Critical Care Nurse. 2006;26: 30-36
Copyright © 2006 by the American Association of Critical-Care Nurses.
Clinical Article
CE Article
Heparin-Induced Thrombocytopenia
Advances in Diagnosis and Treatment
Maureen F. Cooney, RN, MS, FNP, CCRN
Maureen F. Cooney is a nurse practitioner and clinical nurse specialist in the department of anesthesia at Westchester Medical Center in Valhalla, NY.
To purchase electronic or print reprints, contact The InnoVision Group, 101 Columbia, Aliso Viejo, CA 92656. Phone, (800) 809-2273 or (949) 362-2050 (ext 532); fax, (949) 362-2049; e-mail, reprints{at}aacn.org.
* This article has been designated for CE credit. A closed-book, multiple-choice examination follows this article, which tests your knowledge of the following objectives:- Identify patient populations most at risk for development of heparin-induced thrombocytopenia (HIT)
- Recognize early signs and symptoms of HIT
- Describe nursing management of patients with suspected or confirmed HIT
Corresponding author: Maureen F. Cooney, Department of Anesthesia, Westchester Medical Center, Grasslands Rd, Valhalla, NY, 10595 (e-mail: waterford55{at}aol.com).
Heparin is one of the most commonly administered parenteral therapeutic agents in hospitals. Each year, approximately 12 million patients—or one third of all hospitalized patients—are exposed to heparin.1,2 A serious complication called heparin-induced thrombocytopenia (HIT), which is associated with significant morbidity and mortality, may develop in some patients who receive heparin. Among patients exposed to heparin, HIT develops in approximately 1% to 5% (up to 600000 patients). Moreover, many clinicians think that HIT is underrecognized and underdiagnosed.3–5
Consequences of HIT include venous or arterial thrombosis and, rarely, bleeding.1,6 In patients with acute thrombosis, HIT can be fatal. Treatment of HIT includes discontinuation of heparin therapy and the use of parenteral nonheparin anticoagulants such as direct thrombin inhibitors. In order to minimize the impact of HIT, however, preventive measures are essential. Nurses play a critical role in the early detection and prevention of the complications of HIT. This article provides a discussion of the risk factors, pathogenesis, diagnosis, manifestation, and management of HIT from the perspective of critical care nurses.
 |
Risk Factors for HIT
|
|---|
The clinical importance of HIT is influenced by 4 factors: the widespread and increasing use of heparin, the potentially devastating consequences of the disorder, the unpredictability with which HIT occurs, and the uncertainty regarding diagnosis and treatment. All types of heparin, from bovine or porcine sources, can cause HIT.1,6,7 Although both low-molecular-weight heparin (LMWH) and unfractionated heparin can cause HIT, the abnormality is more common in patients treated with unfractionated heparin than in patients treated with LMWH.8,9 However, the incidence of thrombosis in patients with HIT who have received unfractionated heparin and those who received LMWH is thought to be similar.
Use of heparin is ubiquitous in hospitals, and the administration of heparin may not be documented. Use of heparin should be avoided or minimized wherever possible, for example, by flushing peripheral and central catheters with isotonic sodium chloride solution or a nonheparinized solution rather than with heparin.10 All efforts should be made to limit the duration of heparin administration. The use of alternative anticoagulant drugs or LMWH rather than unfractionated heparin should be considered.11
The primary groups of patients affected by HIT are orthopedic, cardiovascular, and trauma patients. In addition, the relationship between the frequency of formation of an immunoglobulin G (IgG) antibody associated with HIT and the risk for HIT appears to vary depending on the population of patients. In a study12 of 744 patients receiving unfractionated heparin during or after cardiac surgery, unfractionated heparin after orthopedic surgery, or LMWH after orthopedic surgery, IgG antibodies associated with HIT were more likely to form in patients undergoing cardiac surgery than in orthopedic patients. Among the patients in whom antibodies did form, HIT was more likely to develop in the orthopedic patients than in the cardiac surgery patients.
