It is estimated that 600000 new cases of heparin-induced thrombocytopenia (HIT) occur each year. Despite this, HIT remains a poorly understood disorder. It is important to increase awareness of the detection and management of this disorder among health care professionals to limit the often-severe complications.
Heparin-induced thrombocytopenia is a serious immune-mediated, prothrombotic disease and is defined by an otherwise unexplained drop in platelet count following heparin treatment, with or without thrombotic complications.1,2
At present, more than 12 million patients are treated each year with heparins in the United States. It is estimated that 600000 new cases of HIT occur each year. Of these, up to 300000 patients will develop thrombotic complications.3
HIT can occur in patients receiving any type of heparin, including unfractionated heparin (UFH) and low-molecular-weight heparins (LMWH), although it is more common after exposure to UFH.3 It is estimated that 3% to 5% of patients receiving UFH will develop HIT, whereas up to 1% of patients exposed to LMWH will develop HIT.4
This discussion will attempt to answer common questions regarding the diagnosis and management of a patient with HIT.
When Do I Suspect HIT as the Cause of Thrombocytopenia in My Patient?
Heparin-induced thrombocytopenia is often referred to as a clinicopathologic syndrome. The first part of the diagnosis begins when the patient clinically meets criteria. HIT is associated with a platelet count less than 100000/[mu]L or a decrease in platelet count by 50% of the baseline value. HIT is rarely associated with severe thrombocytopenia (<10000/[mu]L).1,2 Thrombocytopenia most commonly occurs 5 to 14 days after the initiation of heparin therapy. Patients previously treated with heparin may present with HIT much sooner, often within 24 hours of heparin therapy. Conversely, there have been cases of delayed onset thrombocytopenia, which can be seen days to months after heparin discontinuation. Based on this fact, patients who present with a new onset thromboembolic event should be asked about previous exposure to heparin to rule out HIT as the cause.4,5
The incidence of thrombocytopenia in critically ill patients can reach 50%. Therefore, other causes of thrombocytopenia should be ruled out before HIT is diagnosed. Patients in the ICU have multiple sources of thrombocytopenia. Other medications, sepsis, disseminated intravascular coagulation, and platelet dilution after resuscitation can be added to the differential diagnosis. In addition, critically ill patients are frequently exposed to heparin. It is often difficult to determine whether thrombocytopenia in these patients is due to heparin or another cause.6
To assist with the diagnosis of HIT, a clinical probability score can be assigned to patients. The clinical suspicion of HIT is based on the "4 T's": Thrombocytopenia, Timing of onset of decline in platelets, Thrombosis, or o Ther causes of thrombocytopenia.7 This scoring is further described in Table 1.
The second part of the diagnosis of HIT is pathologic. Several laboratory tests are available to identify the heparin-dependent IgG antibodies. Many hospitals have access to the enzyme-linked immunosorbent assay (ELISA) test. This test is simple and has a rapid turnaround time. However, the ELISA test can produce false positives, so a strong clinical suspicion of HIT must accompany a positive ELISA test. The serotonin-release assay is more specific for detecting heparin antibodies but is more difficult to perform and often has a long turnaround time. One approach is to perform an ELISA test initially. If the finding from the ELISA test is negative, there is a strong likelihood that the patient does not have HIT. If the finding from the ELISA test is positive, it can be confirmed by performing a serotonin-release assay. It is important that if a clinical diagnosis of HIT is made, that treatment is not delayed while waiting for the results of these laboratory confirmations.8,9
If Heparin Causes Thrombocytopenia, Should We Be Concerned With Bleeding?
Hemorrhage is not characteristic of HIT. Petechiae are not typical. Studies have shown that even with a platelet count below 10000/[mu]L, patients with HIT do not have an increased incidence of bleeding.10
Heparin-induced thrombocytopenia is associated with thrombosis. Without alternative anticoagulation, the incidence of thrombosis in patients with HIT may be up to 50%. New thrombosis is often the initial clinical manifestation in 50% of patients. Thrombosis can occur during thrombocytopenia despite discontinuation of heparin. Thrombosis can occur after platelets recover. The most common thromboembolic events are deep vein thrombosis and pulmonary embolism. However, arterial thrombosis can occur (stroke, myocardial infarction). Amputation is necessary in up to 20% of patients with a thrombosis secondary to HIT.1,2
The pathophysiology of HIT helps explain how this disorder causes clotting. Heparin binds to platelet factor 4, which is released from an activated platelet. IgG antibodies recognize and bind to this complex. This immunogenic complex then binds to the Fc receptor on other platelets, leading to additional platelet activation and release of additional platelet factor 4. This cycle of continued platelet activation leads to platelet aggregation and eventually to thrombin generation.11
Is Discontinuing the Heparin Enough?
