Heparin-Induced Thrombocytopenia in COVID-19

COVID-19 (coronavirus disease-2019) infection is a highly prothrombotic state, resulting from a dysregulation of the coagulation cascade. Therefore, thromboprophylaxis is strongly recommended in these patients, with some experts even advocating for therapeutic dosing to prevent thromboembolic events. Heparin-induced thrombocytopenia (HIT) is a well-known complication of heparin therapy. In this article, we report a case of HIT in a patient with COVID-19. A 63-year-old male presented with 1 week of dry cough and diarrhea. He had a positive nasopharyngeal COVID-19 reverse-transcriptase–polymerase chain reaction. On admission, the platelet count and liver function tests were within normal limits. During his hospitalization, he developed a right femoral deep venous thrombosis and was started on therapeutic anticoagulation. Due to worsening respiratory failure, he was intubated and mechanically ventilated. Between days 11 and 12 of hospitalization, platelet count dropped from 304 000 to 96 000 cells/µL. He had a high pretest probability for HIT with a 4T score of 6 and a positive anti-PF4/heparin antibody. Heparin drip was discontinued and was switched to argatroban. The serotonin release assay eventually returned positive, which confirmed the diagnosis of HIT. We also discuss potential overdiagnosis of HIT in COVID-19 through 4 cases with false-positive HIT antibodies.

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Clinical Significance of the Serotonin Release Assay and Platelet Count Monitoring After Cardiac Surgery

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/1076029617734308 ◽

2017 ◽

Vol 24 (6) ◽

pp. 944-949 ◽

Cited By ~ 1

Author(s):

Shinya Motohashi ◽

Takefumi Matsuo ◽

Hidenori Inoue ◽

Makoto Kaneko ◽

Shunya Shindo

Keyword(s):

Cardiac Surgery ◽

Platelet Count ◽

Clinical Course ◽

Serotonin Release ◽

Enzyme Linked Immunosorbent Assay ◽

Heparin Induced Thrombocytopenia ◽

Release Assay ◽

Immunological Assays ◽

Platelet Count Monitoring ◽

The Relationship

Heparin-induced thrombocytopenia (HIT) is one of the serious complications in patients who undergo cardiac surgery. However, there remains a major problem in diagnosing HIT because the current immunological assays for detection of HIT antibody have limitations. Furthermore, the clinical course of thrombocytopenia in this surgery makes it increasingly difficult to diagnose HIT. We investigated the relationship between platelet count and HIT antibody in 59 patients who underwent cardiac surgery using cardiopulmonary bypass (CPB). The number of postoperative HIT antibody-positive patients evaluated using enzyme-linked immunosorbent assay kit (polyanion IgG/IgA/IgM complex antibodies/antiplatelet factor 4 enhanced) was 37 (62.7%). In contrast, platelet activation by HIT antibody was evaluated using the serotonin release assay (SRA). More than 20% and 50% release of serotonin was obtained from 12 patients (20.3%) and 8 patients (13.6%), respectively. The levels of d-dimer were significantly different on postoperative day 14 between SRA-positive and SRA-negative groups; however, postoperative thrombus complication was not detected using sonography in the patients with positive serotonin release at all. After being decreased by the operation, their platelet count recovered within 2 weeks in both groups equally. In our study, although the patients were positive in the platelet activating HIT antibody assay, they remained free from thrombosis and their platelet count recovered after early postoperative platelet decrease. Therefore, in addition to the SRA, monitoring of platelet count might be still considered an indispensable factor to facilitate the prediction of HIT thrombosis prior to manifestation in the patients undergoing cardiac surgery using CPB.

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Heparin-Induced Thrombocytopenia (HIT): A Rural Community Based Experience.

