Susan J. Mandel
Hypothyroidism has several effects on hematopoiesis, the peripheral blood elements, and the coagulation system.
Some patients with hypothyroidism have an anemia. In older studies, it was found in 25% to 50% of patients (1,2), but the percentage is lower now because relatively few patients have either severe or long-standing hypothyroidism. In a 1981 study of children and adolescents with severe hypothyroidism, based on the presence of height below the third percentile, 65% had anemia (3), but there was no correlation between the severity of anemia and serum thyroxine (T4) concentrations. Anemia was present in 13% to 36% of infants with congenital hypothyroidism; in this group, serum T4 concentrations were correlated with hemoglobin concentrations (4).
Anemia in patients with hypothyroidism to some extent may be physiologic, that is, a result of reduced need for delivery of oxygen to peripheral tissues. On the other hand, a reduction in plasma volume may mask a reduction in red cell mass (1). Thus, few patients have hematocrit values below 35%.
The anemia of hypothyroidism is caused by a decrease in erythropoiesis. Serum erythropoietin concentrations are low (1). The bone marrow is hypocellular, with normal red blood cell differentiation and a normal myeloid:erythroid ratio (5). Erythroblast proliferation, as measured by 3H-thymidine incorporation into erythroblast DNA, is decreased, as is the incorporation of iron into red cell precursors (1). These patients usually have normal iron stores, and normal serum iron, vitamin B12, and folate concentrations, and red cell survival is normal (1,6). Their anemia is normochromic and normocytic or slightly macrocytic, and it improves in several weeks or months in response to treatment with T4.
In an early study, patients with hypothyroidism had low red cell concentrations of 2,3-diphosphoglycerate (2,3-DPG), which alter red cell oxygen transport to shift the oxyhemoglobin dissociation curve to the left, thereby reducing the release of oxygen from hemoglobin (7). Such a change would be consistent with the reduced tissue need for oxygen in hypothyroidism; however, in a more recent study, red cell 2,3-DPG concentrations were normal (8).
In addition to the nonspecific anemia described above, some patients with hypothyroidism have iron deficiency anemia and others have megaloblastic anemia. Iron deficiency anemia may be either microcytic or normocytic. The cause may be blood loss, notably menorrhagia, but more often is poor iron absorption (2), caused at least in part by achlorhydria. In thyroidectomized rats, gastrointestinal iron absorption is decreased, and it increases in response to thyroid hormone (9). Similarly, in a group of hypothyroid patients with low serum iron concentrations, the hemoglobin concentrations increased in response to T4, but the increase was greater in response to T4 and iron (2).
Most patients with hypothyroidism have normal serum vitamin B12 and folate concentrations, but the dietary intake or absorption of either substance may be reduced, resulting in macrocytic, and sometimes megaloblastic, anemia (10,11). In these patients, T4 treatment alone may reverse the anemia, but supplementation with vitamin B12 or folate is advisable as well. About 10% of patients with hypothyroidism caused by chronic autoimmune thyroiditis have true pernicious anemia (12). Conversely, about 12% of patients with pernicious anemia have overt hypothyroidism, and an additional 15% have subclinical hypothyroidism (11); thus, screening patients with pernicious anemia for hypothyroidism is recommended (11,13). In patients with pernicious anemia and hypothyroidism, both vitamin B12 and T4 therapy are needed for complete resolution of the anemia (12). In rats, T4 increases absorption of vitamin B12 from the gastrointestinal tract and facilitates mobilization of vitamin B12 from stores in the liver (14).
Granulocyte and lymphocyte counts are normal in patients with hypothyroidism. Examination of the bone marrow may reveal an increase in the proportion of differentiated myeloid cells. Hypothyroidism has been considered to cause basophilia (15), but a 1993 study revealed no difference in basophil counts in normal subjects and patients with hypothyroidism (16). Similarly, T- and B-lymphocyte counts and the ratio of T cells to B cells are normal in patients with hypothyroidism (17).
Bleeding problems such as easy bruising, prolonged bleeding after dental or other procedures or minor injuries, and menorrhagia occur occasionally in hypothyroid patients.
CLOTTING FACTORS AND WARFARIN THERAPY
The biological half-lives of several coagulation factors, including factors II, VII, and X, are prolonged in patients with hypothyroidism (18). The plasma concentrations of these and other factors have been reported as normal or slightly reduced (19,20,21,22,23). These disparities may be due to differences in assay methods or in the duration and degree of hypothyroidism. The most consistent abnormalities in patients with hypothyroidism are a decrease in plasma factor VIII concentrations (19,24) and a prolonged partial thromboplastin time (19,20,21). Slight decreases in plasma factor VIII activity can occur in a few weeks in severely hypothyroid patients with thyroid carcinoma in whom T4 is discontinued to administer radioiodine therapy (24).
