DEFICIENCY, EXCESS, OR DYSFUNCTION OF BLOOD CELLS
Alterations in blood cell concentration are the primary manifestations of clonal hematopoietic disorders. The clinical manifestations of deficiencies or excesses of individual blood cell types are described in the chapters on clinical manifestations of disorders of erythrocytes (Chap. 34), granulocytes (Chap. 64), monocytes (Chap. 69), and platelets (Chap. 116).
Several clonal hematopoietic diseases frequently manifest as qualitative abnormalities of blood cells. Abnormal red cell shapes, red cell or granulocyte enzyme deficiencies, abnormal neutrophil granules, bizarre nuclear configurations, disorders of neutrophil chemotaxis, phagocytosis or microbial killing, giant platelets, abnormal platelet granules, and disturbed platelet function can occur in some patients with oligoblastic myelogenous leukemia and primary myelofibrosis. In oligoblastic myelogenous leukemia, the effects of severe cytopenia usually dominate. In primary myelofibrosis and essential thrombocythemia, functional platelet abnormalities may contribute to the hemorrhagic diathesis, especially if surgery or injury occurs. Paroxysmal nocturnal hemoglobinuria is a hematopoietic multipotential cell disease resulting from a somatic mutation of the PIG-A gene on the active X chromosome. The mutation causes a highly specific alteration in blood cell membranes, a deficiency in the glycosylphosphatidylinositol (GPI) anchor, with decreased cell-surface CD59, rendering the blood cells exquisitely sensitive to complement lysis. In its classic form, chronic hemolytic anemia is coupled with mild decreases in neutrophil and platelet counts but depressions in hematopoiesis often occur (hypoplastic marrow; Chap. 40). Patients with CML or polycythemia vera usually do not have clinically significant functional abnormalities of cells, although in polycythemia vera, neutrophils often are activated with heightened metabolic rates and enhanced phagocytosis.
Secondary clinical manifestations occur as a result of the proliferation and accumulation of the malignant (leukemic) cells.
EFFECTS OF LEUKEMIC BLAST CELLS
Myeloid (granulocytic) sarcomas (also called chloromas or myeloblastomas) are discrete tumors of leukemic cells that form in skin and soft tissues, breast, periosteum and bone, lymph nodes, mediastinum, lung, pleura, gastrointestinal tract, gonads, urinary tract, uterus, central nervous system, and virtually any other site (Chap. 88).57,58,59 They can develop in patients with AML or the accelerated phase of CML and, occasionally, may be the first manifestation of AML, preceding morphologic evidence of the disease in marrow and blood by months or, sometimes, years. AML with the t(8;21) and inv(16) has a predisposition to form myeloid sarcomas, although other AML types may also. Myeloid sarcomas can be mistaken for large cell lymphomas because of the similarity of the histopathology in biopsy specimens from soft tissues. In the past, approximately 50 percent of cases that occur in the absence of blood and marrow involvement initially were misdiagnosed, usually as lymphoma.57 The presence of eosinophils or other granulocytes in the mass may arouse suspicion of a myeloid sarcoma; however, immunohistochemistry should be used on such lesions to identify myeloperoxidase, lysozyme, CD117, CD61, CD68/KP1, and other relevant CD markers of myeloid cells. One of four histopathologic patterns usually is evident by immunocytochemistry: myeloblastic, monoblastic, myelomonoblastic, or megakaryoblastic.
More diffuse collections of leukemic promonocytes or monoblasts can invade the skin, gingiva, anal canal, lymph nodes, central nervous system, or other tissues of patients with AML of the monocytic subtype and may form tumors in those locations. Leukemic monocytes tend to mature to the point at which they develop many of the cytoplasmic and membrane features required for motility and tissue entry.60,61,62 Moreover, leukemic monocytes proliferate and survive in tissues for long periods. Consequently, this AML phenotype has a higher frequency of overt infiltrative tissue lesions than do other forms of AML.
