Multiple Myeloma

DIAGNOSIS.

The diagnosis of MM is determined by clinical factors as well as bone marrow examination. Because other diseases also present with an elevated monoclonal gammopathy, new criteria have been developed by the International Myeloma Working Group to aid in the diagnosis and distinction of these paraprotein diseases in order to provide appropriate treatment.³⁹

Major and minor criteria were created to distinguish MM from asymptomatic myeloma and monoclonal gammopathies of undetermined significance (MGUS). Clients must have at least one major and one minor or three minor criteria to be diagnosed with MM (Table 14-5). Major features consist of an elevated M-protein level or Bence Jones proteinuria, plasmacytoma on a tissue biopsy, and greater than 30% of clonal plasma cells on bone marrow biopsy examination. Individuals who demonstrate increased levels of M-protein but do not exhibit end-organ damage have asymptomatic (smoldering) myeloma.

Clients who express low amounts of protein, have less than 10% of plasma cells in the bone marrow, and have no end-organ damage are diagnosed with MGUS. Approximately 12% of clients with MGUS will develop MM, macroglobulinemia, other lymphoproliferative disease, or amyloidosis within 10 years; this risk increases to 25% at 20 years (i.e., a minority of people with MGUS will develop MM).¹⁰⁵ The factor that correlates best with the progression of MGUS to MM is the concentration of M-protein at diagnosis.

Tests performed to determine if criteria are met for the diagnosis of MM include a bone marrow biopsy, measurement of M-protein in the blood and urine (serum protein electrophoresis and urine protein electrophoresis, respectively, or more sensitive tests such as immunoelectrophoresis and immunofixation), biopsy of any suspect mass, and radiographic skeletal survey (lytic lesions also seen on CT and MRI).

Other tests that are helpful in providing prognostic information include LDH, β₂ microglobulin, plasma cell labeling index (a measurement of the proliferative capacity of the myeloma cells), and cytogenetics (to determine specific mutations and abnormalities). Both plasma cell labeling index and cytogenetic tests are obtained by bone marrow aspiration. PET scans can also reveal probable areas of tumor involvement, while β₂ microglobulin, a small protein, reflects tumor load.

Evaluation of symptoms may include an assessment of serum calcium, kidney function, CBC, quantitative immunoglobulins, and cultures (for any suspected infections).

TREATMENT.

The center of treatment of MM includes the elimination of malignant plasma cells and correction of problems in the bones and other organs. For decades, standard treatment for MM has been intermittent cycles of melphalan plus prednisone or a combination of alkylating agents when progression of disease occurs. Survival with these agents alone is approximately 3 years.

The introduction of high-dose (myeloablative) chemotherapy using melphalan with stem cell support in the initial treatment of MM significantly improved the outcomes, with increased complete remission rate and extended disease-free and overall survival. Later research found that two high-dose courses of melphalan, each followed by an infusion of autologous stem cells, was superior to a single treatment, particularly for clients who did not respond to the first transplant.¹⁴

This double transplant is best for people whose myeloma cells have a normal karyotype. In these clients remission at 10 years was nearly 20%. Efforts are being made to find ways to overcome drug resistance and reduce the ability of environmental cells to aid in the survival and proliferation of myeloma cells.

Three drugs available are thalidomide, lenalidomide, and bortezomib. All three agents have shown superiority to conventional drugs in refractory and relapsed disease, and studies are ongoing to determine their use in earlier treatment. Thalidomide, an infamous oral agent, has shown significant improvement in response rates as a preparatory agent for autologous BMT compared with conventional agents.

When used in maintenance therapy following transplant, thalidomide improved event-free survival compared with no maintenance therapy. Yet thalidomide has not been shown to improve overall survival when used before and after double transplants.¹⁶ Because thalidomide does cause significant fetal malformations, increased thromboembolic risks, and severe neuropathy, an analogue (lenalidomide) was designed in hopes of reduced side effects. While lenalidomide lacks the adverse effect of severe neuropathy, it does cause neutropenia.

Another newly introduced medication is bortezomib, a proteasome inhibitor (a proteasome degrades other proteins, keeping a balance of proteins in a cell). It is currently approved for refractory and relapsed myeloma.¹⁵⁷ Further research is needed to determine which drugs are most effective and when. Oncologists are looking toward individualizing treatment depending on the types of mutations present in the myeloma cells.

Advances have also been made in correcting symptoms caused by the myeloma and surrounding cells. Bone pain is one of the most significant problems faced by clients with MM. Pathologic fractures are treated with surgery and pain control. Lytic lesions often require radiation for pain relief along with opiates. Radiation may be all that is needed to decrease pain and stabilize the cervical spine when metastases occur. In some cases radiation has been shown to stop and even reverse bone destruction.^66a

Monthly infusions of the bisphosphonates pamidronate and zoledronic acid have been shown to be effective when used with chemotherapy, not only in the improvement of bone lesions but also in decreasing the need for radiation, decreasing osteoporotic fractures, and improving survival in some people with myeloma (median survival is 1 year compared with 3 or 4 months with BMT).^20,185

Bisphosphonates are potent inhibitors of osteoclastic activity (resorption) and may exert an antitumor effect that is apoptotic and antiproliferative.⁵² Hypercalcemia is treated with hydration, corticosteroids, and bisphosphonates. Anemia improves with myeloma treatment, but the use of erythropoietin can speed up recovery of erythrocyte production.