|
Immune Versus Nonimmune HIT
|
|---|
The term HIT refers to a decrease in the platelet count shortly after the start of treatment with heparin and is now preferably reserved for describing immune-mediated HIT.1,13 A decrease in platelet count that occurs before day 5 of treatment usually is not immune-mediated HIT, but it may be a form of nonimmune heparin-associated thrombocytopenia (formerly called type I HIT), which generally resolves despite continued exposure to heparin. This transient, benign, and self-limiting form of thrombocytopenia appears to be caused by a direct agglutinating effect of heparin on platelets. In contrast, immune-mediated HIT (formerly called type II HIT and now more simply HIT) is due to an immunoglobulin-mediated reaction to the complex composed of heparin and platelet factor 4 (PF4) that forms during heparin treatment.14
Immune-mediated HIT is characterized by the development of thrombocytopenia 5 to 14 days after initiation of heparin therapy (although time of onset can be sooner in patients who have been exposed to heparin in the preceding 3 months). In addition, thrombocytopenia associated with immune-mediated HIT should be considered when the platelet count decreases to less than 150 x 109/L or by 30% to 50% during treatment. The characteristics of the immune and nonimmune forms of HIT are compared in Table 1
. From here on, the term HIT refers to immune-mediated HIT.
|
Pathophysiology of HIT
|
|---|
The underlying pathophysiology of HIT (Figure 1) is an immune reaction to heparin.1,6,15 First, heparin binds to PF4, forming a highly immunogenic complex on the surface of platelets. Then, in susceptible patients, an IgG antibody to the antigenic heparin-PF4 complex develops. The resulting antibody binds with the heparin-PF4 complex, which in turn activates platelets via Fc receptors present on the surface of the platelets. Thrombocytopenia develops as the reticuloendothelial system destroys activated platelets. In addition, platelet activation leads to the generation of procoagulant-rich microparticles, which contribute to a thrombotic state.
|
Consequences of HIT
|
|---|
HIT thrombotic syndrome (HITTS) is the most serious complication associated with HIT. Without the use of an alternative treatment, the overall risk of thrombosis in patients with HIT is 38% to 76%, according to data from 3 studies involving 425 patients.16 If thrombotic syndrome develops, limb amputation is required in about 20% of patients, and 30% to 50% of patients die. Venous thrombi outnumber arterial thrombi in most patients with this complication, except in patients undergoing cardiovascular or arterial procedures, who experience more arterial thrombi. The morbidity and mortality associated with HITTS support the notion that heparin cessation alone is an inadequate strategy for managing HIT. Alternative therapy with a rapidly acting anticoagulant should be started when heparin therapy is discontinued.
About 50% of patients with HIT develop deep venous thrombosis, and 25% of patients develop pulmonary embolism and acute systemic reaction, respectively.17 Other reported complications related to HIT include skin lesions at the injection site, acute limb ischemia, warfarin-associated venous limb gangrene, and acute thrombotic stroke or myocardial infarction.17
Critical care nurses can assess patients for signs of thrombosis and also use measures to prevent deep venous thrombosis. In addition to initiating anticoagulant therapy, other preventive measures include the following:
- using sequential compression devices and pneumatic compression stockings,
- increasing the patient’s activity,
- encouraging early ambulation,
- ensuring adequate hydration, and
- using exercises for preventing deep venous thrombosis.
|
Diagnosis of HIT
|
|---|
Three factors may help explain why HIT is underdiagnosed. First, the name of the disease creates some confusion, because clinically significant thrombocytopenia may not be present in all patients with HIT. That is, the thrombocytopenia may be relative (a 30%–50% decrease) rather than absolute (less than the upper limit of the reference range). Second, thrombocytopenia in HIT is paradoxically associated with thrombosis, not with bleeding. And third, in hospitalized patients, thrombocytopenia may arise from many other causes, including disseminated intravascular coagulation, septicemia/sepsis hemodilution, hypercoagulable states, hemodialysis, multisystem organ failure, and primary bone marrow disorder.18 Thus, other causes of thrombocytopenia should be ruled out before HIT is diagnosed.
Recognition of HIT is important to proper management of the condition, but the diagnosis of HIT can be challenging. Several clinical indicators can point astute nurses toward a diagnosis of HIT in patients receiving heparin therapy. HIT should be suspected if a patient has recently been exposed to heparin and if evidence of at least one of the following clinical events is apparent: an unexplained decrease in platelet count and/or the presence of thrombosis.6,19,20 The clinical criteria for diagnosing HIT in most patients are listed in Table 2.
