The field of hematology covers a wide spectrum of disorders. Some of these disorders are benign, meaning they resolve completely with therapy or do not cause symptoms and do not affect overall lifespan. Some are chronic and lifelong but again do not affect longevity. Some examples of these benign disorders are:
- Anemia due to chronic disease
- Iron deficiency anemia
- Autoimmune hemolytic anemia, an immune-mediated disease causing a low red blood cell count
- Idiopathic thrombocytopenic purpura (ITP), an immune-mediated disease causing a low platelet count
- Low blood counts (white count, red cell count, or platelet count) due to a drug reaction-for example, heparin-induced thrombocytopenia
- Low blood counts not due to medications but related to underlying medical conditions-for example, anemia of chronic disease, or low platelet count secondary to liver disease
- Thalassemia (mild)
- Hemophilia (mild)
- Von Willebrand’s disease
- Blood clots (not life-threatening)
- Monoclonal Gammopathy of Undetermined Significance (“MGUS”), a disorder of plasma cells causing abnormal proteins in the blood)
Other disorders of the blood are more serious in that they can cause chronic illness or are life-threatening:
- Sickle cell anemia
- Hemophilia (severe)
- Recurrent blood clots (thrombophilia)
- Myelodysplastic syndrome
- Myeloproliferative diseases (characterized by excessive production of blood cells in the bone marrow)
- Polycythemia vera-too many red cells
- Essential thrombocythemia-too many platelets
- Primary myelofibrosis-excess fibrous or scar tissue in the marrow
- Chronic myelogenous leukemia (CML)-excessive white cell production causing leukemia
- Acute leukemias
- Lymphocyte disorders
- Chronic lymphocytic leukemia
- Lymphoma-Hodgkin’s disease
- Plasma cell disorders
- Multiple myeloma
- Waldenström’s macroglobulinemia
- Heavy chain disease
Cancer Information: Classifying Hematological Disease
Another way to classify hematologic disease is whether it is inherited or acquired. For example, hemophilia, certain clotting disorders, thalassemia, and sickle cell anemia are inherited conditions, whereas most of the other disorders listed above are acquired. Inherited blood diseases are usually diagnosed in childhood, but if the individual is mildly affected, such a diagnosis may not be made until he/she reaches adulthood. For example, an abnormal laboratory finding may be discovered at the time of surgery when screening tests – an anemia or a clotting abnormality. These need to be evaluated to be sure the patient is not at increased risk for their operation.
What are the symptoms?
The symptoms of hematologic disease depend on many factors. Symptoms depend on which cell type is affected and how low or high the count. This is determined through a complete blood count (“CBC”). In anemia, there is a low number of red blood cells and therefore a decrease in oxygen delivered to tissues. Symptoms include: extreme fatigue, dizziness, loss of concentration, noise in the ear, shortness of breath with exertion, and fast heartbeat. In patients with impaired heart function, anemia can cause congestive heart failure. A low platelet count or thrombocytopenia can result in excessive bruising, red spots on the lower extremities, nose bleeds, bleeding from the mouth and gums, and blood in the urine or stools. Low numbers of white cells (leukopenia or neutropenia) can cause repeated bacterial infections.
When a particular blood count is only mildly decreased, it may not cause any symptoms whatsoever. However, an abnormal count can be a marker of an underlying bone marrow disorder or other medical condition, and therefore should be investigated. A patient with liver disease, for example, may have a large spleen and low blood counts, particularly thrombocytopenia. The platelet count is usually not low enough to cause serious bleeding, but it should trigger an investigation as to why the spleen is enlarged, whether from cirrhosis of the liver and portal hypertension, Gaucher’s disease, infection or lymphoma.
Other systemic diseases have effects on iron metabolism causing chronic anemias (known as the anemia of chronic disease). They can also suppress bone marrow, as in systemic lupus erythematosis and other chronic inflammatory conditions. In these conditions, the signs and symptoms of the underlying disease are usually more pronounced than those related to low blood counts.