Blood ◽

10.1182/blood.v110.11.3925.3925 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3925-3925

Author(s):

N. Mullai ◽

Amanda Brock ◽

Shona Harper

Keyword(s):

Rural Community ◽

Rapid Test ◽

Heparin Therapy ◽

Serotonin Release ◽

Rural Setting ◽

Thrombin Inhibitor ◽

Test Results ◽

Community Based ◽

Heparin Induced Thrombocytopenia ◽

Release Assay

Abstract Background: Heparin-induced thrombocytopenia (HIT) is a known complication of heparin therapy. This study was planned to assess the experience of a community based medical practice with HIT in a rural setting. Method: A retrospective study was done from medical records of patients suspected clinically of HIT from January 2006 to January 2007. The data were analyzed with regard to test results of patients, especially those who were positive for the HIT antibody and correlated with national statistics. Result: Fifty-two (52) patients were suspected clinically of having HIT during the study period. All 52 patients received heparin and most of them had cardiac surgery before the onset of thrombocytopenia. Six out of fifty-two (6/52) patients were found to have positive HIT antibody. Two out of six (2/6) also had positive serotonin release assay. Two out of six (2/6) developed heparin-induced thrombocytopenia with thrombosis (HITT). One of the two patients with HITT died of complications. The range of time to obtain test results was 5–7 days. Four out of fifty-two (4/52) patients received thrombin inhibitor lepirudin (Refludan) as alternate anticoagulation. Conclusion: The overall incidences, time of onset, relation to heparin treatment were similar to that of national averages. The time to obtain diagnostic test results ranged 5–7 days and heparin was withheld in all of them, and more expensive anticoagulation was used for some of them while waiting for the test results. This dilemma in diagnosis and treatment could be avoided if a rapid test that can help to assess the risk early in about 12–24 hrs, is possible. Such a test would be very beneficial especially in small, rural community settings where the availability of expensive testing and medications for HIT are limited.

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P.038 Bilateral carotid thrombi and cerebral infarction as a manifestation of heparin-induced thrombocytopenia with normal platelet count: a case report

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/cjn.2019.138 ◽

2019 ◽

Vol 46 (s1) ◽

pp. S24 ◽

Cited By ~ 1

Author(s):

P Malla

Keyword(s):

Platelet Count ◽

Sudden Onset ◽

Serotonin Release ◽

Heparin Induced Thrombocytopenia ◽

Platelet Counts ◽

Normal Platelet ◽

Bilateral Carotid ◽

Upper And Lower Extremities ◽

Release Assay ◽

Discharge From Hospital

Background: This is the first report of Heparin induced thrombocytopenia (HIT) presenting as bilateral carotid thrombi and multiple cerebral infarcts. Methods: 54 year old woman presented with sudden onset of right arm numbness and weakness two days after discharge from hospital. During her hospitalization 9 days prior, she underwent colovesicular fistula repair, received heparin subcutaneously for DVT prophylaxis and had normal platelet counts. Results: On this admission, MRI Brain showed scattered multiple acute infarcts within the cortex of bilateral cerebral hemispheres. CT angiography head /neck showed non-occlusive thrombi at the carotid bifurcations bilaterally. Platelet count on admission was 267 K/uL q which decreased to 125 K/uL the next day, after which heparin was started for the carotid thrombi. The platelet count rapidly decreased further to 79 K/uL leading to suspicion for HIT and switching to Argatroban. HIT and serotonin release assay were positive confirming the diagnosis of HIT. CT chest and tranthoracic echocardiogram was normal. Venous Duplex of bilateral upper and lower extremities were negative for DVTs.Hypercoaguable evaluation was negative. Conclusions: This case highlights the importance of identifying HIT as a cause of arterial thrombosis and stroke even with normal platelet counts in the clinical setting of recent heparin use.

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Heparin-induced thrombocytopenia in patients on extracorporeal membrane oxygenation and the role of a heparin-bonded circuit

Perfusion ◽

10.1177/0267659119842056 ◽

2019 ◽

Vol 34 (7) ◽

pp. 584-589 ◽

Cited By ~ 4

Author(s):

Dirk Pabst ◽

Jacqueline B Boone ◽

Behzad Soleimani ◽

Christoph E Brehm

Keyword(s):

