Predictors of Heparin Resistance Before Cardiovascular Operations in Adults

doi:10.1016/j.athoracsur.2018.01.068

The Annals of Thoracic Surgery

Volume 105, Issue 5, May 2018, Pages 1316-1321

https://doi.org/10.1016/j.athoracsur.2018.01.068 Get rights and content

Background

Heparin resistance (HR) is often encountered during cardiovascular operations that require cardiopulmonary bypass. Clinical risk factors and the mechanism underlying heparin resistance are yet to be determined. The aim of this study was to elucidate the clinically valid preoperative predictors related to HR.

Methods

The study evaluated 489 patients undergoing cardiovascular operations. Of these, 25 patients presented with HR and received antithrombin III for the initiation of cardiopulmonary bypass with an effective activated coagulation time. The remaining 464 patients, who did not receive antithrombin III, served as controls (NHR). Preoperative patient demographic and laboratory data were analyzed to identify risk factors for HR.

Results

The preoperative laboratory data showed platelet count, fibrinogen, D-dimer, creatinine, and C-reactive protein were significantly higher in the HR group than in the NHR group. As expected, the antithrombin III level was significantly lower overall in the HR group (86.0% vs 95.5%, p = 0.009); however, 80% of the patients in the HR group showed normal antithrombin III levels preoperatively. Multivariable logistic regression analysis identified chronic aortic dissection, chronic obstructive pulmonary disease, smoking, and elevated fibrinogen levels as independent predictors for HR.

Conclusions

HR was shown to be associated with preoperative high fibrinogen levels, a smoking habit, and a preoperative diagnosis of chronic, but not acute, aortic dissection, with chronic obstructive pulmonary disease as comorbidity. Administration of antithrombin III resolved HR in all of the affected patients, even when their preoperative antithrombin III level was within the normal limit.

Section snippets

Patients and Methods

This was a single-center, retrospective, nonrandomized study conducted at Tohoku University Hospital, Japan. The Institutional Review Board reviewed and approved the study protocol. Considered for inclusion were all adult patients (aged >20 years) who underwent cardiovascular operations that required CPB between January 2010 and December 2012, including those receiving emergency operations and reoperations. Patients’ baseline preoperative characteristics and laboratory data were obtained from

Results

The clinical record review identified 497 adult patients who underwent cardiovascular operations that required CPB during the study period, including emergency cases and reoperations. Of these, 464 patients achieved effective anticoagulation (ACT > 400 seconds) solely through heparin administration (without additional AT-III administration) and were classified as the NHR group. The study excluded 6 patients who were treated with AT-III product simultaneously with the initial dose of heparin at

Comment

The results of this study identified CTAD, smoking, COPD, and elevated fibrinogen as independent predictors for HR. Previous studies have reported that HR is associated with preoperative factors such as age, platelet count, and heparin use, in addition to AT-III level, in patients with congenital heart diseases and those requiring coronary artery bypass grafting 7, 8, 10, 11, 12. To seek reliable predictors for HR that may be relevant to a larger spectrum of disease condition, we conducted the

References (29)

R.A. Esposito et al.
Heparin resistance during cardiovascular bypass. The role of heparin pretreatment
J Thorac Cardiovasc Surg
(1983)
B.D. Spiess
Treating heparin resistance with antithrombin or fresh frozen plasma
Ann Thorac Surg
(2008)
M.S. Avidan et al.
Recombinant human antithrombin III restores heparin responsiveness and decreases activation of coagulation in heparin-resistant patients during cardiopulmonary bypass
J Thorac Cardiovasc Surg
(2005)
G.A. Mitchell et al.
Fluorescent substrate assay for antithrombin III
Thromb Res
(1978)
C. Manlhiot et al.
Challenges with heparin-based anticoagulation during cardiopulmonary bypass in children: impact of low antithrombin activity
J Thorac Cardiovasc Surg
(2016)
M.D. Linden et al.
Decreased concentration of antithrombin after preoperative therapeutic heparin does not cause heparin resistance during cardiopulmonary bypass
J Cardiothorac Vasc Anesth
(2004)
M. Ranucci et al.
Preoperative antithrombin supplementation in cardiac surgery: a randomized controlled trial
J Thorac Cardiovasc Surg
(2013)
J.C. Fredenburgh et al.
Zn2+ mediates high affinity binding of heparin to the αC domain of fibrinogen
J Biol Chem
(2013)
H. Mohri et al.
Fibrinogen binds to heparin: the relationship of the binding of other adhesive proteins to heparin
Arch Biochem Biophys
(1993)
S. Zevin et al.
Cardiovascular effects of carbon monoxide and cigarette smoking
J Am Coll Cardiol
(2001)

