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Ann Thorac Surg 2006;82:21-26
© 2006 The Society of Thoracic Surgeons

Original article: Cardiovascular

Clinical Presentation, Temporal Relationship, and Outcome in Thirty-Three Patients With Type 2 Heparin-Induced Thrombocytopenia After Cardiotomy

Calvin Wan, MD a , Margaret Warner, MD b , Benoit DeVarennes, MD a , Patrick Ergina, MD a , Renzo Cecere, MD a , Kevin Lachapelle, MD a , *

a Division of Cardiac Surgery, McGill University Health Centre, Montreal, Quebec, Canada
b Division of Hematology, McGill University Health Centre, Montreal, Quebec, Canada

Accepted for publication December 20, 2005.

* Address correspondence to Dr Lachapelle, S8.30 Royal Victoria Hospital, 687 O, Av Des Pins, Montreal, Quebec H3A 1A1, Canada (Email: kevin.lachapelle{at}muhc.mcgill.ca).

Presented at the Poster Session of the Fortieth Annual Meeting of The Society of Thoracic Surgeons, San Antonio, TX, Jan 26–28, 2004.


Adult cardiac surgery: The Annals of Thoracic Surgery CME Program is located online at http://cme.ctsnetjournals.org. To take the CME activity related to this article, you must have either an STS member or an individual non-member subscription to the journal.

 

   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 References
 
BACKGROUND: Type 2 heparin-induced thrombocytopenia is an uncommon but often fatal complication of heparin, frequently difficult to diagnose after cardiac surgery. In this series, we record the clinical presentation, temporal relationship, and treatment outcome of patients diagnosed with heparin-induced thrombocytopenia postoperatively.

METHODS: Thirty-three consecutive patients (1.1%) with a diagnosis of heparin-induced thrombocytopenia established by a greater than 50% drop in platelet count with or without a thrombotic event and a positive platelet factor-4 assay were reviewed. We recorded the clinical presentation, the time to presentation, treatment, and outcome (thrombosis, mortality). Univariate analysis was performed on 13 preoperative, operative, and postoperative variables.

RESULTS: The cohort was at increased mortality risk as a result of age (69.4 years), reduced cardiac function (46.8%), nonbypass operations (57.6%), emergency surgery (21.2%), and implantation of three assist devices. The mean time to suspect heparin-induced thrombocytopenia postoperatively was 5.4 days, with 22 cases (66.6%) occurring within 5 days. All patients had previous (within 3 months) exposure to heparin, and 66.6% had ongoing treatment with heparin before surgery. Overall mortality was 33%; thrombotic complications occurred in 15 patients (45.5%), with a mortality of 7 (46.6%) despite immediate cessation of heparin and treatment with a nonheparin analog. Thrombocytopenia without thrombosis occurred in 18 patients (54.5%), but a subgroup of 5 patients with nonthrombotic complications accounted for the 4 (22.2%) deaths.

CONCLUSIONS: Heparin-induced thrombocytopenia after cardiac surgery is uncommon but may occur within 5 days of surgery, further complicating diagnosis and treatment. Thrombotic complications result in a high mortality despite treatment with a nonheparin analog, and a subgroup of patients with thrombocytopenia fared poorly.

Type 2 heparin-induced thrombocytopenia (HIT) is an immune-mediated disorder, caused by the formation of immunoglobulins (IgG) against heparin–platelet factor-4 (PF4) complexes [1, 2]. Binding of heparin molecules to PF4 leads to the production of these IgG antibodies. On reexposure to heparin, these IgG antibodies bind to heparin–PF4 complexes, causing lysis and agglutination of platelets, which can lead to thrombocytopenia without or with thrombosis. In the literature [3, 4], the overall incidence of HIT among postcardiotomy patients is relatively low (up to 1.9%), but the rate of both arterial and venous thrombosis and subsequent mortality is high (up to 33%). Early recognition and treatment is therefore thought to be crucial [3, 4].

The diagnosis of HIT remains a clinical challenge. The diagnosis is based on a clinical picture of a greater than 50% drop in platelets or a rapidly falling platelet count (with or without the presence of thrombosis) and usually a positive test (usually PF4 assay) [5]. The clinical picture tends to occur 5 to 10 days after the start of heparin therapy but may occur rapidly after initiation of heparin if the patient has had previous exposure to heparin within 3 months as circulating IgG antibodies may still be present [5, 6]. Because almost all cardiac surgery patients have had a prior exposure to heparin during cardiac catheterization and frequently have heparin treatment up to the time of surgery, we were interested in examining the clinical presentation and temporal relationships of HIT in the postoperative period.