Overall Survival ◽

Platelet Count ◽

Retrospective Study ◽

Extracorporeal Membrane Oxygenation ◽

Serotonin Release ◽

Single Center ◽

Heparin Induced Thrombocytopenia ◽

Membrane Oxygenation ◽

Release Assay

Background: In patients supported with extracorporeal membrane oxygenation, and who develop heparin-induced thrombocytopenia, there is no clear evidence to support changing to a non-heparin-coated extracorporeal membrane oxygenation circuit. Our goal was to evaluate clinical outcomes of patients who were continued on heparin-bonded circuits despite diagnosed heparin-induced thrombocytopenia. Methods: We completed a single-center retrospective study of all patients who underwent extracorporeal membrane oxygenation support from July 2008 to July 2017 and were tested heparin-induced thrombocytopenia positive while on extracorporeal membrane oxygenation support. After diagnosis of heparin-induced thrombocytopenia, mean platelet count (k/µL) was measured on consecutive days for 14 days. Results: Out of 455 patients, 14 (3.1%) had a diagnosis of heparin-induced thrombocytopenia by serotonin release assay and systemic heparin treatment was discontinued in every case. In total, 11 of the heparin-induced thrombocytopenia patients (78.6%) survived to discharge. The overall survival of all 455 extracorporeal membrane oxygenation patients was 54.1%. Platelets counts after discontinuation of systemic heparin in the heparin-induced thrombocytopenia patients increased from a mean of 59.8 k/µL at time of heparin-induced thrombocytopenia diagnosis to a mean of 280.2 k/µL at 14 days after discontinuation of heparin despite continuation of the heparin-bonded circuit. Platelet count increased in heparin-induced thrombocytopenia patients on extracorporeal membrane oxygenation support after discontinuation of systemic heparin even if maintained on the heparin-bonded circuit. Conclusion: Discontinuation of systemic heparin but continuation of heparin-coated extracorporeal membrane oxygenation circuits appeared to be an appropriate response for our extracorporeal membrane oxygenation–supported patients who developed heparin-induced thrombocytopenia. Survival in this group was not significantly different to those patients on extracorporeal membrane oxygenation without heparin-induced thrombocytopenia. Larger studies should evaluate the safety of heparin-bonded extracorporeal membrane oxygenation systems in heparin-induced thrombocytopenia patients.

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Incidence of Thrombosis in Serotonin Release Assay Negative Patients and Correlation with Pretest Heparin-Induced Thrombocytopenia Scoring System.

Blood ◽

10.1182/blood.v112.11.1816.1816 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1816-1816 ◽

Cited By ~ 1

Author(s):

Christopher Hueser ◽

Anjali J Patel ◽

John N Allan

Keyword(s):