Future treatment under investigation includes peripheral stem cell grafting, posttransplant immunotherapy, gene therapy, new drugs, development of effective oral bisphosphonates, new ways of delivering radiotherapy to specific sites, and radiopharmaceuticals that concentrate at involved marrow sites.²⁰³ A tumor-specific vaccine for active immunization is also under investigation.⁷⁴

PROGNOSIS.

Despite 30 years of clinical trial research conducted by three major cooperative groups under the auspices of the National Cancer Institute, the prognosis for MM has not markedly improved and it remains an incurable disease. With standard therapy, the median survival of clients with MM remains about 3 years.

The advent of double transplants has improved the median survival, with the estimated overall 7-year survival rate of 21% for people receiving a single transplant and 42% for those receiving a double transplant (two high-dose courses).¹⁴ Yet individual responses are varied and a client’s prognosis cannot be accurately predicted. As in lymphomas and leukemias, scientists are looking for genetic factors that will not only aid in directing therapy, but prognosis as well.²⁰⁷

Some of the risk factors for a poor prognosis include a high serum C-reactive protein (a surrogate marker for IF-6 activity), β₂ microglobulin, or LDH (both reflecting tumor load). Other poor risk factors are an elevated plasma cell labeling index, detection of circulating plasma cells, and involvement of the CNS by myeloma cells (malignant cells in the CSF accompanied by signs and symptoms of CNS involvement).

Some of the cytogenetic prognostic factors include deletion of chromosomes 13 and 17 and alterations in chromosome 1. The development of bisphosphonates, thalidomide, and bortezomib has aided in changing the local myeloma environment and in reducing resistance of tumor cells to commonly employed cytotoxic drugs.

If untreated, unstable MM can result in skeletal deformities, particularly of the ribs, sternum, and spine. Diffuse osteoporosis develops, accompanied by a negative calcium balance. Prognosis is affected by the presence of renal failure (poorer prognosis if present at the time of diagnosis), hypercalcemia, or extensive bony disease; infection and renal failure are the most common causes of death.

Future improvements with transplantation may be achieved by providing tumor-free grafts and posttransplant treatment aimed at eradicating minimal residual disease.

Myeloproliferative Disorders

Myeloproliferative disorders are a group of diseases that originate from a hematopoietic stem cell that has undergone a transformation. This transformation allows the cells to mature and function, yet there is uncontrolled production. Myeloproliferative disorders also share other characteristics, including a hypercellular bone marrow, tendency toward thrombosis and hemorrhage, and an increased risk of evolving into acute leukemia over time.²⁸

The four main myeloproliferative diseases are CML, polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis. While all of these disorders can exhibit elevations in all cell lines, each disease has a main cell line that is affected.

Polycythemia vera is an uncontrolled production of erythrocytes. Essential thrombocythemia is characterized by an elevated platelet count. Excessive fibrosis of the marrow is a dominant feature of idiopathic myelofibrosis. Myelofibrosis and other more rare diseases are not covered in this text. CML is discussed with the leukemias.

DIAGNOSIS.

Diagnosis is established by history, examination, and laboratory analysis. The erythrocyte count is greater than 60% of normal for men and 56% for women (without the presence of secondary polycythemic factors). WBC and platelet count are often elevated in people with PV and are normal in most people with secondary polycythemia.

The presence of the JAK2 mutation can be identified by PCR and other sensitive tests. A positive JAK2 and appropriate clinical factors may be enough information to make the diagnosis. However, since not all cases of PV express the JAK2 abnormality, other tests can be performed.

These include labeling RBCs with chromium to distinguish between absolute polycythemia (increased RBC mass) and relative polycythemia (normal RBC mass but decreased plasma volume), growing cells to verify erythropoietin independence, measuring plasma erythropoietin, evaluating cytogenetic studies of the bone marrow, and performing an ultrasound of the spleen to demonstrate splenomegaly.

TREATMENT.

Treatment goals are to reduce erythrocytosis and blood volume, control symptoms, and prevent thrombosis. Repeated phlebotomy is used to maintain stable Hb (less than 45%) by causing iron deficiency.

Clients who are older than 70 years, have a history of thromboembolism, or have a platelet count greater than 400,000/μl are treated with the antimetabolite hydroxyurea, which does not appear to be associated with an increased incidence of acute leukemia (alkylating agents are linked to leukemia).

Aspirin, if no contraindications exist, has been found to be beneficial to all people with PV in reducing the risk of thrombotic events, although overall mortality and cardiovascular mortality rates are not significantly reduced.¹⁰⁷

PROGNOSIS.

The prognosis for PV is good, and median survival is 15 years with appropriate treatment. Without proper treatment, the mortality rate (18 months from the time of symptomatic onset) is 50%. The risk for stroke, myocardial infarction, and thromboembolism is high for people with this condition; thrombosis or hemorrhage is the major cause of death. Late in the course of this disease bone marrow may be replaced with fibrous tissue (myelofibrosis) or transform into AML.

DIAGNOSIS.

The differentiation between reactive thrombocytosis (i.e., secondary thrombocytosis) and ET can be difficult. The presence of the JAK2 mutation (by PCR), splenomegaly, and abnormal bone marrow is indicative of ET since other causes of thrombocytosis do not include these features. For a high percentage of cases other tests must be performed.

TREATMENT.