Once a diagnosis of HIT is made, immediate discontinuation of all forms of heparin or warfarin is recommended, followed by the administration of a nonheparin anticoagulant [1, 5]. However, the decision to treat is not without associated risk, especially in the postoperative period with a nonheparin analog that may not be readily reversible. Little is reported in the literature as to the benefit of early treatment with a nonheparin substitute, such as danaparoid, a factor Xa inhibitor, or thrombin inhibitors such as argatroban or lepirudin. We therefore attempted to determine the outcome of HIT in postcardiotomy patients and to elucidate predictors of adverse outcomes.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 References
 
A retrospective study of HIT in postcardiotomy patients was conducted on those operated on between January 1, 1999, and June 30, 2003. Permission to perform this chart review was obtained in September 2003 from our institution's Director of Professional Services (standard practice in the Province of Quebec). Informed consent from patients was not obtained. We reviewed all 35 positive PF4 assays as read by optical density that were performed for a clinical suspicion of HIT after cardiac surgery. An enzyme immunoassay kit (Asserchrom HPIA, Diagnostica Stago, Abbott Laboratories, Mississauga, Ontario, Canada) was used to detect anti-heparin–PF4 antibodies. Briefly, after mixing the reagents with the patients' blood samples, the intensity of the color produced was compared with the intensity of a positive control. The intensity is related to the antibody level in the sample, and the result is expressed as a percentage of the intensity of the control. Any value greater than 25% was considered positive. We included those patients as having a diagnosis of postcardiotomy HIT if they had the following: (1) a drop in platelet count by more than 50%, and (2) a platelet level of less than 100 x109/L at the time of clinical suspicion. A thrombotic event was considered to have occurred if there was a clearly documented clinical event (eg, arterial thrombosis, venous gangrene) or a diagnostic confirmatory test (angiography, perfusion scan, surgery). It was usually unclear from the chart what was the particular trigger (rapid drop in platelets, a 50% drop in counts, thrombotic event) that led to the workup and subsequent treatment, but in most cases it appeared to be caused by a constellation of the above factors. Two patients where excluded; one had HIT 16 months after cardiac surgery during another hospitalization, and one did not have a 50% drop in platelet count. One patient had a platelet count of 70 x 109/L preoperatively but received platelet transfusions at the time of surgery with a subsequent rapid drop in counts. The patient had a thrombotic episode and was treated with danaparoid and therefore was included in the analysis. This patient may have had HIT preoperatively but required emergency surgery without the benefit of a diagnosis.

We recorded general preoperative and intraoperative risk factors for mortality and recorded the postoperative day when the clinical suspicion of HIT was entertained along with the platelet count. We ascertained whether heparin was discontinued and, if danaparoid was started, on which postoperative day. Patients were followed to discharge, and the outcome was noted. In addition, the following 13 variables were included in a univariate analysis of predictors of death or thrombosis: (1) age older than 75 years, (2) female sex, (3) preoperative heparin, (4) diabetes, (5) preoperative renal insufficiency (creatinine < 150 µmol/L), (6) ejection fraction less than 0.40, (7) emergency operation, (8) early presentation before 5 days, (9) aortic occlusion time greater than 120 minutes, (10) cardiopulmonary bypass time greater than 180 minutes, (11) use of intraaortic balloon counterpulsation, (12) platelet count at the time when a working diagnosis of HIT was established less than 50 x 109/L, and (13) administration of warfarin before normalization of platelet count (>150 x 109/L). Two-tailed paired Student's t test was used with continuous variables, and Fisher's exact test was used with nominal variables. A p value of less than 0.05 is considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 References
 
Characteristics
The basic characteristics of patients with HIT after cardiac surgery are presented in Table 1. Overall, HIT was seen in 1.06% of patients operated on during the study period. This cohort had a high frequency of diabetes (42.4%), renal dysfunction (12.1%), reduced ventricular function (mean ejection fraction, 0.468), and emergency operations (21.2%), of which three required mechanical ventricular support (1 right, 2 left). Only 42.4% were coronary artery bypass graft surgeries. The overall mortality for this high-risk cohort was 33.3%. There were 15 (45.5%) clear-cut thrombotic complications resulting in 7 deaths (46.7%), whereas 18 (54.5%) had thrombocytopenia without evidence of thrombosis, resulting in 4 deaths (22.2%).