Extramedullary tumors may usher in the accelerated phase of CML. These tumors may be composed of myeloblasts or lymphoblasts, although in each case the Ph chromosome or the BCR-ABL1 fusion is present in the cells, indicating the extramedullary Ph-positive lymphoblastomas are the tissue variant of the predisposition of CML to transform into a terminal deoxynucleotidyl transferase-positive lymphoblastic leukemia in approximately 30 percent of patients who enter blast crisis (Chap. 89).
Release of Procoagulants and Fibrinolytic Activators
Microvascular thrombosis is a feature of AML of the promyelocytic type, although thrombosis can occur in other forms of acute leukemia, especially in cases with elevated white cell counts or monocytic phenotypes.63,64 The leukemic promyelocytes liberate tissue factor and other procoagulants, giving rise to disseminated intravascular coagulation, and annexin II, which augments conversion of plasminogen to plasmin and contributes to the activation of fibrinolysis (Chaps. 88, 129, and 135). Each mechanism contributes to hypofibrinogenemia and hemorrhage. Thrombin generation may mediate the microvascular thrombotic aspect of this process, which can occur in acute promyelocytic, acute monocytic, or acute myelomonocytic leukemia, either before or after cytotoxic treatment.65,66 The increased fibrinolytic activity further complicates coagulopathy in patients with promyelocytic leukemia.
Large-vessel arterial thrombosis is very rare as a presenting feature or complication of leukemia but has occurred in the setting of hyperleukocytosis and as a presenting feature of acute promyelocytic leukemia.67,68
The plasma levels of protein C antigen, functional protein C, free protein S, and antithrombin are decreased in some patients with AML. Although these changes are particularly notable in acute promyelocytic leukemia, they occur occasionally in other morphologic variants of AML. The changes are not related to liver disease or white cell count.69,70
A proportion of patients with AML (5 to 15 percent) and CML (10 to 20 percent) manifest extraordinarily high blood leukocyte counts.71,72,73,74,75 These patients present special problems because of the effects of blast cells in the microcirculation of the lung, brain, eye, ear, and penis, and the metabolic effects that result when massive numbers of leukemic cells in blood, marrow, and tissues are simultaneously killed by cytotoxic drugs. Cell concentrations greater than 100,000/μL (100 × 109/L) in AML and greater than 300,000/μL (300 × 109/L) in CML usually are required to produce such problems. In CML, the manifestations of hyperleukocytosis are usually reversed by cytoreduction and may not portend a poor outcome with anti–tyrosine kinase therapy. In AML, intracerebral hemorrhage and the impairment of pulmonary function are the most serious manifestations in predicting early death.74,75 A respiratory distress syndrome attributed to pulmonary leukostasis occurs in some patients with acute promyelocytic leukemia after all-trans-retinoic acid therapy.76 The syndrome is usually, but not always, associated with prominent neutrophilia.
The viscosity of blood is related to the total cytocrit and usually is not increased in hyperleukocytic leukemias because the reduced hematocrit compensates for increased leukocrit. This compensatory change is invariably present in AML. In CML there is a very close negative correlation of hematocrit with leukocrit, preventing an increase in bulk viscosity.71 Occasional patients with hyperleukocytic CML who are transfused initially with red cells may have a blood viscosity increased above normal.
Pathologic studies of patients who have died with hyperleukocytosis have identified leukoocclusion and vascular invasion in small vessels of the lung, brain, or other sites. Because viscosity in the microcirculation is a function of the plasma viscosity and the deformability of individual cells in capillaries, leukocytes should transiently raise the viscosity in such small channels. Flow in microvascular channels decreases if poorly deformable blast cells enter capillary channels.77 With high leukocyte counts, chronically reduced flow may reduce oxygen transport to tissues because the probability of leukocytes being in microchannels should increase as a function of white cell count. Moreover, trapped leukemic cells have an oxygen consumption rate that contributes to deleterious effects in the microcirculation. Leukocyte aggregation, leukocyte microthrombi, release of toxic products from leukocytes, endothelial cell damage, and microvascular invasion can contribute to vascular injury and flow impedance. Adhesive interactions between leukemic blast cells and endothelium may also be involved but have not been defined.
