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Ann Thorac Surg 2000;70:2173-2181
© 2000 The Society of Thoracic Surgeons

---

Current review

Cardiopulmonary bypass in patients with heparin-induced thrombocytopenia and thrombosis

^a Department of Cardiothoracic Surgery, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
^b Department of Cardiac Surgery, St. Anthony’s Central Hospital, and Department of Cardiac Surgery, Lutheran Medical Center, Denver, Colorado, USA

Address reprint requests to Dr Follis, Department of Cardiac Surgery, Ospedale Civico di Palermo, via Carmelo Lazzaro, Palermo, Italy
e-mail: follis99{at}hotmail.com

	Abstract

Top Abstract Introduction Material and methods What is HITT? How do you make... What are the antithrombotic... What about HITT and... What conclusions and... Acknowledgments References

 
Heparin-induced thrombocytopenia and thrombosis (HITT) is an immunomediated disorder induced by the administration of heparin for therapeutic purposes. The presence of this condition in patients requiring full heparinization for cardiopulmonary bypass constitutes a formidable challenge for the cardiac surgeon. In this review, the clinical and experimental experience described in the literature are discussed in the perspective of the normal coagulation and the pathophysiology of HITT and in the light of a variety of old and new alternative anticoagulants.

	Introduction

Top Abstract Introduction Material and methods What is HITT? How do you make... What are the antithrombotic... What about HITT and... What conclusions and... Acknowledgments References

 
Although it occurs rarely, the presence of heparin- induced thrombocytopenia and thrombosis (HITT) in a patient requiring cardiopulmonary bypass (CPB) for correction of cardiac diseases may represent for the unprepared surgeon a formidable challenge and may result in poor outcomes. The problem becomes even more critical if surgery is needed on an emergency basis and a quick literature search or a consultation with colleagues that have more experience is not possible.

When faced with this situation, we too felt unprepared and wished we could consult a concise and informative review on the subject in order to properly manage such a patient. Herein stemmed the need for the present review which includes a summary of the pathophysiology of HITT, a collection of all cases reported in literature, including four of our own, and a discussion of the various alternatives to heparin for institution of CPB in patients with HITT.

	Material and methods

Top Abstract Introduction Material and methods What is HITT? How do you make... What are the antithrombotic... What about HITT and... What conclusions and... Acknowledgments References

 
In order to include all the pertinent and important literature in this review, a comprehensive search employing several major bibliographic databases was used. In addition, perusal of the references of all the relevant papers found and personal communication with investigators in the area were performed. Including our own, we were able to collect 84 cases in the literature (Table 1) reported as a single case or in small series with different therapeutic approaches. It is not surprising then that the validity of primary studies was difficult to assess on the usually accepted methodologic guidelines (random and blind allocation, consistency of relevant endpoints, and monitored variables). Therefore, being aware of these limitations, we have compiled this collected series with the purpose of presenting the spectrum of the available approaches rather than using the data to support rigid recommendations [1, 2].

	What is HITT?

Top Abstract Introduction Material and methods What is HITT? How do you make... What are the antithrombotic... What about HITT and... What conclusions and... Acknowledgments References

Although several links in the mechanistic chain leading to HITT are still poorly understood, recent evidence [6] {Kelton and colleagues, 1994, ID: 1600} suggests that a heparin-platelet-antibody interaction initiates the syndrome. Heparin binds to platelet factor 4 (PF4), a protein normally found in the alpha granule of platelets, to form a strongly antigenic hapten on the platelets surface. Specific immunoglobulin G (IgG) antibodies are produced which, on reexposure to heparin, react with heparin-PF4 complexes and bind to Fc receptor of circulating platelets. Activation of platelets results in their lysis (thrombocytopenia) or agglutination (thrombosis). In addition, more PF4 than can be neutralized by available heparin is released and binds to heparin-like molecules on the endothelial surface to provide targets for antibody binding and local injury (Fig 1). The stage of the syndrome is set: Thrombocytopenia leads to hemorrhagic diathesis whereas agglutination plus endothelial injury can initiate arterial or venous thrombosis, typically characterized by the presence of white clots rich in platelets (white clot syndrome) [7].

View larger version (70K): [in this window] [in a new window]   Fig 1. The pathophysiology of heparin-induced thrombocytopenia and thrombosis (HITT). [Reprinted with permission from Aster RH. Heparin-induced thrombocytopenia and thrombosis. N Engl J Med 1995;332:1374–6. Copyright ©1995 Massachusetts Medical Society. All rights reserved.] (EC = endothelial cells.)

