ALTERATIONS OF LEUKOCYTE, LYMPHOID, AND HEMOSTATIC FUNCTION

Granulocytes and Monocytes

Increased numbers of circulating granulocytes (neutrophils, eosinophils, basophils) and monocytes are primarily a response to infection. Increased numbers also occur as a result of myeloproliferative disorders (i.e., polycythemia vera, chronic myelogenous leukemia, chronic neutrophilic leukemia, chronic eosinophilic leukemia) that increase stem cell proliferation in bone marrow.

Decreased numbers occur when infectious processes exhaust the supply of circulating granulocytes and monocytes by drawing them out of the circulation and into infected tissues faster than they can be replaced. Decreases also can be caused by disorders that suppress marrow function.

Granulocytosis—an increase in granulocytes (neutrophils, eosinophils, basophils)—begins with the release of stored leukocytes from the venous sinuses of the marrow. Neutrophilia is another term that may be used to describe granulocytosis because neutrophils are the most numerous of the granulocytes (Table 27-1). Neutrophilia occurs in the early stages of infection or inflammation and is established when the absolute neutrophil count exceeds 7500/μL. Stored neutrophils are approximately 20 to 40 times greater in number than circulating neutrophils. When the neutrophil count increases greatly—more than 100,000/μL (usually seen only in those with myelocytic leukemia)—the blood viscosity may increase greatly so that thrombosis or occlusion of blood vessels occurs. Release and depletion of stored neutrophils from the venous sinuses stimulate granulopoiesis to replenish neutrophil reserves. Specific conditions associated with neutrophilia are identified in Table 27-1.

When the demand for circulating mature neutrophils exceeds the supply, the marrow begins to release immature neutrophils (and other leukocytes) into the blood. Premature release of the immature white cells is responsible for the phenomenon known as a shift-to-the-left or leukemoid reaction. This refers to the microscopic detection of disproportionate numbers of immature leukocytes in peripheral blood smears. Many diagrams present cellular differentiation and maturation progressing from left to right within the drawing, instead of vertically as shown in Figure 25-9. An early release of immature leukocytes would shift the distribution of cells in the blood toward those on the left side of the diagram. This phenomenon is also seen in the blood smear of individuals with leukemia, hence the term leukemoid reaction. As infection or inflammation diminishes and as granulopoiesis replenishes circulating granulocytes, a return to normal occurs.

Neutropenia is a condition associated with reduction in circulating neutrophils. Clinically, neutropenia exists when the neutrophil count is less than 2000/μL.¹ A reduction in neutrophils occurs in severe prolonged infections when production of granulocytes cannot keep up with demand. Neutropenia is considered mild with a neutrophil count between 1000 and 1500/μL. Moderate neutropenia is a neutrophil count between 500 and 1000/μL, and severe neutropenia is a count less than 500/μL. Neutrophil reduction results from severe or prolonged infections when granulocyte production does not keep up with demand.

Other causes of neutropenia, in the absence of infection, may be (1) decreased neutrophil production or ineffective granulopoiesis, (2) reduced neutrophil survival, and (3) abnormal neutrophil distribution and sequestration. Neutropenia also is categorized as primary or secondary; primary disorders are further identified as congenital or acquired.

Congenital defects in neutrophil production include cyclic neutropenia and neutropenia with congenital immunodeficiency diseases, as well as multiple syndromes (e.g., Kostmann, Shwachman-Diamond, Diamond-Blackfan, Griscelli, Chédiak-Higashi, and Barth syndromes). Primary acquired neutropenia is associated with multiple conditions, for example, hypoplastic anemia or aplastic anemia, leukemia (acute myelogenous leukemia [AML]/chronic lymphocytic leukemia [CLL]), lymphomas (Hodgkin, non-Hodgkin), and myelodysplastic syndrome (MDS). The megaloblastic anemias (vitamin B₁₂ and folate deficiency) as well as starvation and anorexia nervosa cause neutropenia because of an inadequate supply of vitamins and nutrients for protein production.

Reduced neutrophil survival and abnormal distribution and sequestration are usually secondary to other disorders. Neutropenia occurs in a variety of immunologic disorders, particularly systemic lupus erythematosus, rheumatoid arthritis, Felty and Sjögren syndromes, splenomegaly, and drug-related causes.

Severe granulocytopenia (less than 500/μL) or agranulocytosis (complete absence of granulocytes in blood) is usually secondary to arrested hematopoiesis in the bone marrow or massive cell destruction in the circulation. Chemotherapeutic agents used to treat hematologic and other malignancies cause generalized bone marrow suppression. Several other drugs and large doses of ionizing radiation cause agranulocytosis, which occurs rarely but carries a high mortality rate (10% to 50%). Clinical manifestations of agranulocytosis include recurrent and persistent life-threatening infection (particularly of the respiratory system) leading to septicemia, general malaise, fever, tachycardia, and ulcers in the mouth and colon. If untreated, sepsis caused by agranulocytosis results in death within 3 to 6 days.

Eosinophilia is an absolute increase (more than 450/μL) in the total numbers of circulating eosinophils. Allergic disorders (type I hypersensitivity) associated with asthma, hay fever, and drug reactions, as well as parasitic infections (particularly with metazoal parasites) are often cited as causes. Hypersensitivity reactions and the normal defense against parasites trigger the release of eosinophil chemotactic factor of anaphylaxis (ECF-A) from mast cells, attracting eosinophils to the area. (These processes are described and illustrated in Chapters 7 and 8.) Tissues with abundant mast cells, such as the respiratory and gastrointestinal tracts, are particularly common sites for eosinophil invasion. Mast cells also release interleukin-5 (IL-5), which stimulates the bone marrow to produce and release more eosinophils into the blood. Eosinophilia may also be associated with dermatologic disorders, such as atopic dermatitis, eczema, and pemphigus. Various types of eosinophilic scleroderma-like diseases also have been reported to occur in association with hemato-oncogenic disorders (i.e., eosinophilic cellulitis [Wells syndrome] and eosinophilic fasciitis [Schulman syndrome]). Increased numbers of eosinophils have been observed in individuals with eosinophilia-myalgia syndrome (EMS), which is associated with ingestion of tryptophan, and a relationship between EMS and fibromyalgia syndrome (FMS) has been suggested.

Eosinopenia, a decrease in circulating numbers of eosinophils, generally is caused by migration of eosinophils into inflammatory sites. It also may be seen in Cushing syndrome and as a result of stress caused by surgery, shock, trauma, burns, or mental distress. Other conditions causing eosinopenia are detailed in Table 27-1.

Basophilia, an increase in circulating numbers of basophils, is rare and generally is a response to inflammation and immediate hypersensitivity reactions. Basophils contain histamine that is released during an allergic reaction. An increase in levels of basophils is seen also in myeloproliferative disorders, such as chronic myeloid leukemia and myeloid metaplasia. Other conditions associated with basophilia are listed in Table 27-1.

Basopenia (also known as basophilic leukopenia), a decrease in circulating numbers of basophils, is seen in hyperthyroidism, acute infection, and long-term therapy with steroids. A decrease in basophils may be seen during ovulation and pregnancy. Other conditions associated with basopenia are listed in Table 27-1.

Monocytosis is an increase (generally greater than 800/μL) in numbers of circulating monocytes. The condition is often transient and not related to a dysfunction of monocyte production. When present, it most commonly occurs with neutropenia associated with bacterial infections, particularly in the late stages or recovery stage, when monocytes are needed to phagocytize surviving microorganisms and debris. Monocytosis often is seen in chronic infections, usually with intracellular bacteria, such as tuberculosis (TB), brucellosis, and listeriosis, and subacute bacterial endocarditis (SBE). Peripheral monocytosis has been found to correlate with the extent of myocardial damage following myocardial infarction. Increased numbers of monocytes also may indicate marrow recovery from agranulocytosis. Other conditions associated with monocytosis are identified in Table 27-1.

Monocytopenia, a decrease in numbers of circulating monocytes, is rare, and not much is known about this condition because of the small numbers of monocytes generally present in the blood. Monocytopenia, however, has been identified with hairy cell leukemia and prednisone therapy.

Lymphocytes

Quantitative alteration of lymphocytes occurs when lymphocytes are activated by antigenic stimuli, usually microorganisms (see Chapter 7). A lymphocytosis is rare in acute bacterial infections and occurs most commonly in acute viral infections, particularly those caused by the Epstein-Barr virus (EBV), a causative agent in infectious mononucleosis. Other specific disorders associated with lymphocytosis are listed in Table 27-1.

Lymphocytopenia may be attributable to (1) abnormalities of lymphocyte production associated with neoplasias and immune deficiencies, and (2) destruction by drugs, viruses, or radiation. It also can occur in individuals for no apparent reason. Other conditions associated with lymphocytopenia are identified in Table 27-1. The lymphocytopenia associated with heart failure and other acute illnesses may be caused by elevated levels of cortisol. Lymphocytopenia is a major problem in acquired immunodeficiency syndrome (AIDS) in which the human immunodeficiency virus (HIV) is cytopathic for T helper lymphocytes. (For a more detailed discussion of AIDS, see Chapter 9.)

Acute Leukemias

Acute leukemias consist of two types: acute lymphocytic leukemia (ALL) and acute myelogenous leukemia (AML). Acute leukemias are seen in both genders and in all ages, with the incidence increasing dramatically in individuals older than 50 years. Mortality for all acute leukemias in the United States is about 7 per 100,000. In children younger than 15 years, leukemia accounts for a third of all deaths from cancer. North American and Scandinavian countries have the highest mortality; Eastern European countries, Asia (except Japan), and Central America have the lowest mortality. Japan’s higher mortality is the result of the atomic bombs dropped in World War II. Blacks have consistently shown a lower mortality than whites. More than 5400 new cases of ALL and 4800 cases of AML occurred in 2008, with more than 1400 deaths attributed to ALL and 450 to AML.^4,8

PATHOPHYSIOLOGY ALL is a progressive neoplasm defined by the presence of greater than 30% lymphoblasts in the bone marrow or blood. Most cases of ALL occur in children (80% of ALL), and it is the most common leukemia in children, most often occurring in the first decade. The median age of diagnosis of ALL is age 13. Although adults with ALL account for only 20% of all cases, their mortality rate is significantly higher (see Table 27-2). The significant difference between the incidence of ALL in adults and children is thought to be determined by differences in the biology of the disease.