The treatment of ET depends on the age and symptoms of the person. Asymptomatic, young clients (age less than 60 years) with a platelet count less than 1,500,000/μl may not require treatment. Hydroxyurea is used for people who are older than 60 years with a history of a thrombotic event to reduce the platelet count to less than 400,000/μl. This therapy significantly reduces the risk of another thrombotic event.

Anagrelide is another medication used to reduce the platelet count; however, it has been linked to a higher risk of arterial thrombosis, bleeding, and transformation of the bone marrow to myelofibrosis compared with hydroxyurea.¹⁹²

Aspirin may be of benefit for clients who are at high risk for thrombosis and do not have a history of bleeding. Persons who develop acute ischemic events and have a platelet count greater than 1,500,000/μl should receive immediate plateletpheresis. If surgery is required, the platelet count should be brought to near normal levels to reduce the risk of bleeding and thrombosis perioperatively.

PROGNOSIS.

Most people with ET have near normal life expectancies. ET carries a small (3% to 4%) risk of transforming into acute leukemia and rarely develops into myelofibrosis. Bleeding and thrombotic events are the most serious complications and can be life threatening. Better understanding of the mutations resulting in ET may lead to improved treatment and prophylaxis against bleeding and thrombotic complications.

von Willebrand’s Disease

DIAGNOSIS.

The most common screening laboratory tests used to assess coagulation are the activated partial thromboplastin time and the prothrombin time. Despite available tests, many clinicians find making the diagnosis very difficult—particularly for clients with mild disease. Test results are often normal in clients with vWD. vWD cannot be diagnosed with just one laboratory test; the clinician relies on at least four tests to aid in the diagnosis: a platelet function test, vWF antigen test, ristocetin cofactor activity, and factor VIII level.

Two tests help assess platelet function: the bleeding time and a machine called the Platelet Function Analyzer 100 (PFA-100, Dade Behring, Deerfield, IL). The bleeding time test is performed by making small punctures in the skin and then measuring the time until clotting occurs. This test has numerous technical variables and is neither specific nor sensitive for the diagnosis of mild vWD (which may have a normal bleeding time).

The PFA-100 assesses the time required for a small collagen-coated tube to close when exposed to a person’s blood. Although this test has fewer technical problems, anemia and other factors may distort the results. Prolonged clotting times can be indicative of a platelet problem, but more specific tests are needed to confirm the diagnosis of vWD.

vWF antigen can be measured in the blood (if vWF is present, the test will be positive). Ristocetin is an antibiotic that binds to vWF and leads to platelet aggregation. Using this information, the quantity of vWF can be approximated by adding plasma from the client to platelets and adding ristocetin. Platelet aggregation will occur at a specific rate depending on the vWF concentration.

Factor VIII levels can be directly measured in the plasma. Subtypes with very low levels of vWF also have low levels of factor VIII (particularly type 3). Collagen binding activity is often measured (since one function of vWF is to bind collagen to platelets) using an enzyme-linked immunosorbent assay type test. Gel electrophoresis can be used to ascertain the subtype of vWD.

Because of the increased frequency of menorrhagia and other bleeding problems related to obstetrics and gynecology, guidelines have been developed that may lead to improved diagnosis and treatment of women with bleeding disorders, particularly vWD.^2,45

TREATMENT AND PROGNOSIS.

The treatment of vWD centers on the replacement of vWF and/or factor VIII as needed during times of bleeding or prophylactic administration prior to an invasive procedure.¹¹⁸ Most clients with vWD (especially type 1) do not require treatment except during times of surgery or trauma or after delivery of a fetus. Those persons exhibiting more serious complications such as hemarthrosis or frequent GI bleeding (type 3 or some type 2) may require scheduled prophylactic treatment.

Desmopressin is the principal drug of choice for treating most cases of vWD. It is a synthetic antidiuretic-hormone derivative that induces the secretion of vWF and factor VIII from storage. This medication can be given intravenously, subcutaneously, or intranasally.

Since treatment is often needed during emergencies, intravenous dosing is the most practical, although subcutaneous and nasal routes are useful when used for prophylaxis. Vasopressin can increase the levels of vWF and factor VIII three to five times the baseline level within 60 to 90 minutes. It is not effective for type 3 cases (these clients do not make enough to store) and is contraindicated or ineffective for most persons with type 2. Since type 2 vWD results from an abnormal vWF, it is useless to secrete increased amounts of abnormal vWF.

People with types 2 and 3 vWD often require concentrates of factor VIII/vWF for spontaneous bleeding, surgery, or trauma. Humate-P (CSL Behring, King of Prussia, PA), which contains more vWF than factor VIII, and Alphanate (antihemophilic factor), containing equal amounts of vWF and factor VIII, are synthetic concentrates currently available. Both products are virus inactivated through a heat treatment. Wilfactin (LFB, Les Ulis, France), another concentrate, replaces vWF and contains little factor VIII, allowing for the use of the client’s own factor VIII (with vWF in the plasma, autologous factor VIII is stable).

If concentrates are not available, other plasma replacements can be used. Fresh frozen plasma contains both vWF and factor VIII but is accompanied by a large volume, and multiple bags can cause volume overload. Cryoprecipitate contains both proteins in a smaller, concentrated volume yet has the potential of being infectious (although rare with current screening).

Other available medications, which are used for dental or minor mucosal bleeding, include antifibrinolytic agents. Along mucosal linings of the body there is fibrinolytic activity, which prevents fibrin from forming a clot.