High leukemic blast cell counts in AML and CML may be associated with pulmonary, central nervous system, special sensory, or penile circulatory impairment (Table 83–3). Sudden death can occur in patients with hyperleukocytic acute leukemia as a result of intracranial hemorrhage.74,75 Hyperleukocytosis can be treated initially with hydration, leukapheresis, and/or cytotoxic therapy, usually hydroxyurea (Chaps. 88 and 89). In patients with CML, leukapheresis reverses the hyperleukocytic syndrome and can reduce the extent of cytolysis-induced hyperuricemia, hyperkalemia, and hyperphosphatemia by reducing tumor cell mass before hydroxyurea therapy. Hydroxyurea may follow as, or soon after, the tumor cell burden is decreased. Unfortunately, the specific effect of leukapheresis, hydroxyurea therapy, or cranial irradiation in patients with hyperleukocytic AML on duration of survival appears to be negligible.73,74,75
Table 83–3.Clinical Features of the Hyperleukocytic Syndrome ||Download (.pdf) Table 83–3. Clinical Features of the Hyperleukocytic Syndrome
I. Pulmonary circulation
A. Tachypnea, dyspnea, cyanosis
B. Alveolar–capillary block
C. Pulmonary infiltrates
D. Postchemotherapy respiratory dysfunction
II. Predisposition to tumor lysis syndrome
III. Central nervous system circulation
A. Dizziness, slurred speech, delirium, stupor
B. Intracranial (cerebral) hemorrhage
IV. Special sensory organ circulation
A. Visual blurring
D. Tinnitus, impaired hearing
E. Retinal vein distention, retinal hemorrhages
V. Penile circulation
VI. Spurious laboratory results
A. Decreased blood partial pressure of oxygen (PO2); increased serum potassium
B. Decreased plasma glucose; increased mean corpuscular volume, red cell count, hemoglobin, and hematocrit
THROMBOCYTHEMIC SYNDROMES: HEMORRHAGE AND THROMBOPHILIA
Hemorrhagic or thrombotic episodes can develop during the course of essential thrombocythemia or thrombocythemia associated with other clonal myeloid diseases.76,77,78 Arterial vascular insufficiency and venous thromboses are the major vascular manifestations of thrombocythemia. Peripheral vascular insufficiency with gangrene and cerebral vascular thrombi can develop. Thrombosis of superficial or deep veins of the extremities occurs frequently.79 Mesenteric, hepatic, portal, splenic, or penile venous thrombosis can ensue. Patients with essential thrombocythemia who have the CALR mutation have a significantly lower risk of thrombotic disease than those with a JAK2 or MPL mutation.80 Hemorrhage is an occasional manifestation of thrombocythemia and can occur concomitantly with thrombotic episodes. Gastrointestinal hemorrhage and cutaneous hemorrhage, the latter especially after trauma, happen most frequently, but bleeding from other sites also can result (Chap. 85).
Procoagulant factors, such as the content of platelet tissue factor and blood platelet neutrophil aggregates, are more frequent in patients with essential thrombocythemia than normal subjects and are more frequent among patients with the JAK2V617F mutation than patients with the wild-type gene.79,81
Thrombotic complications occur in approximately 40 percent of patients with polycythemia vera.79,82 The presence of homozygosity for the JAK2 mutation as a result of uniparental disomy in as many as one-third of patients with polycythemia vera increases the risk of thrombosis. Erythrocytosis and thrombocytosis may interact and cause hypercoagulability, especially in the abdominal venous circulation. A syndrome of splanchnic venous thrombosis associated with endogenous erythroid colony growth, the latter characteristic of polycythemia vera, but without blood cell count changes indicative of a myeloproliferative disease, has accounted for a high proportion of patients with apparent idiopathic hepatic or portal vein thrombosis.83,84 These cases may have blood cells with the JAK2 gene mutation without a clinically apparent myeloproliferative phenotype.85
Nearly half of patients with paroxysmal nocturnal hemoglobinuria have thrombosis, especially in the venous system. Thrombosis of the veins of the abdomen, liver, and other organs, characteristic complications of paroxysmal nocturnal hemoglobinuria, may result from a complex thrombophilic state related to nitric oxide depletion, formation of prothrombotic platelet microvesicles, the dysfunction of tissue factor pathway inhibitor, and other factors.86,87 Thrombosis is more common in paroxysmal nocturnal hemoglobinuria (PNH) patients with the classical hemolytic syndrome than in those with the PNH-aplastic anemia hybrid (Chap. 40).