Immunotyping of leukemic blast cells allows for the identification of subtypes of ALL. Approximately 75% of ALL in children originate from transformed precursor B cells, whereas adult ALL is a mixture of cancers of precursor B-cell or precursor T-cell origin. A small percentage of ALL cases have neither B- nor T-cell origination and are called null cell (Table 27-3). Precursor B-cell ALL can be subdivided into different phenotypes, depending on their progression through the B-cell maturation process before becoming malignant.^9,10 The general phenotype of precursor B-cell ALL expresses CD19, human leukocyte antigen DR (HLA-DR), and other B-cell–associated antigens in the cytoplasm. The most immature form (pro-B ALL) occurs in about 5% of precursor B-cell ALL and is characterized by lack of expression of CD10. CD10 (common acute lymphocytic leukemia antigen [CALLA]) is a cell surface metalloprotease. Lack of CD10 is frequently associated with translocation of the myeloid/lymphoid leukemia (MLL) gene and a poor prognosis. The common precursor B-cell ALL makes up approximately 80% of precursor B-cell ALL cases; these express surface CD10, but have not yet undergone rearrangement of the immunoglobulin genes. The remaining individuals have a more mature form of precursor B-cell ALL (pre–B-cell ALL) in which the cells express immunoglobulin molecules in the cytoplasm. Less common variations include cells that are intermediate between the common precursor and pre–B-cell phenotypes and express immunoglobulin heavy chain, but no light chain, and cells that are more mature than the pre–B-cell ALL and express surface immunoglobulin and the absence of staining for the enzyme—terminal deoxynucleotidyl transferase (TdT).

The T-cell lineage ALL (precursor T-cell ALL) is distinguished by T-cell–associated markers.^9,10 Cytoplasmic CD3 is the most common T-cell lineage specific marker, but CD7, CD2, and CD5 are frequently used. In addition to lymphoid markers, T-cell receptor (TCR) gene rearrangements are the most common genetic alteration in T-cell ALL. No specific cytogenetic abnormality, however, has been linked to the subtype of T-cell ALL. ALL blast cells also can express myeloid markers in 15% to 50% of adults and 5% to 35% of children.

Precursor B-cell ALL is strongly associated with aneuploidy of various types, ranging from hypodiploid to hyperdiploid with more than 50 chromosomes.^6,9,10 Individuals with hyperdiploid ALL usually have a better prognosis than those with fewer than 46 chromosomes. Precursor T-cell ALL generally have fewer cytogenetic abnormalities, and the majority involve deletions. Genetic translocations between the MYC locus on chromosome 8 and one of the loci for the Ig heavy or light-chain genes (14q32, 2p12, and 22q11) are characteristic (also see Chapters 7 and 11). Several other translocations are commonly observed in ALL, including the Philadelphia chromosome and translocations involving the ETV6 (formerly TEL) and MLL genes (Figure 27-5).⁶ Philadelphia chromosome–positive ALL carries the worst prognosis of all types of ALL and is found in 25% to 30% of adult ALL cases but less than 5% of childhood ALL cases. A translocation between chromosomes 12 and 21 (t[12;21]) results in fusion of the ETV6 oncogene from chromosome 12 with the AML1 (acute myeloid leukemia 1) gene on chromosome 21 to produce a fusion protein, ETV6-AML1. AML1 is a transcription factor for several genes important in hematopoiesis (e.g., IL-3, granulocyte-macrophage colony-stimulating factor [GM-CSF], CSF1 receptor).⁶ The t(12;21) translocation occurs in 25% to 30% of childhood pre–B-cell ALL cases but in only 2% of adult ALL cases. This translocation significantly affects the prognosis of childhood ALL; children younger than 10 years with pre–B-cell ALL and the ETV6-AML1 translocation have a 5-year cure rate of 90%, compared with 60% to 65% in those without the translocation.

Translocations of the MLL gene on chromosome 11 occur in about 10% of individuals with ALL and in 70% of infants with AML or ALL.⁶ Infants and adults with this translocation develop a very aggressive form of leukemia with a very poor prognosis and frequent treatment failure, although children with this abnormality have better outcomes. The most common translocations involving MLL are t(4;11) and t(11;19). The t(4;11) translocation results in a fusion of MLL with the AFF1 (ALL1 fused gene from chromosome 4) gene, and the t(11;19) translocation fuses MLL with the MLLT1(formerly ENL) gene.

Specific causes of ALL are unknown, but multiple factors may contribute to its development.^9,10 Risk factors for childhood ALL include prenatal exposure to x-rays and postnatal exposure to high-dose radiation. Individuals with Down syndrome have an increased risk for developing ALL and AML. Increased risk for ALL is also seen in individuals with other genetic conditions, including neurofibromatosis, Shwachman syndrome, Bloom syndrome, and ataxia telangiectasis (see Chapter 8). A unique characteristic of ALL, unlike other forms, is that ALL develops at different rates in different locations. Individuals in developed countries and in higher socioeconomic categories have an increased incidence of ALL. Prevention is almost impossible because there are no known causes.

AML is the most common adult leukemia; the mean age of diagnosis is 67 years of age. It results from an abnormal proliferation of myeloid precursor cells, decreased rate of apoptosis, and an arrest in cellular differentiation.¹¹ Therefore, the bone marrow and peripheral blood are characterized by leukocytosis and a predominance of blast cells. As the immature blasts increase, they replace normal myelocytic cells, megakaryocytes, and erythrocytes. This displacement eventually leads to complications of bleeding, anemia, and infection. AML increases with age, peaking in the sixth decade of life. Certain risk factors have been identified as possible causes, including exposure to radiation, benzene, and chemotherapy. Hereditary conditions, such as Down syndrome, Fanconi aplastic anemia, Bloom syndrome, ataxia telangiectasis, trisomy 13 (Patau syndrome), Wiskott-Aldrich syndrome, and congenital X-linked agammaglobulinemia, are known to be associated with a higher risk for AML (see Table 27-2). AML subtypes are classified based on the stage of development myeloblasts have reached at the time of diagnosis. These subtypes are included in Box 27-1.

More than 150 structural chromosomal abnormalities and several duplications or deletions within genes have been identified in AML.⁶ The most common abnormalities are balanced translocations or inversions that disrupt genes critical to hematopoiesis of myeloid cells. The most common translocation is between chromosomes 8 and 21 in which the RUNX1T1(formerely ETO) (encodes a transcription factor) gene on chromosome 8 is fused with the AML1 gene on chromosome 21 resulting in an AML1-RUNX1T1 fusion gene and a fusion gene product, AML1-RUNX1T1. Production of AML1-RUNX1T1 disrupts the normal hematopoiesis process for myeloid cells and directly leads to the AML malignant phenotype.

Many kinds of mutations have been found in AML; however, a mutation in the receptor tyrosine kinase FLT3 occurs in about one third of AML persons. FLT3 conveys a proliferation signal normally expressed early in the development of bone marrow stem cells, but mutated FLT3 remains active and promotes blast cell proliferation. Several FLT3 inhibitors are in various stages of clinical development. Another mutation in receptor tyrosine kinases is c-KIT, which also provides a proliferative and/or survival signal to progenitor cells. Together these mutations result in proliferation but not differentiation.

CLINICAL MANIFESTATIONS The clinical manifestations of all the varieties of acute leukemia are generally similar. (Mechanisms associated with common manifestations are summarized in Table 27-4.) Signs and symptoms related to bone marrow depression include fatigue caused by anemia, bleeding resulting from thrombocytopenia (reduced numbers of circulating platelets), and fever caused by infection. Sites of infection include the oral cavity, throat, respiratory tract, lower colon, urinary tract, and skin. Common organisms include the gram-negative bacilli Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae. Fever is an early sign, often accompanied by chills. Bleeding can occur in skin, gums, mucous membranes, and gastrointestinal and genitourinary tracts. Visible signs of bleeding include petechiae and ecchymosis, as well as discoloration of the skin, gingival bleeding, hematuria, and midcycle or heavy menstrual bleeding.

Anorexia can occur in all varieties of acute leukemia and is associated with weight loss, diminished sensitivity to sour and sweet tastes, wasting away of muscle, and difficulty in swallowing. Liver, spleen, and lymph node enlargement is more common in ALL than in AML (Figure 27-6). Splenomegaly and hepatomegaly usually occur together. The leukemic individual often experiences abdominal pain and tenderness and breast tenderness. Pain in the bones and joints is thought to result from leukemia infiltration with secondary stretching of the periosteum.

Central nervous system (CNS) involvement is common and may be caused by either leukemic infiltration or cerebral bleeding. Headache, vomiting, papilledema, facial palsy, blurred vision, auditory disturbances, and meningeal irritation can occur if leukemic cells infiltrate the cerebral or spinal meninges. CNS involvement at the time of diagnosis is rare, and less than 5% of children and less than 10% of adults are affected. Without CNS prophylaxis, approximately one third of individuals will develop CNS complications. Interventions associated with CNS prophylaxis include cranial irradiation, chemotherapy, and high doses of systemic chemotherapy. Specific treatment modalities or combinations of treatment vary and are determined by age and risk status.

EVALUATION AND TREATMENT Leukemia is often confused with other conditions, making early detection difficult. Persistent symptoms need intensive medical investigation. The diagnosis is made through examination of blood cells and bone marrow. A stained peripheral blood smear will exhibit low red blood cell and platelet counts along with the presence of leukemic blast cells (Figure 27-7). Examination of bone marrow demonstrates hypercellularity with 60% to 100% blast cells, an occasional normal myeloid, and erythroid precursors and rare to no megakaryocytes.

