Thrombocytopenia

Thrombocytopenia is a common problem in cardiovascular patients, but the etiology and management of this condition may be different than those in other populations. Around the time that percutaneous coronary interventions are performed, the drugs most commonly associated with thrombocytopenia are the glycoprotein (GP) IIb/IIIa receptor inhibitors and heparin. Thienopyridines only rarely cause thrombocytopenia. Patients with non-ST-elevation acute coronary syndromes may be exposed to prolonged heparin infusions, GPIIb/IIIa inhibitors, and thienopyridines. After open-heart surgery, as opposed to other surgical procedures, the platelet count falls, primarily due to platelet damage and destruction in the bypass circuit and hemodilution. Heparin is the most common drug to be implicated in thrombocytopenia in ICU patients. Determining the etiology for the low platelet count is important for the implementation of appropriate management. The use of a direct thrombin inhibitor in treatment should be considered early if a diagnosis of heparin-induced thrombocytopenia is possible.

Key words: acute coronary syndrome; heparin-induced thrombocytopenia; open-heart surgery; percutaneous coronary intervention; thrombocytopenia

Abbreviations: ACS = acute coronary syndrome; ACT = activated clotting time; GP = glycoprotein; HIT = heparin-induced thrombocytopenia; IABP = intraaortic balloon pump; MI = myocardial infarction; PCI = percutaneous coronary intervention; SRA = serotonin release assay; TTP = thrombotic thrombocytopenic purpura

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Thrombocytopenia, relative to baseline or absolute, is commonly encountered in cardiology and cardiac surgery patients. A platelet count of < 100 x [10.sup.9] cells/L following percutaneous coronary intervention (PCI) using abciximab, clopidogrel, and aspirin as antiplatelet therapy occurs in 2.4 to 9.2% of patients. (1,2) The platelet count falls after open-heart surgery by approximately 30% by the conclusion of surgery, reaching a nadir of 40 to 60% on the second or third postoperative day. (3) While the general differential diagnosis of immunologic or nonimmunologic thrombocytopenia continues to hold true, the specific etiologies of the platelet disorder are often different than those seen in other populations. Therefore, diagnostic strategies and management options may be different. This article will review some of the more common and more unusual presentations of thrombocytopenia in the cardiovascular population.

THROMBOCYTOPENIA AND ANTI-HEPARIN-PLATELET FACTOR 4 ANTIBODIES AS INDEPENDENT RISK FACTORS

Some studies have suggested that the diagnosis of thrombocytopenia alone is important, even without the occurrence of bleeding or, in the ease of heparin-induced thrombocytopenia (HIT), thrombosis. Patients with thrombocytopenia in the absence of obvious thrombosis or bleeding in cardiac populations including patients with ST-elevation myocardial infarction (MI) (4) and acute coronary syndromes (ACSs) (5,6) or those who have undergone PCI, (7) have a twofold to 12-fold increased risk of mortality than those without thrombocytopenia (Table 1).

In addition, the occurrence of an abnormal result of an anti-platelet factor 4/heparin antibody assay in the absence of thrombocytopenia also may confer increased risk. Stored samples from patients without thrombocytopenia or thrombosis in the Global Utilization of Streptokinase and Tissue Plasminogen

Activator for Occluded Arteries IV-ACS (GUSTO IV-ACS) Trial (8) were evaluated for the presence of the antibody. Patients with a positive test result were four times more likely to die or experience a M1 in the 30 days after presentation than those with a normal result, 8) Similarly, Mattioli et al (9) demonstrated that patients with ACSs and with a positive antibody assay result were more likely to experience a major adverse cardiovascular event at 1 year than those with a negative antibody test result (66% vs 44%, respectively; p < 0.01).

While the incidence of major adverse events is widely recognized to be high in patients with HIT, (10,11) it also appears that thrombocytopenia in the absence of a clinical diagnosis of HIT or a positive finding for a heparin-platelet factor 4 antibody assay in the absence of thrombocytopenia or thrombosis may confer increased risk. Whether there is a relationship among these three clinical scenarios is not clear, but the possibility is certainly intriguing. Did some of the thrombocytopenia occur due to HIT that was not appreciated but subsequently resulted in a thromboembolic event? Did some of these cardiac patients with an abnormal finding on a HIT antibody assay have subclinical HIT with later clinical manifestation? The answers to these questions have not been determined at this time.