Timing of Onset
In most patients, the classical signs and symptoms of HIT develop between 5 and 14 days after heparin treatment is started. However, HIT can develop quickly in patients reexposed to heparin. Therefore, knowing a patient’s history of exposure to heparin is crucial. In addition, delayed-onset HIT has occurred 9 to 45 days after treatment with heparin was discontinued.
Rapid-onset HIT is due to platelet activation caused by residual circulating antibodies associated with HIT. It is characterized by a decrease in the platelet count that begins soon after treatment with heparin is started and can occur within minutes, hours, or days of heparin administration. The patient will have recently been exposed to heparin, typically within the past 100 days,21 although rapid-onset HIT after a 165-day heparin-free interval has been described.22 In contrast, delayed-onset HIT occurs days or weeks after heparin has been stopped, perhaps after the patient has been discharged from the hospital.23–25 The patient may then again have signs or symptoms of thrombosis and be readmitted to the hospital. In patients with a delayed onset of HIT, development of new thromboses is typical, and further exposure to heparin can quickly worsen a patient’s clinical condition.
Degree of Thrombocytopenia
The actual platelet counts in patients with HIT may not be as important as the occurrence of a sudden decrease in platelet count of 30% to 50% from the patient’s baseline count. Decreases exceeding 50% are particularly indicative of HIT.26
Laboratory Testing
To date, no reference standard diagnostic test for HIT is available. Current tests for HIT include activation assays, which detect the presence of functional antibodies, and antigen assays, which detect the presence of heparin-PF4 antibodies (Figure 2). Laboratory confirmation of the presence of antibodies to heparin can verify a diagnosis, but the assays used for HIT have variable sensitivity and specificity.19 In addition, assays often require a long turnaround time, and because of the hypercoagulable state of HIT, confirmatory results may not be available before treatment has been started. Thus, diagnosis of HIT is primarily based on clinical signs and symptoms; laboratory confirmation should be sought, but treatment must not be delayed.1,6
|
Guidelines for Managing Patients With HIT
|
|---|
The first step in managing a patient with confirmed or suspected HIT is to stop administration of all forms of heparin. These include, but are not limited to, use of heparin infusions, LMWH, heparin flushes, heparin in dialysate, continuous hemofiltration catheters, heparin-coated pulmonary catheters, guidewires, and devices containing heparin. In addition, when HIT is suspected, or if a history of HIT is determined, critical care nurses must document this finding in the patient’s chart. In September 2004, the American College of Chest Physicians published clinical guidelines on the management of HIT6 that were developed by consensus of a nationwide panel of 87 physicians (Table 3).
View this table:
[in this window]
[in a new window]
|
Table 3 American College of Chest Physicians 2004 guidelines for treatment of confirmed or strongly suspected cases of heparin-induced thrombocytopenia6
|
|
Alternative Anticoagulants
In addition to discontinuation of heparin, the guidelines for management of HIT recommend the use of alternative anticoagulants in patients with strongly suspected or confirmed HIT, whether or not HIT is complicated by thrombosis. Discontinuation of heparin therapy alone is not sufficient, because it leaves patients in a hypercoagulable state. Currently, only 2 nonheparin anticoagulants, argatroban and lepirudin, are approved for use in the medical management of HIT. Argatroban is indicated in the United States for the prophylaxis or treatment of thrombosis associated with HIT and in patients undergoing percutaneous coronary intervention who have HIT or are at risk for HIT. Lepirudin is indicated for anticoagulation in patients with HIT and associated thromboembolic disease in order to prevent further thromboembolic complications (Table 4). These agents are known as direct thrombin inhibitors (Table 5).
Unlike heparin, direct thrombin inhibitors directly block the activation of thrombin and do not trigger the antibody-mediated reactions that lead to HIT. A third direct thrombin inhibitor, bivalirudin, is approved for use in patients with or at risk for HIT during percutaneous coronary intervention but is not approved for medical use in HIT.
Many patients with HIT require long-term anticoagulation for an underlying condition and therefore may be candidates for warfarin therapy. HIT is a consumptive process and may cause depletion of the natural anticoagulant protein C. Early introduction of warfarin may exacerbate protein C depletion when the highly prothrombotic HIT state exists. The resulting imbalance between the natural anticoagulant and procoagulant proteins could lead to greater thrombotic risk and cause warfarin-induced thrombosis and venous limb gangrene.27,28 Warfarin is contraindicated in any patient with acute HIT until the patient has received treatment with an alternative anticoagulant for several days and the platelet count has recovered (or is >100 x 109/L). Guidelines for the use of oral anticoagulants and conversion of direct thrombin inhibitors to warfarin in patients with HIT are described in Table 6 and Figure 3.28
Platelet Count Monitoring
Monitoring platelet counts is essential for the timely detection of HIT. The guidelines for management of HIT recommend monitoring platelet counts during specific periods, depending on the patient’s history with heparin and the risk of HIT developing (Table 7).