Chemotherapy, used in varying combinations, is the treatment of choice for leukemia.^9,10,12 Supportive measures include blood transfusions, antibiotics, antifungals, and antivirals. Allopurinol is used for preventing production of uric acid (which is elevated from cellular death because of treatment). Stem cell transplantation is now considered standard therapy for selected individuals with leukemia.

Bone marrow transplantation as a treatment has been increasing during the past two decades. Two controversial treatments are immunotherapy agents that induce differentiation of immature granulocytes (i.e., cis-retinoic acid) and marrow transplants. Although there has not been a marked improvement in response or survival of AML, dramatic improvements in survival and response of people with ALL have occurred.

The 5-year survival rate for those with leukemia is 38%, largely because of poor survival rates of individuals with certain types of leukemia (e.g., acute myelogenous). Since the 1970s, 5-year survival rates for those with ALL have increased from 38% to 65% for adults and from 53% to 85% for children. Factors influencing increased survival rate include the use of combined and multimodality treatment methods, improved supportive services such as blood banking and nutritional support, and antimicrobial treatment. The presence of the Philadelphia chromosome (observed in about 5% of children with ALL, in 30% of adults with ALL, and occasionally in AML) is a poor prognostic indicator.

Stimulation of blood cell growth and development with hematopoietic drugs has increased neutrophil recovery during chemotherapy and bone marrow transplant. Blood granulocyte numbers (e.g., eosinophils, neutrophils, basophils or mast cells) are normally in the range of 4000 to 6000 cells/μL, and susceptibility to infection develops below 1000 cells/μL. During a natural response to a bacterial infection, granulocytes usually rise in number to 10,000 to 20,000 cells/μL. Leukemia itself as well as the chemotherapeutic agents used to treat the disease can result in dramatic decreases in circulating granulocytes. The administration of colony-stimulating factors (CSFs) can raise white cell numbers and afford protection from infections.

Chronic Leukemias

The two main types of chronic leukemia are (1) chronic myelogenous leukemia (CML) and (2) chronic lymphocytic leukemia (CLL) (see Table 27-2). Several forms of CML can occur, depending on the lineage of the malignant cells (e.g., chronic neutrophilic leukemia [CNL], chronic eosinophilic leukemia [CEL]). Unlike cells in acute leukemia, chronic leukemic cells are well differentiated and can be readily identified. Individuals with chronic leukemia have a longer life expectancy, usually extending several years from the time of diagnosis.

The chronic leukemias account for the majority of cases in adults, accounting for approximately 30% of leukemias in the Western world. It is estimated that in 2008 more than 15,000 cases of CLL and 4500 cases of CML will be newly diagnosed in the United States.^13,14 The incidences of CLL and CML increase significantly in individuals older than 40 years, with prevalence in the sixth through eighth decades. CML is a group of diseases called myeloproliferative disorders, which also include polycythemia vera, primary thrombocytosis, and idiopathic myelofibrosis (invasion of bone marrow by fibrous tissue).

PATHOPHYSIOLOGY CLL involves malignant transformation and progressive accumulation of monoclonal B lymphocytes; rarely (less than 5%) are CLL malignancies of T-cell origin. The characteristic immunophenotype is expression of CD5, CD19, and CD23 molecules and low amounts of surface membrane Ig and CD20 molecules.¹⁵ CD5 is a signal transduction molecule linked to the B-cell receptor (BCR), CD19 is a low-affinity antigen receptor expressed on maturing B cells, but is lost in plasma cells, and CD23 is a low-affinity receptor for the Fc portion of IgE. Thus CLL is derived from transformation of a partially mature B cell that has not yet encountered antigen. The gene for the variable region of the antibody heavy chain (IGHV) is frequently mutated (30% to 40% of persons). (See Chapter 7 concerning immunoglobulin heavy-chain structure.) Clients with a mutated IGHV tend to have a more benign condition with a more slowly developing and less malignant disease.

The etiology of CLL is unknown. A familial tendency suggests a genetic linkage; first-degree relatives have a three times greater risk of developing the disease. It is rare in individuals less than 45 years of age, and when diagnosed, 95% of individuals are older than age 50. Genetic anomalies occur in approximately 90% of cases, frequently as deletions, although none has been linked to the etiology of CLL.

CLL cells that accumulate in the marrow do not interfere with normal blood cell production to the extent found in acute leukemias. This is a significant feature explaining the reduced severity in the beginning stage of disease. Accumulation of malignant B cells is the result of cell cycle arrest in the G₀/G₁ phase. CLL cells tend to express increased levels of proapoptotic proteins (e.g., BCL2) and suppress antiapoptotic proteins (e.g., BCL2L.1), which reduces their sensitivity to apoptosis. Because the major pathophysiologic deficit in CLL is the failure of B cells to mature into plasma cells that synthesize immunoglobulin, this often results in hypogammaglobulinemia (60% of clients).

CML is a member of the family of myeloproliferative disorder that also includes polycythemia vera (see Chapter 26), essential thrombocythemia, chronic idiopathic myelofibrosis (invasion of bone marrow by fibrous tissue), chronic neutrophilic leukemia, and chronic eosinophilic leukemia. CML is clonal and thought to arise from a hematopoietic stem cell. The cells observed in CML are heterogeneous in differentiation, depending on the stage of the disease.¹⁶ During the chronic phase the predominant cell is a long-lasting hematopoietic stem cell. A leukemic granulocyte-monocyte progenitor cell is seen. The Philadelphia chromosome is present in more than 95% of CML, and the presence of the BCR-ABL1 protein is responsible for initiation of CML. In advanced disease, the accumulation of additional mutations leads to the more aggressive leukemic phenotype.

CLINICAL MANIFESTATIONS Chronic leukemia advances slowly and insidiously. Approximately 70% of individuals with CLL are asymptomatic at the time of diagnosis. When symptoms do appear, the most common finding is lymphadenopathy. The most significant effect of CLL is suppression of humoral immunity and increased infection with encapsulated bacteria. Frequently the level of neutrophils is depressed, which adds to the risk of infection. Invasion of most organ cells is uncommon but infiltration does occur in lymph nodes, liver, spleen, and salivary glands. CNS involvement is rare. Approximately 10% of individuals develop a more aggressive malignancy, usually a diffuse large B-cell lymphoma. In these individuals, extreme fatigue, weight loss, night sweats, low-grade fever, and elevated levels of the enzyme lactic dehydrogenase, hypercalcemia, anemia, and thrombocytopenia are common.

Individuals with CML may progress through three phases of the disease; a chronic phase lasting 2 to 5 years during which symptoms may not be apparent, an accelerated phase of 6 to 18 months during which the primary symptoms develop, and a terminal blast phase (“blast crisis”) with a survival of only 3 to 6 months. The accelerated phase is characterized by excessive proliferation and accumulation of malignant cells. Splenomegaly is the most common finding, which is prominent and painful, but lymphadenopathy generally is not present. Liver enlargement also occurs, but liver function is rarely altered. Hyperuricemia is common and produces gouty arthritis. Infections, fever, and weight loss also are seen often. The terminal blast phase is characterized by rapid and progressive leukocytosis with an increase in basophils. In the later stages of the terminal phase, which then resembles AML, blast cells or promyelocytes predominate, and the individual experiences a blast crisis.

The acute effects of CML resemble those of acute leukemia but with more prominent and painful splenomegaly. Liver function rarely is altered despite enlargement, and lymphadenopathy generally is found only in the acute phase of the disease. Hyperuricemia invariably is present and produces gouty arthritis. Infections, fever, and weight loss are common findings in clients with CML.

EVALUATION AND TREATMENT Diagnosis of chronic leukemia depends on laboratory analyses of peripheral blood and bone marrow. Diagnosis of CLL is based on detection of a monoclonal B-cell lymphocytosis in the blood. The cells must have the immunophenotype characteristic of CLL (CD5+, CD19+, CD20 [weak], CD23+), at levels in excess of 5000 cells/μL, over a sustained period of time (usually 4 weeks). Bone marrow may contain more than 30% lymphocytes and be normocellular or hypercellular.

Treatment is frequently based on prognostic indicators. Typically, individuals with CLL survive 10 years or more. However, those with certain risk markers have a more aggressive disease that shortens survival to less than 3 years. Markers of high risk include anemia, thrombocytopenia, and no mutations in the IGHV gene. Mutations in IGHV correlate very closely with levels of intracellular ZAP-70, detection of which may be substituted for tests of IGHV mutation. ZAP-70 is a tyrosine kinase that is linked to the T-cell receptor (see Chapter 7). It is not normally detected in CLL cells with mutated IGHV, but is easily detectable by immunohistology in cells with an unmutated IGHV.

Chlorambucil, administered with or without corticosteroids, on a daily or intermittent schedule is the most common treatment for individuals with the most aggressive disease. Relief of symptoms is often achieved, but there is no substantial effect on survival. Combination therapy (CHOP) that includes cyclophosphamide, hydroxydaunomycin (Adriamycin), vincristine (Oncovin), and prednisone has an improved response rate but still does not demonstrate improved survival. Fludarabine, a purine analog, has a higher response rate and disease-free intervals, although survival is not affected. Promising results also have been obtained with the use of monoclonal antibodies (rituximab and alemtuzumab). Stem cell (autogenic and allogeneic) transplant also is being investigated as treatment; however, the advanced age at which individuals contract CLL makes its use less desirable.

Present treatment modalities for CML do not cure the disease, prevent blastic transformation, or prolong the average survival time. Standard treatment consists of combined chemotherapy, biologic response modifiers, and allogeneic stem cell transplant. Although transplantation is potentially curative, its use is limited by donor availability and high toxicity in older adults thus limiting use to those older than 65 years. Allogeneic bone marrow transplantation had increased survival time significantly (20% to 30%) when used after high-dose radiation and chemotherapy and with concurrent treatment with interferon. Traditional chemotherapy agents used are hydroxyurea and busulfan. The development and introduction of the tyrosine kinase inhibitor imatinib mesylate (Gleevec) as a treatment modality have changed current management of CML. Imatinib mesylate is highly specific for CML and suppression of BCR-ABL kinase activity. Suppression of hematologic symptoms occurs in 97% of treated individuals, and the use of imatinib mesylate has become the standard of care for CML. A small percentage of clients develop additional mutations in BCR-ABL that confer resistance to imatinib mesylate.¹⁷ Several new tyrosine kinase inhibitors are under investigation as treatments for CML.