The time onset of immune HITT, by contrast, varies from 3 to 15 days (median 10) after starting heparin therapy and the disorder may present with simple thrombocytopenia (heparin-induced thrombocytopenia or HIT) or more serious bleeding and thrombotic complications (heparin-induced thrombocytopenia and thrombosis or HITT). Any form of heparin, even trivial amounts like that present in heparin flushes, and heparin coated catheters [8] and cardiopulmonary bypass circuits [9], can trigger the syndrome.

	How do you make the diagnosis?

Top Abstract Introduction Material and methods What is HITT? How do you make... What are the antithrombotic... What about HITT and... What conclusions and... Acknowledgments References

 
The laboratory diagnosis of HITT is made functionally and serologically. In functional tests, the patient’s plasma causes platelet aggregation or secretion of serotonin in the presence of heparin. In serologic tests, antibodies to heparin-PF4 complexes or platelets-associated IgG are detected in patient’s serum.

In the platelet aggregation test, platelet poor plasma from the patient is mixed with normal donor platelets and heparin. The plasma of a patient with HITT causes activation and aggregation of platelets. Although specificity may be high (> 92%), sensitivity may vary from 40% to 80% [10, 11]. Another functional test is the ¹⁴C-serotonin release test [12], currently the most accurate standard for the diagnosis of HITT. Donor platelet from healthy volunteers are incubated with ¹⁴C-serotonin, which is taken up by the platelet membrane. After washing, the platelets are mixed with the serum from the patient to be tested and with heparin (100 U/ml). In presence of HITT, platelet activation leads to increased release of serotonin and, thus, radioactivity. The test is sensitive (up to 94%) and specific (up to 100%).

The best serologic test is a rapid ELISA for antibodies in the patient’s serum to heparin-PF4 complexes [13]. The sensitivity is about 90% and the specificity 99%. Among other serologic tests, platelet associated IgG or IgG already bound to platelets can be detected using radiolabeled or fluoresceinated anti-IgG. Levels are increased in HITT but also in other immune causes of thrombocytopenia, therefore the test lacks specificity {Greinacher and associates, 1992, ID: 1603}.

Overall, the heparin-PF4, ELISA and the ¹⁴C-serotonin tests are highly accurate and can be used, depending on local availability.

	What are the antithrombotic agents available for cardiopulmonary bypass?

Top Abstract Introduction Material and methods What is HITT? How do you make... What are the antithrombotic... What about HITT and... What conclusions and... Acknowledgments References

 
Although it is beyond the scope of this review to examine all existing antithrombotic agents, we will focus our discussion on those that have been used both clinically and in the experimental animal to perform cardiopulmonary bypass.

Heparin
Commercially available heparin is partially purified from either porcine intestinal mucosa or bovine lung and has a molecular weight that ranges from 3,000 to 30,000 daltons, with an average of 15,000. Standard heparin blocks both thrombin formation and thrombin activity by catalyzing antithrombin III, which inactivates thrombin, factor Xa, IXa, XIa, and XIIA. Thrombin and Xa are the most sensitive to ATIII. Once heparin binds to ATIII, it promotes a conformational change in ATIII that accelerates its activity approximately 100 to 1,000 fold.

Low molecular weight heparin (LMWH)
LMWHs are derived from standard heparin by either chemical or enzymatic depolymerization to yield fragments that are approximately one third the size of heparin (4,000 or 5,000 daltons). This molecular rearrangement results in: (1) a change in their anticoagulant profile with more anti-Xa activity than heparin (anti-Xa to anti-IIa ratio of 4:1 for LMWHs versus 1:1 of heparin); (2) reduced protein binding with excellent bioavailability at low doses; and (3) reduced interaction with platelets and a lower incidence of HITT. Many preparations exist, including Fragmin, Enoxaparin, Fraxiparin, Tedelparin, and CY216.

Besides one experimental study in dogs [14] and one clinical study in 6 patients without HITT [15], only 4 cases have been reported where different types of LMWHs were successfully used during cardiopulmonary bypass (CPB). Two of them, however, experienced excessive bleeding postoperatively. This phenomenon could be explained by only partial reversal with protamine sulfate, because only the anti-IIa activity is lowered to baseline. In contrast, the anti-Xa activity, although significantly lowered, remains elevated [16–18].

