NEJM
Editorial
|
Sandor S. Shapiro, M.D.
The seemingly magical transmutation of shed blood into a solid has
fascinated inquisitive observers for millennia. Hippocrates, in De
Carnibus, and Aristotle, in Meteorology, postulated that the
phenomenon was due to cooling, and as late as the 1790s John Hunter
suggested that exposure to air was the cause. In 1832, Johannes M�ller
identified the insoluble clot substance 
fibrin,
and Rudolf Virchow named its hypothetical soluble plasma precursor fibrinogen.
Fibrinogen was isolated by Prosper Sylvain Denis in 1856. Alexander
Schmidt demonstrated that the transformation of fibrinogen into
fibrin was a fermentative
(enzymatic) process and named the fibrin ferment thrombin;
he called its presumed plasma precursor prothrombin.
Nicolas Maurice Arthus, in 1890, discovered the anticoagulant effect
of citrate and oxalate and demonstrated that there is an absolute
requirement for calcium ions in coagulation.
What, then, initiated the coagulation process? It was known that
tissue and blood cells contained a substance or substances capable of
hastening the clotting of blood � an activity now identified with
the membrane protein called tissue factor.
It was presumed that this potent material was physically prevented from
admixing with plasma constituents, either by the barrier of the
blood-vessel wall or by the intact structure of blood cells.
Moreover, it was suspected that platelets, first described convincingly
by Giulio Bizzozero in 1882, were probably a necessary element in
blood coagulation. In 1905, Paul Morawitz synthesized these
observations into the first formulation of the biochemistry of blood
coagulation: prothrombin, he hypothesized, was converted into the
enzyme thrombin by thrombokinase
(tissue factor) in the presence of calcium; thrombin, in turn,
converted fibrinogen to fibrin.
The Morawitz formulation inspired Armand Quick, in the early 1930s,
to develop the prothrombin time
test with the intent of measuring prothrombin. This test was
instrumental in the discovery of plasma coagulation factors V, VII,
and X and, of course, is in ubiquitous clinical use today as a
screening test and as a method of monitoring the effects of warfarin
therapy. Other tests developed during the same period led to the
recognition that the direct proteolytic activator of prothrombin was
the enzyme factor Xa. Subsequent work has shown that several steps
in the coagulation cascade normally occur on the surface of platelets
but can occur on the surface of other cells as well.
The basis for pharmacotherapy of thrombotic disorders was established in
the first half of the 20th century, when Jay McLean, L. Emmett Holt,
Jr., and William Henry Howell isolated an anticoagulant from the
liver (hepar) and named it heparin.
Using their experience in purifying insulin, Charles Best and
colleagues in Toronto succeeded in producing relatively large amounts
of heparin by 1936, and soon thereafter the drug was used by Gordon
Murray, of the same city, for the treatment of postsurgical
thrombosis.
Meanwhile, in the early 1930s, Karl Paul Link, at the University of
Wisconsin, identified dicumarol as a component of spoiled sweet
clover, the ingestion of which caused a bleeding disease in cattle,
described earlier by F.W. Shofield and L.M. Roderick. Coincidentally,
the basis for understanding the action of warfarin was established in
the late 1920s, when the Danish scientist Henrik Dam discovered
vitamin K (koagulation),
the absence of which caused a hemorrhagic disease in chicks. The
diseased chicks and cattle had deficient plasma levels of prothrombin
and, as subsequently shown, of the other vitamin K�dependent
factors (factors VII, IX, and X) as well. In 1939, Link, searching
for a better rat poison, synthesized dicumarol and a series of
congeners and assigned the patents to the Wisconsin Alumni Research
Foundation. He called the most potent of the congeners warfarin,
a name derived from the organization's initials. Warfarin, introduced
as a rat poison in 1948, was thought to be unsafe for human use;
its first clinical use was reported only in 1955, after an
unsuccessful suicide attempt suggested its relative lack of toxicity
in humans. By 1999, warfarin was the 11th most frequently prescribed
drug in the United States.
For nearly 50 years, the mainstays of antithrombotic therapy have been heparin1 and coumarin compounds, primarily warfarin.2 Heparin, though acting immediately, exerts its anticoagulant effect indirectly, by binding to antithrombin and thereby dramatically enhancing the ability of that protein to inhibit coagulation-system enzymes, particularly factor Xa and thrombin. Warfarin inhibits the vitamin K�dependent, post-translational carboxylation of certain N-terminal glutamic acid residues in prothrombin and factors VII, IX, and X � a modification that endows these proteins with the ability to bind calcium ions strongly and thereby to function normally.