Hodgkin Lymphoma

Hodgkin lymphoma (HL) is a malignant lymphoma first characterized by Thomas Hodgkin in 1832. It is estimated that more than 8000 individuals will be newly diagnosed with HL in 2008 (see Table 27-2). The incidence of HL is approximately 3.1 per 100,000 men and 2.5 per 100,000 women.¹⁹ The median age of diagnosis is age 38. Incidence rates for HL have declined, especially among older adults. The decrease in incidence in older adults is attributed to improved diagnostic accuracy. The incidence is greater in whites than blacks. Denmark, the Netherlands, and the United States have the highest incidence of HL, and Japan and Australia have the lowest incidence. HL peaks at two different ages: early in life in the second and third decades and later in life during the sixth and seventh decades.

PATHOPHYSIOLOGY HL is characterized by its progression from one group of lymph nodes to another, the development of systemic symptoms, and the presence of Reed-Sternberg (RS) cells (Figure 27-8). It is widely accepted that the RS cell represents the malignant transformed lymphocyte. The RS cells are often large and binucleate, with occasional mononuclear variants. The RS cells are necessary for the diagnosis of HL; however, they are not specific to HL. In rare instances, cells resembling them can be found in benign illnesses, as well as in other forms of cancer, including non-Hodgkin lymphomas and solid tissue cancers and in infectious mononucleosis.

The triggering mechanism for the malignant transformation of cells remains unknown. Classical HL appears to be derived from a B cell in the germinal center that has not undergone successful immunoglobulin gene rearrangement (see Chapter 7) and would normally be induced to undergo apoptosis. Survival of this cell may be linked to infection with EBV. Laboratory and epidemiologic studies have linked HL with EBV infections and EBV DNA. RNA, and proteins are frequently observed in HL cells. The RS cells secrete and release cytokines (e.g., IL-10, transforming growth factor-beta (TGF-β) that result in the accumulation of inflammatory cells that produces the local and systemic effects. HL is subcategorized into two main types: classical Hodgkin and nodular lymphocyte–predominant Hodgkin. Classical HL is subclassified into four types (Table 27-5) based on the morphology of RS cells, and the characteristics of the inflammatory cell infiltrate in the tumor.

The molecular events causing malignant transformation remain controversial; although RS cells are apparently from B-cell lineage, they express very few B-cell markers and express markers normally not found on B cells. For instance, RS cells do not express immunoglobulin, but do express CD15 (a carbohydrate adhesion molecule found on neutrophils), TARC (a Th2-cell specific chemokine), and T-cell–associated antigens (e.g., β-chain of the T-cell receptor).¹⁸ The precise genetic defects leading to development of HL are unknown, although several have been suggested. These generally include defects in immunoglobulin variable region gene rearrangement or defects in other B-cell–specific differentiation genes.

CLINICAL MANIFESTATIONS Many of the characteristic clinical features (Box 27-3) of HL can be explained by the complex action of cytokines and other growth factors that are secreted by the malignant cells. These substances induce infiltration and proliferation of inflammatory cells, resulting in an enlarged, painless lymph node in the neck (often the first sign of HL) (Figure 27-9). The discovery of an asymptomatic mediastinal mass on routine chest x-ray is not uncommon and is often an initial sign of HL. The cervical, axillary, inguinal, and retroperitoneal lymph nodes are commonly affected in HL (Figure 27-10). Local symptoms caused by pressure and obstruction of the lymph nodes are the result of the lymphadenopathy.

About one third of individuals will have some degree of systemic symptoms.²⁰ Intermittent fever, without other symptoms of infection, drenching night sweats, itchy skin (pruritus), and fatigue are relatively common. These constitutional symptoms accompanied by weight loss are associated with a poor prognosis. The Cotswold staging classification system used for HL is able to establish a correlation between the anatomic extent of the disease and prognosis (Table 27-6). This classification system is based on the individual’s medical history, examination (presence of symptoms and palpable lymph nodes), and other radiologic and hematologic results. Prognostic indicators include clinical stage, histologic type, tumor cell concentration and tumor burden, constitutional symptoms, and age.

Although HL rarely arises in the lung, mediastinal and hilar node adenopathy can cause secondary involvement of the trachea, bronchi, pleura, or lungs. Retroperitoneal nodes can involve vertebral bodies and nerves, causing displacement of ureters. Spinal cord involvement is more common in the dorsal and lumbar regions than in the cervical region. Although uncommon, skin manifestations include psoriasis and eczematoid lesions, causing itching and scratching.

As a result of direct invasion from mediastinal lymph nodes, pericardial involvement can cause pericardial friction rub, pericardial effusion, and engorgement of the neck veins. The gastrointestinal (GI) tract and urinary tract rarely are involved. Anemia often is found in individuals with HL, accompanied by a low serum iron and iron-binding capacity. Other laboratory findings include elevated sedimentation rate, leukocytosis, and eosinophilia. Leukopenia occurs in advanced states of HL.

Splenic involvement of HL depends on histopathologic type (see Table 27-5). The spleen is involved in 60% of cases of mixed cellularity and lymphocytic depletion types. With lymphocyte predominance and nodular sclerosis types, only 34% of cases reveal splenic involvement.

EVALUATION AND TREATMENT Because of the variability in symptoms, early definitive detection may be difficult. Asymptomatic lymphadenopathy can progress undetected for several years. Careful evaluation, including chest x-rays, lymphangiography, and biopsy, should be carried out for individuals with fever of unknown origin and peripheral lymphadenopathy.²⁰ A lymph node biopsy with scattered RS cells and a cellular infiltrate is highly indicative of HL. The effectiveness of treatment is related to the age of the individual and the extent of the disease. Approximately 75% of individuals diagnosed with HL are cured, largely because of successful treatment with irradiation and chemotherapy (Figure 27-11). More recent treatments include high-dose chemotherapy with bone marrow or stem cell transplant. Monoclonal antibodies also are being developed and nonmyeloablative allogeneic stem cell transplant has been found to help certain individuals even though this treatment is still under development.

The 5-year survival rate varies depending on which stage is identified at diagnosis.²⁰ The 5-year survival rate for stage I and II is 90% to 95%, 80% to 85% for stage III, and 75% for stage IV. Those with stage I or II disease are candidates for chemotherapy, combined, or radiation therapy alone. Individuals with stage III or IV disease, bulky disease (more than 10-cm mass or mediastinal disease with a transverse diameter exceeding 33% of the transthoracic diameter), or presence of B symptoms require combined chemotherapy with or without additional radiation treatment. Other factors, if present, have an influence on survival. Poorer survival is related to a high white blood cell count (greater than 15,000) or low hemoglobin (Hb) (less than 10.5); low lymphocyte count (less than 600); and being male. Cure for HL can be achieved in 70% of cases with current therapies.

Non-Hodgkin Lymphoma

The previously used generic classification of non-Hodgkin lymphoma (NHL) has been reclassified in the WHO/REAL scheme into B-cell neoplasms, which includes a variety of lymphomas including myelomas that originate from B cells at various stages of differentiation, and T-cell and NK-cell neoplasms, which includes lymphomas that originate from either T or NK cells. These cancers are differentiated from HL by lack of RS cells and other cellular changes not characteristic of HL.

More than 66,000 cases of NHL and 19,000 deaths are predicted for 2008 (see Table 27-2).²¹ The median age of diagnosis is 67 years of age. The incidence of NHL has increased from 8 persons per 100,000 in 1973 to 23.5 per 100,000 in 2006. Lymphomas from HIV and EBV have accounted for some of the increase but an actual cause has yet to be determined. Conversely, the mortality rate has risen at a slower rate. It is thought that newer treatment modalities are improving survival rates.

PATHOPHYSIOLOGY NHL is best described as a progressive clonal expansion of B cells, T cells, or NK cells. The genetic lesions affecting proto-oncogenes or tumor-suppressor genes result in cell immortalization and the resultant increase in malignant cells. Oncogenes may be activated by chromosomal translocations or the tumor-suppressor loci may be inactivated by deletion or mutation of chromosomes. Oncogenic viruses also may alter the genome of certain subtypes. The various subtypes of NHL may be identified by specific diagnostic markers related to various cytogenic lesions.

Lymphomas most likely originate from mutations in cellular genes (many of which are environmentally induced) in a single cell that lead to loss of control of proliferation and other aspects of cell growth. The most common type of chromosomal alteration in NHL is translocation, which disrupts the genes encoded at the breakpoints. Risk factors include a family history, exposure to a variety of mutagenic chemicals, irradiation, infection with certain cancer-related viruses (e.g., EBV, human herpesvirus-8, HIV, HTLV-1, hepatitis C), and immune suppression related to organ transplantation. Gastric infection with Helicobacter pylori increases the risk for gastric lymphomas. NHL is a disease of middle age, usually found in individuals more than 50 years old.

B cells account for approximately 85% of NHLs, with T cells and NK cells accounting for the remaining 15%. A very small percent originates from macrophages. NHL tumors are categorized by the level of differentiation, cell of origin, and rate of cellular proliferation. Tumor aggressiveness of many B-cell NHLs may be predicted by the pattern of cell growth and size. Tumors with a characteristic nodular pattern, vaguely resembling lymphoid follicular structures, are generally less aggressive than lymphomas with a diffuse pattern of proliferation. Small lymphocyte lymphomas are less aggressive than large cell lymphomas, which are generally intermediate to high grade in aggressiveness. However, small cells are characteristic of some subtypes of high-grade lymphomas.

