Thrombosis and Anemia

Alvin H. Schmaier, MD

Case Western Reserve University, Cleveland, OH

Copyright of the American Society of Hematology, 2012. ISSN: 1931-6860.


Pathophysiology of B12 deficiency

In summary, vitamin B12 deficiency arises from a deficiency of vitamin B12 in diet or a defect in the alimentary adsorption system anywhere in the GI tract. Any reason that interferes with GI adsorption will produce vitamin B12 deficiency. Loss of the gastric parietal cells that produce 1) intrinsic factor and 2) hydrochloric acid may result in reduced adsorption of the vitamin. This is seen, for example, with partial or total gastrectomy, lye injury to gastric mucosa, or autoimmune disorders. Pernicious anemia is an autoimmune disorder associated with anti-intrinsic factor antibodies. Additionally, the intrinsic factor-vitamin B12 complex is adsorbed in the distal ileum. Removal of the distal ileum from any cause, e.g., in patients with post-op regional enteritis, may also result in vitamin B12 deficiency. Thus, vitamin B12 deficiency can arise from multiple single etiologies. However, in all cases they will present with a common feature. They will show a macrocytic anemia with hypersegmented PMNs on the peripheral blood smear in a patient that may have a neurologic defect of the lateral dorsal columns of the spinal cord.

Relationship of vascular disease and thrombosis to vitamin B12 deficiency

N5,N10-methylene-tetrahydrofolate reductase enzyme is present in vessel walls. Polymorphisms (e.g., C677T) in this enzyme, which exist in 35% of the population in the United States, do not contribute to either elevation of homocysteine or thrombosis. However, defective function of MTHFR, as seen in B12 deficiency, is associated with higher homocysteine levels and arterial and venous thrombosis risk. Deficiency of cystathionine β-synthase results in elevation of plasma homocysteine and severe arterial and venous thrombosis. Both arterial and venous thrombosis have been associated with homocysteine elevations (values > 11µM). Homocysteine leads to accelerated atherosclerosis and thrombosis.

Role of homocysteine in thrombosis. Elevation of plasma homocysteine results in endothelial cell dysfunction (see figure below).

Endothelial cell dysfunction with elevated homocysteine is associated with both venous and arterial thrombosis. The normal anticoagulant surface of endothelium is converted to a prothrombotic surface manifested by reduced protein C activation as result of reduced thrombomodulin (a receptor protein for protein C activation by thrombin on endothelium) expression, reduction in tissue plasminogen activator activation of plasminogen, increased tissue factor expression, reduced nitric oxide production, increased factor V expression, and enhanced LP(a) binding to fibrin. Elevation of plasma homocysteine also results in smooth muscle cell proliferation, lipid peroxidation, and oxidation of LDL, all factors that contribute to atherogenesis and arterial thrombosis. Patients with elevated homocysteine from vitamin B12 deficiency should be treated. Thus, the elevated homocysteine in the patient in this case is most likely the link between her vitamin B12 deficiency and thrombosis.

For additional information about the evaluation and management of venous thrombosis embolism, see the ASH teaching case Thrombosis, by Thomas G. DeLoughery, MD.

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