a skin rash, gastrointestinal illness, or liver disease. The risk of GVHD can be minimized through careful tissue matching.

Even when a donor antigen match is identical, roughly 40 percent of recipients still develop GVHD, rising to 60 to 80 percent when only a single antigen is mismatched. Because of the danger of this complication, autologous transplants are more commonly performed.

Bone marrow transplantation was not previously recommended for patients aged over 50 years, due to a higher mortality and morbidity rate and an increased incidence of GVHD in those over the age of 30 years. However, many transplant centers have performed successful bone marrow transplantations in patients well beyond the age of 50 years.

There is little risk to those who donate, because they generate new marrow to replace that which has been removed. There is, however, a slight risk of infection and a reaction to anesthesia can occur with any surgical procedure.

Aplastic Anemia

Blood consists of blood cells floating in plasma. Plasma is mostly made of water. It also includes salts, proteins, hormones, minerals, vitamins and other nutrients and chemicals your body needs.

What are the 3 Basic Types of Blood Cells?

  • Red blood cells (RBCs) are also called erythrocytes. They make up almost half of blood. Red blood cells are filled with the protein hemoglobin that picks up oxygen in the lungs and brings it to cells all around the body.
  • White blood cells (WBCs) are also called leukocytes. They fight disease and infection by attacking and killing germs that get into the body. There are several kinds of white blood cells, each of which fights a different kind of germ.
  • Platelets are also called thrombocytes. They are small pieces of cells that help blood clot and stop bleeding.

How are Blood Cells Formed?

The process of making blood cells is called hematopoiesis. Blood cells are made in the bone marrow, a spongy tissue located inside certain bones. Marrow contains blood-forming stem cells that make copies of themselves to create all three types of blood cells. When blood cells are fully mature and functional, they leave the bone marrow and enter the bloodstream. Healthy people have enough stem cells to make all the blood cells they need.

What is Bone Marrow Failure?

Bone marrow failure happens when the marrow doesn’t produce enough red cells, white cells or platelets, or the blood cells that are produced are damaged or defective. This means the body can not supply itself with the blood it needs. Aplastic anemia, MDS and PNH are bone marrow failure diseases.

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