Antifibrinolytic amino acids can be given to inhibit this activity. Aminocaproic acid and tranexamic acid are two antifibrinolytic amino acids that can be dosed topically, orally, or intravenously. For clients with minor bleeding problems, these agents may be sufficient for minor procedures. Frequently they are used as adjuvant medications along with concentrates and desmopressin during major and minor surgery.¹¹⁸

Despite advancement in treatment, clients with type 3 vWD still face the challenge of developing inhibitors to available treatment. These inhibitors are typically antibodies that clear vWF from the plasma. Further use of concentrates with vWF can lead to anaphylaxis. Concentrates of factors VIII and VII have been utilized to aid with clot formation with success (and antibodies do not form to pure factor VIII concentrates), although factor VIII has a short half-life without vWF. Research is ongoing to determine strategies for overcoming these issues.

Women with severe symptoms can suppress menstruation with the use of oral contraceptives or receive concentrates when needed for menorrhagia. Studies are pending that may provide better information concerning best treatment options for women with bleeding disorders.

vWF and factor VIII levels do rise with pregnancy, but pregnant clients must be followed very carefully; concentrates and desmopressin are used at birth and during the immediate postpartum period. Care must also be taken when treating the fetus since the baby may have vWD as well. Intramuscular injections, surgery, and circumcision should be avoided in babies with a high risk of a bleeding disorder until an adequate diagnosis is made.^2,45

Clients with minor bleeding manifestations have problems that can often be avoided with proper care. Individuals with more serious symptoms and complications have significant alterations in quality of life; surgery and trauma can be life threatening. Currently a vWF concentrate that is produced by recombinant technologies (thereby avoiding all risk for viral infections) is under investigation.¹⁶⁸

Recombinant activated factor VII shows promise as another concentrate that can be used for vWD and for clients with vWD who have developed inhibitors to routine medications and concentrates.⁶⁶ The cytokine interleukin-11 has been noted to increase both factor VIII and vWF levels, and studies are underway to determine efficacy and safety.⁴⁶ Gene therapy is less hopeful since the size of the DNA coding for the many dimers that make up vWF is so large.

Hemophilia

DIAGNOSIS.

Effective treatment of hemophilia is based on an accurate diagnosis of the deficient clotting factor and its level in the blood. Diagnosis is not always straightforward, as a variety of factors can confound the test results (e.g., blood type; factor levels can be elevated by stress, hyperthyroidism, and pregnancy, yet decreased in hypothyroidism).

Additionally, cord blood sample at birth may have physiologically low levels of factor IX that only reach adult values by 3 to 6 months of age. Blood tests include assays for clotting factors, CBC (differential and platelets), and activated partial thromboplastin time. Other tests may be added depending on individual variables. It is also important for female relatives of those with hemophilia to identify their carrier status through factor level analysis and DNA testing.

If possible, genetic studies to determine carrier status should be completed before pregnancy. However, prenatal diagnosis of hemophilia A and B is possible if a specific mutation has been found or if linkage studies have provided enough information about carrier status in the family. If one of these two criteria has been met, prenatal diagnosis can be performed, analyzing DNA for specific mutations.

The most common method is through chorionic villus sampling at 10 to 12 weeks of gestation. Ultrasound at 14 to 16 weeks’ gestation to determine the gender of the unborn child, amniocentesis at approximately 16 weeks’ gestation, percutaneous umbilical blood sampling at 18 weeks’ gestation, and preimplantation genetic diagnosis (involving polar body, blastomere, and blastocyst biopsy) are other methods of diagnosis. The advantages and disadvantages of these tests as well as management issues are reviewed in the literature.¹⁰⁴

TREATMENT.

Currently no known cure or prenatal treatment for hemophilia exists. Until a medical cure is developed, primary goals for intervention in the case of bleeding episodes are to stop any bleeding that is occurring as quickly as possible and to infuse the missing factors until the bleeding stops.

Treatment for severe forms of hemophilia is recommended to take place in specialized hemophilia treatment centers across the United States and its territories. In these centers the specialized care required can be provided through a multidisciplinary team approach with appropriately trained and experienced health care providers. Treatment at a hemophilia treatment center has been shown to minimize disability, morbidity, and mortality rates.^31,176

Factor replacement therapy, given intravenously, is currently the mainstay of hemophilia treatment. Treatment with infusion of the missing factor at a 25% to 30% plasma factor level is recommended for minor bleeding; at least a 50% level is recommended before minor surgery and dental extractions or in case of minor injury, and it may be recommended before physical or occupational therapy interventions. Infusion at 75% to 100% may be recommended before major surgery or in the case of life-threatening bleeding.

Permanent prophylaxis of recombinant factors for severe hemophilia (i.e., factor infusion given on a regularly scheduled basis) to maintain blood factor levels in the moderate range is now widely accepted. Most clients should receive infusions on at least a weekly basis, although questions remain of when to initiate prophylaxis (first joint bleed vs. early age).¹ Prophylaxis therapy is very expensive, but treatment of target joints can increase the cost as much as twofold.⁹⁸ Uncertainty exists as to whether prophylaxis helps prevent joint disease, and studies are pending completion that would help answer these questions.

Most factor VIII concentrates are produced using recombinant techniques to provide virus-free products. First-generation factor VIII products contain animal or human plasma proteins, while second-generation concentrates contain these proteins in the cell culture medium but not in the final product. Third-generation products do not contain animal or human plasma proteins in either the cell culture medium or the final product.