Acquired von Willebrand's disease, with decreases in plasma factor VIII coagulant activity and von Willebrand antigen activity, can occur in patients with hypothyroidism (21,25). Proposed mechanisms include a decreased response to adrenergic stimulation (which stimulates release of factor VIII coagulant activity from endothelial cells) or decreased protein synthesis (22). As in patients with other coagulation disorders, a surgical procedure may unmask the clinical manifestations. Most hypothyroid patients with acquired von Willebrand's disease presented with prolonged bleeding after a dental procedure (21,26). The abnormalities are reversed by T4 therapy (21,25,26).
Desmopressin has been used to treat patients with acquired von Willebrand's disease caused by disorders other than hypothyroidism because it stimulates release of factor VIII from endothelial cells and platelets (27). Its efficacy in hypothyroid patients with this disorder is not known, but it could be of value if treatment other than T4 was considered necessary.
A recent study described biphasic alterations in the fibrinolytic system depending on the degree of hypothyroidism (28). Compared with patients with severe hypothyroidism [serum thyrotropin (TSH) concentrations greater than 50 mU/L], those with milder hypothyroidism (mean serum TSH, 21 mU/L) had lower plasma concentrations of D-dimers, higher plasma α2-antiplasmin activity, and higher plasma concentrations of plasminogen activator inhibitor type 1 (PAI-1) and tissue plasminogen activator antigen. This profile in patients with mild hypothyroidism may indicate a relative hypofibrinolytic state, and provide insight into the association between mild hypothyroidism and cardiovascular disease (29). Whether the seeming activation of the fibrinolytic system in patients with severe hypothyroidism confers any protection against myocardial infarction is not known (28).
Patients with hypothyroidism are relatively refractory to the hypoprothrombinemic effects of warfarin, because the clearance of coagulation factors is slowed. Therefore, it may take longer to prolong the prothrombin time with warfarin in these patients than in euthyroid patients (18). In a warfarin-treated woman who became hypothyroid, a dose of warfarin three times higher than the original dose was required to maintain adequate anticoagulation until she was treated with T4, after which the original warfarin dose was again adequate (30). Hypothyroidism should be considered in patients who seem to become “resistant” to warfarin. In patients beginning heparin and warfarin therapy, it may be necessary to administer heparin longer than the usual 4 to 5 days (18).
A few patients with hypothyroidism note increased bruising or bleeding, and more have prolonged bleeding times, with a rough correlation between the bleeding time and the severity and duration of hypothyroidism (21,31,32). Prolonged bleeding times may be present in patients with normal plasma factor VIII activity (31). In addition, severely hypothyroid patients may be more sensitive to aspirin and therefore have a prolonged bleeding time after aspirin ingestion (33). There are reports of untreated or partially treated hypothyroid patients who bled profusely after taking aspirin (33). Therefore, aspirin should be given cautiously to patients with hypothyroidism.
Platelet counts are usually normal in hypothyroid patients, although the bone marrow megakaryocyte count may be low (5). Mean platelet volume is also normal (22). Hypothyroidism, however, may alter platelet function, with increased adenosine diphosphate–and collagen-induced aggregation of platelets (34). This increase may be due to an increase in platelet myosin light-chain kinase, which increases the activity of the contractile proteins of platelets (35). On the other hand, ristocetin-induced platelet aggregation is impaired in hypothyroid patients; however, ristocetin induces aggregation by facilitating platelet interaction with factor VIII (32), and the low plasma factor VIII activity found in hypothyroid patients probably accounts for the diminished ristocetin response. All these abnormalities improve during T4 treatment.
In a group of 12 patients with chronic autoimmune thyroiditis, of whom two were hypothyroid and ten euthyroid, serum levels of platelet-bound immunoglobulin G were high in six, of whom two had thrombocytopenia (36). Autoimmune thrombocytopenic purpura only rarely is associated with chronic autoimmune thyroiditis (37). In addition, low serum concentrations of anticardiolipin antibodies were found in two of five patients with chronic autoimmune thyroiditis (38), but there are no reports of the antiphospholipid syndrome in hypothyroid or euthyroid patients with autoimmune thyroiditis.
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