THROMBOCYTOPENIA COMPLICATING PCI

The differential diagnosis of thrombocytopenia early after a patient undergoes PCI must include laboratory error and drug-induced thrombocytopenia from thienopyridines, glycoprotein (GP) IIb/IIIa inhibitors, and heparin. The first response to a laboratory result demonstrating thrombocytopenia must be the confirmation of the result. Pseudo-thrombocytopenia occurs due to platelet clumping in tubes containing ethylendiaminetetraacetic acid as an anticoagulant. One third of the "thrombocytopenia" found in patients receiving abciximab is due to pseudothrombocytopenia, which has no clinical significance. (12 The demonstration of platelet clumping on a review of a peripheral smear or a normal platelet count when citrate rather than ethylendiaminetetraacetic acid is used as the anticoagulant in the specimen sent for a repeat testing will confirm the presence of pseudothrombocytopenia.

Clopidogrel and ticlopidine are thienopyridines that inhibit adenosine diphosphate-mediated platelet activation. Because the use of ticlopidine is associated with a higher incidence of serious side effects, clopidogrel is the drug of choice in most cases. It is used routinely with aspirin after stent implantation and may be used in patients with ACSs or other vascular diseases. Thienopyridine-associated thrombocytopenia clinically presents as classic thrombotic thrombocytopenic purpura (TTP) with severe thrombocytopenia, microangiopathic hemolytic anemia, renal failure, and neurologic changes. The diagnosis is based on a review of the peripheral smear and the clinical presentation. Clopidogrel-associated TTP occurs so rarely that an accurate incidence is not possible to calculate. Ticlopidine-associated TTP occurs more commonly, in 1 of approximately 5,000 cases. (13) As opposed to TTP associated with ticlopidine, which occurs within 2 to 12 weeks of the initiation of therapy, TTP related to elopidogrel occurs within the first 2 weeks of use (14) and so must be considered in the differential diagnosis of thrombocytopenia early after PCI. The optimal treatment for this condition has not been defined, but plasma exchange has been recommended. (15) The mortality rate without plasma exchange exceeds 50% but is < 20% if this therapy is used.

After thrombocytopenia due to laboratory error, or to clopidogrel or ticlopidine therapy have been quickly eliminated from consideration, in most cases the differential diagnosis of thrombocytopenia early after PCI includes only HIT and thrombocytopenia due to therapy with a GPIIb/IIIa inhibitor. Because the management of these two conditions is very different and each condition has significant long-term implications for future management, it is important to accurately determine the cause of the low platelet count.

With the introduction of GPIIb/IIIa inhibitors and the recognition that every member of this class of drugs may cause thrombocytopenia, this event is now considered in most interventional cardiology trials. There are three GPIIb/IIIa inhibitors that have been approved for use (abciximab, tirofiban, and eptifibatide). The incidence of thrombocytopenia in PCI varies, largely dependent on the use and choice of the GPIIb/IIIa inhibitor. As noted above, thrombocytopenia, defined as a platelet count of < 100 x [10.sup.9] cells/L, occurs in 2.4 to 9.2% of procedures in which abciximab is used, while profound thrombocytopenia, a platelet count < 20 x [10.sup.9] cells/L, occurs in approximately 0.3%. (1) The small-molecule inhibitors tirofiban and eptifibatide have a much lower incidence of thrombocytopenia than abciximab. Mild thrombocytopenia occurs in 0.5 to 3.2% of patients, and profound thrombocytopenia is rare. (1,16,17) While there is a trend toward more thrombocytopenia with therapy using the small-molecule inhibitors than with heparin alone, a statistically significant difference has not been demonstrated during PCI, (16, 18, 19) possibly due the shorter course of therapy in PCI trials than in ACS trials.