Methods used prior to the availability of recombinant technology to manufacture factor VIII concentrates utilized plasma pooled from thousands of donors that was then purified for factor VIII. This purified concentrate was treated to deplete viruses (heating in an aqueous solution, treated by a solvent detergent, or immunoaffinity purification). While this type of product is still available and there have been no reports of clients being infected with hepatitis B or C or HIV, the risk remains that these pooled-plasma products could possibly lead to viral transmission. This possible increased risk of transmitting a virus makes recombinant concentrates the recommended treatment of choice.

With the use of recombinant factor, human viruses are not easily transmitted through factor use, and the possibility of any other contaminants being transmitted is unlikely. Product manufacturers are continuing to develop products with a higher recovery level and to increase the efficiency of the factor products (i.e., percent of factor protein that remains active in the blood after infusion; the higher the level of a factor product’s recovery, the more efficient the product).

Persons with mild hemophilia can use the drug desmopressin when possible (see above section under vWD). If this medication does not provide adequate hemostasis or the client is pregnant or younger than 2 years, factor VIII concentrates should be utilized.

Treatment for clients with hemophilia B consists of factor IX concentrates. Recombinant factor IX concentrates do not use animal or human plasma proteins in the purification process, making the product safe from viruses. Pooled plasma–derived factor IX products are available, and like the factor VIII concentrates from pooled plasma, undergo a viral-depletion step. However, due to the safety factor of recombinant technology, recombinant factor IX concentrate is the medication of choice.

For those clients who developed chronic hepatitis C from the use of blood products prior to the mid 1980s, progression and treatment response appear to be similar to those people without hemophilia.^109,127 Treatment and prognosis for hepatitis are discussed in Chapter 17.

Administration of the hepatitis A and hepatitis B vaccines is recommended for anyone with chronic hepatitis C because of the potential for increased severity of acute hepatitis superimposed on existing liver disease. Younger children are now vaccinated against hepatitis A and B, but no vaccine is available for hepatitis C at this time. Although treatment for hepatitis B is available, liver transplantation may be required. Liver transplantation is successful in people who have hemophilia with advanced liver disease but is often unavailable.

Comprehensive medical management of hemophilia may involve the use of drugs to control pain in acute bleeding and chronic arthropathies. People with hemophilia cannot use the common pain relievers aspirin or ibuprofen because these agents inhibit platelet function. More precisely, platelets do form an initial clot, but factor VIII or IX is unavailable to stabilize the clot.

Some medications contain derivatives of aspirin and must be used cautiously. Corticosteroids are used occasionally for the treatment of chronic synovitis. Acetaminophen (Tylenol) is a suitable aspirin substitute for pain control, especially in children. Clients who have had continued target joint bleeding often require surgical synovectomy or radioactive synovectomy to decrease bleeding and reduce the rate of destruction of the joint. Clients have also demonstrated stable or improved range of motion following these procedures.^55,56

Physical therapy intervention (see Special Implications for the Therapist: Hemophilia in this chapter) has been effective in reducing the number of bleeding episodes through protective strengthening of the musculature surrounding affected joints, muscle reeducation, gait training, and client education. Physical therapy is used during episodes of acute hemorrhage to control pain and additional bleeding and to maintain positioning and prevent further deformity.

Gene therapy is still in experimental stages but appears very promising. When successful, gene therapy will deliver a normal (unaffected) copy of a gene into a target cell that contains a defective gene. Human trials are underway for hemophilia A and B using a variety of different delivery techniques. In fact, hemophilia is considered a model disease for treatment with gene therapy because it is caused by a single malfunctioning gene, and only a small increase in clotting factor could provide a great benefit.¹¹⁷

PROGNOSIS.

Years ago most men with hemophilia died in their youth. Currently, the majority of deaths in persons with hemophilia are viral related (hepatitis B and C, HIV), yet with improved diagnosis and significantly improved treatment (including safety), they can reach a longer life expectancy.¹⁵²

Tremendous improvement has been made in carrier detection and prenatal diagnosis to provide early treatment and prevent complications. Gene therapy for hemophilia A and B, now in clinical trials, holds promise of a cure. Additionally, home infusion therapy provides immediate treatment with clotting factor for joint and muscle bleeds recognized early. Early treatment has significantly reduced the morbidity formerly associated with hemophilia.

Medical treatment prolongs life and improves quality of life associated with improved joint function, but HIV and hepatitis can significantly reduce longevity and quality of life. Fortunately, improvements in blood screening tests, more stringent donor exclusion criteria, improved viral inactivation methods, and the introduction of recombinant hemophilia therapies have combined to dramatically reduce the rate of new bloodborne viral infections among people with hemophilia, especially those children born in the last decade.

From the period of 1979 to 1998, the death rate of persons with hemophilia A and HIV decreased 78%.³⁵ Much of this decrease was related to improved HIV therapy. With the advent of safer factor concentrates, there is a trend of increased life expectancy for people with hemophilia. Those people with hemophilia but without HIV or hepatitis have a life expectancy near normal.

ICH still remains a deadly complication of hemophilia, but prophylaxis treatment and improved understanding of the signs and symptoms associated with ICH may help to improve outcomes.