The main argument against the use of LMWH in patients with HITT, however, is the high rate of cross reactivity in platelet aggregation tests (up to 80%) [19].

Orgaran (Org 10172)
Included by some in the category of LMWHs, Orgaran is a mixture of glycosaminoglycuronans (heparan, dermatan, and chondroitin sulfates). It does not contain heparin or heparin fragments and has a greater capacity to inactivate thrombin through heparin cofactor II (another endogenous thrombin inhibitor) than LMWH. It has been shown to have a low cross-reactivity rate (10% to 18%) [19] in the platelet aggregation test. It is eliminated by liver and kidneys and its half-life is 25 hours, an added concern in patients with reduced liver and kidney function. Because standard clotting essays (partial thrombin time [PTT], prothrombin time [PT], and activated clotting time [ACT]) are unsatisfactory because of a relatively flat dose-response relationship [20], direct monitoring of anti-Xa activity [21] or the measurement of plasma Orgaran levels [22] are recommended. If bleeding complication occurs, the anti-Xa activity can be only partially antagonized by protamine, and transfusion of fresh frozen plasma and platelets does not entirely reinstitute coagulation [23]. A specific antidote does not exist. The clinical and animal experience is limited to 9 reported HITT patients and one experimental study in dogs [24].

Finally, Dermatan sulfate, a component of Orgaran has been employed successfully in the pig CPB model [25, 26].

Old platelet inhibitors
Platelet and endothelial cell membrane phospholipids are converted into arachidonic acid by the enzyme phospholipase A2, which is activated by both thrombin and collagen and inhibited by dipyridamole. Arachidonic acid is converted into prostaglandin intermediates, prostaglandin G2 (PGG2) and prostaglandin H2 (PGH2), by the enzyme cyclooxygenase. In the platelet membrane thromboxane synthetase converts PGH2 into thromboxane A2, a potent aggregating agent. In the endothelial cell prostacyclin synthetase converts PGH2 into prostacyclin, a potent inhibitor of aggregation and vasodilator. Aspirin, by irreversibly (covalent acetylation with permanent effect) acetylating cyclooxygenase both in platelets and endothelial cells, inhibits prostaglandin endoperoxide formation and thromboxane A2 synthesis. In the literature, 5 patients with HITT underwent CPB with heparin after pretreatment with aspirin and dipyridamole. Although this approach is attractive for its simplicity, there is no measure of the completeness and degree of platelet inhibition.

Iloprost (ZK36374) is another antiplatelet agent that stimulates adenyl cyclase. The latter catalyzes the formation of cyclic adenosine monophosphate (cAMP) from adenosine triphosphate (ATP). In contrast to most other cells where it promotes reactivity, increased cAMP is a strong inhibitor of platelet function. Iloprost is similar to prostacyclin in its chemical structure and antiplatelet properties, but it possesses a half-life of approximately 30 minutes, so that it is considerably more stable at neutral pH and less vasoactive. It has been used successfully in 20 patients with HITT as a continuous drip started before heparinization and CPB, and discontinued after protamine reversal. The dosage has varied from 6 to 48 ng/kg/min depending on the amount required to achieve a negative aggregation test. Its main drawback is the profound vasodilation induced with the need for phenylephrine drip up to 11 µg/kg/min. The drug is not Food and Drug Administration (FDA) approved and can be used only on a compassionate basis.

Novel platelet inhibitors
Activation of platelets results in the expression of functional receptors for fibrinogen on the platelet surface, known as GPIIb/IIIa, which binds bivalent fibrinogen on adjacent platelets and forming aggregates (see above). A monoclonal antibody has been developed (c7E3-Fab or abciximab) that is specific for the receptor and blocks platelet aggregation.

Abciximab has been used for the first time by our group in 2 patients with HITT. The drug is administered as a bolus of 0.25 mg/kg and then as infusion of 10 µg/kg/min on induction of anesthesia, resulting in greater than 80% blockade of GPIIb/IIIa receptors and suppression of platelet aggregation to less than 20% of baseline [27]. Heparin is then given in the usual fashion and reversed at the end of the procedure. Abciximab infusion is then discontinued and donor platelets are transfused for hemostasis because the circulating platelets cannot aggregate. One of our 2 patients had excessive postoperative bleeding but did not require reexploration. This agent is available in any hospital as it is being used frequently by interventional cardiologists.