CLINICAL MANIFESTATIONS Clinical manifestations of NHL usually start out as localized or generalized lymphadenopathy, similar to HL. The cervical, axillary, inguinal, and femoral chains are the most commonly affected sites. Generally, the swelling is painless and the nodes have enlarged and transformed over a period of months or years. Other sites of involvement are the nasopharynx, GI tract, bone, thyroid, testes, and soft tissue. Some individuals have retroperitoneal and abdominal masses with symptoms of abdominal fullness, back pain, ascites (fluid in the peritoneal cavity), and leg swelling.

Lymphomas are classified as low, intermediate, or high grade. A low-grade lymphoma, which also may be termed indolent, has a slow progression. Individuals with low-grade lymphoma commonly present with a painless, peripheral adenopathy. Spontaneous regression of these nodes may occur, mimicking the presence of an infection. Night sweats with an elevated temperature (more than 38° C [100.4° F]) and weight loss, as well as extranodular involvement, are not commonly present in the early stages but are common in advanced or end stage. Cytopenia, reflective of bone marrow involvement, is often observed. Hepatomegaly is common; however, splenomegaly is present in approximately 40% of individuals. Fatigue and weakness are more prevalent with advanced stages.

Immediate and high-grade lymphomas, which are more progressive, have a more varied clinical presentation. A high-grade lymphoma also may be termed aggressive. Adenopathy is common with more than one third of individuals having extranodal involvement. Common sites are the GI tract, skin, bone marrow, sinuses, genitourinary (GU) tract, thyroid, and CNS. Night sweats, with an increased temperature (more than 38° C [100.4° F]), as well as weight loss (more than 10% from baseline within 6 months) are present in approximately 30% to 40% of individuals. Some individuals have retroperitoneal and abdominal masses with symptoms of abdominal fullness, back pain, ascites (fluid in the peritoneal cavity), and leg swelling. Hepatomegaly and splenomegaly are often present. Differences in clinical features are noted in Table 27-7.

EVALUATION AND TREATMENT Biopsy is considered the primary means for diagnosis of NHL. Staging of NHL is necessary to identify treatment and make a prognosis. In addition to biopsy, computed tomography (CT) scans of the neck, chest, abdomen, and pelvis, as well as bilateral bone marrow aspirate, are performed. Data from all three procedures is necessary for appropriate staging. A common finding in NHL is noncontiguous lymph node involvement, which is not common in HL. The Ann Arbor staging system is most commonly used to stage NHL (Table 27-8). Treatment for NHL is quite diverse and depends on type (B cell or T cell) of tumor stage, histologic status (low, intermediate, or high grade), symptoms, age, and any comorbidities.

In general, treatment is initiated at the time of diagnosis; however, some low-grade lymphomas are widely disseminated at diagnosis, and because current therapy is not curative, observation without treatment may be the most appropriate choice. A partial remission may be achieved in some cases in which evidence of the disease remains but it does not progress.

Success of treatment is dependent on several parameters, including the type of lymphoma, stage of disease, cell type, involvement of organs outside the lymph nodes, age of the person, and the severity of the body’s reaction to the disease (e.g., fever, night sweats, weight loss).^20,22 Treatment with chemotherapy alone may be adequate in many cases, although radiation therapy is frequently included. Low-dose chemotherapy has been followed by autologous stem cell transplantation in some NHLs or for recurrent disease. Treatment of B-cell lymphomas with rituximab has proven effective. Rituximab is a commercial monoclonal antibody against antigen CD20, which is expressed on the surface of all B cells, including those that are malignant. Administration of rituximab depletes most B cells and allows the replenishment of normal B cells from the lymphoid stem cell pool. It has also proven useful in a variety of autoimmune diseases, including immune thrombocytopenia purpura, autoimmune anemias, systemic lupus erythematosus, and rheumatoid arthritis.

Individuals with NHL can survive for extended periods.^20,22 Survival with nodular lymphoma ranges up to 15 years, but those with diffuse disease generally do not survive as long. Overall, the survival rates of NHL are less than for Hodgkin lymphoma. For NHL, the survival rates are 1 year, 77%; 5 years, 59%; and 10 years, 42%. Many investigators believe that more aggressive treatment increases the cure rate. High-grade NHL is seen with increasing frequency in persons with AIDS and has an extremely poor prognosis.

Burkitt Lymphoma

Burkitt lymphoma is a B-cell tumor with unique clinical and epidemiologic features that accounts for 30% of childhood lymphomas worldwide. It occurs in children from east-central Africa and New Guinea and is characterized by a rapidly growing tumor primarily in the jaw and facial bones (Figure 27-12). In the United States, Burkitt lymphoma is rare, usually involves the abdomen, and is characterized by extensive bone marrow invasion and replacement. EBV, found in nasopharyngeal secretions, is associated with Burkitt lymphoma in African children.

PATHOPHYSIOLOGY EBV is associated with almost all cases (more than 90%) of Burkitt lymphoma. It is suspected that suppression of the immune system by other illnesses (e.g., HIV infection, chronic malaria) increases the individual’s susceptibility to EBV. B cells are particularly sensitive because of specific surface receptors for EBV. As a result, the B cell undergoes chromosomal translocations that result in overexpression of the C-MYC proto-oncogene and loss of control of cell growth (Figure 27-13). The most common translocation (75% of individuals) is between chromosomes 8 (containing the C-MYC gene) and 14 (containing the immunoglobulin heavy-chain genes). Other translocations have been reported between chromosome 8 and chromosomes 2 or 22, which contain genes for immunoglobulin light chains.

CLINICAL MANIFESTATIONS In non-African Burkitt lymphoma the most common presentation is abdominal swelling. More advanced disease may involve other organs—eye, ovaries, kidneys, glandular tissue (breast, thyroid, tonsil)—and presents with type B symptoms (night sweats, fever, weight loss).

EVALUATION AND TREATMENT The distribution of tumors and biopsies of enlarged lymph nodes or the bone marrow containing malignant B cells are usually indicative of Burkitt lymphoma. It is one of the most aggressive and quickly growing malignancies. However, the African variety in children has been successfully treated with radiotherapy and cyclophosphamide (60% survival overall; 90% survival with limited disease). The American type is more resistant to treatment.

Lymphoblastic lymphoma

Lymphoblastic lymphoma (LL) is a relatively rare variant of NHL (2% to 4%) but accounts for almost one third of cases of NHL in children and adolescents, with a male predominance. The vast majority of LL (more than 85%) is of T-cell origin, and the remainder arises from B cells. LL is similar to acute lymphoblastic leukemia and may be considered a variant of that disease.

PATHOPHYSIOLOGY The disease arises from a clone of relatively immature T cells that becomes malignant in the thymus. As with most lymphoid tumors, LL is frequently associated with translocations, primarily of the chromosomes that encode for the T-cell receptor (chromosomes 7 and 14). These aberrations result in increased expression of a variety of transcription factors and loss of growth control.

CLINICAL MANIFESTATIONS The first sign of LL is usually a painless lymphadenopathy in the neck. Peripheral lymph nodes in the chest become involved in about 70% of individuals, mostly above the diaphragm. LL is a very aggressive tumor that presents as stage IV in most people. T-cell LL is associated with a unique mediastinal mass (up to 75%) because of the apparent origin of the tumor in the thymus. The mass results in chest pain and may cause compression of bronchi or superior vena cava. The tumor may infiltrate the bone marrow in about half of those affected, and suppression of bone marrow hematopoiesis leads to increased susceptibility to infections. Other organs, including the liver, kidney, spleen, and brain, may also be affected. Many individuals express type B symptoms: fever, night sweats, and significant weight loss.

EVALUATION AND TREATMENT The most common therapeutic approach is combined chemotherapy with multiple drugs. In early disease, the response rate is high with increased survival; the 5-year survival in children is 80% to 90%, and it is 45% to 55% in adults. Although LL is easily treated, there is a high relapse rate: 40% to 60% of adults.

Conditions That Mimic Lymphomas

Certain other clinical conditions mimic the malignant lymphomas. These conditions include TB, syphilis, systemic lupus erythematosus, lung cancer, and bone cancer. An important distinction between lymphomas and other conditions is that lymphomas usually involve localized lymphadenopathy. Infectious precursors of malignant lymphomas are characterized by more generalized lymphadenopathy with systemic signs and symptoms.

Multiple Myeloma

Multiple myeloma (MM) is a clonal plasma cell cancer characterized by the slow proliferation of malignant cells as tumor cell masses in the bone marrow that usually results in destruction of the bone. Most MMs secrete large amounts of monoclonal proteins that resemble intact immunoglobulins. The reported incidence of myeloma has doubled in the past two decades, possibly as a result of more sensitive testing used for diagnosis. The annual incidence rate in the United States is 5.6 per 100,000, with almost 20,000 new cases and almost 11,000 deaths estimated for 2008.²⁴ Multiple myeloma occurs in all races, but the incidence in blacks is about twice that of whites. It rarely occurs before the age of 40 years—peak age of incidence is about 70 years. It is slightly more common in men than women. Neoplastic cells of multiple myeloma reside in the bone marrow and are usually not found in the peripheral blood. Occasionally it may spread to other tissues, especially in very advanced disease.

PATHOPHYSIOLOGY Many myelomas are aneuploidy, with chromosomal numbers ranging from 44 chromosomes to near tetraploid. Chromosomal translocations (break points) are responsible for development of myeloma in most individuals. The primary translocation involves the immunoglobulin heavy chain on chromosome 14 that relocates to sites of containing genes that cell cycle (cyclins) on chromosomes 11(q13), 12(p13), and 6(p21); oncogenes on chromosomes 16(q23), 8(q24), and 20; and fibroblast growth factor receptor on chromosome 4(p16).⁶ A progression of further secondary genetic alterations causes progression to an aggressive MM (Figure 27-15). The molecular pathogenesis of multiple myeloma also involves proto-oncogene mutations and, more rarely, inactivation of tumor-suppressor genes. The precise timing and reason for the genetic alteration and accumulation are unknown, but probably occur initially late in B-cell development after exposure to antigen.