Fever, weight loss, and malaise occur as early manifestations of AML. At the time of diagnosis, low-grade fever is present in nearly 50 percent of patients.88 Although minor infections may be present, severe systemic infections are relatively uncommon at the time of AML diagnosis.89 However, fever during cytotoxic therapy, when neutrophil counts are extremely low, nearly always is a sign of infection. Fever also may be a manifestation of the acute leukemic transformation of CML and can occur in patients with oligoblastic myelogenous leukemia (refractory anemia with excess blasts).
Weight loss occurs in nearly 20 percent of patients with AML.89 Loss of well-being and intolerance to exertion may be disproportionate to the extent of anemia and may not be corrected by red cell transfusions. The pathogenesis of these effects is unknown.
Hyperuricemia and hyperuricosuria are common manifestations of AML and CML. Acute gouty arthritis and hyperuricosuric nephropathy are less common. If therapy is instituted without a reduction in plasma uric acid and without adequate hydration, saturation of the urine with uric acid can lead to precipitation of urate (gravel) and obstructive uropathy. If the uropathy is severe, urine flow can be obliterated, and renal failure ensues. Hyponatremia can occur in AML, and in some cases results from inappropriate antidiuretic hormone secretion. Hyponatremia also can result from an osmotic diuresis of urea, creatinine, urate, and other substances released from blast cells and wasting muscles. Hypernatremia is rare but may be seen in cases with central diabetes insipidus. Hypokalemia is commonly seen in AML89,90,91 and is thought to be caused by injury to the kidney by increased plasma and urine lysozyme and subsequent kaliuresis. Hypokalemia is related to excessive urinary potassium loss, but the correlation with lysozymuria is imperfect. Other mechanisms probably are responsible in most cases, including osmotic diuresis and tubular dysfunction. Kaliuretic antibiotics, often administered to patients with AML, may accentuate the hypokalemia. Hyperkalemia is very unusual, but may be seen with tumor lysis syndrome. Hypercalcemia occurs in occasional patients with AML. Several causes have been proposed, including bone resorption as a result of leukemic infiltration. This explanation is in keeping with the normal serum inorganic phosphate in most patients. Occasional patients with hypercalcemia, and hypophosphatemia can have ectopic parathyroid hormone secretion by leukemic blast cells. Hypophosphatemia also can occur because of rapid utilization of plasma inorganic phosphate in some cases of myelogenous leukemia with a high blood blast cell count and a high fraction of proliferative cells. Hyperphosphatemia is uncommon, except as a reflection of the tumor lysis syndrome. Approximately 10 percent of persons with AML show varying degrees of tumor lysis syndrome in the week after onset of therapy, reflected in at least doubling of baseline creatinine, and increases in serum phosphate (>1.6 mmol/L [>5 mg/dL]), uric acid (>416 mmol/L [>7mg/dL]), or potassium (>5 mmol/L [>5 mEq/L]).92 Hypomagnesemia is common as a result of low intake coupled with gastrointestinal loss and a shift of magnesium to the intracellular compartment.
Acid–base disturbances occur in approximately 25 percent of patients, the majority having respiratory or metabolic alkalosis.91 The latter may be secondary to volume depletion, upper gastrointestinal fluid loss, and hypokalemia. Lactic acidosis also has been observed in association with AML, although the mechanism is obscure. True hypoxia can result from the hyperleukocytic syndrome as a consequence of pulmonary vascular leukostasis (see also “Factitious Laboratory Results” below).
