Stephanie A. Fish
Susan J. Mandel
Thyrotoxicosis affects hematopoiesis in several ways, although clinically important abnormalities are rare. This chapter discusses the effects of thyrotoxicosis on erythrocytes, leukocytes, platelets, and coagulation factors.
Thyrotoxicosis stimulates erythropoiesis both indirectly and directly. Serum erythropoietin concentrations are higher in thyrotoxic patients as compared with normal subjects, probably as a result of the increase in metabolic activity and the concomitant increase in need for peripheral oxygen delivery (1,2,3,4). Thyroid hormone may also stimulate mononuclear cells to release tissue-specific erythroid stimulatory factors (5) and directly stimulate the formation of erythroid progenitor cells and the synthesis of the globin chains of hemoglobin in those cells (3,5). The result is erythroid hyperplasia (2).
Despite the stimulatory effect of thyroid hormone on erythropoiesis, most patients with thyrotoxicosis have normal hemoglobin concentrations and hematocrit values (1,2,6,7). This may be explained in part by an increase in plasma volume, which is a frequent finding, as well as shortened red blood cell survival (2,5). Red cell morphology is usually normal, but the cells tend to be slightly smaller than normal (7). Some patients seem to have ineffective erythropoiesis, based on increased numbers of sideroblasts and increased amounts of hemosiderin in their marrow (8). However, other patients have low marrow iron stores (2). Serum iron concentrations are usually normal, those of transferrin tend to be low, and those of ferritin high (9).
Pernicious anemia occurs in 1% to 3% of patients with thyrotoxicosis, and 15% to 20% have high serum concentrations of parietal cell antibodies (6,10). These abnormalities are linked with Graves' thyrotoxicosis, not other types of thyrotoxicosis, and probably reflect the patients' vulnerability to autoimmune disorders rather than some interaction between thyroid hormone and vitamin B12 metabolism. In fact, patients with both type 1 diabetes mellitus and Graves' disease may be at even higher risk for the development of pernicious anemia (11). In addition to immunologic mechanisms, patients with thyrotoxicosis may have increased requirements for vitamin B12 and folate (3,10). Serum vitamin B12 concentrations in patients with thyrotoxicosis who do not have pernicious anemia are lower than in normal subjects and increase after successful antithyroid therapy (12). Serum folate concentrations are high or normal in patients with thyrotoxicosis (2,3,12).
Thyroid hormone also exerts effects within erythrocytes. Thyrotoxic patients have high red blood cell 2,3-diphosphoglycerate concentrations, which shifts the oxyhemoglobin curve to the right (1,3,5). This change, like the stimulation of erythropoiesis, augments oxygen delivery to peripheral tissues. Red cell Na+,K+-ATPase activity is low in thyrotoxicosis, due to a decrease in the number of pump units per cell; therefore, the red cell sodium concentration is increased. In contrast, Na+,K+-ATPase activity is increased in most other tissues, including leukocytes, and indeed the increase is thought to contribute importantly to the increases in oxygen consumption and substrate utilization that are characteristic of thyrotoxicosis (see Chapter 38).
Red blood cell zinc concentrations are low in patients with thyrotoxicosis, as are the red cell concentrations of the zinc-containing enzyme carbonic anhydrase (13). In a study of patients with thyrotoxicosis before and during treatment, red cell zinc concentration and serum thyroxine (T4) and triiodothyronine (T3) concentrations were inversely correlated, but during treatment red cell zinc concentrations increased more slowly than serum T4 and T3 concentrations decreased, suggesting that red cell zinc concentrations reflect mean serum T4 and T3 concentrations over time, and therefore that measurements of red cell zinc could serve as a marker of time-integrated serum T4 and T3 concentrations (13).