Typically, the platelet count begins to fall very early after drug initiation, and so the platelet count should be checked 2 to 4 h after therapy with the agent has been started. Should a significant drop in the platelet count be documented, therapy with the GPIIb/IIIa inhibitor should be discontinued (unless pseudothrombocytopenia is confirmed). (20) If therapy with the agent is continued in this situation, profound thrombocytopenia with platelet counts of < 20 X [10.sup.9] cells/L are more likely to result. Early discontinuation of therapy may blunt the decline in platelet count.

While platelet transfusions are not used in patients with some types of thrombocytopenia unless bleeding occurs, platelet transfusions are often used in cases of thrombocytopenia due to GPIIb/IIIa inhibitors to maintain a platelet count of > 20 x [10.sub.9] cells/L. (20) Life-threatening bleeding, intracranial hemorrhage in particular, may occur if profound thrombocytopenia is not treated. (21)

HIT can often be differentiated from thrombocytopenia due to GPIIb/IIIa inhibitor therapy by the time course and degree of thrombocytopenia. Thrombocytopenia due to HIT generally occurs between days 5 and 14 of heparin therapy. If the duration of heparin therapy falls within this window in a patient with thrombocytopenia who has undergone PCI, HIT must be considered as a diagnosis. With evidence favoring early intervention in patients with ACSs, most PCI patients have received little or no heparin prior to the procedure, and so HIT is unlikely. The exception to this rule is the patient who has been exposed to heparin in the previous 3 months. These patients may experience thrombocytopenia early after reexposure, complicating the diagnosis of the cause of the thrombocytopenia. In patients with HIT, the platelet fall is generally modest, and profound thrombocytopenia is very rare. Despite thrombocytopenia, patients with HIT rarely experience spontaneous bleeding, which is not the case in patients with GPIIb/IIIa inhibitor-related thrombocytopenia. The presence of petechiae or gingival hemorrhage, for example, suggests a diagnosis other than HIT. In a patient with recent heparin exposure and moderate thrombocytopenia, the presence of spontaneous bleeding may be key in determining the cause of thrombocytopenia.

Two conditions associated with abciximab use, thrombocytopenia associated with reexposure to abciximab and delayed thrombocytopenia, merit further discussion. While the overall incidence of thrombocytopenia following the readministration of abciximab is not different from that of the initial administration, those patients who develop thrombocytopenia are more likely to develop profound thrombocytopenia (2.4% incidence) after readministration than after a first administration. (22) In addition, while patients who experience profound thrombocytopenia after a first administration usually respond to a single platelet transfusion, those with profound thrombocytopenia may require multiple platelet transfusions to achieve an acceptable platelet count or may have recurrent thrombocytopenia, again requiring multiple platelet transfusions. (22) The readministration of abciximab within 2 weeks after the first administration may be associated with a very high incidence of severe thrombocytopenia (approximately 12%). (23)

While abciximab-associated thrombocytopenia usually presents within hours of administration of the drug, delayed thrombocytopenia has been reported. (22,24-25) Severe thrombocytopenia may suddenly develop > 48 h after administration (but within a week of administration) or after hospital discharge, and may present as mucocutaneous bleeding. This phenomenon appears to be quite rare.

The mechanisms of thrombocytopenia due to abciximab and due to the small-molecule inhibitors tirofiban and eptifibatide appear to be different, and so, if thrombocytopenia has developed with one agent, another agent may be used with care if clinically indicated. (26) If HIT is a concern, however, heparin readministration should be avoided, and a direct thrombin inhibitor can be used as an anticoagulant during the PCI. Argatroban has been approved for use during PCI in patients with HIT. The approved dose, 350 [micro]g/kg bolus followed by 25 [micro]g/kg/min with a goal activated clotting time (ACT) of 300 to 450 s, is based on use of argatroban without concomitant GPIIb/IIIa inhibitor use. (28) A lower dose with a bolus of 250 to 300 [micro]g/kg and an infusion of 15 [micro]g/kg/min with a goal ACT of > 275 s can be used with a GPIIb/IIIa inhibitor. (29) There is significant experience with the use of bivalirudin in patients undergoing PCI, although the published experience in patients with HIT is limited. The dose used in the Randomized Evaluation of PCI Linking Angiomax to Reduced Clinical Events (REPLACE) 2 trial (30) was a bolus of 0.75 mg/kg with an infusion of 1.75 mg/kg/h without ACT monitoring and with or without GPIIb/IIIa inhibitor use. There has been no systematic evaluation of lepirudin therapy in patients undergoing PCI.

