Guía de la American Heart Association (1996)

Complications of Anticoagulation Treatment of patients who develop complications during anticoagulant therapy involves management of the actual complication and subsequent management of the thromboembolic event for which the patient is being treated. Bleeding is by far the most important complication of anticoagulant therapy. The approach to bleeding depends on the severity of bleeding, the anticoagulant and dose used, results of laboratory tests at the time of bleeding, the length of time the patient has been treated with anticoagulants, and the seriousness of the thromboembolic event for which the patient is being treated. Heparin The frequency of clinically important bleeding during a 5- to 10-day course of heparin therapy varies between 3% and 10%, depending on whether the patient is at high or low risk.148,151,153,160,162,271,272 In many cases bleeding is not life-threatening and does not require discontinuation of heparin. Because heparin has a relatively short circulating half-life (60 minutes),273-276 the anticoagulant effect is reversed fairly rapidly after treatment is discontinued. In most cases bleeding is treated by discontinuing heparin, applying local pressure as appropriate, and replacing blood if necessary. If bleeding is potentially life-threatening (eg, intracerebral, intraspinal, retroperitoneal, or severe gastrointestinal), heparin should be stopped and the anticoagulant effect reversed with protamine sulfate. Protamine sulfate is a strong basic substance that rapidly neutralizes the effect of heparin. The appropriate neutralizing dose depends on the dose of heparin and route and time of administration. If protamine sulfate is used within minutes of intravenous heparin injection, then a full neutralizing dose, 1 mg protamine per 100 U heparin, should be given. Since the half-life of heparin is ~60 minutes, only 50% of a full neutralizing dose is required 1 hour after the last heparin injection, and only 25% of the full neutralizing dose is required after 2 hours.147 Protamine sulfate can produce a hypotensive response if given rapidly, so the dose should be injected slowly over a 20-minute period.277-279 Some patients may also develop a hypersensitivity reaction to protamine sulfate. Heparin rebound may occur if very large doses of heparin are given.280-283 Therefore, it may be necessary to repeat administration of protamine if laboratory tests demonstrate a residual heparin effect.169 A direct assay of heparin activity, thrombin time, or aPTT should be performed both before and immediately after protamine is infused, and the test should be repeated 2 hours later to determine whether the neutralizing effect of protamine on heparin is permanent or transient. If bleeding occurs when the aPTT response is in the therapeutic range or just beyond the therapeutic range, or if the anticoagulant-associated bleeding is potentially life-threatening, treatment with anticoagulant therapy should be stopped, and an alternative form of treatment should be used to manage the thromboembolic event. If the patient has proximal vein thrombosis or major PE, a caval interruption procedure should be considered.284 If the patient has calf vein thrombosis, the course of the thrombus can be monitored with serial venous ultrasound imaging99,111 and a caval interruption procedure used if thrombosis is extended. The risk of bleeding is influenced by five variables: the patient's clinical condition,151 the dose of heparin,285,286 the anticoagulant response,286,287 method of administration,151,288 and concomitant use of aspirin or thrombolytic agents.289-292 The most important risk factor for bleeding is recent surgery or trauma. Other risk factors are renal failure, old age, and peptic ulcer disease. There is a relation between bleeding and both heparin dose and anticoagulant effect.285-287,293,294 Bleeding is greater when heparin is administered by intermittent intravenous injection.162,288 Other Complications of Heparin Therapy Other complications of heparin are thrombocytopenia,295,296 with or without thrombosis296; osteoporosis,297-302 which occurs only with long-term treatment; and local skin hypersensitivity and skin necrosis confined to subcutaneous injection sites.303 Other complications are very rare and include anaphylaxis, hypoaldosteronism,304-306 and alopecia. In addition, patients treated with heparin can develop hyperkalemia307 and often develop an asymptomatic increase in plasma levels of hepatic transaminases.308 If a patient develops local skin reactions at the site of injection, the source of heparin should be changed because local reactions may not occur with a different preparation of heparin, including LMWHs. Thrombocytopenia Thrombocytopenia is a well-recognized complication of heparin therapy. Two forms of thrombocytopenia are described: an early benign, reversible nonimmune thrombocytopenia and a late, more serious IgG-mediated immune thrombocytopenia. The mechanism of the early form, which is not associated with adverse clinical sequelae, is uncertain but could be the result of direct weak activation of platelets by