Platelet counts should be tracked until recovery. Because patients with HIT rarely bleed spontaneously, thrombocytopenia does not usually need to be treated with platelet transfusions. Platelet transfusions may increase the risk for platelet-mediated thrombosis.
Because of the availability of acceptable alternative anticoagulants, such as the direct thrombin inhibitors, it is advisable to avoid both unfractionated heparin and LMWH in patients with a history of HIT. In a prospective study,29 argatroban provided adequate anticoagulation for venous or arterial thrombosis in patients with a history of HIT, without major bleeding or thrombotic complications. In special circumstances, such as in the event of cardiac or vascular surgery, it may be necessary to expose a patient to heparin again. Repeat administration of heparin may be considered if HIT occurred a long time before (>100 days), the patient is negative for antibodies to the heparin-PF4 complex, and the exposure time will be limited to the surgical procedure itself.
|
Conclusion
|
|---|
Although techniques for preventing HIT have yet to be developed, the risk of HIT can be reduced by limiting the duration and extent of patients’ exposure to heparin. The risk of HIT may be somewhat reduced by the use of LMWH rather than unfractionated heparin because, although the risk of HIT still exists, the risk is lower with LMWH. Increasing use of non-heparin anticoagulants such as fondaparinux, a factor Xa inhibitor, or the direct thrombin inibitors may result in a reduced incidence of HIT.
HIT can develop rapidly and can cause serious or even fatal consequences if it is not detected and treated early. Clearly, the most effective way to manage HIT is to try to prevent it from occurring in the first place. However, increased awareness of the signs and symptoms of the disorder is essential to prevent potentially dire, if not fatal, consequences. Critical care nurses can facilitate recognition by educating physicians, pharmacists, other nurses, and patients about HIT. Critical care nurses can ensure that heparin protocols address parameters for monitoring platelet count. Nurses can monitor patients for early signs of any HIT complications and clearly document and communicate each patient’s history of HIT. Critical care nurses can participate in quality control and surveillance programs and read literature to find and communicate HIT-related research. In short, the actions of critical care nurses can play a central role in treating, preventing, and building awareness of HIT.
|
References
|
|---|
- Jang IK, Hursting MJ. When heparins promote thrombosis: review of heparin-induced thrombocytopenia. Circulation. 2005;111: 2671–2683.
- Fahey VA. Heparin-induced thrombocytopenia. J Vasc Nurs. 1995;13:112–116.[Medline]
- Rice L. Heparin-induced thrombocytopenia: myths and misconceptions (that will cause trouble for you and your patient). Arch Intern Med. 2004;164:1961–1964.[Free Full Text]
- Levine RL. Finding haystacks full of needles: from Opus to Osler. Chest. 2005;127: 1488–1490.
- Begelman SM, Hursting MJ, Aghababian RV, McCollum D. Heparin-induced thrombocytopenia from venous thromboembolism treatment. J Intern Med. 2005;258:563–572.[Medline]
- Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia: recognition, treatment, and prevention: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(3 suppl):311S–337S.