As effective as these anticoagulants are, they have drawbacks. Heparin, for example, must be given parenterally; it is a heterogeneous mixture of molecules, only a fraction of which have anticoagulant activity; it binds to a number of plasma proteins and to the vessel wall and is neutralized by platelet factor 4; the heparin�antithrombin complex is not very effective in neutralizing clot-bound thrombin; and, in some patients, heparin causes an immunologic thrombocytopenia and, even more disastrously, immune-mediated thrombosis. Warfarin, up to now our only oral anticoagulant, acts indirectly, and its antithrombotic effect takes hold only after three to five days, when previously synthesized vitamin K�dependent plasma clotting factors have been catabolized and replaced by insufficiently carboxylated molecules. Thus, in most situations, warfarin must be instituted in conjunction with a rapidly acting anticoagulant, such as heparin; it also must be stopped several days before surgery, and heparin or a related drug used in the interim, while the liver is replenishing the normal vitamin K�dependent factors. In addition, warfarin interacts with a host of other drugs, often making anticoagulant control difficult to achieve. Finally, use of either drug requires careful laboratory monitoring, an inconvenience to both patient and doctor.
Two main approaches have been taken to develop new anticoagulants. Heparin preparations have been partially digested to produce low-molecular-weight heparins, which have been extensively studied and are replacing unfractionated heparin in many clinical settings. Since low-molecular-weight heparins do not bind to a significant extent to plasma proteins, they have more reproducible pharmacokinetics and can be given on a weight basis with little or no laboratory monitoring. Moreover, they appear to cause immunologic thrombocytopenia relatively infrequently. In a further development, the minimal antithrombin-binding unit of heparin, a pentasaccharide called fondaparinux, has been synthesized and is undergoing clinical trials. To inhibit thrombin, unfractionated heparin must bind not only to antithrombin but also to thrombin itself, whereas fondaparinux binds only to antithrombin and is thus a specific inhibitor of factor Xa. This drug requires subcutaneous administration but can be given once a day, on a weight basis, and its use does not require laboratory monitoring.
The second approach took its cue from the medicinal leech, Hirudo medicinalis, which produces hirudin, a direct thrombin inhibitor. Hirudin acts independently of antithrombin and other plasma proteins. As the result of intensive physicochemical investigations, the interaction of hirudin with thrombin is now understood in great detail and has led to the discovery of other direct thrombin inhibitors, such as argatroban and melagatran, both of which can neutralize clot-bound thrombin. Melagatran is poorly absorbed but has been chemically modified and, in the form of ximelagatran, is the first new oral anticoagulant since warfarin. Ximelagatran is metabolized to melagatran and, like fondaparinux, does not require laboratory monitoring. Both drugs are in the process of being tested in large-scale clinical studies.
How well do they work? This issue of the Journal contains three reports3,4,5 of clinical trials with these two agents, one with fondaparinux and two with ximelagatran. The Matisse Investigators,3 who previously described the efficacy and safety of fondaparinux as compared with low-molecular-weight heparin in the treatment of deep-vein thrombosis, now report that fondaparinux, given as a single daily subcutaneous injection, is at least as effective as unfractionated heparin in the primary treatment of pulmonary embolism. But is fondaparinux better than low-molecular-weight heparin for the treatment of pulmonary embolism? Several large studies1 and one smaller, more recent one6 have concluded that low-molecular-weight heparins are as effective and safe as unfractionated heparin for the treatment of pulmonary embolism. Furthermore, close examination of the experience with fondaparinux leaves open the possibility that bleeding may occur with a slightly greater frequency than with low-molecular-weight heparins. In terms of costs, treatment with fondaparinux is probably 25 to 35 percent more expensive than treatment with a low-molecular-weight heparin, but both drugs are undoubtedly less costly overall than unfractionated heparin because of savings in costs associated with hospitalization and laboratory monitoring.