Malignant plasma cells arise from one clone of B cells that produce abnormally large amounts of one class of immunoglobulin (usually IgG, occasionally IgA, and rarely IgD or IgE). The malignant transformation may begin early in B-cell development, possibly before encountering antigen in the secondary lymphoid organs. The myeloma cells return to either the bone marrow or other soft tissue sites. Their return is aided by cell adhesion molecules that help them target favorable sites that promote continued expansion and maturation.

Myeloma cells in the bone marrow directly secrete hepatocyte growth factor and parathyroid hormone-related peptide and adhere to stromal cells inducing their production of several cytokines (e.g., IL-6, IL-1, tumor necrosis factor-alpha (TNF-α), IL-11, macrophage inflammatory protein). (Lymphocytes and cytokines are described in Chapter 7.) All of these factors, IL-6 in particular, act as an osteoclast-activating factor and stimulate osteoclasts to reabsorb bone. This process results in bone lesions and hypercalcemia (high calcium levels in the blood) resulting from release of calcium from the breakdown of bone.

The antibody produced by the transformed plasma cell is usually defective, containing truncations, deletions, and other abnormalities, and is frequently referred to as a paraprotein (abnormal protein in the blood). Because of the large number of malignant plasma cells, the abnormal antibody, called the M protein, becomes the most prominent protein in the blood in 80% of myeloma clients (Figure 27-16). Suppression of normal plasma cells by the myeloma results in diminished or absent normal antibodies. The excessive amount of M protein may also contribute to many of the clinical manifestations of the disease. The myeloma may produce free immunoglobulin light chain (Bence Jones protein) that is present in the blood and urine in approximately 80% of clients and contributes to damage of renal tubular cells.

CLINICAL MANIFESTATIONS The common presentation of MM is characterized by elevated levels of calcium in the blood (hypercalcemia) (13% of persons), renal failure (19%), anemia (72% of persons), and bone lesions (80% of persons).²⁵ The hypercalcemia and bone lesions result from infiltration of the bone by malignant plasma cells and stimulation of osteoclasts to reabsorb bone. This process results in the release of calcium (hypercalcemia) and development of “lytic lesions” (round, “punched out” regions of bone) (Figure 27-17). Destruction of bone tissue causes pain, the most common presenting symptom, and pathologic fractures. The pain may be felt in a single bone of the entire skeleton, and the bones most commonly involved, in decreasing order of frequency, are the vertebrae, ribs, skull, pelvis, femur, clavicle, and scapula. Spinal cord compression, because of the weakened vertebrae, occurs in about 10% of individuals. The pain is initially aching, intermittent, and aggravated by weight-bearing. As the disease progresses, pain becomes severe and prolonged. It is common for the individual with myeloma to be treated for a slipped disk or arthritis before the correct diagnosis of myeloma is established. The individual may complain of weakness, fatigue, weight loss, and anorexia in addition to pain.

Proteinuria is observed in 90% of individuals. Renal failure may be either acute or chronic and is usually secondary to the hypercalcemia. Bence Jones protein may lead to damage of the proximal tubules. Anemia is usually normocytic and normochromic and results from inhibited erythropoiesis caused by tumor cell infiltration of the bone marrow.

The high concentration of paraprotein in the blood may lead to hyperviscosity syndrome. The increased viscosity interferes with blood circulation to various sites (brain, kidneys, extremities). Hyperviscosity syndrome is observed in up to 20% of individuals with MM. Additional neurologic symptoms (e.g., confusion, headaches, blurred vision) may occur secondary to hypercalcemia or hyperviscosity.

Suppression of the humoral (antibody-mediated) immune response results in repeated infections, primarily pneumonias and pyelonephritis. The most commonly involved organisms are encapsulated bacteria that are particularly sensitive to the effects of antibody; pneumonia caused by S. pneumoniae, Staphylococcus aureus, or K. pneumoniae or pyelonephritis caused by E. coli or other gram-negative organisms. Cell-mediated (T cell) function is relatively normal. Overwhelming infection is the leading cause of death from MM.

MM is a progressive disorder and is often preceded by a condition known as monoclonal gammopathy of undetermined significance (MGUS). MGUS is diagnosed by the presence of an M protein in the blood or urine without additional evidence of MM.²⁵ MGUS is present in approximately 1% of the general population and in 3% of individuals older than 70 years. Although MGUS is considered nonpathologic and requires no treatment, about 16% of individuals with MGUS progress to malignant plasma cell disorders. Progression of MM following MGUS advances to asymptomatic MM and finally symptomatic MM. Asymptomatic MM also may be referred to as smoldering myeloma and indolent myeloma.²⁵ Smoldering myeloma is usually characterized by the presence of an M protein and clonal bone marrow plasma cells, but with no indication of end-organ damage.

Most cases of symptomatic plasma cell tumors are multiple myeloma (about 94%). The remaining 6% is divided equally between solitary plasmacytomas and extramedullary plasmacytomas.²³ Solitary plasmacytoma is characterized by a solitary tumor of malignant plasma cells that may result in a single bone lesion or may be in the tissues (extramedullary plasmacytoma).²⁵ Extramedullary plasmacytoma can be found in a variety of soft tissues, but commonly in those of the upper respiratory tract (e.g., tonsils, nasopharynx, sinuses). Additionally, MM is staged to help determine prognosis and appropriate treatment (Table 27-9).

EVALUATION AND TREATMENT Diagnosis of MM is made by symptoms, radiographic and laboratory studies, and a bone marrow biopsy. Quantitative measurements of immunoglobulins (IgG, IgM, IgA) are usually performed. Typically, one class of immunoglobulin (the M protein produced by the myeloma cell) is greatly increased, whereas the others are suppressed. Serum electrophoretic analysis reveals increased levels of M protein. Because the M protein is monoclonal, each molecule has the same electric change and migrates at about the same site on electrophoresis, resulting in a highly concentrated protein (M spike). Bence Jones protein is observed in the urine or serum by immunoelectrophoresis or in the serum using enzyme-linked immunosorbent assay (ELISA) assays. Usually individuals with Bence Jones protein also have M protein in their blood. However, variants of MM include individuals in which free light chain only is produced and a rare variant that produces only free heavy chain, and approximately 1% are nonsecretory so that neither an M protein nor Bence Jones protein is produced. The amount of M protein in the blood may be used as a measure of the extent of the disease or as a measure of response to therapy. The serum level of another protein, free β₂-microglobulin, is a useful indicator of prognosis or effectiveness of therapy.

A bone marrow biopsy is performed to confirm the presence of myeloma cells in the marrow (Figure 27-18). Radiographic studies include x-ray, CT scans, and magnetic resonance imaging (MRI) to document the presence of bone lesions and areas of destruction. Diagnosis is based on findings and the degree of involvement. The individual must have all three major criteria (Box 27-4).

Combinations of chemotherapy, radiation therapy, and plasmapheresis (exchange), and marrow transplantation have been the standards of treatment.²³ Conventional combinations of chemotherapeutic agents have included melphalan and prednisone (MP); MP with vincristine, carmustine, and cyclophosphamide; vincristine, doxorubicin, and dexamethasone; and thalidomide and dexamethasone. The drug thalidomide disrupts the stromal marrow–MM cell interaction by modulating cell surface adhesion molecules and inhibiting angiogenesis. In addition, it increases apoptosis and G₁ growth arrest (i.e., the cell cycle gap 1; see Chapter 1) of MM cells.

Dose intensification improves the outcomes in younger clients; however, long-term remissions are obtained in a minority of clients. Thus intensive research measuring the effect of novel new therapies is the objective of ongoing trials. Gene expression profiling (GEP) helps improve the treatment of MM because it identifies prognostic subgroups and defines the molecular pathways associated with these subgroups. Newer agents (e.g., bortezomib, lenalidomide) have broadened the therapeutic regimens for end-stage myeloma.

High-dose chemotherapy followed by blood-forming stem cell transplantation (SCT) has become standard treatment for younger individuals (up to 70 years old in some trials).^23,26 Survival is increased with SCT compared with chemotherapy alone. SCT uses the client’s own blood-forming stem cells (autologous) or a donor’s cells (allogeneic). Survival may be prolonged by performing a second autologous transplant within 6 to 12 months from the first transplant.

Radiation with high-energy x-rays is used more for a localized effect rather than systemic. It is most often used to treat areas of the bone that have been damaged and are not responding to chemotherapy. In addition, it may be used to treat sites where tumor has led to collapse of vertebrae and spinal cord compression.

Additional interventions are used to prevent and treat complications arising from progression of the disease. Drugs that inhibit bone resorption—bisphosphonates—reduce the incidence of skeletal damage, which also reduces hypercalcemia and decreases bone pain. Hydration and diuretics may be used to maintain a high urine output, and antibiotics to treat recurring infections.

The prognosis for persons with MM remains poor. The median survival for all states of MM is 3 years. Individuals with multiple bone lesions, if untreated, rarely survive more than 6 to 12 months. Individuals with inactive (indolent) myeloma, however, can survive for many years. With chemotherapy and aggressive management of complications, median survival may increase to 24 to 30 months, with a 10-year survival rate of 3%.

Waldenström Macroglobulinemia

Waldenström macroglobulinemia (WM), also called lymphoplasmacytic lymphoma, is a rare type of slow-growing plasma cell tumor that secretes a monoclonal IgM molecule. Approximately 1500 new cases are diagnosed yearly in the United States; the median age of diagnosis is 63 years of age.²⁷ WM shares a great deal of similarity with multiple myeloma regarding its plasma cell origin, diagnosis, and treatment. However, the overproduction of the macromolecule IgM leads to certain unique clinical characteristics.

PATHOPHYSIOLOGY WM arises from plasma cells that have undergone genetic rearrangement of the variable region genes (V, D, J), but have not undergone class switch. Therefore, the principal secretory product of the tumor is IgM. Although no definitive genetic defect has been identified, WM may originate from aberrant B cell maturation and class switch.