heparin.309-312 The immune form of heparin-induced thrombocytopenia is characterized by strong IgG-mediated platelet activation170,296,313 and is associated with a substantial risk of thrombotic complications. The incidence of serologically confirmed heparin-induced thrombocytopenia was investigated in a large clinical trial that compared unfractionated heparin (7500 U twice daily) with LMWH (30 mg enoxaparin twice daily) for prophylaxis after elective hip surgery.170 The incidence of heparin-induced thrombocytopenia was ~1% at 7 days and ~3% at 14 days in patients receiving unfractionated heparin and 0% in those receiving LMWH. Other prospective studies with higher (therapeutic) doses of heparin have reported a similar incidence of thrombocytopenia.314-324 Heparin-induced thrombocytopenia usually begins between 5 and 15 days after the start of heparin therapy (median, 10 days),170,295,325 but it has been reported within hours of starting heparin in patients who have received heparin within the previous 3 months.295,303,326 Thrombosis associated with heparin-induced thrombocytopenia can be heralded by a fall in platelet count without overt thrombocytopenia (eg, from 350 000 to 150 000). For this reason, patients who receive heparin should undergo a platelet count daily, and if the platelet count falls by 50% or more, heparin should be stopped and an alternative management strategy instituted. Thrombocytopenia and Paradoxical Thrombosis Heparin-induced thrombocytopenia is a highly prothrombotic disorder. In a large prospective study of heparin therapy after elective hip surgery, risk for thrombosis was dramatically increased (odds ratio, 37) in patients with heparin-induced thrombocytopenia, compared with those who did not develop it.173 Although many case series have emphasized the association of heparin-induced thrombocytopenia with arterial thrombosis ("white clot syndrome"), it is now clear that venous thrombosis is much more common with heparin-induced thrombocytopenia than arterial thrombosis.170,327 Overall, prospective studies suggest that thrombosis associated with heparin-induced thrombocytopenia occurs in ~1% of patients who receive unfractionated heparin for more than 5 days.170,324 Bleeding complications have been described in patients with heparin-induced thrombocytopenia, but they are less frequent and much less important than thrombotic complications.325 Laboratory Manifestations and Pathogenesis Typically, the platelet count nadir in heparin-induced thrombocytopenia is between 20 and 150 000 per milliliter (median nadir, 50 000).325 Approximately 5% of patients have concomitant hypofibrinogenemia associated with disseminated intravascular coagulation.325 The platelet count usually returns to baseline levels within 1 week of discontinuing heparin. Heparin-induced thrombocytopenia is caused by an IgG that activates platelets via their FcII receptors.328,329 The major target antigen is a heparin sulphate/platelet factor IV complex that localizes the IgG on the platelet surface.330-333 The thrombogenic diathesis results from in vivo platelet activation334 as well as generation of procoagulant platelet-derived microparticles.335 In addition, heparin-induced thrombocytopenia IgG has been shown to activate endothelium in vitro via recognition of a heparin sulfate/platelet factor IV complex.332,333,336 Laboratory Testing Platelet activation assays that use washed target platelets337,338 have a sensitivity and specificity for heparin-induced thrombocytopenia of at least 95%.170 Typically, heparin-induced thrombocytopenia IgG activates platelets at low (0.5 to 1.0 U/mL) but not high (10 to 100 U/mL) concentrations of heparin.337,339,340 Aggregation studies in which citrated plasma is used are much less sensitive to heparin-induced thrombocytopenia IgG than assays in which washed platelets are used.340-342 An ELISA assay with the platelet factor IV/heparin target antigen has been developed330 that shows good concordance with the platelet activation assay.342 Although heparin-induced thrombocytopenia is much less common with LMWH preparations than standard heparin, in vitro studies indicate that LMWHs show immune cross-reactivity in ~70% of instances.170,343 In contrast, in vitro cross-reactivity is much less common (~10%) with the heparinoid Orgaran,344 which has been used successfully as a substitute for heparin in patients with heparin-induced thrombocytopenia.345 Treatment Two different antithrombotic agents have been evaluated in descriptive studies. These are Orgaran344,345 and the defibrinogenating snake venom ancrod (Arvin).346,347 Intravenous administration of Orgaran produces immediate onset of anticoagulation after bolus administration. Ancrod has the advantage of exhibiting no cross-reactivity with heparin, but there is a delay of ~12 hours before effective defibrinogenation can be achieved. In addition, neither thrombin generation nor platelet activation are inhibited by ancrod348 and the magnitude of the anticoagulant effect is less predictable than with Orgaran. Ancrod is also contraindicated in patients with disseminated intravascular coagulation or septicemia.349 