For Physicians

Uncommon Reactions to Commonly Used Anticoagulants

The usual side effects of warfarin, heparin, and clopidogrel are well-known to all practitioners who treat patients with these anticoagulants. However, several rare and rather unique reactions to these commonly prescribed drugs frequently have been overlooked.

Purple Toe Syndrome

Warfarin, and very rarely heparin, can cause a violaceous and often painful discoloration of the toes and sides of the feet. Occasionally the same findings are noted on the hands, and net-like skin changes appear on the abdomen (livedo reticularis). This occurs mainly in an older patient population, especially those with atherosclerosis. The pathogenesis of this syndrome is thought to be caused by bleeding into atheromatous plaques with resultant cholesterol embolization to the small arteries and arterioles of the feet. ^1,2

The diagnosis can be challenging, because several serious, and non-serious conditions can mimic this condition. Serious syndromes include those associated with hypoxemia or trauma, erythromelalgia, as well as cold-associated syndromes like Raynaud phenomenon, cryoglobulinemia, and frostbite. Syndromes of lesser severity are benign acrocyanosis and pernio. ³

A patient with purple, painful, blanching, nonhemorrhagic lesions on the toes and sides of feet with normal arterial pulses requires a systematic and thoughtful approach to diagnosis. However, the true purple toe syndrome typically occurs within the first 3-8 weeks after initiating warfarin, and regresses completely after its discontinuation. Usually, there are no long -term sequelae. If anticoagulants must be continued, it would be appropriate to change. ¹

Warfarin Skin Necrosis

This rare complication of warfarin therapy is associated with a high morbidity and potential mortality. It starts with erythema and petechiae that progress rapidly to ecchymoses and hemorrhagic bullae, most often occurring in fatty areas such as breasts, buttocks, hips, and abdomen. Skin biopsy is very helpful in confirming this diagnosis, as it shows diffuse dermal microthrombi with endothelial damage and red cell extravasation, progressing to coagulative necrosis. ⁴ Extreme pain often is present as bleeding into the swollen necrotic skin progresses and the lesion eventually becomes gangrenous. ¹

Warfarin skin necrosis is a very serious complication that usually occurs within the first few days after initiating warfarin therapy. It develops most often when warfarin is initiated in the setting unrecognized heparin-induced thrombocytopenia (HIT), as for example while bridging from heparin to warfarin. The presumed mechanism is an abrupt lowering of the concentration of the natural anticoagulant protein C (half-life 9 hours) by warfarin, resulting in deficiency of protein C and consequent hypercoagulability just as the extreme hypercoagulability of HIT is evolving. This intense thrombotic event occurs quite rapidly on day 2 or 3 of warfarin due to deficient protein C regulation of the increased thrombin generation occurring with HIT. ^1,5 (Warfarin is not an effective anticoagulant until about 4-5 days after its inception.) To prevent this clinicians must be quite certain that HIT is not present upon initiation of warfarin.

Warfarin skin necrosis also has been reported in patients receiving high initial loading doses. ¹ In addition, it has been described in cases of acquired or inherited protein C or S deficiency. ¹ Although warfarin has been considered a standard of care in patients with thrombosis and deficiency of either protein C or S, it has a distinct risk in these cases. With the guidance of a hematologist-expert in thrombophilia management, therapeutic options other than warfarin should be considered as well. ¹

Venous Gangrene

Venous gangrene may mimic warfarin skin necrosis clinically, but actually is defined by the triad of skin necrosis, documented venous thrombosis, and a palpable or doppler-identifiable arterial pulsation. It is most commonly described in cancer patients, a population with at least a five fold increase in the annual incidence of VTE as compared to the general population. ⁶ It also has been described in patients with HIT, ⁶ and after the administration of vitamin K antagonists to patients with HIT. ⁷ The pathogenesis of venous gangrene is obscure. However, it has been theorized that some cases paradoxically are due to over-anticoagulation with warfarin therapy, a situation in which protein C is severely depleted tipping the usual procoagulant:anticoagulant balance in favor of macro-and microvascular venous thrombosis. ⁶

Ticlopidine (Ticlid®) and Clopidogrel(Plavix®)-Induced TTP

Thrombotic thrombocytopenic purpura is an extremely serious disease characterized by platelet aggregation with resultant small vessel thromboses, thrombocytopenia, neurological changes, and renal insufficiency. The most common type is idiopathic and autoimmune, but the disease also may be grouped as congenital, or secondary to drugs such as cyclosporine A, mitomycin, ticlopidine, and clopidogrel. ⁹ The latter two platelet inhibitors are the most common drugs associated with TTP. Ticlopidine is seldom used now because the incidence of TTP and other side effects is much less with clopidogrel. Clopidogrel has usurped this market and become one of the most commonly prescribed drugs in the U.S. ⁸

Ticlopidine and clopidogrel both are thienopyridine derivatives and differ only slightly in structure. Both inhibit platelet aggregation by blocking a platelet membrane ADP receptor which in turn prevents activation of the glycoprotein IIb/IIIa complex which is essential for platelet cross-linking with fibrin. ⁸

Despite similarities, there are differences in the presentation and outcome of TTP induced by each drug. Ticlopidine-induced TTP usually develops after two weeks or more of treatment and has severe thrombocytopenia but preserved renal function. It is almost always associated with an autoantibody directed against ADAMTS13, a protease that cleaves ultralarge vonWillebrand factor multimers. Therefore, this protease marker is present in very low concentrations (<5%), a situation similar to acquired idiopathic autoimmune TTP. In contrast, clopidogrel TTP usually (but not always) develops within the first two weeks, and has mild thrombocytopenia but significant renal insufficiency. ADAMTS13 levels are 15% or higher. These observations suggest two distinct mechanisms for TTP, immunologic for ticlopidine, and nonimmunologic and poorly understood for clopidogrel. ⁸ Both types respond to therapeutic plasma exchange, although survival with this technique is better for the immunologic type (84% ticlopidine v.70% clopidogrel). If plasma exchange is not performed, mortality for ticlopidine TTP is very high (62%), but only about half of that for clopidogrel TTP (33%). ⁸ Fortunately, this disastrous complication is quite rare, an incidence of 1 per 100,000 treated patients according to the manufacturer of clopidogrel.

Heparin-Induced Osteoporosis

For several decades it has been known that osteoporosis is a complication of long-term unfractionated heparin (UFH) administration. Although a significant reduction in bone mineral density is estimated to occur in up to one-third of patients on extended heparin, many times this is overlooked.

The precise mechanism for heparin-induced osteoporosis is not completely understood. When introduced into osteoblast cell cultures, UFH causes a profound reduction in osteoblast cell numbers and protein synthesis, an observation thought to be responsible for heparin-induced osteopenia. ¹⁰ Also, it has been hypothesized that heparins block cytokines critical for the differentiation of mesenchymal cells into osteoblasts. Whether by direct or indirect inhibition, the result is decreased bone formation and a concomitant increase in osteoclastic activity (bone destruction). Low molecular weight heparin (LMWH) has a similar but less pronounced effect in suppressing osteoblastic activity, ⁸ and little or no effect on bone resorption. ¹⁰ These observations support the results of recent clinical trials that show a substantially lower risk of developing osteoporosis when LMWHs are used instead of UFH for the long-term. ¹¹ Periodic bone density scans still are indicated whichever type of heparin is used.

References

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