THROMBOCYTOPENIA COMPLICATING UNSTABLE ANGINA AND NON-ST-ELEVATION MI

The recommended therapy for patients with unstable angina with high-risk markers or non-ST-elevation MI includes heparin anticoagulation and the use of tirofiban or eptifibatide in addition to aspirin, with the possible addition of clopidogrel. (31) The differential diagnosis of thrombocytopenia in this population, therefore, is similar to that already discussed for thrombocytopenia after PCI. Possibly due to the longer duration of treatment, the incidence of thrombocytopenia is higher in patients with ACSs than in those undergoing PCI, (32) and the incidence of thrombocytopenia in patients treated with a GPIIb/IIIa inhibitor is somewhat higher than those treated without these drugs. (19,32-34) Despite the move toward early intervention in patients with ACSs, the hospital stay and exposure to drugs that may cause thrombocytopenia is not short. The median length of stay in the early intervention arm of the Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis in Myocardial Infarction (TACTICS-TIMI) 18 trial (35) was 3.9 days. Therefore, it is possible that the timing of thrombocytopenia may lead to the inclusion of therapy with GPIIIb/IIIa inhibitors, heparin, and clopidogrel in the differential diagnosis. Diagnosis and management decisions regarding the GPIIIb/IIIa inhibitors and clopidogrel are the same as those made around the time of PCI. If HIT is a concern, all heparin therapy must be discontinued and alternative anticoagulation therapy should be started, not only to prevent thrombosis associated with HIT, but also to manage the underlying coronary disease. Lepirudin, which has been approved for the treatment of HIT, has been evaluated in patients with ACSs in a series of large randomized trials. (36) Combined data from the OASIS-1 and Organization to Assess Strategies for Ischemic Syndromes (OASIS)-2 trials demonstrated a 14% reduction of MI or death at 35 days in the lepirudin arm (0.15 mg/kg/h, adjusted to the activated partial thromboplastin time) when compared to the heparin control arm. Argatroban, also approved for the treatment of HIT, has not been evaluated in trials of ACSs alone, but a significant proportion of the population in the trials that led to the approval of argatroban (2 [micro]g/kg/min, adjusted to the activated partial thromboplastin time. The initial dose was reduced in patients with hepatic impairment) had circulatory disease. (11) While there are limited data for the use of bivalirudin in patients with ACSs (37, 38) outside of PCI, an infusion dose has not been defined.

THROMBOCYTOPENIA AND OPEN-HEART SURGERY

Surgery is the most common cause for secondary thrombocytosis. (39) In contrast to most other operative procedures, however, cardiopulmonary bypass results in an initial fall in the platelet count. (40) In addition to drug-induced thrombocytopenia, the mechanical destruction of platelets and hemodilution in the bypass circuit play important roles in the occurrence of postoperative thrombocytopenia. Sepsis, intraaortic balloon pumping, and posttransfusion purpura must also be considered in selected cases.

On the initiation of bypass, the platelet count falls to approximately 50% of the prebypass level. The fall in platelet count is reduced by one third to one half in off-pump bypass surgery when compared to surgery performed using cardiopulmonary bypass. (41) Typically, the nadir platelet count is on the second or third day after surgery, but > 10% of patients continue to have a platelet count of < 50% of baseline on the fourth postoperative day. (42)

Intraaortic balloon pumps (IABPs) are another possible cause of platelet destruction that some cardiac patients face. Platelet counts fall steadily until the fourth day that the IABP is in use and then stabilize. The platelet count falls to < 50% of baseline in 26% of patients who use an IABP. (43) Postoperative use of an IABP may further complicate the definition of the etiology of a low platelet count in this population.