Platelet Count ◽

Scoring System ◽

Thrombotic Event ◽

Study Groups ◽

Serotonin Release ◽

Single Institution ◽

Heparin Induced Thrombocytopenia ◽

Significant Difference ◽

Release Assay ◽

4T Score

Abstract Introduction: Heparin-induced thrombocytopenia (HIT) is an immune mediated, adverse effect related to both unfractionated heparin (UFH) and low-molecular weight heparin (LMWH). HIT may result in significant morbidity and mortality. The serotonin release assay (SRA) is utilized in conjunction with clinical information to diagnosis HIT. Employment of the pretest clinical scoring system, known as the “4Ts”, classifies patients as having a low, intermediate or high probability for developing HIT. Previous investigators have reported clinically diagnosed HIT in patients with a negative SRA. However, there is no systematic study evaluating such a group of patients. We determined the frequency of thromboses in SRA negative patients and determined the correlation between the 4T score in patients with and without thromboses. Methods: We report a descriptive, single institution, retrospective study of 181 consecutive samples over the course of one year sent to the Coagulation Laboratory of St. Louis University for the work up of suspected HIT. A total of 142 patients were eligible. Patients with SRA negative samples were evaluated for evidence of thrombosis. Diagnosis of a thrombotic event was made by computed tomography (CT), venous Doppler ultrasonography (US), and ventilation-perfusion scanning (V/Q). Defined patient study groups were: all evalulable patients (PALL), patients with thromboses (TPOS) and patients without thromboses (TNEG). Analyses, between each patient group, the 4T score, mean platelet count prior to heparin therapy, and mean platelet nadirs were performed. Results: The overall incidence of proven thromboses in evaluable SRA negative patients was 14.8% (n=21). Of the 21 thromboses, 17(81.0%) were deep venous thromboses (DVT), 3(14.3%) were DVT and pulmonary embolus (PE), and 1(0.7%) was an isolated PE. A significant difference in 4T score was observed between TPOS vs PALL (p<0.0001) and TPOS vs TNEG (p<0.0001) groups. There was no difference between the patient groups PALL vs TNEG (p=0.985). No statistically significant difference between the study groups was seen for either initial platelet averages (TPOS vs PALL [p=0.8923], TPOS vs TNEG [p=0.2091], PALL vs TNEG [p=0.2550]) or nadirs (TPOS vs PALL [p=0.4664], TPOS vs TNEG [p=0.3763], PALL vs TNEG [p=0.7860]). Total Evaluable Patients (PALL) Patients without Thrombosis (TNEG) Patients with Thrombosis (TPOS) * Missing data was included in calculations for patients without thrombosis n 142 (100%) 110 (77.46)/121(85.2%)* 21(14.8%) Avg. 4T Score 3.23 (±1.81) 2.79 (±1.61)* 5.50 (±0.83) Avg. Initial Platelet Count (1X10 9 /L) 198.98 (±97.19) 194.16 (±99.39)* 223.90 (±79.31) Avg. Platelet Nadir (1X10 9 /L) 75.02 (±48.57) 73.41 (±46.47)* 82.86 (±59.42) Avg. Platelet Drop (1X10 9 /L) 123.96 (62.30%) 94.77 (48.81%)* 141.04 (62.99%) NO Data* 11 11(7.75%)* NA Conclusions: A higher incidence of thrombotic events in SRA negative patients was seen compared to historical data. A strong positive and negative correlation exists between high and low 4T scores, respectively, and the probability of thromboses from HIT. Prospective data are needed to address the incidence of thrombosis for patients in whom the pretest probability of HIT is high and in whom the SRA is negative. Studies evaluating the utility of serial SRA testing in such patients may lead to earlier identification of those at high risk for thromboses. Limitations of this study were the retrospective design, single institution, and the lack of serial SRA testing.

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The Clinical Usefulness of the Platelet Aggregation Test for the Diagnosis of Heparin-Induced Thrombocytopenia

Thrombosis and Haemostasis ◽

10.1055/s-0038-1651610 ◽

1993 ◽

Vol 69 (04) ◽

pp. 344-350 ◽

Cited By ~ 175

Author(s):

B H Chong ◽

J Burgess ◽

F Ismail

Keyword(s):

Platelet Aggregation ◽

Heparin Therapy ◽

Serotonin Release ◽

Point System ◽

Control Groups ◽

Heparin Induced Thrombocytopenia ◽

Heparin Concentration ◽

Release Test ◽

The Mean ◽

Normal Controls

SummaryThe platelet aggregation test is widely used for the diagnosis of heparin-induced thrombocytopenia (HIT), a potentially serious complication of heparin therapy. We have evaluated its sensitivity and specificity in comparison with those of the 14C-serotonin release test. The sensitivity of the platelet aggregation test was found to vary with the heparin concentration and the donor of the platelets used in the test. The optimal heparin concentrations were between 0.1 and 1.0 U/ml. Using these heparin concentrations, the mean sensitivity varied from 39% (with the least reactive platelets) to 81% (with the most reactive platelets). In comparison, the sensitivity of the release test ranged from 65% to 94%. The specificities of the platelet aggregation test were 82%, 90% and 100% for the following control groups: (1) non-thrombocytopenic patients given heparin, (2) patients with thrombocytopenia due to other causes, and (3) normal controls not given heparin, respectively. The corresponding specificities for the release test was 94%, 90% and 100%. The specificities can be further increased to 100% for all controls with the adoption of a two-point system which defines a positive result as one in which platelet aggregation occurs with a low heparin concentration (0.5 U/ml) but not with 100 U heparin/ml. For optimal results, a two-point platelet aggregation test should be performed with heparin concentrations of 0.5 and 100 U/ml and using platelets of more reactive donors.