Increased serum concentrations of lipoprotein (a) and decreased concentrations of both low-density and high-density lipoproteins have been observed in a high proportion of patients with AML.93 The increased level of lipoprotein (a), which returns to normal after successful treatment, correlates with the presence of leukemic blast cells. Serum prolactin also is increased in some patients with AML.94 Leukemic blast cells may be an ectopic source of this hormone.94
Colony-stimulating factor-1 is elevated in a variety of lymphoid and hemopoietic malignancies, including AML and CML.95 The malignant cells have been proposed as the source of excess cytokine.
FACTITIOUS LABORATORY RESULTS
Elevations of serum potassium levels have resulted from the release of potassium from platelets or, less often, leukocytes in patients with myeloproliferative diseases and extreme elevations in those blood cell concentrations. If blood is collected in a tube that contains an anticoagulant and the plasma is removed after high-speed centrifugation, the potassium concentration is normal. Glucose can be falsely decreased, especially because autoanalyzer techniques call for omission of glycolytic inhibitors such as sodium fluoride in collection tubes. Blood with high leukocyte counts, if it stands prior to separation of the plasma, may have a significant amount of glucose metabolism by leukocytes. Factitious hypoglycemia also can occur as a result of red cell utilization of glucose, especially in polycythemic patients. True hypoglycemia has been observed rarely in patients with leukemia. Arterial blood oxygen content also can be lowered spuriously as a result of in vitro utilization by large numbers of leukocytes, while the anticoagulated blood awaits measurement.
SPECIFIC ORGAN INVOLVEMENT
Clonal myeloid diseases lead to disturbances principally in marrow, blood, and spleen. Although clusters of cells may be found in all organs, major infiltrates and organ dysfunction are unusual. In AML and the acute blastic phase of CML, clinically significant infiltration of the larynx, central nervous system, heart, lungs, bone, joints, gastrointestinal tract, genitourinary tract, skin, or virtually any other organ can occur.
In AML, palpable splenomegaly is present in approximately one-third of cases, but usually is slight in extent. In the chronic myeloproliferative diseases, palpable splenomegaly is present in a high proportion of cases (polycythemia vera ~80 percent, CML ~90 percent, primary myelofibrosis ~100 percent). In essential thrombocythemia, splenic enlargement is present in approximately 30 percent of patients. A predisposition to silent splenic vascular thrombi, infarction, and subsequent splenic atrophy, analogous to that occurring in sickle cell anemia, is postulated as the cause of the lower frequency of splenic enlargement in essential thrombocythemia. Early satiety, left-upper-quadrant discomfort, splenic infarctions with painful perisplenitis, diaphragmatic pleuritis, and referred shoulder pain may occur in patients with splenomegaly, especially in the acute phase of CML and in primary myelofibrosis. In primary myelofibrosis, the spleen can become enormous, occupying the left hemiabdomen. Blood flow through the splenic vein can be so great as to lead to portal hypertension and gastroesophageal varices. Usually, reduced hepatic venous compliance also is present (Chap. 86). Bleeding and, occasionally, encephalopathy can result from portal–systemic venous shunts.
Extensive marrow necrosis, an uncommon event, can occur in any clonal myeloid disease, especially AML, and less often, primary myelofibrosis, CML, essential thrombocythemia, and polycythemia vera. Bone pain and fever are the most common initial findings. Anemia and thrombocytopenia are very common, as are nucleated red cells and myelocytes in the blood (leukoerythroblastic reaction).96,97 Marrow aspiration does not result in a useful sample but biopsy early in the process usually shows hypocellularity with loss of marrow cell structural definition (blurred staining of residual cells), evidence of cell necrosis, gelatinous transformation of marrow, and, often, an amorphous eosinophilic material throughout. The mechanism is thought to be microvascular dysfunction. Restitution of marrow and repopulation of hematopoietic tissue often may follow. The prognosis is a function of the underlying disease.