Francis and coworkers4 report that ximelagatran given in two daily oral doses of 36 mg is superior to warfarin for the prevention of venous thromboembolism after total knee-replacement surgery. However, the greater efficacy of ximelagatran was due almost entirely to a decreased incidence of distal deep-vein thromboses, which are not frequently the origin of pulmonary emboli, although some of the data did suggest (without reaching statistical significance) that there were less frequent proximal deep-vein thromboses as well. Can this drug be used in place of warfarin for long-term prevention of venous thromboembolism, thus avoiding the cost and annoyance of laboratory monitoring?
Although it does not deal with this question directly, the report by Schulman and coworkers5 is an important start. In their study, patients who had completed six months of anticoagulant therapy for an episode of venous thromboembolism were given ximelagatran or placebo for approximately 18 months. The frequency of symptomatic venous thromboembolism was 2.8 percent among those receiving ximelagatran, a rate that was 78 percent lower than that in the placebo group. A direct comparison of ximelagatran and warfarin is clearly warranted, and efficacy will need to be weighed carefully against the expense of the new drug, with savings in monitoring costs taken into account, since the usual daily cost of warfarin is $1 or less. In addition, liver-function abnormalities developed in about 1 in 16 patients receiving ximelagatran; even though almost all the abnormalities were transient, this problem is worrisome and requires careful study. Finally, it may be worth considering that long-term use of a direct thrombin inhibitor may have other effects, both salutary and deleterious, since thrombin interacts not just with fibrinogen and platelets but also with endothelial and smooth-muscle cells and may be involved in smooth-muscle proliferation, angiogenesis, inflammation, and, perhaps, metastatic spread of tumor cells.7,8 None of these effects are likely to be seen as a result of short-term use of these agents.
The authors of the three reports have been doing an outstanding service in bringing the potential of these agents to the attention of the medical community in a convincing manner. Nevertheless, a great deal remains to be learned regarding the place of the new drugs, used alone or in combination with antiplatelet agents, in the treatment of diseases associated with arterial thrombosis, particularly myocardial infarction and stroke. Moreover, we have not exhausted other possible modes of intervention in the hemostatic system: witness the early trials of agents inhibiting the tissue factor�dependent initiation of hemostasis.9 It is likely that the first decade of the 21st century will continue to be a time of great advances in the treatment of thrombotic disorders.
Source Information
From the Department of Physiology, Jefferson Medical College, Philadelphia.
References
- Hirsh J, Anand SS, Halperin JL, Fuster V. Guide to anticoagulant
therapy: heparin: a statement for healthcare professionals from the American
Heart Association. Circulation 2001;103:2994-3018.
[Full Text] - Hirsh J, Fuster V, Ansell J, Halperin JL. American Heart
Association/American College of Cardiology Foundation guide to warfarin
therapy. Circulation 2003;107:1692-1711.
[Full Text] - The Matisse Investigators. Subcutaneous fondaparinux versus
intravenous unfractionated heparin in the initial treatment of pulmonary
embolism. N Engl J Med 2003;349:1695-1702.
[Abstract/Full Text] - Francis CW, Berkowitz SD, Comp PC, et al. Comparison of
ximelagatran with warfarin for the prevention of venous thromboembolism
after total knee replacement. N Engl J Med 2003;349:1703-1712.
[Abstract/Full Text] - Schulman S, W�hlander K, Lundstr�m T, Clason SB, Eriksson H.
Secondary prevention of venous thromboembolism with the oral direct thrombin
inhibitor ximelagatran. N Engl J Med 2003;349:1713-1721.
[Abstract/Full Text] - Findik S, Erkan ML, Selcuk MB, Albayrak S, Atici AG, Doru F. Low-molecular-weight heparin versus unfractionated heparin in the treatment of patients with acute pulmonary thromboembolism. Respiration 2002;69:440-444. [CrossRef][ISI][Medline]
- Patterson C, Stouffer GA, Madamanchi N, Runge MS. New tricks for
old dogs: nonthrombotic effects of thrombin in vessel wall biology. Circ Res
2001;88:987-997.
[Abstract/Full Text] - Coughlin SR. PARticipation in inflammation. J Clin Invest
2003;111:25-27.
[Full Text] - Moons AH, Peters RJ, Bijsterveld NR, et al. Recombinant nematode anticoagulant protein c2, an inhibitor of the tissue factor/factor VIIa complex, in patients undergoing elective coronary angioplasty. J Am Coll Cardiol 2003;41:2147-2153. [CrossRef][ISI][Medline]