Inherited disorders of hemoglobin, such as thalassemia and sickle cell anemia, cause a range of complications from mild to severe. In sickle cell disease, small blood vessels are sometimes blocked by red blood cells that have become deformed (“sickle”-shaped). Patients often have periodic pain episodes usually in the extremities and back, but occasionally in the abdomen. Although pain can be triggered by infection, surgery, weather changes, and even emotional stress, we usually don’t know what triggers a particular pain crisis. No matter what the cause, sickle cell pain and other complications are incapacitating, and lead to frequent hospitalization.
Just as inherited or acquired disorders can cause excessive bleeding, other inherited and acquired defects cause abnormal or excessive blood clotting. The coagulation system includes several important, naturally-occurring inhibitors of clotting, which if deficient or dysfunctional, lead to the formation of a blood clot. If the clot is in the veins just under the surface of the skin it’s called a superficial thrombophlebitis. If it’s in the deep venous system of the extremities, the diagnosis is a deep venous thrombosis or “DVT”. This results in painful swelling of the extremity (usually the leg) associated with redness and increased skin temperature. If the blood clot is not treated immediately with blood thinning medication, there is an increased likelihood that a portion of the clot will break off and travel up through the right side of the heart and into the lung. This is known as a pulmonary embolism. The symptoms consist of sudden, sharp chest pain, shortness of breath, dizziness, palpitations, and coughing (sometimes coughing up blood). If the embolus is massive, sudden cardiovascular collapse and death can occur.
Our clotting mechanism tends to become more active as we grow older, increasing the chances of having a DVT. Usually, there is some aggravating event that adds to a person’s risk of thrombosis. This can include surgery, prolonged immobility (bed rest, long automobile or plane trips), smoking and estrogens (oral contraceptives, hormone replacement therapy). When these factors are absent, or when a younger patient presents with an unexplained DVT, an inherited tendency towards thrombosis (thrombophilia) is suspected. This suspicion is further bolstered by a positive family history of blood clots, history of frequent miscarriage, or a blood clot occurring in an unusual location, such as the blood vessels of the abdomen, venous channels of the brain, or blood vessels in the eye. In these circumstances a laboratory work-up is indicated to try and identify the defect in one or more of the inhibitory coagulation proteins.
How is it diagnosed?
A hematologist uses physical examinations, the patient’s medical history and laboratory testing to assess hematological diseases. Whether the blood counts are too high or too low, one of the more common diagnostic dilemmas is separating a secondary or “reactive” phenomenon from a primary hematologic or bone marrow condition. Frequently a bone marrow biopsy will be needed for this purpose. This usually includes a study of the chromosomes (cytogenetics) and an examination of the surface proteins or receptors on the bone marrow cells (flow cytometry). The latter is a very sensitive test for ruling out a lymphoproliferative disorder, such as chronic lymphocytic leukemia or lymphoma. Other specialized testing is needed to rule out hemolysis or the rapid breakdown or destruction of red blood cells. Still further testing is required to look for the presence of organ problems (kidney, liver, lung, thyroid), connective tissue disorders (lupus erythematosis, rheumatoid arthritis), and cancer, all of which can have indirect effects on the bone marrow or blood.
Diagnosing coagulation disorders can be relatively straightforward or difficult. Not infrequently, a patient will have bleeding symptoms, but even after extensive testing no abnormalities can be identified. This can be frustrating for both patient and physician, especially when deciding whether or not it’s safe to proceed with surgery. This same scenario applies to disorders of excessive clotting, when patients have multiple episodes of thrombosis, yet no specific defect is uncovered after extensive testing. Despite these difficulties, coagulation medicine is an area of intense research and much progress has been made in just the last decade.
What are the treatment options?
Treatments vary depending on the type of disease, and can include simple observation, use of steroids and other immune-modulating therapies, transfusions or coagulation factor support, growth factor supplementation, complex chemotherapy and bone marrow transplantation. (See leukemia, myelodysplasia, lymphoma, bone marrow transplantation for more information.)
For chronic anemia, the underlying disease (infection, arthritis, heart, lung or kidney disease) is attended to, often improving the anemia. If that’s not possible and the patient’s anemia is causing symptoms, red blood cell transfusions may be necessary. Recombinant human erythropoietin can be given, weekly or biweekly, and usually indefinitely. The erythropoietins are also useful in other types of anemia in which there is an underproduction of red blood cells in the bone marrow, such as chemotherapy-induced anemia, myelodysplastic syndrome, and aplastic anemia. They are particularly useful in the anemia of kidney disease which is caused by an underproduction of erythropoietin in certain specialized cells of the kidney.