In summary, erythropoiesis is increased in patients with thyrotoxicosis, largely to meet the need to increase oxygen delivery to peripheral tissues. Nevertheless, 10% to 25% of patients have anemia, which may be normocytic, microcytic, or macrocytic, but it is rarely severe (1,3,5,6,7). Among patients who are anemic, the causes include ineffective erythropoiesis, iron deficiency, vitamin B12 deficiency, and folate deficiency; among these causes only ineffective erythropoiesis is likely to be a direct effect of thyrotoxicosis.
Most patients with thyrotoxicosis have normal leukocyte counts, normal or slightly low granulocyte counts, and normal or slightly increased lymphocyte counts (7,14,15,16,17,18). Furthermore, a few thyrotoxic patients have lymphoid enlargement and splenomegaly, and rare patients have thymic enlargement; these changes seem to occur mostly in patients with Graves' thyrotoxicosis, implying they are in some way related to immune activation rather than to thyrotoxicosis. No consistent abnormalities in the proportions of circulating B and T lymphocytes have been found in patients with Graves' thyrotoxicosis (19), but lymphocyte function may be abnormal, in that the cytotoxic activity of natural killer cells is lower in these patients than in normal subjects or patients with toxic nodular goiter (15).
Most patients with thyrotoxicosis caused by Graves' disease have normal granulocyte counts, but some have granulocytopenia (5,14,17). The cause is unknown. In a study of 17 patients with Graves' thyrotoxicosis, 8 had reduced bone marrow reserves of granulocytes, although only 1 had granulocytopenia (16). Although antineutrophil antibodies may be detected in up to 50% of patients with Graves' thyrotoxicosis, the contribution of the antibodies to the observed granulocytopenia is unclear (20). In a study of 63 patients with thyrotoxicosis, 17 (27%) had a granulocyte count less than 2,000/mm3, 36 (57%) had a count of 2,000 to 4,000/mm3 (2 to 4×109/L), and 10 (16%) had a count of greater than 4,000/mm3 (4×109/L) (16); the patients' mean granulocyte count was 3,100/mm3 (3.1×109/L), as compared with 3,600/mm3 (3.6×109/ L) in normal subjects (17). In the patients the granulocyte counts were correlated positively with serum concentrations of granulocyte colony-stimulating factor (G-CSF), which were on average slightly higher than in normal subjects, but not with their serum free T4 concentrations. In patients with granulocyte counts of less than 2,000/mm3 (2×109/L), the counts tended to increase after initiation of methimazole therapy. The three patients whose granulocyte counts declined transiently during methimazole therapy (none had agranulocytosis) had no change in serum G-CSF concentrations.
In another study of 37 patients treated with carbimazole in doses of 25 or 100 mg/day, granulocyte counts increased during the first 2 weeks of therapy in the former group and decreased in the latter group; however, there were no differences between the groups subsequently (18). Thus, the granulocyte count can increase during antithyroid drug treatment, even in patients with granulocytopenia (see Chapter 45).
An occasional patient with thyrotoxicosis, nearly always caused by Graves' disease, has clinically important thrombocytopenia [platelet count < 100,000/mm3(100×109/L)], and many [42% in one study (21)] have platelet counts of less than 150,000/mm3 (150×109/L) (22). Only rare patients, however, have clinical manifestations of thrombocytopenia or other disturbances in coagulation.
The thrombocytopenia has several causes (23). First, some patients with Graves' thyrotoxicosis have antiplatelet antibodies; they thus can be said to have autoimmune thrombocytopenia purpura (24). Its incidence may be increased in patients with Graves' disease (25), and it may precede the onset of thyrotoxicosis (26). In a study of 25 patients with Graves' thyrotoxicosis, 11 (44%) had high serum levels of platelet-bound immunoglobulin G (IgG) (24). Among the 11 patients, most had easy bruising or bleeding, and 3 had thrombocytopenia. Because of this association between autoimmune thrombocytopenia and Graves' disease, screening for hyperthyroidism should be considered in patients with unexplained thrombocytopenia (27). Another possible explanation for thrombocytopenia in patients with Graves' thyrotoxicosis is binding of thyrotropin (TSH) receptor–stimulating or other thyroid antibodies to truncated actin-binding protein on platelets, which links both the glycoprotein and the high-affinity Fc receptor for immunoglobulin G on the platelet membrane to the cytoskeleton of platelets, providing a mechanism whereby the antibodies could bind to platelets and accelerate their destruction (23).