- Francis JL, Palmer GJ, Moroose R, Drexler A. Comparison of bovine and porcine heparin in heparin antibody formation after cardiac surgery. Ann Thorac Surg. 2003;75:17–22.[Abstract/Free Full Text]
- Warkentin TE, Levine MN, Hirsh J, et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med. 1995;332:1330–1335.[Abstract/Free Full Text]
- Gruel Y, Pouplard C, Nguyen P, et al. Biological and clinical features of low-molecular-weight heparin-induced thrombocytopenia. Br J Haematol. 2003;121:786–792.[Medline]
- McNulty I, Katz E, Kim KY. Thrombocytopenia following heparin flush. Prog Cardiovasc Nurs. 2005;20:143–147.[Medline]
- Greinacher A, Eichler P, Lietz T, Warkentin TE. Replacement of unfractionated heparin by low-molecular-weight heparin for postorthopedic surgery antithrombotic prophylaxis lowers the overall risk of symptomatic thrombosis because of a lower frequency of heparin-induced thrombocytopenia. Blood. 2005;106:2921–2922.[Free Full Text]
- Warkentin TE, Sheppard JA, Horsewood P, Simpson PJ, Moore JC, Kelton JG. Impact of the patient population on the risk for heparin-induced thrombocytopenia. Blood. 2000;96:1703–1708.[Abstract/Free Full Text]
- Rice L, Attisha WK, Francis JL. Delayed-onset heparin-induced thrombocytopenia [letter]. Ann Intern Med. 2003;139:790–791.[Free Full Text]
- Warkentin TE. Heparin-induced thrombocytopenia: pathogenesis and management. Br J Haematol. 2003;121:535–555.[Medline]
- Warkentin TE, Hayward CPM, Boshkov LK, et al. Sera from patients with heparin-induced thrombocytopenia generate platelet-derived microparticles with procoagulant activity: an explanation for the thrombotic complications of heparin-induced thrombocytopenia. Blood. 1994;84:3691–3699.[Abstract/Free Full Text]
- Hirsh J, Heddle N, Kelton JG. Treatment of heparin-induced thrombocytopenia: a critical review. Arch Intern Med. 2004;164:361–369.[Abstract/Free Full Text]
- Warkentin TE. Heparin-induced thrombocytopenia: a clinicopathologic syndrome. Thromb Haemost. 1999;82:439–447.[Medline]
- Kiefel V. Differential diagnosis of acute thrombocytopenia. In: Warkentin TE, Greinacher A, eds. Heparin-Induced Thrombocytopenia. 3rd ed. New York, NY: Marcel Dekker Inc; 2004:25–52.
- Warkentin TE. Platelet count monitoring and laboratory testing for heparin-induced thrombocytopenia: recommendations of the College of American Pathologists. Arch Pathol Lab Med. 2002;126:1415–1423.[Medline]
- Warkentin TE, Heddle NM. Laboratory diagnosis of immune heparin-induced thrombocytopenia. Curr Hematol Rep. 2003;2:148–157.[Medline]
- Lubenow N, Kempf R, Eichner A, Eichlet P, Carlsson LE, Greinacher A. Heparin-induced thrombocytopenia: temporal pattern of thrombocytopenia in relation to initial use or reexposure to heparin. Chest. 2002; 122:37–42.
- DeEugenio DL, Ruggiero N, Thomson LJ, et al. Early-onset heparin-induced thrombocytopenia after a 165-day heparin-free interval: case report and review of the literature. Pharmacotherapy. 2005;25:615–619.[Medline]
- Rice L, Attisha WK, Drexler A, Francis JL. Delayed-onset heparin-induced thrombocytopenia. Ann Intern Med. 2002;136:210–215.[Abstract/Free Full Text]
- Smythe MA, Stephens JL, Mattson JC. Delayed-onset heparin-induced thrombocytopenia. Ann Emerg Med. 2005;45:417–419.[Medline]
- Warkentin TE, Kelton JG. Delayed-onset heparin-induced thrombocytopenia and thrombosis. Ann Intern Med. 2001;135: 502–506.[Abstract/Free Full Text]
- Warkentin TE, Roberts RS, Hirsh J, et al. An improved definition of immune heparin-induced thrombocytopenia in postoperative orthopedic patients. Arch Intern Med. 2003; 163:2518–2524.[Abstract/Free Full Text]
- Warkentin TE, Elavathil LJ, Hayward CP, Johnston MA, Russett JI, Kelton JG. The pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopenia. Ann Intern Med. 1997;127:804–812.[Abstract/Free Full Text]
- Srinivasan AF, Rice L, Bartholomew JR, et al. Warfarin-induced skin necrosis and venous limb gangrene in the setting of heparin-induced thrombocytopenia. Arch Intern Med. 2004;164:66–70.[Abstract/Free Full Text]
- Matthai WH, Hursting MJ, Lewis BE, Kelton JG. Argatroban anticoagulation in patients with a history of heparin-induced thrombocytopenia. Thromb Res. 2005;116:121–126.[Medline]
Top
Risk Factors for HIT
Immune Versus Nonimmune HIT