Thrombocytopenia

Thrombocytopenia, a decrease in the platelet count below 150,000/mm³ of blood, is caused by inadequate platelet production from the bone marrow, increased platelet destruction outside the bone marrow, or splenic sequestration (entrapment of blood and enlargement in the spleen). Thrombocytopenia is a common complication of leukemia or metastatic cancer (bone marrow infiltration) and aggressive cancer chemotherapy (cytotoxic agents). Thrombocytopenia may also be a presenting symptom of aplastic anemia (bone marrow failure); other causes are listed in Box 14-8.

Mucosal bleeding is the most common event and occurs by simply blowing the nose or brushing the teeth. Other sites of mucosal bleeding may include the uterus, GI tract, urinary tract, respiratory tract, and brain (ICH). Symptoms include epistaxis (frequent and difficult to stop), petechiae and/or purpura in the skin (especially the legs) and oropharynx, easy bruising, melena, hematuria, excessive menstrual bleeding, and gingival bleeding.

Diagnosis requires laboratory examination of blood and perhaps bone marrow (if clinically indicated) to confirm the diagnosis. Treatment depends on the precipitating cause (e.g., treatment of underlying leukemia or cessation of cytotoxic drugs until platelet count elevates).

Other treatment methods for immune-related thrombocytopenia (e.g., immune thrombocytopenic purpura) may include use of corticosteroids (e.g., prednisone); intravenous immune globulin and Rh_o(D); splenectomy; monoclonal antibody agents (e.g., rituximab); and plasmapheresis, a procedure that removes blood from the body, separates the portion containing the antiplatelet antibodies, and then returns the cleansed blood to the body. Newer drugs, thrombopoietic agents, are being tested to provide medications with fewer adverse events.²⁵

Transfusions with platelets are avoided in clients with immune thrombocytopenic purpura unless severe bleeding occurs. However, clients with a secondary cause for thrombocytopenia (e.g., acute leukemia treatment and severe complications of chemotherapy agents that cause thrombocytopenia) may require platelet transfusions for bleeding and/or counts less than 15,000/mm³.

The prognosis is variable depending on the underlying cause; it is poor when associated with leukemia or aplastic anemia but good with conditions amenable to treatment.

Effects of Aspirin and Other Nonsteroidal Antiinflammatory Drugs on Platelet Function

Acquired disorders of platelet function can occur through the use of aspirin and other NSAIDs that inactivate platelet cyclooxygenase. This key enzyme is required for the production of thromboxane A₂, a potent inducer of platelet aggregation and constrictor of arterial smooth muscle.

A single dose of aspirin can suppress normal platelet aggregation for 48 hours or longer (up to 1 week) until newly formed platelets have been released. Platelets are anucleated, and once aspirin irreversibly inhibits cyclooxygenase, the platelet is unable to synthesize new enzyme and remain inactive for the rest of its lifespan.

NSAIDs have less-potent antiplatelet effects than aspirin since they reversibly inhibit cyclooxygenase. Symptoms from this phenomenon are mild and may consist of easy bruising and bleeding, usually confined to the skin. The use of aspirin or NSAIDs is usually contraindicated before any surgical procedure. Prolonged oozing following dental procedures or surgery may occur.

Disseminated Intravascular Coagulation

DIAGNOSIS, TREATMENT, AND PROGNOSIS.

Diagnosis is made based on clinical presentation in combination with client history; laboratory blood tests can aid in the diagnosis (e.g., D-dimer test, coagulation tests).

Treatment is always directed toward the underlying cause and must be highly individualized according to the person’s age, nature and origin of DIC, site and severity of hemorrhage or thrombosis, and other clinical parameters. The hemorrhagic or thrombotic symptoms may be alleviated by appropriate blood product replacement or anticoagulants, but the coagulopathy will continue until the causative process is reversed.

Researchers are investigating strategies aimed at inhibiting coagulation activation with protein C, antithrombin, and tissue factor pathway inhibitor.²⁰⁶

The mortality rate for DIC is no longer high with early recognition and treatment, but DIC does contribute to significant morbidity and some mortality as it occurs often with sepsis and cancer. Acute DIC can be fatal depending on the response to treatment.

Hemoglobinopathies

Several diseases are a result of an abnormality in the formation of Hb. Because Hb is essential for life, anomalies in the shape, size, content, or oxygen-carrying capacity can lead to severe problems. Sickle cell disease and thalassemia are two hemoglobinopathies with potential for serious complications and are discussed further.

Hereditary spherocytosis, hereditary elliptocytosis, hereditary stomatocytosis, and pyropoikilocytosis are rare diseases that occur because of defects in the erythrocyte membrane that cause premature clearance of RBCs (hemolysis). Glucose-6-phosphate dehydrogenase deficiency also leads to hemolysis. Discussions of these diseases can be found elsewhere.

PREVENTION.

Sickle cell anemia can be prevented. Couples at risk of having affected children can be identified by inexpensive and reliable blood tests; chorionic villus sampling from 9 weeks of gestation can be performed for prenatal diagnosis.

Adoption of such measures goes hand in hand with health education. However, prenatal diagnosis can raise ethical questions that differ from one culture to another. Experience has clearly shown that genetic counseling, coupled with the offer of prenatal diagnosis, can lead to a large-scale reduction in births of affected children.

The risk of having affected children can be detected before marriage or pregnancy; however, to do so requires a carrier screening program. There is extensive experience with such programs in low-and high-income countries. For example, in the case of thalassemia prevention, unmarried people in Montreal (Canada) and the Maldives are offered screening. Premarital screening is a national policy in Cyprus and the Islamic Republic of Iran, and prereproductive screening is emphasized in Greece and Italy.