Most of the pathology is associated with the production of large amounts of IgM, a large-molecular-weight protein (about 900,000 daltons). Excessive production leads to thickening of the blood and abnormally high blood viscosity (hyperviscosity syndrome). The increased viscosity interferes with circulation to various sites (e.g., eyes, brain, kidneys, extremities). IgM paraprotein may also result in cryoglobulins (proteins that precipitate from the blood at lower than body temperature). Hyperviscosity syndrome is observed in up to 20% of individuals with WM.

CLINICAL MANIFESTATIONS Many clients with WM are asymptomatic. The most common symptoms include weakness and fatigue, bleeding (from gums and nose), weight loss, and bruising. Bleeding may result secondary to formation of complexes among the macroglobulin, clotting factors, and platelets that diminish hemostatic capacity. If hyperviscosity syndrome occurs, the individual may develop neurologic problems (e.g., blurred vision, loss of vision, headaches, dizziness, vertigo), The macromolecules may also precipitate in colder regions of the body (cryoglobulins) leading to Raynaud phenomenon.

Although the malignant plasma cells invade the bone marrow, erosion of the bone is not commonly observed; less than 5% of individuals have lytic bone lesions. The tumor often disseminates to other organs, including the spleen, lymph nodes, and liver. Anemia occurs in about 10% of clients, secondary to tumor infiltration of the bone marrow. Peripheral hemolysis can also result from production of cold agglutinins.

EVALUATION AND TREATMENT Diagnosis is made based on high levels of monoclonal IgM in the blood and the identification of malignant cells in bone marrow aspirates. Other hematologic abnormalities may be observed, especially anemia (80% of clients with symptomatic WM) but also thrombocytopenia and leukopenia. Bence Jones protein may be observed in almost half of individuals with WM.

Treatment is similar to that described for multiple myeloma.²⁸ First-line therapy includes combined chemotherapy with nucleoside analogs, alkylating agents, and monoclonal antibody (e.g., rituximab). Bone marrow stem cell transplantation has also proven effective in some individuals. The current recommendations include treatment with a combination of dexamethasone, rituximab, and cyclophosphamide, with the use of other drugs (e.g., doxorubicin, vincristine, and nucleoside analogs) in individuals with very high levels of M protein.

Thrombocytopenia

Thrombocytopenia is defined as a platelet count less than 150,000 platelets/mm³ of blood, although most health care providers do not consider the decrease of significance unless the count falls to less than 100,000 platelets/mm³ of blood.³⁰ Hemorrhage resulting from minor trauma does not usually occur until the count falls below 50,000/mm³. Spontaneous bleeding without apparent trauma can occur with counts between 10,000 and 15,000/mm³, resulting in petechiae, ecchymoses, larger purpuric spots, or frank bleeding from mucous membranes. Severe spontaneous bleeding may result if the count is less than 10,000/mm³ and can be fatal if it occurs in the gastrointestinal tract, respiratory system, or CNS.

Before the diagnosis of thrombocytopenia is made, pseudothrombocytopenia must be ruled out. This phenomenon occurs in approximately 1 in 1000 to 1 in 10,000 laboratory samples and is an in vitro artifact that may occur when a blood sample is analyzed by an automated cell counter. Platelets in the sample may become nonspecifically agglutinated by immunoglobulins in the presence of ethylenediaminetetraacetic acid (EDTA), a preservative in banked blood. The agglutinated platelets are not counted, thus giving an apparent, but false, thrombocytopenia. Thrombocytopenia also may be falsely diagnosed because of a dilutional effect observed after massive transfusion of platelet-poor packed cells to treat a hemorrhage. This occurs when more than 10 units of blood have been transfused within a 24-hour period. The hemorrhage that necessitated the transfusion also accelerates the loss of platelets, which further contributes to the pseudothrombocytopenic state. Splenic sequestering of platelets secondary to hypersplenism (congestive) induces an apparent thrombocytopenia, as does hypothermia (less than 25° C [77° F]), which is reversed when temperatures return to normal, suggesting an increased platelet sequestration in response to chilling.

PATHOPHYSIOLOGY Thrombocytopenia results from decreased platelet production, increased consumption, or both. The condition also may be congenital or acquired and primary or secondary to other acquired or congenital conditions. Thrombocytopenia secondary to congenital conditions occurs in a large number of different diseases, although each is relatively rare. These include thrombocytopenia with absence of radius (TAR) syndrome, Wiskott-Aldrich syndrome (see Chapter 8), various forms of MYH9 gene mutation (e.g., May-Hegglin syndrome), X-linked thrombocytopenia, and many other examples.

Acquired thrombocytopenia is more common and may occur as a result of decreased platelet production secondary to viral infections (e.g., EBV, rubella, CMV, HIV), drugs (e.g., thiazides, estrogens, quinine-containing medications, chemotherapeutic agents, ethanol), nutritional deficiencies (vitamin B₁₂ or folic acid in particular), chronic renal failure, bone marrow hypoplasia (e.g., aplastic anemia), radiation therapy, or bone marrow infiltration by cancer. Most common forms of thrombocytopenia are the result of increased platelet consumption. Examples include heparin-induced thrombocytopenia, idiopathic (immune) thrombocytopenic purpura, thrombotic thrombocytopenic purpura.

Thrombocythemia

Thrombocythemia (also called thrombocytosis) is defined as a platelet count greater than 400,000/mm³ of blood.³⁹ Thrombocythemia may be primary or secondary (reactive) and is usually asymptomatic until the count exceeds 1 million/mm³ of blood. Then intravascular clot formation (thrombosis), hemorrhage, or other abnormalities can occur.

PATHOPHYSIOLOGY Secondary thrombocythemia may occur after splenectomy because platelets that normally would be stored in the spleen remain in circulating blood. The increase in platelets may be gradual, with thrombocythemia not occurring for up to 3 weeks after splenectomy. Reactive thrombocythemia may occur during some inflammatory conditions, such as rheumatoid arthritis and cancers. In these conditions, excessive production of some cytokines (e.g., IL-6, IL-11) may induce increased production of thrombopoietin in the liver, resulting in increased megakaryocyte proliferation. Reactive thrombocythemia may also occur during a variety of physiologic conditions, such as after exercise. Because of the relatively self-resolving nature of secondary thrombocythemia, the remaining discussion will focus on the more severe primary form.

Essential (primary) thrombocythemia (ET) is a chronic myeloproliferative disorder characterized by excessive platelet production resulting from a defect in bone marrow megakaryocyte progenitor cells.⁴⁰ The overall incidence of ET is 0.8 per 100,000 in the United Kingdom, 2.53 in the United States, and 0.59 in Denmark. It is more common in middle-age individuals, with the majority of cases occurring between ages 50 and 60 years. There is no known gender preference. There also is a rare hereditary type of ET called familial essential thrombocythemia (FET) that is inherited in an autosomal dominant pattern.

The thrombocythemia is secondary to increased plasma thrombopoietin levels resulting from defects in the thrombopoietin receptor. The defective receptor cannot adequately bind and remove thrombopoietin from the blood, thus circulating levels remain high. Along with increased platelet levels, there may be a concomitant increase in red cells, indicating a myeloproliferative disorder; however, the increase in red cells is not to the extent seen in polycythemia vera (see Chapter 26). The bone marrow of affected individuals with ET is characterized by hyperplasia of megakaryocytes. The platelets of affected individuals appear to have a normal survival time, compatible with a defect in production rather than an increase in platelet life span.

RBCs in ET tend to aggregate and contribute to the blockage of flow in the microvasculature and altered interactions between platelets and the vascular endothelium.⁴¹ Increased adherence of erythrocytes to the endothelium appears to result from a mutation in an erythrocyte Janus kinase 2 (JAK2) that is responsible for phosphorylation of the erythrocyte receptor for endothelial laminin.^42,43 The frequency of JAK2 mutations in ET is about 30%. Increased platelet aggregation arises from several mutations that result in altered platelet membrane glycoproteins, particularly resulting in increased expression of GPIV, and increased secretion of thromboxane.

CLINICAL MANIFESTATIONS Clinical manifestations vary significantly among individuals. Those with ET are at risk for large-vessel arterial or venous thrombosis, and, particularly, microvasculature thrombosis leading to ischemia in the fingers, toes, or cerebrovascular regions.⁴¹ The primary presenting symptoms of microvasculature thrombosis are erythromyalgia, headache, and paresthesias. Erythromyalgia is characterized by unilateral or bilateral warm, congested, red hands and feet with painful burning sensations, particularly in the forefoot sole and one or more toes. The lower extremities are affected more often, and only one side may be involved. The pain is initiated by standing, exercise, or warmth and relieved by elevation and cooling. In extreme situations, acrocyanosis and gangrene may result.

Arterial thrombosis is more common than venous thrombosis and may involve the coronary and renal arteries. The carotid, mesenteric, and subclavian arteries also may be affected. Myocardial ischemia and infarction have occurred without clear evidence of coronary artery disease. Deep venous thrombosis of the lower extremities and pulmonary embolism are the major sites for venous involvement. Intra-abdominal venous thrombosis (portal and hepatic) also are common sites of venous thrombosis.

Microvascular thrombosis in the CNS is usually associated with headache and dizziness, with paresthesias, transient ischemic attacks, strokes, visual disturbances, and seizures also being reported. Major thrombotic events, not directly related to the platelet count, occur in about 20% to 30% of individuals with ET. Prior history of thrombotic events, advanced age, and duration of thrombocytosis are predictors of future thrombotic complications. Individuals older than age 60 are at greatest risk.

Although thrombosis is the most common symptom, hemorrhage can also occur. Sites for bleeding include the GI tract, skin, mucous membranes, urinary tract, gums, tooth sockets (after extraction), joints, eyes, and brain. GI bleeding may be mistaken for a duodenal ulcer. Hemorrhage is not severe, and generally occurs in the presence of very high platelet counts, and occasionally requires transfusion. Important is recognition that bleeding and clotting may exist simultaneously and individuals will not necessarily be “bleeders” or “clotters.”