E.F. Anderson

Heparin resistance prior to cardiovascular bypass

Anesthesiology

(1986)

S. Garvin et al.

Heparin dose response is independent of preoperative antithrombin activity in patients undergoing coronary artery bypass graft surgery using low heparin concentrations

Anesth Analg

(2010)

M. Ranucci

Antithrombin III. Key factor in extracorporeal circulation

Minerva Anestesiol

(2002)

M. Ranucci et al.

Predictors for heparin resistance in patients undergoing coronary artery bypass grafting

Perfusion

(1999)

Cited by (21)

Antithrombin concentrates may benefit cardiopulmonary bypass patients with suspected heparin resistance: A retrospective analysis of real-world data
2023, Heliyon
Heparin resistance is a common complication of surgical patients requiring anticoagulation, such as those undergoing cardiopulmonary bypass (CPB). Treatments to address heparin resistance include supplementation of antithrombin (AT) or fresh frozen plasma (FFP). This retrospective database analysis compared key outcomes in suspected heparin-resistant patients undergoing CPB treated with AT or FFP.
De-identified United States electronic health records (Cerner Health Facts®) were queried. International Classification of Diseases (ICD-9/10) codes were used to determine CPB procedures and FFP administration. AT administration was identified using medication data, while a combination of lab and medication data examining activated clotting times detected heparin resistance in FFP patients. Adult inpatients (≥18 years old) seen between 2001 and 2018 were included. Differences in mortality, intensive care unit (ICU) length of stay (LOS), and hospital-free days (using a 30-day post-discharge period) were assessed with univariate models as well as adjusted logistic regression models controlling for patient characteristics and Charlson Comorbidity Index (CCI) scores.
Of the 502 patients identified, 247 received AT and 255 received FFP. The FFP cohort was associated with a higher CCI compared to the AT cohort (3.3 ± 2.4 vs. 2.3 ± 2.0, P < .001). The AT cohort was associated with a 71% (Odds Ratio [OR]: 0.29, 95% Confidence Interval [CI]: P = .003) and 66% (OR: 0.34, 95% CI: P = .01) reduction in mortality when compared to FFP using univariate and adjusted logistic regression models, respectively. Similarly, use of AT also showed a 22% shorter ICU LOS (P = .02) and 10% more hospital-free days in the 30 days following discharge (P = .004) according to the univariate models, though statistical significance was absent within adjusted models in both ICU LOS (P = .08) and hospital-free days (P = .53).
Compared to FFP, AT use suggests a reduction in the odds of mortality in suspected heparin-resistant patients undergoing CPB, though larger prospective studies are necessary to elucidate potential differences in hospital-free days or ICU LOS across treatment modalities.
Infective Endocarditis Is a Risk Factor for Heparin Resistance in Adult Cardiovascular Surgical Procedures: A Retrospective Study
2021, Journal of Cardiothoracic and Vascular Anesthesia
Citation Excerpt :
Categorical variables were compared using Pearson's x2 test and reported as n (%). Multivariate logistic regression analysis was performed to assess the relationship between HR and a priori indicated risk factors, including age,5 preoperative heparin use,6,7 platelet count,7,8 serum fibrinogen,9 serum albumin,7,8 and IE10 after adjusting for baseline ACT and the initial dose of heparin. In subgroup analyses with available preoperative AT data, the authors evaluated the relationship of AT activity levels to both HR and HSI.
Heparin resistance (HR), defined as a decrease in heparin responsiveness, can result in adverse events with prolonged duration of surgery. Although some clinical risk factors have been suggested, the relationship with the surgical diagnosis is unclear. The aim of present study was to elucidate the clinical predictors of HR including the surgical diagnosis.