The WHO recommends these approaches be practiced in conformity with the three core principles of medical genetics: the autonomy of the individual or the couple, their right to adequate and complete information, and the highest standards of confidentiality.²⁰¹

DIAGNOSIS.

It is required in every state that all infants be screened for SCD regardless of race or ethnic background (universal screening). This recommendation is based on several factors: (1) one out of every 200 Hispanic and 400 white children in Texas carries the sickle cell trait; (2) although SCD is more prevalent in certain racial and ethnic groups, it is not possible to define accurately an individual’s heritage by physical appearance or surname; and (3) prophylactic penicillin and pneumococcal vaccination reduce both morbidity and mortality from pneumococcal infections in infants with sickle cell anemia and sickle thalassemia.

Screening targeted to specific racial and ethnic groups will therefore miss some affected infants, subjecting them to an increased risk of early mortality. Universal screening is the best, most reliable, and most cost-effective screening method to identify affected infants.¹⁴³ The cord blood of newborns is tested in the United States.

The diagnosis of sickle cell trait or any of the other sickle syndromes depends on the demonstration of sickling under reduced oxygen tension. A sickle turbidity test (Sickledex, Streck, Inc., Omaha, NE) can confirm the presence of Hb S in peripheral blood, and Hb electrophoresis (separation and identification of Hb under the influence of an applied electric field) is used to determine the amount of Hb S in erythrocytes.

Electrophoresis is used to screen blood for sickle cell trait and will also detect SCD and heterozygosity (carrier state) for other Hb disorders, such as Hb C. Because the Hb S and Hb C amino acid substitutions change the electrical charge of the protein, the migration patterns of the Hb with electrophoresis result in distinct diagnostic patterns.¹⁴⁵

Safe, accurate methods for performing prenatal diagnosis for SCD are possible as early as the tenth gestational week. Analyses of DNA from fetal cells obtained by amniocentesis or chorionic villus sampling can be performed at the sixteenth gestational week. The sickle and Hb C genes can be detected directly in fetal DNA samples, as can most Hb S β-thalassemia genes.

TREATMENT.

In the past decade, impressive progress has been made in directing treatment to the unique pathophysiology of SCD. A large number of antisickling regimens are being investigated. Although some have been shown to be effective in vitro, unacceptable toxicity prevents their use in human beings at this time.

BMT cures SCD, but minimal availability and associated risks prevent its widespread use. In selected cases BMT may be considered, and the data confirm that allogeneic BMT establishes normal erythropoiesis and is associated with improved growth and stable CNS imaging and pulmonary function in most recipients.^193,194 The event-free survival rate after allogeneic-matched sibling hematopoietic cell transplant for SCD is 82% at an experienced center.^13,84

Supportive care is essential (e.g., rest, pain medication, oxygen, administration of intravenous fluids, electrolytes, and antibiotics, and physical and occupational therapy for joint and bone involvement). Preventive measures (see risk factors above) are used to reduce the incidence of episodes.

Acute stroke is managed with exchange transfusions (i.e., transfusion with erythrocytes and removal of blood) to reduce the amount of Hb S to less than 30% while keeping the total Hb (through transfusions) at 10 g/dl.

The likelihood of a second stroke is increased, and prophylactic transfusions (this inhibits their own erythropoiesis of Hb S) have been shown to help decrease the risk of stroke and reduce the stenosis of arteries.³ Complications with iron overload are common and can have significant long-term problems. Chelating therapy is available but is often difficult for children to tolerate.

Acute chest syndrome is treated with transfusions; oxygen, antibiotics, and hydration may also be needed. Optimal treatment for pulmonary hypertension requires more research. Once the early stages of pulmonary hypertension have been identified, treatments such as hydroxyurea, vasodilators, anticoagulation, oxygen inhalation, and experimental agents such as arginine or nitric oxide can be utilized.

Acute aplastic episodes can be treated with a transfusion if the anemia is severe and the reticulocyte count is low. Most often this is self-limiting and erythropoiesis resumes in a few days. Splenic or hepatic sequestration requires aggressive rehydration and transfusion.

Exchange transfusions to reduce Hb S levels below 30% of total Hb may be used therapeutically for neurologic, cardiac, or retinal symptoms; hypoxemia; severe prolonged or infarctive episodes; acute splenic sequestration in infants; and chronic leg ulcers. These transfusions also can be used prophylactically during pregnancy or before general anesthesia, but they carry the risk of hepatitis, RBC sensitization, hemosiderosis (increased iron storage), and transfusion reactions.

Hydroxyurea is a medication that stimulates Hb F production and is used as a treatment for sickle cell anemia. It is considered safe in the pediatric population. Dramatic reduction of painful episodes, fewer hospitalizations, decreased need for transfusions, and fewer cases of acute chest syndrome occur with the use of hydroxyurea.¹⁷⁹ Neutropenia is a potential side effect requiring frequent monitoring.¹⁰⁰ Erythropoietin may be useful to increase erythropoiesis in clients with renal disease.

Vaccinations are vital, particularly an annual influenza vaccine and a pneumococcal vaccine every 5 years.

Prenatal and neonatal screening can identify this disorder and significantly reduce morbidity and mortality through the use of prophylactic antibiotics. Infants with documented SCD (sickle cell anemia or Hb S βthalassemia) should be started on twice-daily oral prophylactic penicillin as soon as possible but no later than 2 months of age. Children who have experienced pneumococcal sepsis should remain on prophylactic penicillin indefinitely.