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  		Table 1. Characteristics of Patients With Heparin-Induced Thrombocytopenia After Cardiac Surgery
 
Clinical Presentation and Outcome
Table 2 lists all patients with their temporal clinical presentation from the day of surgery, platelet counts, treatment with danaparoid, and outcome. For simplicity, the mortalities are listed first, followed by those who had a thrombotic episode but survived, then those with thrombocytopenia only. In all patients, on the postoperative day when HIT was suspected, the heparin was stopped and blood was drawn for PF4 assay. The assay result was usually available in 24 to 72 hours. The result of the assay is expressed as a percentage of a positive control. All were above 30% and deemed to be clearly positive; 21 were above 50%, which points to a high level of circulating antibody. As stated, the clinical suspicion of HIT was usually based on a rapidly dropping platelet count that was greater than 50% in all patients. In cases of thrombosis, this event with the presence of a dropping count was the usual clinical trigger. In those with thrombosis, 14 of 15 were treated with danaparoid within 24 hours of the event. One patient (number 8) succumbed rapidly after the thrombotic event and did not receive danaparoid. In those who survived, danaparoid was continued until the platelet count was greater than 150 x 109/L, at which time the patient was overlapped with warfarin sodium (Coumadin). In general, those with thrombocytopenia were not treated with danaparoid (only 5 were treated), and only 3 patients were treated at the time of clinical suspicion. In those without thrombosis, 13 of 18 had thrombocytopenia only and a benign outcome. The remaining 5 had complications (numbers 2, 5, 9, 11, and 27) at the time of clinical suspicion of HIT that could not be ascribed to a thrombotic complication but which eventually led to death in 4 of the 5. Table 3 lists the factors that were evaluated in a univariate analysis and revealed no predictors of adverse outcome (mortality and mortality plus thrombosis) in this cohort. Multivariate analysis was not performed.


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  		Table 2. Presentation, Temporal Relationship, Treatment, and Outcome in 33 Patients With Heparin-Induced Thrombocytopenia After Cardiac Surgery
 

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  		Table 3. Univariate Analysis of Preoperative, Operative, and Postoperative Variables
 
The list of all major complications of this cohort with HIT include the following: gangrenous or ischemic extremities or digits, 8 (24.2%); pulmonary embolus or deep vein thrombosis, 6 (18.1%); renal failure, 9 (27.3%); hepatic failure, 5 (15.1%); sepsis, 5 (15.1%); and ischemic bowel, 2 (6%).

Temporal Relationship
The temporal presentation of HIT is plotted in Figure 1. The mean time to clinical suspicion of HIT was 5.42 days. There were 22 cases that occurred earlier than 5 days after surgery, with a peak of 9 cases at 4 days and subsequent rapid decline and only 6 cases after 7 days. Of note, all patients had a previous heparin exposure within 3 months of surgery as a result of a cardiac catheterization, and 66.6% had ongoing intravenous heparin therapy. Table 4 compares the average time to presentation with outcome. There was a trend toward earlier presentation in the mortality group compared with those who survived, but this did not reach significance (p = 0.09).


Figure 1
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  		Fig 1. Postoperative temporal distribution of suspected heparin-induced thrombocytopenia.

 

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  		Table 4. Outcome and Average Time to Presentation
 

   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
References
 
In our study, 33 postcardiotomy patients with HIT were identified, a frequency of approximately 1% with mortality greater than 30%. These rates are comparable with those found in the literature [3, 4], and, at least in our patients with thrombotic complications, treatment with danaparoid did not seem to reduce mortality when compared with historic outcomes [3]. The demographics of this cohort suggest that these were moderate to high-risk patients, evident with a higher than normal proportion of women, depressed ejection fraction, and low percentage of only coronary artery bypass graft operations. It is likely that the outcome of these patients was negatively affected by the high-risk profile inherent in this particular cohort.

Heparin-induced thrombocytopenia continues to be a challenging clinical and hematologic diagnosis. The use of a highly sensitive PF4 assay to detect HIT antibodies helps mainly to rule out the diagnosis if negative. The subclinical HIT antibody seroconversion rate after cardiac surgery can be up to 50% [7–10]. We did not have easy access to the more specific platelet serotonin release assay to confirm the diagnosis in all cases. As such, one must rely on the clinical scenario. In our patient group, it was the clinical suspicion of HIT that resulted in the assay being ordered, and the clinical suspicion was strong enough to stop heparin in all patients and treat thrombotic complications with danaparoid. We therefore had a strong pretest likelihood of HIT, and all assays were read as clearly positive.

We found that HIT tended to present early after cardiac surgery. We noted a trend among those who died to have an earlier presentation postoperatively compared with those who survived, but this did not quite reach significance. Two thirds of our patients had HIT before 5 days after cardiac surgery. Classically, HIT is thought to occur 5 to 10 days after heparin treatment as it takes time to build clinically significant levels of antibodies [1, 5, 10]. One may argue that these early presenters did not have HIT. However, patients who have had a prior exposure to heparin within 3 months may develop an early onset of thrombocytopenia (within 5 days of restarting heparin) if reexposed to heparin [6]. Two thirds of our patients had heparin therapy up to the day of surgery, and of course all had prior exposure to heparin during the cardiac catheterization that was performed within 3 months of surgery. Furthermore, ongoing heparin exposure in the postoperative period is unavoidable and is used in monitoring catheters and as part of deep vein thrombosis prophylaxis. The ubiquitous use of heparin in cardiac surgical patients means they often have been previously exposed to heparin. It is possible therefore that some patients had developed HIT preoperatively (especially number 1), which became clearly manifest postoperatively, although there is no way of being absolutely sure. The fact that we have a 1% frequency of HIT, which is in line with the literature, suggests that we have not overdiagnosed this entity.