The treatment of HIT consists of the following 3 steps:
Step 1: Interrupt the immune response. It is widely agreed that after a clinical diagnosis of HIT, the first line of action is to remove the offending agent-the heparin. Not only do pure or UFH products need to be discontinued, but all LMWH products must be discontinued as well. Unfortunately, heparin is such a highly used agent that it is often hiding in unsuspected places that may or may not seem obvious at first glance. It is imperative that the team seek out the nonobvious sources, such as heparin-coated catheters, pressure catheters, and heparin flushes used to maintain catheter patency.
Step 2: Inhibit thrombin generation. Despite the rapid intervention of stopping the heparin, the drug reaction can continue for some time.12 In some instances, even the asymptomatic patient may develop a thrombotic event despite platelet recovery. An alternative form of anticoagulation should be initiated to treat active thrombosis and prevent new thrombosis. The direct thrombin inhibitors (DTIs) do not interact with heparin-dependent antibodies. These drugs directly inhibit the procoagulant and prothrombotic actions of thrombin.13Table 2 highlights essential information about the DTIs argatroban, lepirudin, and bivalirudin.
Step 3: Minimize the complications of HIT. Studies have shown that 38% to 52% of HIT patients managed by heparin cessation alone developed thrombotic complications, including deep vein thrombosis, pulmonary embolism, stroke, or myocardial infarction within 1 month. A mortality rate of 22% to 28% has been reported in patients with HIT-associated thrombosis that is not treated with alternative anticoagulation.14
Institutions should regularly reevaluate the need for heparin in everyday practices to reduce unnecessary heparin exposure. These uses include, but are not limited to, heparin-coated catheters, heparinized pressure catheters, intermittent hemodialysis, and continuous renal replacement therapy. For example, many institutions use sodium citrate as a primary anticoagulant alternative to heparin for continuous renal replacement therapy, removing one more opportunity for exposure to patients. Unfortunately, the body of evidence does not provide a clear answer to the efficacy of using heparinized versus nonheparinized flush solutions in pressure catheters to maintain patency. As demonstrated by the AACN Thunder Project, there is evidence to support heparinizing pressure tubing for arterial catheters.15 The authors concluded that for long-term patency, heparinized solutions may have better efficacy. The clinician at the bedside should have some foresight into the long-term versus short-term use of the pressure catheter so that an informed decision can be made to use heparin. If long-term patency is critical, the risk of exposing the patient to heparin needs to be weighed heavily. The question of heparin versus nonheparinized pressure catheters continues to be ripe as an area for further research.
Can My Patient Ever Receive Heparin Again? Is This a Heparin Allergy?
A patient with both a current clinical and laboratory-confirmed diagnosis of HIT should not receive any form of heparin. This includes UFH, LMWH, and heparin flushes. It is recommended that a note be placed at the bedside or on the chart to inform health care practitioners that the patient cannot receive heparins.
The antibodies for HIT are usually undetectable after 3 months. However, there have been case reports of patients who developed HIT with thrombosis years after the original diagnosis. Because other anticoagulants are available, it may be best to avoid heparin in these patients with a remote or distant history of HIT. Special circumstances, such as cardiac surgery in which other anticoagulants may not be recommended or preferred, may warrant the use of heparin in patients with a history of HIT.16
If Heparin Is Associated With Thrombocytopenia, Then Why Is It Still Commonly Used?
A query of MEDLINE elicits more than 70000 articles related to heparin, more than 9500 related to LMWH, more than 800 in reference to argatroban, and only 386 related to lepirudin. It is clear that there is a vast body of evidence related to heparin use. A level of comfort and experience with heparin is shared by the health care team as most members have a high level of understanding of its dosing, adverse effects, and management of overdose. Therefore, UFH and LMWH are recommended as first-line therapy for patients with or at risk for various clotting disorders.17
Not only do many practitioners have experience with heparin, but heparin has a cost benefit over other anticoagulants. Heparin is a very cost-effective drug when used appropriately and with adequate surveillance. Because episodes of HIT are life threatening, cost should not be the only factor in the decision of which anticoagulant to use. As additional pharmaceutical agents enter the market, our comfort level and experience with these agents increase, and the incidence of HIT increases, the use of alternative anticoagulants may also increase.
Unfortunately, the myth persists that the DTIs are expensive and have no improved outcomes in patients with a diagnosis of HIT. This not only is false, but the DTIs have demonstrated clear and consistent benefits in the prevention of new thrombi.18
Conclusion
Although HIT does occur infrequently in heparin-treated patients, the disease is often life threatening. Health care providers need to be knowledgeable about the disease and available treatment options, as well as about the inherent frequent exposures to heparin in clinical practice settings.
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