This retrospective cohort study determined the incidence of HR (defined as activated clotting time [ACT] <400 seconds after 250-350 IU/kg of heparin administration) and heparin sensitivity index (HSI) was calculated from the rate of change in ACT per heparin dose. Preoperative demographic data, medication history, and laboratory data also were analyzed.
Single institution, tertiary care hospital.
Adult patients who underwent cardiovascular surgery with cardiopulmonary bypass between January 2012 and September 2018.
None.
Of 287 patients, 88 (30.7%) were classified as HR. In univariate analysis, infective endocarditis (IE), platelet count, and serum fibrinogen and albumin levels were associated with HR. After adjustment for baseline ACT and initial heparin dose, IE (odds ratio 4.57, [95% CI: 1.10-19.1]; p = 0.037) and albumin ≤3.5 g/dL (3.17, [1.46-6.93]; p = 0.004) were associated independently with HR. Patients with IE had significantly lower HSI than those with other diseases. All HR patients were treated with additional heparin, and 17 of them received human antithrombin-III concentrate.
Infective endocarditis and preoperative hypoalbuminemia were associated independently with HR. The optimal anticoagulation strategy for patients with these risk factors requires further investigations based on the authors’ findings.
A Case of Covid-19 Patient with Acute Limb Ischemia and Heparin Resistance
2020, Annals of Vascular Surgery
Citation Excerpt :
However, the inability to achieve the target aPTT when treating with UFH, known as HR, has been observed in hospitalized Covid-19 patients.9 HR is often observed during cardiovascular operations, mainly in procedures that require a cardiopulmonary bypass.12 HR is defined as the need for a high dose of UFH of more than 35,000 IU/day to achieve the target aPTT ratio or the failure to achieve the desired ACT after a full UFH dose.
Heparin resistance is an uncommon phenomenon defined as the need for high-dose unfractionated heparin (UFH) of more than 35,000 IU/day to achieve the target activated partial-thromboplastin time ratio or the failure to achieve the desired activated clotting time after a full UFH dose. This rare phenomenon is being more commonly observed in Covid-19 patients in a hypercoagulable state. We describe a Covid-19 patient confirmed by reverse-transcriptase polymerase chain reaction assay, with acute limb ischemia, who developed heparin resistance. The patient was managed by the departments of vascular surgery, anesthesia and intensive care, and the Coagulation Service and Thrombosis Research from San Raffaele Scientific Institute, Milan, Italy.
Anticoagulation With an Inhibitor of Factors XIa and XIIa During Cardiopulmonary Bypass
2019, Journal of the American College of Cardiology
Exposure of blood to polyanionic artificial surfaces, for example, during cardiopulmonary bypass (CPB), induces a highly procoagulant condition requiring strong anticoagulation. Unfractionated heparin (UFH) is currently used during CPB but can lead to serious bleeding complications or development of a hypercoagulable state culminating in life-threatening thrombosis, highlighting the need for safer antithrombotics. Ixodes ricinus contact phase inhibitor (Ir-CPI) is a protein expressed by I. ricinus ticks, which specifically inhibits both factors XIIa and XIa, 2 factors contributing to thrombotic disease while playing a limited role in hemostasis.
This study assessed the antithrombotic activity of Ir-CPI in animal contact phase-initiated thrombosis models, including CPB. The safety of Ir-CPI also was evaluated.