This tendency for HIT to present early after cardiac surgery may further add to the clinical difficulty in establishing a diagnosis and treatment recommendations. Immediately postoperatively, the platelet count is frequently low as a result of hemodilution and platelet activation or destruction owing to cardiopulmonary bypass and use of the cardiotomy suction. Thrombocytopenia occurs in patients with multiorgan failure as a result of postoperative cardiac shock and in those with sepsis. In clinical practice, once the diagnosis of HIT is established or clinically suspected, it is recommended that all heparin as well as low-molecular-weight heparin be stopped, followed by treatment with a nonheparin anticoagulant [1, 5, 10, 11]. The use of an agent such as danaparoid in the early postoperative period, which has a long half-life and no known antidote, places the patient at risk for bleeding and tamponade. The decision to treat empirically is not easy but should be a consensus among the surgeon, the intensivist, and the hematology consultant. We tended to treat those with clear-cut thrombotic complications and only rarely those with thrombocytopenia. One may speculate that the high mortality in this HIT cohort was indeed the result of early presentation and an inability to diagnose and treat before the development of a thrombotic event on an already fragile patient. Although the subsequent risk of a thrombotic episode is up to 50% in those with thrombocytopenia managed with heparin cessation alone [10, 11], this was not seen in our group.

Although the majority of mortalities occurred in those with HIT and thrombosis, we found that there was a small group of patients with thrombocytopenia who did not fare well (numbers 2, 5, 6, 9, and 11). These patients all had complications at the time of clinical suspicion of HIT that could not be ascribed to a clear-cut thrombotic event. Four of the 5 died after a prolonged course in multiorgan failure or sepsis. Whether they had or eventually developed a subclinical thrombotic event is unclear. Their outcome underlines the contention that not all HIT patients who present with thrombocytopenia have a benign course [1, 10].

In summary, this paper demonstrates that HIT after cardiac surgery appears to occur in high-risk patients, is associated with a poor outcome, and may occur early in the postoperative period, further complicating the diagnosis and treatment of this disorder.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 References
 

  1. Warkentin TE. Heparin-induced thrombocytopeniapathogenesis and management. Br J Haematol 2003;121:535-555.[Medline]
  2. Follis F, Schmidt CA. Cardiopulmonary bypass in patients with heparin-induced thrombocytopenia and thrombosis Ann Thorac Surg 2000;70:2173-2181.[Abstract/Free Full Text]
  3. Walls JT, Curtis JJ, Silver D, Boley TM, Schmaltz RA, Nawarawong W. Heparin-induced thrombocytopenia in open heart surgical patientssequelae of late recognition. Ann Thorac Surg 1992;53:787-791.[Abstract]
  4. Singer RL, Mannion JD, Bauer TL, Armenti FR, Edie RN. Complications from heparin-induced thrombocytopenia in patients undergoing cardiopulmonary bypass Chest 1993;104:1436-1440.[Abstract/Free Full Text]
  5. Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia and cardiac surgery Ann Thorac Surg 2003;76:638-648.[Abstract/Free Full Text]
  6. Lubenow N, Kempf R, Eichner A, Eicher P, Carlsson LE, Greinacher A. Heparin-induced thrombocytopeniatemporal pattern of thrombocytopenia in relation to initial use or reexposure to heparin. Chest 2002;122:37-42.[Abstract/Free Full Text]
  7. Bauer TL, Arepally G, Konkle BA, et al. Prevalence of heparin-associated antibodies without thrombosis in patients undergoing cardiopulmonary bypass surgery Circulation 1997;95:1242-1246.[Abstract/Free Full Text]
  8. Visentin GP, Malik MI, Cyganiak KA, Aster RH. Patients treated with unfractionated heparin during open heart surgery are at high risk to form antibodies reactive with heparin:platelet factor 4 complexes J Lab Clin Med 1996;128:376-383.[Medline]
  9. Trossaert M, Gaillard A, Commin PL, Amiral J, Vissac A, Fressinaud E. High incidence of anti-heparin/platelet factor 4 antibodies after cardiopulmonary bypass surgery Br J Haematol 1998;101:653-655.[Medline]
  10. Pouplard C, May MA, Iochmann S, et al. Antibodies to platelet factor 4–heparin after cardiopulmonary bypass in patients anticoagulated with unfractionated heparin or a low-molecular-weight heparin Circulation 1999;99:2530-2536.[Abstract/Free Full Text]
  11. Warkentin TE, Kelton JG. A 14-year study of heparin-induced thrombocytopenia Am J Med 1996;101:502-507.[Medline]



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