If nutritional deficiencies are the cause, oral iron tablets, vitamin B12 injections, or and oral folic acid may be prescribed.
For patients who have anemia due to autoantibodies against their own red cells (autoimmune hemolytic anemia), steroids suppress the immune system and interrupt red cell destruction. Prednisone given orally at moderately high doses is usually successful in slowing the process and increasing the hemoglobin level. However, steroids cannot be continued indefinitely without causing long-term side effects such as osteoporosis. The majority of patients respond, but in those who relapse, other agents such as intravenous immunoglobulin (IVIG), cyclophosphamide or cyclosporine are sometimes used. The spleen may need to be removed in some cases.
Sickle cell anemia often is difficult to treat. If an underlying cause of a sickle cell crisis (such as infection) can be identified, prompt treatment will lessen the severity or duration of the crisis. The management of a severe pain episode requires potent pain-relieving narcotic medications. Transfusions are frequently given for severe anemia that compromises normal heart and lung function or when patients are going into surgery. They are also used in children and adults who have had strokes, since it’s been demonstrated that regular transfusion or exchange transfusion prevents recurrence of stroke in patients with sickle cell disease. Unfortunately, chronic transfusion leads to problems with iron overload which results in the deposition of iron into the liver, heart and other sites, and this causes problems with those organs. We can use desferrioxamine or deferasirox (Exjade™) to help avoid these problems. Another drug, hydroxyurea, has been found to lessen the frequency and severity of sickle cell crises.
Thrombocytopenia (low platelet count)
Unlike anemia, there is no agent available that reliably increases the platelet count for conditions involving underproduction of platelets in the bone marrow. However, even a relatively low number of platelets may not require treatment because it does not cause life-threatening bleeding. In patients who have bone marrow conditions that result in severely low platelet counts or if severe thrombocytopenia and bleeding occur after chemotherapy, platelet transfusions must be given to either lessen the risk of bleeding or stop bleeding. Because transfused platelets do not last long in the circulation (average 3-4 days), and anti-platelet antibodies can develop upon repeated exposure to transfused or “foreign” cells, platelet transfusion is only used briefly to see the patient through a period of highest risk.
Patients who have autoantibodies against platelets may develop severe thrombocytopenia (idiopathic thrombocytopenic purpura or ITP). This requires therapy to interrupt the destruction of platelets or to suppress the immune system. The first treatment usually consists of steroids, but other therapies such as intravenous immunoglobulin (IVIG), anti-Rh antibody (WinRhoSD ), and rituximab (Rituxan ) have been used successfully. Splenectomy is used in selected cases, resulting in long-term periods of remission of the disease. New agents are being developed for ITP, and we are participating in clinical trials to test new medications.
Another disorder causing severe thrombocytopenia is thrombotic thrombocytopenic purpura or TTP. TTP is an acute illness affecting multiple organ systems. TTP causes platelets to aggregate and obstruct blood flow in small arterial vessels. This leads to neurological and kidney dysfunction as well as a type of anemia called microangiopathic hemolytic anemia. TTP is treated by exchanging the patient’s own plasma for new plasma. Plasma exchange is usually available only in referral centers that have the sophisticated equipment and trained personnel required to perform this procedure in a safe and expeditious manner.
Myeloproliferative diseases-polycythemia vera, essential thrombocythemia, and primary myelofibrosis
Myeloproliferative disorders all result in the overproduction of blood cells. Because of the detrimental effects of high numbers of blood cells of all types, treatment is directed towards lowering their numbers. Polycythemia vera is treated with phlebotomy, a simple technique that involves removal of units of blood at appropriate intervals. This keeps the red cell count (hematocrit) within the normal range, lessening the risk of stroke or heart attack.