Long-term (ie, >3 weeks) anticoagulation with ancrod is limited by development of antibodies that render patients resistant to its effects.346,350 Unfortunately, neither of these agents is approved for use in the United States, but they can be obtained for compassionate use. Initial experience with hirudin from Europe is very promising, but it is not approved for use in North America. Complications of Oral Anticoagulants Bleeding is by far the most common complication of oral anticoagulant therapy.351 Randomized studies have shown that the risk of bleeding is influenced by the intensity of anticoagulation,37,352-354 and several studies have shown that the risk of clinically important bleeding is reduced by lowering the therapeutic range for the INR from 3.0 to 4.5 to 2.0 to 3.0. Although this difference in anticoagulant intensity is produced by a mean reduction in the dose of warfarin of only ~1 mg, the effect on bleeding is profound. Randomized studies have also shown that the rate of oral anticoagulant-induced bleeding is increased by concomitant use of high doses of aspirin that both impair platelet function and produce gastric erosions.351,355,356 Multivariate analysis of cohort studies also suggests that risk of bleeding is influenced by the underlying clinical disorder.354,357 These studies reported that the risk of major bleeding is increased by age >65 years, a history of stroke or gastrointestinal bleeding, and the presence of serious comorbid conditions such as renal insufficiency or anemia.358-360 Bleeding that occurs when the INR is <3.0 is frequently associated with an obvious underlying cause37 or an occult gastrointestinal or renal lesion.353 Drugs that are known to interact with coumarins should be avoided if possible.361 However, if concomitant use of drugs that interact with warfarin is necessary, PT should be monitored more frequently in the first few days to weeks of combined use to anticipate a change in dosage. Furthermore, all new drugs should be viewed as having the potential to interact with coumarins, and the frequency of PT monitoring should be increased in the initial period after introduction. Drugs known to inhibit platelet function should be avoided unless prescribed to augment the antithrombotic effects of warfarin. For example, low-dose aspirin (100 mg/d) augments the antithrombotic effects of coumarins in patients with prosthetic heart valves but at an increased risk of minor bleeding.362 The frequency of bleeding depends very much on intensity of the anticoagulant effect and patient-related risk factors.352,358,363 If moderate-dose anticoagulant therapy is used to prolong the INR to between 2.0 and 3.0, bleeding is relatively uncommon.352,358,363-367 Most episodes occur in patients with a potential bleeding source such as a peptic ulcer, gastritis, renal calculus, or malignancy. Bleeding complications in patients on long-term anticoagulant therapy tend to occur early and may unmask an underlying local source. In randomized trials of moderate-intensity warfarin (INR, 2.0 to 3.0) in patients with nonvalvular atrial fibrillation versus untreated control subjects, the typical annual incidence of major bleeding was between 1.0% and 1.5% in the warfarin groups and 0.5% to 1.0% in the control groups. However, patients selected for these trials were at low risk for bleeding, so in practice, bleeding on warfarin is higher than reported by these studies. Management of Bleeding If bleeding occurs during oral anticoagulant treatment in a patient with VTE, management depends on severity of bleeding, INR at the time of bleeding, and whether or not the patient has completed most of the prescribed course of anticoagulant therapy. If the INR is above the therapeutic range, treatment can be discontinued until bleeding has stopped and then reintroduced cautiously at a lower intensity. If the INR is within the therapeutic range, a local source of bleeding should be sought, particularly if bleeding is gastrointestinal or from the urinary tract. However, if the INR is markedly prolonged, it is not usually necessary to look for a source of bleeding. If bleeding is life-threatening and the INR prolonged, the coagulation defect should be reversed immediately by infusion of plasma, and vitamin K1 should be administered in a dose of 10 mg to 25 mg either intravenously by slow infusion or by subcutaneous injection. If bleeding is not life-threatening and the INR is markedly prolonged, then the anticoagulant effect can be reversed by administering 5 mg vitamin K1 by subcutaneous injection. Vitamin K1 can interfere with subsequent warfarin therapy when doses of 10 mg or more are used, and it can cause refractoriness to further warfarin therapy for up to 2 weeks. Skin Necrosis The most important nonhemorrhagic side effect of warfarin is skin necrosis. This uncommon complication is usually observed on the third to eighth day of therapy353-373 and is caused by extensive thrombosis of the venules and capillaries within the subcutaneous fat. An association has been reported between warfarin-induced skin necrosis and protein C deficiency,368,372,373 and less commonly, protein S deficiency,374 