After open-heart surgery, patients may receive a host of medications, such as antibiotic or antiarrhythmic agents, which are known to cause thrombocytopenia. The drug most likely to cause thrombocytopenia in ICU patients, however, is heparin. (44) The diagnosis of HIT, however, may be very difficult. As noted, some patients may have prolonged, significant thrombocytopenia when compared with the preoperative platelet count, making the degree of thrombocytopenia and the timing of thrombocytopenia less useful as diagnostic tools. Laboratory support is limited as well. There are several enzyme-linked immunoassays available. This test is relatively easy to perform and inexpensive, and it is often the first test performed to evaluate the possibility of HIT. This assay, however, yields a positive result in approximately 50% of patients after cardiopulmonary by pass, while the true incidence of HIT is thought to be around 1%. (45) A negative test result, however, has a high negative predictive value. The functional serotonin release assay (SRA) has a higher positive predictive value, but 20% of patients will have a positive SRA result after bypass surgery as well. Clues to the diagnosis HIT after open-heart surgery are listed in Table 2.

The occurrence of HIT in the period after open-heart surgery is associated with a high incidence of arterial and venous thromboembolic events and high perioperative mortality. (46,47) Venous bypass grafts fare particularly poorly, as approximately two thirds will occlude early. Arterial grafts, however, do not appear to have the same fate, (48) suggesting that the use of arterial grafts rather than venous grafts carries particular importance in patients with HIT.

Once HIT has been suggested in the postoperative period, it is essential that all heparin therapy be discontinued immediately. Attention must be paid to "hidden" sources of heparin exposure that may not immediately be apparent. These include heparin bonded to pulmonary artery catheters, heparin used to maintain the patency of indwelling central access catheters, and heparin flushes in peripheral IV access ports. The prompt initiation of therapy with a direct thrombin inhibitor should be considered to avoid the high incidence of thromboembolic events early in the course of HIT until the diagnosis can be confirmed or excluded.

The management of anticoagulation therapy during open-heart surgery in a patient with HIT is extremely complex, and requires the cooperation of the surgeons, anesthesiologists, perfusionists, hematologists, and cardiologists. If the need for surgery is not acute, surgery should be postponed until HIT antibodies are absent (median time, 80 days). Surgery can then be performed using unfractionated heparin for the surgery only. (49) Heparin therapy should be avoided in the postoperative period, and an alternative anticoagulant can be used if anticoagulation therapy is required. Should surgery be required prior to the disappearance of the HIT antibody, the use of heparin must be avoided. In the United States, a direct thrombin inhibitor should be used in this case. There is experience with lepirudin and bivalirudin, (51,52) although this experience is limited. The performance of off-pump bypass surgery is preferred in these patients. A lower dose of the direct thrombin inhibitor can be used, allowing the monitoring of anticoagulation with the ACT rather than with the ecarin clotting time, which is often required for higher degrees of anticoagulation therapy (particularly with lepirudin), eliminating the need for anticoagulation of the bypass circuit and potentially reducing bleeding. (3)

CONCLUSIONS

Thrombocytopenia in cardiovascular patients, particularly those who are in critical care units and following open-heart surgery, is common, and the differential diagnosis can be extensive. In almost all of these patients, heparin therapy and HIT are included in this differential diagnosis due to the extensive use of heparin in cardiac patients. The diagnosis of HIT is particularly important because of the high incidence of early thromboembolic events after this diagnosis has been entertained. A diagnosis of HIT, as opposed to other causes of thrombocytopenia, may often be made based on clinical or laboratory testing results, allowing appropriate management over both the short and long term. The early initiation of therapy with a direct thrombin inhibitor is recommended when HIT is suspected after PCI or open-heart surgery, or in patients with ACSs. If a diagnosis other than HIT is made, heparin therapy can be safely reinitiated.

* From the University of Pennsylvania Medical School, Philadelphia, PA.

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The preparation of this article was supported by a grant from GlaxoSmithKline.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: permissions@chestnet.org).

Correspondence to: William H. Matthai, Jr, MD, University of Pennsylvania Medical Center-Presbyterian, 39th and Market St, Philadelphia, PA 19104; e-mail: william.matthai@uphs.upenn.edu

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