The authors evaluated the antithrombotic activity of Ir-CPI by using in vitro catheter-induced clotting assays and rabbit experimental models of catheter occlusion and arteriovenous shunt. During CPB with cardiac surgery in sheep, the clinical applicability of Ir-CPI was investigated and its efficacy compared to that of UFH using an uncoated system suitable for adult therapy. Taking advantage of the similar hemostatic properties of pigs and humans, the authors performed pig liver bleeding assays to evaluate the safety of Ir-CPI.
Ir-CPI prevented clotting in catheter and arteriovenous shunt rabbit models. During CPB, Ir-CPI was as efficient as UFH in preventing clot formation within the extracorporeal circuit and maintained physiological parameters during and post-surgery. Unlike UFH, Ir-CPI did not promote bleeding.
Preclinical animal models used in this study showed that Ir-CPI is an effective and safe antithrombotic agent that provides a clinically relevant approach to thrombosis prevention in bypass systems, including highly thrombogenic CPB.
Off target: Case report of heparin resistance in a neurosurgical intensive care unit patient
2021, Critical Care Nurse
Heparin resistance was discovered in a patient in the surgical intensive care unit who underwent emergency endovascular coiling and later an anterior communicating artery clipping procedure to treat subarachnoid hemorrhage due to rupture of an anterior communicating artery aneurysm.
On intensive care unit day 17/postoperative day 3, the patient experienced shortness of breath, persistent tachycardia, and hypoxia. Bilateral pulmonary emboli, a saddle embolus, and lower-extremity and upper-extremity deep vein thrombi were diagnosed. The patient received high-dose unfractionated heparin (>35 000 U/24 h), and activated partial thromboplastin times remained subtherapeutic over the next 72 hours.
Factor VIII activity, fibrinogen, antithrombin activity, antithrombin antigen, and platelet factor 4 were measured. The results demonstrated an increase in factor VIII activity to 342% (reference range, 50%-200%), elevated fibrinogen level of 441 mg/dL (reference range, 200-400 mg/dL), antithrombin antigen level of 92% (reference range, 80%-130%), elevated antithrombin activity of 108% (reference range, 80%-100%), and negative platelet factor 4 result, indicating that the patient did not have heparin-induced thrombocytopenia and confirming the diagnosis of heparin resistance.
Risk factors for heparin resistance include antithrombin deficiency, elevation of factor VIII or fibrinogen level, elevation in heparin-binding proteins, increased heparin clearance, sepsis, trauma, and burns. The astute critical care nurse may be the first to recognize this condition in a patient, preventing a potentially fatal complication.
Andexanet alpha-induced heparin resistance treated by nafamostat mesylate in a patient undergoing total aortic arch repair for Stanford type A acute aortic dissection: a case report
2024, JA Clinical Reports

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Original articleAdult cardiacPredictors of Heparin Resistance Before Cardiovascular Operations in Adults

Background

Methods

Results

Conclusions

Section snippets

Patients and Methods

Results

Comment

J Thorac Cardiovasc Surg

Ann Thorac Surg

J Thorac Cardiovasc Surg

Thromb Res

J Thorac Cardiovasc Surg

J Cardiothorac Vasc Anesth

J Thorac Cardiovasc Surg

J Biol Chem

Arch Biochem Biophys

J Am Coll Cardiol

Heparin resistance prior to cardiovascular bypass

Anesthesiology

Heparin dose response is independent of preoperative antithrombin activity in patients undergoing coronary artery bypass graft surgery using low heparin concentrations

Anesth Analg

Antithrombin III. Key factor in extracorporeal circulation

Minerva Anestesiol

Predictors for heparin resistance in patients undergoing coronary artery bypass grafting

Perfusion

Original article
Adult cardiac
Predictors of Heparin Resistance Before Cardiovascular Operations in Adults