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Heparin-induced thrombocytopenia: when a low platelet count is a mandate for anticoagulation

Hematology ◽

10.1182/asheducation-2009.1.225 ◽

2009 ◽

Vol 2009 (1) ◽

pp. 225-232 ◽

Cited By ~ 14

Author(s):

Thomas L. Ortel

Keyword(s):

Platelet Count ◽

Heparin Therapy ◽

Severe Thrombocytopenia ◽

Drug Induced ◽

Platelet Factor ◽

Heparin Induced Thrombocytopenia ◽

Immune Mediated ◽

Number Of Patients ◽

Increased Risk ◽

Antibody Levels

Abstract Heparin-induced thrombocytopenia (HIT) is an immune-mediated disorder caused by the development of antibodies to platelet factor 4 (PF4) and heparin. The thrombocytopenia is typically moderate, with a median platelet count nadir of ~50 to 60 × 109 platelets/L. Severe thrombocytopenia has been described in patients with HIT, and in these patients antibody levels are high and severe clinical outcomes have been reported (eg, disseminated intravascular coagulation with microvascular thrombosis). The timing of the thrombocytopenia in relation to the initiation of heparin therapy is critically important, with the platelet count beginning to drop within 5 to 10 days of starting heparin. A more rapid drop in the platelet count can occur in patients who have been recently exposed to heparin (within the preceding 3 months), due to preformed anti-heparin/PF4 antibodies. A delayed form of HIT has also been described that develops within days or weeks after the heparin has been discontinued. In contrast to other drug-induced thrombocytopenias, HIT is characterized by an increased risk for thromboembolic complications, primarily venous thromboembolism. Heparin and all heparin-containing products should be discontinued and an alternative, non-heparin anticoagulant initiated. Alternative agents that have been used effectively in patients with HIT include lepirudin, argatroban, bivalirudin, and danaparoid, although the last agent is not available in North America. Fondaparinux has been used in a small number of patients with HIT and generally appears to be safe. Warfarin therapy should not be initiated until the platelet count has recovered and the patient is systemically anticoagulated, and vitamin K should be administered to patients receiving warfarin at the time of diagnosis of HIT.

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Diagnosis and treatment of heparin-induced thrombocytopenia

Perfusion ◽

10.1191/0267659103pf637oa ◽

2003 ◽

Vol 18 (1) ◽

pp. 47-53 ◽

Cited By ~ 6

Author(s):

William J DeBois ◽

Junli Liu ◽

Leonard Y Lee ◽

Leonard N Girardi ◽

Charles Mack ◽

...

Keyword(s):

New York ◽

Platelet Inhibition ◽

Heparin Therapy ◽

Serotonin Release ◽

Antibody Detection ◽

Thrombin Inhibitor ◽

Heparin Infusion ◽

Platelet Factor ◽

Heparin Induced Thrombocytopenia ◽

Life Threatening

Heparin-induced thrombocytopenia (HIT) is a major side effect secondary to the administration of heparin. This syndrome is serious and potentially life threatening. This response is the result of antibodies formed against the platelet factor 4 (PF4)/heparin complex. The incidence of this immune-mediated syndrome has been estimated to be 1-3% of all patients receiving heparin therapy. The occurrence of HIT in patients requiring full anticoagulation for cardiopulmonary bypass (CPB), therefore, presents a serious challenge to the cardiac surgery team. The diagnosis of HIT should be based on both clinical and laboratory evidence. While functional assays, platelet aggregation tests, and the serotonin release assay can be used to support the diagnosis, the negative predictive value of these tests is generally less than 50%. In contrast, although non-functional antibody detection assays are more sensitive, they have a low specificity. HIT can be treated in several ways, including cessation of all heparin and giving an alternative thrombin inhibitor, platelet inhibition followed by heparin infusion, and the use of low molecular weight heparins. In this presentation, the pathology and current diagnostic tests, as well as the successful management of patients with HIT undergoing CPB at New York Presbyterian Hospital, are reviewed.

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Incidence of Heparin-Induced Thrombocytopenia in Patients With Newly Implanted Mechanical Circulatory Support Devices

Annals of Pharmacotherapy ◽

10.1177/10600280211038705 ◽

2021 ◽

pp. 106002802110387

Author(s):

Long To ◽

Dana Attar ◽

Brittany Lines ◽

Melissa McCarty ◽

Hassan Nemeh ◽

...