Other factors that may contribute to thrombocytopenia in these patients are the thyrotoxicosis itself, which may increase the phagocytic activity of the reticuloendothelial system, including the spleen, and splenomegaly. Either would accelerate the clearance of platelets, whether sensitized or not (21,22,28).
All these effects are to some extent counterbalanced by increased production of platelets. The number of megakaryocytes in the bone marrow may be increased (29). The number of reticulated (young) platelets in the circulation is increased. These platelets are larger than more mature ones, and thus mean platelet volume is increased (28,30).
Platelet counts usually increase, platelet size decreases, and the amount of platelet-associated immunoglobulin G (IgG) decreases during antithyroid therapy (22,31). Patients with severe thrombocytopenia have been given concomitant glucocorticoid therapy (26), as would be done for thrombocytopenia alone. Antithyroid drugs may have immunosuppressive as well as antithyroid actions (see Chapter 45), which may reduce the production of IgG capable of binding to platelets.
Thyrotoxicosis may also alter platelet function; platelet aggregation in response to adenosine diphosphate (ADP), collagen, and ristocetin is decreased (32,33). These changes in platelet function may be due to inhibition of myosin light chain kinase, an enzyme that stimulates platelet contractile proteins (34). These abnormalities also improve during antithyroid therapy (32,33).
Clotting Factors and Warfarin Therapy
In thyrotoxicosis, the rate of clearance of most if not all coagulation factors is increased (35). However, the plasma concentrations of most of these factors are normal, except for small decreases in factor II concentrations and increases in factor VIII concentrations (36,37,38). Some thyrotoxic patients have shortened partial thromboplastin times, perhaps resulting from the increase in plasma factor VIII concentrations (36,38). Factor VIII deficiency due to an acquired circulating antibody that inhibited factor VIII coagulant activity was reported in two patients with Graves' thyrotoxicosis who presented with spontaneous bleeding (39,40). Serum concentrations of thrombomodulin, an endothelial surface glycoprotein that serves as a thrombin receptor, are high in patients with thyrotoxicosis (41).
The sensitivity of thyrotoxic patients to the anticoagulant effects of warfarin is increased. In one study in which thyrotoxic patients were given a single dose of warfarin, the decrease in both factors II and VII was greater and the increase in prothrombin time was greater before than after antithyroid treatment, but the responses of factors IX and X were similar (36). The explanation for the increased effect of warfarin in thyrotoxicosis is multifactorial, probably involving both more rapid clearance of clotting factors and reduced plasma protein binding of the drug. However, the results of pharmacokinetic studies of warfarin in thyrotoxic patients have been conflicting. In one study, the single-dose warfarin plasma half-life, plasma clearance, and volume of distribution were similar in patients studied when they were thyrotoxic and again when they were euthyroid (36); on the other hand, in a thyrotoxic patient receiving chronic warfarin therapy (5 mg/day), the plasma free warfarin concentration was high (37), consistent with decreased plasma protein binding of the drug (42). In addition, patients with thyrotoxicosis may be relatively resistant to reversal of warfarin-induced hypoprothrombinemia by vitamin K. Therefore, patients with thyrotoxicosis treated with warfarin may require lower doses.
Anticardiolipin antibodies have been found in the serum of patients with Graves' thyrotoxicosis, especially those with coexisting ophthalmopathy (43,44). These antibodies, especially those belonging to the immunoglobulin G isotype, may be associated with hypercoagulable states. With antithyroid therapy, the antibody concentrations decreased (44). Fortunately, thromboembolic events, the primary antiphospholipid syndrome, and recurrent abortions are rare occurrences in patients with Graves' thyrotoxicosis, and the presence of these antibodies may be a nonspecific marker of immune system activation (45).
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