In essential thrombocythemia, and in some cases of polycythemia vera, the high platelet count needs to be lowered, also to prevent stroke, heart attack, or life-threatening blood clotting. The optimal platelet count in this situation is unknown, largely because the degree of platelet activation, and therefore increased potential for clotting, cannot be routinely measured. Generally, however, a count of 600,000/ l (normal: 150,000 to 450,000/ l) is used as a threshold for initiating therapy in myeloproliferative diseases. If the patient is experiencing a life-threatening thrombotic event, the platelet count can be brought down very rapidly by mechanical means (plateletpheresis). Otherwise, medications, either hydroxyurea or anagrelide (Agrylin™), are used. Both of these drugs suppress the bone marrow cells that make platelets (megakaryocytes) and platelet production, although hydroxyurea has a more global effect on bone marrow function.
Coagulation disorders (excess bleeding or clotting)
Severe inherited bleeding disorders usually come to light in childhood, when parents observe excessive bleeding with mild or no obvious cause. If the diagnosis is hemophilia, therapy is directed toward replacing the clotting factor that’s missing. With the range of factor VIII and IX concentrates available today, either purified from human plasma or produced by molecular techniques (recombinant), this is a relatively straightforward process. There are, however, several caveats to be taken into account. First, the dosage has to calculated correctly and adjusted for the type of bleeding episode. Second, patients or their parents must be taught to administer the factor at home, since prompt administration after a bleed into a joint or soft tissue limits the total amount of bleeding and prevents further tissue damage. Third, some patients develop inhibitors (antibodies) to the infused factor product. This greatly complicates the management of a bleeding episode since the antibody acts to immediately neutralize the activity of the transfused factor. In such cases other types of factor products that bypass the block imposed by the inhibitor are used to treat bleeding. Fourth, the management of patients with hemophilia should be undertaken only by hematologists and surgeons well versed in the disease and its complications and familiar with the wide assortment of clotting factor products available.
In mild forms of hemophilia and in most types of von Willebrand’s disease, the disorder is often not diagnosed until adulthood, when the individual has a pre-operative assessment for elective surgery that shows abnormal clotting times. Usually the surgery has to be delayed and the abnormality assessed by a hematologist. If an underlying abnormality is found, the patient is then given a test dose of DDAVP (Desmopressin), which causes an increase in FVIII or von Willebrand’s factor levels. If enough of an increase is demonstrated, then this agent can be used to support hemostasis during a minor surgical procedure. If not, or if it is a major operation (cardiac or brain surgery), FVIII or von Willebrand’s factor concentrates must be given immediately before the procedure and continued for several days afterwards.
Certain thrombotic (blood clotting) diseases are also inherited, but usually don’t manifest themselves until later in life. Some clots can occur spontaneously and without obvious cause, but more common is the type of blood clot that develops after surgery or prolonged periods of immobility. No matter what the setting, the treatment is anticoagulant therapy. After certain types of surgery, such as orthopedic procedures on the lower extremities, or surgery on the spine, the risk of postoperative thrombosis is very high. Multiple clinical trials have demonstrated the benefit of giving prophylactic anticoagulation to reduce the incidence of thrombotic events. Either heparin or warfarin is used, starting as soon as feasible after the operation and continuing until the patient is ambulatory.
Anticoagulants also are used to treat an already established blood clot. Therapy consists of intravenous heparin, followed by oral warfarin (Coumadin). In uncomplicated thrombosis, the patient may be able to self-administer medications at home. Usually anticoagulant therapy is continued for 3 to 6 months. Patients who have recurrent episodes of thrombosis, especially pulmonary emboli, or who have laboratory markers of thrombophilia, usually receive longer and occasionally indefinite periods of treatment.
The field of hematology comprises a broad spectrum of disorders of the blood and bone marrow. Because problems in other organs often affect the blood, deciding whether a blood abnormality is secondary to some other illness or a primary disorder in and of itself can be a very complex and sometimes irresolvable issue. Sophisticated coagulation and hematology laboratory tests, plus the input of other medical specialists, are often required to make the correct diagnosis and rational treatment decisions.
Ongoing basic science and clinical research studies in hematology have improved our understanding of the pathophysiology of blood and coagulation diseases and improved our diagnostic tools. Such research holds the promise of new therapeutic agents to treat our patients, improving their overall outcome and quality of life.