but this complication can also occur in persons without a deficiency. A role for protein C deficiency seems probable and is supported by the similarity of the lesions to those seen in neonatal purpura fulminans, which complicates homozygous protein C deficiency. The reason for the unusual localization of the lesions to subcutaneous fat deposits remains a mystery. The optimal technique for initiating anticoagulant therapy in patients with known protein C or protein S deficiency is uncertain. A reasonable empirical approach is to start with an initial course of heparin, begin warfarin at a maintenance dose of 5 mg, and give both anticoagulants in combination for ~7 days. In patients who develop warfarin-induced skin necrosis, warfarin should be discontinued, vitamin K1 should be given to increase levels of protein C, and full doses of heparin should be administered to achieve a rapid anticoagulant effect. Treatment of patients with warfarin-induced skin necrosis who require anticoagulant therapy for an indefinite period is difficult. These patients can be treated with subcutaneous heparin long term, but this is inconvenient and carries a risk of osteoporosis. It might be safe to reintroduce warfarin in low doses initially in combination with heparin and to use combined treatment for 10 to 14 days, during which time the warfarin dose is gradually increased.373 It should be noted, however, that heparin may not terminate coumarin necrosis,375,376 and some have reported that heparin failed to prevent continuing skin necrosis in homozygous protein C deficiency with very low protein C levels.377-380 Management When Anticoagulants Are Stopped Management of thromboembolism is influenced by the nature of the thromboembolic event, the time during the course of anticoagulant therapy that bleeding occurred, and the INR level during bleeding. If bleeding occurs in a patient with calf vein thrombosis who has received an adequate course of heparin therapy, then oral anticoagulant therapy can be stopped and replaced with low-dose heparin 5000 U twice daily SC. If bleeding occurs toward the end of a course of anticoagulant therapy (eg, >2 months after starting treatment) in a patient with proximal vein thrombosis, a decision can be made to terminate the course of anticoagulants. Long-term Warfarin Therapy and Elective Surgery Long-term anticoagulation is indicated in patients with a sustained high risk of arterial or venous thromboembolism. Elective surgery in such patients can be difficult. A number of approaches are available, but none have been evaluated in appropriately designed clinical studies. In general, the management choice should take into account the risk of thromboembolism if the patient is left untreated and the risk of bleeding if aggressive perioperative-operative anticoagulation is used. The least complicated approach is to stop oral anticoagulants and perform elective surgery when the INR has returned to the normal range. Oral anticoagulants can then be started postoperatively in combination with low-dose or full-dose heparin, the choice of heparin regimens depending on the anticipated risk of postoperative bleeding. White and associates381 have reported that it takes ~4 to 5 days for an INR between 2.0 and 3.0 to return to the normal range after warfarin is discontinued. Stopping anticoagulants 4 to 5 days preoperatively is appropriate in patients with atrial fibrillation or mechanical prosthetic valves because the risk of thrombosis in untreated patients is <10% per year.382,383 This annual incidence translates to a risk of thromboembolism of <0.1% over the 2 or 3 days that patients are without protection. A modification of this approach, which would further decrease risk, is to delay stopping warfarin until 2 days before surgery and reverse the anticoagulant effect with a 1- or 2-mg dose of vitamin K by subcutaneous injection, repeated if the INR is still prolonged 24 hours after injection. Low doses of vitamin K1 (1 to 2 mg) have been reported to lower the INR within 24 hours without producing warfarin resistance when anticoagulant treatment is reintroduced postoperatively.384 A more aggressive approach should be considered for patients who are at high risk of developing postoperative venous thrombosis. These include patients with a past history of venous thrombosis or recurrent venous thrombosis, particularly if they have a persistent risk factor for venous thrombosis. Two treatment options are available for these high-risk patients. The first is to lower the dose of warfarin and perform the operation at an INR of ~1.5; this approach has been shown to be safe and effective in preventing postoperative venous thrombosis in high-risk orthopedic surgical patients.385 The second option is to stop warfarin and replace the oral anticoagulant with full-dose heparin by continuous intravenous infusion preoperatively, stop heparin 6 hours before surgery, and restart anticoagulant therapy with heparin and warfarin postoperatively. Postoperative heparin should be delayed for at least 12 hours or longer if there is evidence of excessive bleeding or risk of serious postoperative bleeding.