Case

A 22-year-old man was admitted with CNS symptoms and found to have a cavernous sinus thrombosis. While in the hospital at bed rest, he developed a deep vein thrombosis and a pulmonary embolus resulting in pulmonary infarction. He was evaluated for congenital disorders known to cause a tendency to thrombosis but was found to have normal levels of antithrombin, protein C, protein S and fibrinogen. His CBC was normal, as was his thrombin time, and there was no evidence of a lupus anticoagulant or anticardiolipin. He was maintained at home on oral anticoagulation uneventfully.

The appearance of thrombosis in a young person in the absence of either injury, infection, autoimmune disease or some genetic disorder is, to say the least, very unusual. Yet, without an idea as to the etiology of the patient's initial thrombotic episode, we were forced to assign it to some sudden inapparent insult because, except for the deep vein thrombosis which we could attribute to bed rest and hospital life, the fact that the patient did so well on anticoagulant made us all relax a little.

Three months later, however, the patient's 18-year-old brother developed deep vein thrombosis and a pulmonary embolus.

Clearly, something familial, something genetic was involved.

On physical examination it was noted that the younger brother had high arched feet. As a result of that finding, further examination of both brothers was conducted. In brief, neither of the brothers had dislocated lenses, mental retardation or other skeletal abnormalities usually associated with arched feet.

Our two patients did not have the complete genetic syndrome but, as we were without any other reasonable possibility, we decided to determine plasma homocysteine levels.

The plasma homocysteine levels for the brothers were found to be elevated -- 250 to 280 micromol per liter. Subsequent treatment with oral folic acid and pyridoxine and vitamin B-12 injections lowered the homocysteine levels to about 150 micromol per liter but both brothers have been kept on oral anticoagulation. The younger brother actually had a recurrence of thrombosis when his anticoagulation was at the lower range of therapeutic efficacy (INR 2.0). His INR is now being maintained between three and four.

Homocystinuria

Classic homocystinuria is a group of disorders in which there is an inherited defect of one of several enzymes directly or indirectly affecting methionine metabolism. The most common inherited defect is a lack of an enzyme called cystathionine beta-synthase. This is associated with a syndrome that is not present at birth but slowly evolves and includes dislocated lenses, skeletal abnormalities (such as pectus excavatum and high arched feet) and mental retardation.

The principal biochemical feature of the disease is a markedly elevated blood level of homocysteine (homocystine is the dimeric form of homocysteine) which is known to be damaging to blood vessels resulting in arterial and venous thromboembolic disease. Our understanding of the problem is still evolving and new data are being published actively, with 26 new articles on homocysteine and thrombosis in the last three years.

Pathogenesis

Dr. Peter Harpel has reviewed recent studies on possible pathogenetic mechanisms whereby homocysteine might predispose to thrombosis.(1) Homocysteine inhibits the expression and activity of endothelial cell surface thrombomodulin, the thrombin cofactor responsible for protein C activation. Another effect is inhibition of antithrombin III effect by blocking its binding to endothelial cell heparan sulfate. Homocysteine also inhibits endothelial cell induced breakdown of the platelet aggregating agent ADP and stimulates the endothelial cell to produce the potent procoagulant tissue factor. Tissue plasminogen activator binding is also inhibited. Which of these mechanisms have clinical relevance is yet to be determined but, for now, it seems prudent to investigate patients with unexplained, premature, recurrent or familial thrombotic disease.

Clinical Research Issues

Dr. Hanna Mandel and a group from Israel recently suggested that the coexistence of another genetic defect such as Factor V Leiden might explain why only a third of patients with hereditary homocystinuria develop thromboembolic disease.(2) They studied 45 members of seven unrelated consanguineous kindreds in which at least one member was homozygous for homocystinuria. They found that venous or arterial thrombosis occurred in six of 11 patients with homocystinuria and that all six also had the factor V Leiden mutation. They also found four patients with homocystinuria who did not have the factor V Leiden mutation and they did not have thrombosis, although they were still young. They suggest that a search for other hereditary thrombotic disorders should be conducted in patients who are found to carry mutant genes predisposing them to thrombosis.

In the same issue of the New England Journal of Medicine Dr. Martin den Heijer and the group from Leiden reported that mild elevations of plasma homocysteine (>18.5 micromol per liter) in the general population are a risk factor for deep-vein thrombosis.(3) They measured plasma homocysteine levels in patients and matched control subjects participating in the Leiden Thrombophilia Study and found that 10 percent of patients with deep-vein thrombosis had high levels, as compared to five percent of controls, and that exclusion of subjects with other risk factors, such as factor V Leiden, did not affect the risk estimates.

However, not all of the literature is in agreement. Amundsen et al carried out a case control study which found no difference in plasma homocysteine levels between young adults with deep venous thrombosis and control subjects.(4)

Not only is it unclear how much of a risk factor mild elevations of plasma homocysteine is for thrombotic disease, it is also unknown whether any intervention to lower the level would be beneficial. This is of very real interest, since alterations in dietary intake of vitamin B-6 and folic acid can affect the level of homocysteine. A brief summary can be found in the April 1994 issue of Medical Sciences Bulletin.

Note

The INR (International Normalized Ratio) is currently the preferred laboratory value to be used when relying on prothrombin times to regulate oral anticoagulation. The INR is an arithmetically derived number which represents the prothrombin time ratio that would be obtained if the prothrombin time were done with a standard reference thromboplastin, rather than the reagents used in that particular laboratory. This allows direct comparability between laboratories. The formula is:

The ISI is the International Sensitivity Index, a measure of the sensitivity of the reagent supplied to the laboratory. It is determined by the manufacturer and the value is included with the laboratory reagents shipped to the laboratory. It was developed when it became obvious that, over the years, the prothrombin time ratio used in the U.S.A. was lower than that used in the U.K., but still resulted in more bleeding. When studies were done comparing the two methods on the same plasma samples from patients receiving oral anticoagulants, it became obvious that the rabbit brain thromboplastin employed in the U.S.A. resulted in less prolongation of the prothrombin time than the human brain thromboplastin in use in the U.K. As a result of the INR, the intensity of anticoagulation in the U.S.A. has been lowered and the likelihood, therefore, of bleeding has decreased with no loss of therapeutic efficacy.