EVALUATION AND TREATMENT Initial diagnosis is not difficult; as many as two thirds of affected individuals are diagnosed from a routine CBC. Secondary thrombocytosis may present as a moderate rise in the platelet count that resolves with treatment or resolution of the underlying condition. ET is diagnosed by a platelet count greater than 600,000/mm³ and remains elevated, with no other indicated cause, such as arthritis, iron deficiency anemia, cancer, or splenectomy. Many individuals present with a mild anemia and a slightly elevated white blood cell count.

After diagnosis, these individuals may recall events related to thrombosis or hemorrhage. Manifestations of ET may be mistaken for CML; therefore, differentiation of the two is important because treatment varies significantly. Identification of the Philadelphia chromosome is recommended in all cases of ET.

Treatment of ET is directed toward preventing thrombosis or hemorrhage.⁴⁴ Whether to reduce platelet count remains a significant treatment issue. Historically treatment of ET relied on the use of alkylating agents (busulfan) or radiophosphorus (³²P) to suppress platelet production. Hydroxyurea, a nonalkylating myelosuppressive agent, has been the drug of choice to suppress platelet production: however, long-term use may cause progression to other myelodysplastic disorders, particularly AML or myelofibrosis.⁴⁴ Conversion to myelofibrosis occurs approximately 8% of the time and conversion to AML occurs approximately 3.5% of the time when treated with Vhydroxyurea as a single cytotoxic agent, but increases to 14% when more than one cytotoxic agent is used.

Interferon (TFN) also may be used and has a response rate of 80%. TFN may not work for everyone because it has many side effects and 20% of individuals may be intolerant. Anagrelide is now considered to be the drug of choice. Anagrelide specifically interferes with platelet maturation rather than production, thus not affecting erythropoiesis or leukopoiesis.

Aspirin also is used in the treatment of ET; however, its action is not to reduce the platelet count but to prevent adherence of platelets to each other and prevent thrombus formation. Early studies with aspirin found hemorrhage to be a major contraindication for its use; however, in lower doses (80 to 160 mg/daily) it effectively alleviates erythromyalgia and transient neurologic manifestations.

Prognosis and survival of individuals with ET have been somewhat difficult to establish. ET is not necessarily considered life threatening, but in those older than age 60 and who have had previous incidences of thrombosis, complications are more common and have a higher risk of mortality.

Alterations of Platelet Function

Qualitative alterations in platelet function occur with an increased bleeding time in the presence of a normal platelet count. Associated clinical manifestations include spontaneous petechiae and purpura, bleeding from the GI tract, genitourinary tract, pulmonary mucosa, and gums. Congenital alterations in platelet function (thrombocytopathies) are quite rare and may be categorized into several types of disorders: (1) platelet-vessel wall adhesion, (2) platelet-platelet interactions, (3) platelet granules and secretion, (4) arachidonic acid pathways, and (5) membrane phospholipid regulation (coagulation protein-platelet interactions).⁴⁵

Disorders of platelet-vascular wall adhesion result from aberrations of the platelet membrane glycoprotein GPIb-IX-V (Bernard-Soulier syndrome), the collagen receptor (GPVI) or deficiencies of vWF. The GPIb protein is the most commonly mutated in individuals with Bernard-Soulier syndrome. Lack of these proteins prevents platelets from adhering to collagen, resulting in impaired hemostasis and clinical hemorrhage.

Disorders of platelet-platelet interactions result in failure of platelets to aggregate in response to adenosine diphosphate (ADP), collagen, epinephrine, or thrombin because of a deficiency in the glycoprotein (αIIbβ3) that acts as a receptor for fibrinogen, vWF, and fibronectin (Glanzmann thrombasthenia). Lack of this protein results in a failure to build “fibrinogen bridges” between platelets (see Figure 25-20). Defects also can occur in platelet receptors for platelet activators. These include mutations in the receptors for thromboxane or ADP.

Disorders of platelet granules and secretion and arachidonic pathways are characterized by initial normal platelet aggregation with collagen or ADP; however, there is failure of subsequent processes, specifically secretion of prostaglandins and release of granules. Defective α-granule numbers or release (gray platelet syndrome) results from mutations in several aspects of granule function, including biosynthesis or loading of proteins normally found in these granules. Defects in dense granules include Hermansky-Pudlak syndrome, Chédiak-Higashi syndrome, and delta-storage pool disease. These usually result from mutations in proteins involved in formation of dense granules or their movement to the plasma membrane. Defects in the thromboxane pathway prevent the release of this mediator.

Externalization of plasma membrane phosphatidylserine (PS) is necessary for effective platelet function. In Scott syndrome, the enzyme responsible for PS efflux is defective, thus platelets are unable to support the activation of factor X and prothrombin. The inreverse of Scott syndrome is Stormorken syndrome, in which platelets constitutively externalize PS.

Acquired disorders of platelet function are more common than the congenital disorders and may be categorized into three principal causes: (1) drug effects, (2) systemic inflammatory conditions, and (3) hematologic conditions.

Multiple drugs are known to affect platelet function in several ways: inhibition of platelet membrane receptors, inhibition of prostaglandin pathways, and inhibition of phosphodiesterase activity. Aspirin is the most commonly used drug that affects platelets and the only drug specifically used for its platelet effects. It irreversibly inhibits cyclooxygenase function for several days after administration. Nonsteroidal anti-inflammatory drugs also affect cyclooxygenase, although in a reversible fashion.

Systemic disorders that affect platelet function are chronic renal disease, liver disease, cardiopulmonary bypass surgery, severe deficiencies of iron or folate, and antiplatelet antibodies associated with autoimmune disorders. Hematologic disorders that cause platelet dysfunction are chronic myeloproliferative disorders, multiple myeloma, leukemias, myelodysplastic syndromes, and dysproteinemias.

Impaired Hemostasis

Impaired hemostasis, or the inability to promote coagulation and the development of a stable fibrin clot, is commonly associated with liver disorders, either resulting from the lack of vitamin K or specific diseases of the liver.

Consumptive Thrombohemorrhagic Disorders

Consumptive thrombohemorrhagic disorders are a heterogeneous group of conditions that demonstrate the entire range of hemorrhagic and thrombotic pathologic conditions. Symptoms range from subtle to devastating and generally are considered to be intermediary disease processes that complicate many primary disease states. These disorders also are characterized by confusion and controversy regarding diagnosis, treatment, and management. No one definition can cover all possible varieties of these disorders; however, disseminated intravascular coagulation is the most common term used in the clinical setting to describe a pathologic condition associated with hemorrhage and thrombosis.

Thromboembolic Disease

Certain conditions within the blood vessels predispose an individual to develop clots spontaneously.⁵² A stationary clot attached to the vessel wall is called a thrombus (Figure 27-21). A thrombus is composed of fibrin and blood cells and can develop in either the arterial or venous system. Arterial thrombi form under conditions of high blood flow and are composed mostly of platelet aggregates held together by fibrin strands. Venous thrombi form in conditions of low flow and are composed mostly of red cells with larger amounts of fibrin and few platelets.

A thrombus may eventually grow large enough to reduce or obstruct blood flow to tissues or organs, such as the heart, brain, or lungs, depriving them of essential nutrients critical to survival. A thrombus also has the potential of detaching from the vessel wall and circulating within the bloodstream (referred to as an embolus). The embolus may become lodged in smaller blood vessels, blocking blood flow into the local tissue or organ and leading to ischemia. Whether episodes of thromboembolism are life threatening depends on the site of vessel occlusion.

Therapy consists of removal or breakdown of the clot and supportive measures. Anticoagulant therapy is effective in treating or preventing venous thrombosis; it is not as useful in treating or preventing arterial thrombosis. Parenteral heparin is the major anticoagulant used to treat thromboembolism. Oral coumarin drugs also are widely used, particularly for individuals not hospitalized. More aggressive therapy may be indicated for such conditions as pulmonary embolism, coronary thrombosis, or thrombophlebitis. Streptokinase and urokinase activate the fibrinolytic system and are administered to accelerate the lysis of known thrombi. Thrombolytic therapy has limited uses and is prescribed with a high degree of caution because it can cause hemorrhagic complications.

The risk for developing spontaneous thrombi is related to several factors, referred to as the Virchow triad: (1) injury to the blood vessel endothelium, (2) abnormalities of blood flow, and (3) hypercoagulability of the blood.

Vascular endothelial injury can result from atherosclerosis (plaque deposits on arterial walls). Atherosclerosis initiates platelet adhesion and aggregation, promoting the development of atherosclerotic plaques that enlarge, causing further damage and occlusion. Other causes of vessel endothelial injury may be related to hemodynamic alterations associated with hypertension and turbulent blood flow. Injury also is caused by radiation injury, exogenous chemical agents (toxins from cigarette smoke), endogenous agents (cholesterol), bacterial toxins or endotoxins, or immunologic mechanisms. Whatever the precipitating cause of endothelial injury, it is a potent thrombogenic agent.

Sites of turbulent blood flow in the arteries and stasis of blood flow in the veins are at risk for thrombus formation. In areas of turbulence, platelets and endothelial cells may be activated, leading to thrombosis. In sites of stasis, platelets may remain in contact with the endothelium for prolonged times, and clotting factors that would normally be diluted with fresh-flowing blood are not diluted and may become activated. The most common clinical conditions that predispose to venous stasis and subsequent thromboembolic phenomena are major surgery (e.g., orthopedic surgery), acute myocardial infarction, congestive heart failure, limb paralysis, spinal injury, malignancy, advanced age, the postpartum period, and bed rest longer than 1 week. Turbulence and stasis occur with ulcerated atherosclerotic plaques (myocardial infarction), hyperviscosity (polycythemia), and conditions with deformed red cells (sickle cell anemia).

Hypercoagulability, or thrombophilia, is the condition in which an individual is at risk for thrombosis. Hypercoagulability is differentiated according to whether it results from primary (hereditary) or secondary (acquired) causes. Primary causes include defects in proteins involved in hemostasis. Secondary causes include a variety of clinical disorders or conditions (Box 27-9). It is not well understood why there is not a greater incidence of thrombosis formation in hypercoagulable states associated with various disease states and conditions.