Direct thrombin inhibitors
Unlike standard heparin and LMWH, the direct thrombin inhibitors act independently of antithrombin II and inactivate both free thrombin and thrombin bound to fibrin. Although all the inhibitors bind directly to thrombin, their sites of interaction are different. R-hirudin, a 65 amino acid polypeptide originally isolated from the salivary glands of the medicinal leech Hirudo is now available through recombinant DNA technology. The globular aminoterminal "head" region of r-hirudin interacts with the active center of thrombin whereas the carboxy-terminal "tail" binds to the substrate recognition site (Fig 2). Because it is eliminated by the kidneys, dosage is dependent on creatinine clearance. In addition, both ACT and activated partial thromboplastin time (APTT) are inadequate for monitoring anticoagulation [28, 29] and only the ecarin clotting time (ECT) has been shown to correlate well (r = 0.94) with hirudin blood levels [30]. The test is obtained by recording the clotting time of undiluted citrated anticoagulated plasma added with the snake venom enzyme ecarin [31]. There is no known antagonist to r-hirudin but several studies have shown reversal of bleeding effects by factor VIIa concentrates or prothrombin complex concentrates [32]. Including ours, 15 cases are reported in literature of its use for CPB in HITT patients. In addition, experimental studies have been carried out in dogs [33–35], pigs [36], in isolated human blood [37], and in patients without HITT undergoing CPB [38, 39]. In patients with normal renal function, a bolus injection of 0.25 mg/kg is administered 10 minutes before the start of CPB, and 0.2 mg/kg are added to the priming solution of the heart and lung machine. Additional boli are given to keep hirudin blood levels greater than 2.0 µg/ml or ECT greater than 250. In presence of impaired renal function dosage should be adjusted according to creatinine clearance.

View larger version (24K): [in this window] [in a new window]   Fig 2. Mechanism of action of various direct thrombin inhibitors. [Reprinted with permission. Adapted from Chest 1995;108(Suppl 4):474S.]

Similarly, Hirulog was developed from hirugen and interacts with both the recognition site and the active center on thrombin. For these two compounds there is no experimental or clinical experience with CPB.

Argatroban (Novastan, Texas Biotechnology Corp, Houston, TX), a synthetic arginine derivative, interacts with the active site of thrombin and has been found a safe and effective alternative to heparin in a dog model of CPB [40].

Finally, a single stranded, 15 nucleotide DNA aptamer has been developed that interacts with anion binding exosite 1 on thrombin. Preliminary data in the canine model support its safety and efficacy [41] during CPB.

Defibrinating agents
Ancrod (Arvin) is derived from the Malayan pit viper (Agkistrodon rhodostoma) and selectively depletes the plasma of fibrinogen by catalyzing the hydrolysis of an arginine-glycine sequence of the alpha chain of fibrinogen. This produces an unstable form of fibrin that is rapidly removed from circulation [42]. Activated clotting time does not provide a reliable measure of the anticoagulant effect of ancrod, and repeated measurement of fibrinogen concentration is the only effective means of ensuring adequate anticoagulation. A kit (Hemocron Fibrinogen assay) for intraoperative measurement is available from International Technidyne Corporation, (Edison, NJ). An infusion of 8.4 U/hour is begun 12 hours prior to CPB: Fibrinogen concentration is determined every 4 hours and when the target of 0.2 to 0.4 g/L is reached, the infusion is stopped and fibrinogen measured intermittently until completion of CPB. Circulating ancrod has a half-life of 3 to 5 hours and is excreted largely unchanged in the urine. Reversal of its effects can be achieved by infusion of cryoprecipitate, rich in fibrinogen, or by the administration of the specific antivenom, usually not recommended because of the risk of severe allergic reactions. Anticoagulation with ancrod during CPB has been employed successfully in 5 patients with HITT and in 20 patients without HITT [43, 44]. Animal studies also confirm the feasibility of ancrod as an alternative to heparin for CPB [45, 46].

Factor IX inhibitor
A novel inhibitor of activated factor IX has been produced and used successfully for anticoagulation during CPB in the dog and baboon models [47, 48].

	What about HITT and CPB in children?