Keyword(s):

Negative Predictive Value ◽

Predictive Value ◽

Mechanical Circulatory Support ◽

Serotonin Release ◽

Circulatory Support ◽

Anticoagulation Management ◽

Heparin Induced Thrombocytopenia ◽

Mechanical Circulatory Support Devices ◽

High Negative Predictive Value ◽

Release Assay

Background: Heparin exposure and device-related thrombocytopenia complicate the diagnosis of heparin-induced thrombocytopenia (HIT) in patients receiving mechanical circulatory support (MCS). To improve anticoagulation management for patients with newly implanted MCS devices, incidence of confirmed HIT needs to be further characterized. Objectives: The purpose of this study is to describe the incidence of HIT and clinical utility of the 4Ts score in patients with newly implanted MCS devices. Methods: This is a retrospective analysis of MCS patients receiving unfractionated heparin from 2014 to 2017. The primary end point was incidence of laboratory-confirmed HIT. Strong positive, likely positive, low probability, and negative HIT categories were established based on heparin-induced platelet antibody (HIPA) and serotonin release assay (SRA). Secondary end points include characterization of platelet trends, argatroban use, incidence of HIT among each of the MCS devices, and utility of 4Ts score. Results: A total of 342 patient encounters met inclusion criteria, of which 68 HIPA tests and 25 SRAs were ordered. The incidence of HIT was 0.88% (3/342) and 4.4% (3/68) in patients with suspected HIT. Of the 68 HIPA tests, 3 (4.4%) were considered strong positive and 3 of the 25 SRAs were positive. Median 4Ts score was 4 [2.5-4] and optical density 0.19 [0.11-0.54]. The positive predictive value for the 4Ts score was 0.15 (CI = 0.03-0.46) and negative predictive value, 0.93 (CI = 0.82-0.98). Conclusion and Relevance: HIT occurs infrequently with newly implanted MCS devices. The 4Ts score appears to have a high negative predictive value for ruling out HIT.

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Pathophysiology of Heparin-Induced Thrombocytopenia

Archives of Pathology & Laboratory Medicine ◽

10.5858/2000-124-1657-pohit ◽

2000 ◽

Vol 124 (11) ◽

pp. 1657-1666 ◽

Cited By ~ 4

Author(s):

Fabrizio Fabris ◽

Sarfraz Ahmad ◽

Giuseppe Cella ◽

Walter P. Jeske ◽

Jeanine M. Walenga ◽

...

Keyword(s):

Platelet Activation ◽

Serotonin Release ◽

Platelet Factor 4 ◽

Thrombin Inhibitors ◽

Platelet Factor ◽

Cellular Activation ◽

Heparin Induced Thrombocytopenia ◽

New Information ◽

Study Selection ◽

Release Assay

Abstract Objective.—This review of heparin-induced thrombocytopenia (HIT), the most frequent and dangerous side effect of heparin exposure, covers the epidemiology, pathophysiology, clinical presentation, diagnosis, and treatment of this disease syndrome. Data Sources and Study Selection.—Current consensus of opinion is given based on literature reports, as well as new information where available. A comprehensive analysis of the reasons for discrepancies in incidence numbers is given. The currently known mechanism is that HIT is mediated by an antibody to the complex of heparin–platelet factor 4, which binds to the Fc receptor on platelets. New evidence suggests a functional heterogeneity in the anti-heparin-platelet factor 4 antibodies generated to heparin, and a “superactive” heparin-platelet factor 4 antibody that does not require the presence of heparin to promote platelet activation or aggregation has been identified. Up-regulation of cell adhesion molecules and inflammatory markers, as well as preactivation of platelets/endothelial cells/leukocytes, are also considered to be related to the pathophysiology of HIT. Issues related to the specificity of currently available and new laboratory assays that support a clinical diagnosis are addressed in relation to the serotonin-release assay. Past experience with various anticoagulant treatments is reviewed with a focus on the recent successes of thrombin inhibitors and platelet GPIIb/IIIa inhibitors to combat the platelet activation and severe thrombotic episodes associated with HIT. Conclusions.—The pathophysiology of HIT is multifactorial. However, the primary factor in the mediation of the cellular activation is due to the generation of an antibody to the heparin-platelet factor 4 complex. This review is written as a reference for HIT research.

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