The use of inhaled nitrous oxide to treat SCD is also under investigation because of its ability to prevent pulmonary hypertension and endothelial damage. The onset of peripheral neuropathy associated with nitric oxide use in this population has delayed the final development of treatment protocols incorporating nitric oxide.^138,183

Researchers are continuing to investigate the use of fetal Hb as a treatment possibility. Fetal Hb is produced during fetal development and for the first 6 months after birth. Hb F has some ability to prevent sickling and reduce hemolysis; some adults with SCD who naturally make substantial amounts of Hb F have less pain and better spleen function than others with SCD who do not have elevated levels of Hb F.

Other researchers are investigating drugs to reverse cellular dehydration (dehydration increases the rate of polymerization) and fetal cord blood transplantation (see Chapter 21). Stem cell transplantation has been shown to help, and possibly cure, individuals with SCD.⁸⁸

Stem cells taken from a brother or sister may provide bone marrow that is a perfect match (same tissue type) for the recipient. Unfortunately, only about 10% to 20% of children with sickle cell have a matched sibling donor. Stem cells from partially matched (partial tissue match) family members have been tried with a few children who have SCD.⁸⁸

The risk and benefits of these types of transplants are not as well known as transplants using a matched donor. When children with SCD have no matched brother or sister donor, allogeneic transplants are a possible treatment available for these patients.

PROGNOSIS.

Historically, SCD has been associated with high mortality in early childhood due to overwhelming bacterial infections, acute chest syndrome, and stroke. In the mid-1970s the average life expectancy was only 14.3 years. By 1994 the life expectancy had increased to 42 years for men and 48 years for women with sickle cell anemia.^151,201 This increase is attributed to better general medical treatment.

SCD remains a devastating condition with recurrent episodes leading to early death. The complications of SCD can be life threatening depending on their location. Recovery may be complete in some cases, but serious neurologic damage is more likely to occur, and repeated cerebrovascular accidents may lead to increased neurologic involvement, permanent paralysis, or death. Permanent damage from blood clots to the heart, kidney, lungs, liver, or eyes (blindness) can occur.

DIAGNOSIS.

Diagnosis is by laboratory testing. The peripheral blood smear may demonstrate target cells (RBCs that appear like a target), fragments of erythrocytes (because of hemolysis), and very small RBCs (see Fig. 14-2). The serum bilirubin and fecal and urinary urobilinogen levels may be elevated due to the severe hemolysis of abnormal cells. Electrophoresis is usually diagnostic for all types of thalassemia except αthalassemia trait.

TREATMENT.

The anemia associated with thalassemia intermedia may range from mild (not requiring transfusions) to more moderate, requiring occasional transfusions. The goal is to maintain an Hb level of 9 to 10 g/dl, which allows for more normal development and growth and reduces the incidence of hepatosplenomegaly and bone deformities. Clients requiring more frequent transfusions can develop clinical manifestations as described above.

Treatment for thalassemia major consists of optimizing transfusions, providing chelation therapy for iron overload, and implementing hormone replacement as needed. Thalassemia major requires lifelong transfusion, which places these persons at risk for transfusion-related infectious diseases.

The blood supply in the United States is rigorously tested, resulting in a significantly decreased incidence of hepatitis B and C and HIV, although transmission of these viruses can still occur. Most blood is also leukodepleted (WBCs removed) to reduce the problems of transfusion reactions and cytomegalovirus transmission.

Chelators remove iron from the bloodstream, and routine use in these clients has led to a doubling of life expectancy.⁸⁰ Deferoxamine is the most common agent given, although intravenous dosing and side effects make its use difficult. Newer oral chelating agents are being developed, including deferiprone. This drug also has several significant adverse effects, although it does provide the advantages of oral administration and the ability to enter cells and chelate intracellularly.

An experimental approach is to combine the two drugs to provide intracellular chelation along with good plasma chelation. Progressive disease (or in clients who do not respond to chelation therapy) often requires hormone replacement. Clients can receive growth hormone, hormone replacement for testicular and ovarian failure, insulin for diabetes, levothyroxine for hypothyroidism, and calcium and vitamin D (and perhaps bisphosphonates) for osteoporosis.

BMT is an option for clients without severe complications (e.g., liver cirrhosis). Other experimental treatments include agents that increase fetal Hb production, such as 5-azacytidine, butyric acid, and hydroxyurea (see Sickle Cell Anemia: Treatment above), although transfusion decreases the responsiveness of the bone marrow to these agents.

Human recombinant erythropoietin and antioxidants may aid in treatment, but guidelines and study results are still pending. Gene therapy has been successful in animal (mice) studies, but enormous hurdles need to be crossed to be clinically feasible.^58,120,188

PROGNOSIS.

Thalassemia trait does not affect life expectancy, but clients who carry the mutation need genetic counseling. Until recently the outlook for clients with thalassemia major has been poor, with lethal, severe hemolytic anemia and subsequent iron overload and dysfunction of almost all organ systems.

Children are significantly delayed in growth and development; delay of puberty is universal and many die before puberty. Treatment with blood transfusion and early chelation therapy has improved life expectancy from early puberty to early adulthood. Death from hydrops fetalis occurs in homozygous α-thalassemia and consistently results in stillbirth or death in utero.

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