Top Abstract Introduction Material and methods What is HITT? How do you make... What are the antithrombotic... What about HITT and... What conclusions and... Acknowledgments References

 
Most likely owing to the lesser exposure to heparin, HITT is seldom diagnosed in children and does not seem to occur in the population of patients requiring cardiac surgery. To our knowledge, only 1 case of a 2-year-old girl requiring CPB for a conduit revision has been reported (personal communication). Orgaran was employed as an alternative anticoagulant.

	What conclusions and recommendations can be drawn from the available experience and technology?

Top Abstract Introduction Material and methods What is HITT? How do you make... What are the antithrombotic... What about HITT and... What conclusions and... Acknowledgments References

 
With approximately 700,000 cardiac operations performed each year in the USA [49], and with an estimated incidence of HITT in cardiac surgical patients of 0.7% to 1.9%, it is quite surprising that only 84 cases (Table 1) have been reported in the literature of the past 15 years. This observation leads to postulations that either the real incidence of HITT is much lower than reported, or the majority of patients with this condition are undiagnosed and undergo CPB with the use of heparin. In the latter instance, some probably do well despite HITT, whereas others account for those with a complicated course characterized by bleeding, thrombotic complications, and perhaps multiorgan failure. Interestingly, several isolated case reports have implicated HITT in the pathogenesis of a variety of syndromes like adult respiratory distress syndrome [50], global amnesia [51], adrenal hemorrhage [52–55], and acute renal failure [56]. Likewise, the high morbidity and mortality of cardiac surgery patients with HITT diagnosed after exposure to heparin for CPB has been repeatedly underscored by Walls and associates [3, 4].

Thus, it appears that the diagnosis of HITT can emerge any time along the clinical course of the cardiac patient, not excluded in emergency circumstances, and that the lack of appropriate interventions can result in poor outcomes. Such considerations take us back to the opening questions and the choice of an alternative to heparin for emergency CPB. This should be readily available, allow safe CPB, and, at the end of the procedure, should be rapidly cleared from circulation or reversed in order to assure postoperative hemostasis. Recombinant hirudin is now FDA approved, available on request from Hoechst Marion Roussel (Frankfurt, Germany) and is becoming the generally accepted treatment in this subset of patients. However, it will probably take 24 hours to obtain it, it might not be the best choice in critically ill patients with decreasing renal function, and it is best monitored with the ecarin clotting time, a laboratory test not easily set up in short time. Orgaran (Organon Pharmaceuticals, West Orange, NJ) is also FDA approved and should be available in 24 or 48 hours; its drawbacks, though, are similar to recombinant hirudin (elimination by liver and kidney, long half-life, need for monitoring of anti-Xa activity or plasma levels). Ancrod (Knoll Pharmaceuticals, Whippany, NJ) and Iloprost (Bertex Laboratories Inc, Wayne, NJ) are not FDA approved but can be obtained on a compassionate basis, a bureaucratic process likely to take a few days. Aspirin and persantin and LMWH are inadequate, as it has been shown that platelet aggregation persists in a significant number of patients.

When confronted with this problem, we have used the novel platelet inhibitor abciximab plus heparin, which to our knowledge has not been reported before for CPB in patients with HITT. A study in vitro published by Fareed and colleagues [57] supports this approach: Platelet rich plasma from HITT patients supplemented with abciximab does not produce aggregation response in presence of heparin/HITT serum. Although we did not monitor platelet function in our cases, this should be probably performed routinely in order to assure adequate inactivation of platelets. Finally, in response to those concerned with an increase in bleeding complications, the use of abciximab was not associated with increased bleeding risk following emergent CABG after percutaneous transluminal coronary angioplasty in 42 patients randomized to either placebo (n = 22) or abciximab (n = 20) [58].

Outside the emergency situation, in the elective patients, more options are available. The simplest strategy is to postpone surgery for 6 to 8 weeks, measure again the level of antibodies, and proceed with heparin if they are absent. In the event specific antibodies are still present, all the previously described alternative anticoagulants are adequate and the choice will depend on the surgeon’s and hematologist’s experience and preference.

	Acknowledgments

Top Abstract Introduction Material and methods What is HITT? How do you make... What are the antithrombotic... What about HITT and... What conclusions and... Acknowledgments References

 
We thank Dr Maureen Andrews from the Division of Haematology and Oncology, the Hospital for Sick Children, Toronto, Ontario, Canada, for her assistance with this manuscript.

	References

Top Abstract Introduction Material and methods What is HITT? How do you make... What are the antithrombotic... What about HITT and... What conclusions and... Acknowledgments References

 

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