HEPARIN-INDUCED Thrombocytopenia (HIT) is an immune-mediated adverse drug reaction, caused by an interaction between the heparin-PF4 (platelet factor 4) complex and antibodies. This reaction can occur after administration of any heparin product, including low-molecular-weight heparin (LMWH) and unfractionated heparin injections, infusions, flushes, and dialysate fluids. As a negatively charged polysaccharide, heparin has affinity for the positively charged PF4 found on surfaces of platelets and endothelial cells.1 When this interaction occurs and a complex is formed between heparin and PF4, the conformation of heparin is changed and the complex becomes immunogenic, stimulating antibody formation.2 Antibodies may bind the heparin-PF4 complex, forming an immune complex, which stimulates activation and aggregation of platelets and monocytes, causing further release of PF4, thrombin, tissue factors, and prothrombotic microparticles leading to subsequent thrombosis and endothelial injury.3 Thrombocytopenia presents due to clearance of the activated and antibody-bound platelets.2
Heparin-induced thrombocytopenia typically presents as a moderate thrombocytopenia, characterized by more than 50% decrease in platelet count and commonly reaching less than 150 × 109/L,1 with typical platelet nadirs found to be near 54 × 109/L by Warkentin and Kelton.4 The onset of thrombocytopenia can vary but is typically characterized by thrombocytopenia occurring 5 to 10 days after heparin initiation. Less common presentations include rapid HIT, where platelet counts decline immediately after heparin exposure, associated with previous heparin exposure within the past 100 days.4 Additionally, patients can present with a delayed HIT presentation, where thrombocytopenia does not occur for more than 10 days after heparin exposure, although this pattern is rare.4
Aside from thrombocytopenia, patients are at risk for development of thrombosis, and detection of new thrombosis often triggers one to suspect HIT. HIT is associated with a 17% to 30% mortality rate and 50% to 89% chance of thrombosis if left untreated.3,4 Thrombosis can develop in the arterial or venous circulation, and manifestations include pulmonary embolism, deep vein thrombosis, ischemic stroke, myocardial infarction, arterial limb occlusion, graft occlusion, and death.3,4 Additionally, a smaller subset of patients may develop skin lesions and necrosis at injection sites, as well as systemic reactions such as fever, chills, tachycardia, and hypotension.2
Overall, HIT occurs in 0.2% to 5% of patients who received heparin products.1 HIT occurs more commonly in patients who were given unfractionated heparin versus LMWH, highlighted by the orthopedic surgery population where frequency of HIT was 4.8% versus 0.6%, respectively.1 Risk factors for HIT include being female, and prolonged heparin exposure (>5 days). Additional populations with observed increase in HIT frequency include cardiac transplant patients, cardiac surgery patients, orthopedic surgery patients treated with heparin, and newly treated hemodialysis patients.1
In these populations identified to be at higher risk for HIT, a thorough clinical assessment is crucial to aid in diagnosis as there may be factors other than heparin contributing to thrombocytopenia. Examples of the many different causes of thrombocytopenia in a critically ill patient include but are not limited to sepsis, cardiac devices, cardiopulmonary bypass (CPB), extracorporeal membrane oxygenation, antimicrobials, end-stage renal disease, major bleeding, disseminated intravascular coagulation, severe infection, and pulmonary embolism.5 Differentiation of the possible causes of thrombocytopenia may be difficult and time-consuming; however, given the extreme morbidity and mortality, it is imperative that caregivers are identifying and treating HIT as early as possible. Nurses can play a vital role in this situation, given they are on the front lines in regard to taking care of the hospitalized patient. To do this effectively, the American Society of Hematology (ASH) and the American College of Chest Physicians (CHEST) have made specific recommendations regarding early recognition of HIT.6,7
Current Guideline Recommendations
Both ASH and CHEST guidelines recommend platelet monitoring in patients who are at increased risk for HIT.6,7 Per the CHEST guidelines, this is defined as patients receiving unfractionated heparin for 1 week or more, or patients who have a risk of HIT of more than 0.1%.7 This recommendation is supported by the ASH guidelines, which further defines patients at low risk of HIT (<0.1%) as medical and obstetrical patients receiving LMWH, minor surgery or minor trauma patients receiving LMWH, and any patients receiving fondaparinux.6 It is recommended that platelet monitoring begins at day 4 and is checked at least every other day until day 14 or until heparin discontinuation in most patients, but may be indicated to begin earlier or be checked more frequently if the patient has had a recent exposure to heparin or acute systemic symptoms after heparin administration.7 Guidelines support suspicion of HIT when platelet count decreases by 50% or more, or a new thrombotic event occurs in patients who have received heparin in the prior 14 days, although HIT may also be suspected in many other clinical scenarios.6 To further differentiate the cause of thrombocytopenia when HIT is suspected, ASH guidelines recommend using pretest probability scoring (the 4 T's score) to exclude HIT from the differential prior to sending heparin antibody laboratories and discontinuing heparin.
The 4 T's score is the most common pretest probability score that is used, and considers degree of thrombocytopenia, timing of thrombocytopenia, presence of thrombosis, and other causes of thrombocytopenia to generate a total score, which can be correlated to risk of HIT (see the Table).7 Validation of this tool determined that a “low” 4 T's score (0-3 points) has a negative predictive value of 99.8%, while an intermediate (4-5 points) and high score (≥6 points) have positive predictive values of 16% and 64%, respectively.8 Given this information, clinicians can exclude a diagnosis of HIT if a 4 T's score is calculated and determined to be low risk, however; laboratory diagnosis and empiric management of HIT should be initiated if the calculated 4 T's score estimates intermediate or high probability of HIT. This is reflected in the ASH guidelines, which recommend against HIT laboratory testing and empiric treatment of HIT if the 4 T's score is low risk, but if the 4 T's score is intermediate or high risk, it is recommended to send HIT laboratory testing, and empirically treat HIT by discontinuation of all heparin agents and initiation of nonheparin anticoagulation.7
The 4 T's Clinical Scoring System for Heparin-Induced Thrombocytopenia
||Platelet count fall >50% and platelet nadir ≥20 000/μL
||Platelet count decrease 30%-50% or nadir 10 000-19 000/μL
||Platelet count decrease <30% or nadir ≤10 000/μL
|Timing of onset
||d 5-10 or fall ≤1 d if recent heparin exposure in last 30 d
||d >10 or unclear exposure or fall ≤1 d of recent heparin exposure in last 30-100 d
||Platelet count fall <4 d without recent exposure
||New thrombosis or skin necrosis or anaphylactoid reaction after heparin bolus
||Progressive or recurrent thrombosis, or nonnecrotizing skin lesions, or suspected thrombosis (not proven)
|Other causes of thrombocytopenia
In addition to the 4 T's score, alternative pretest probability scoring systems have been developed and may be used by providers in clinical practice. First, the CPB scoring system was developed specifically for patients who had undergone a surgical procedure requiring CPB. This scoring system takes into account the pattern of platelet decline after bypass, the time of onset of platelet decrease after bypass, and bypass duration, to generate a risk of low (<2 points), or high (≥2 points).9 Authors of this scoring system have indicated a negative predictive value of 97% for low-risk scores, and a positive predictive value of 62% for high-risk scores.9 Use of this scoring system is limited to the CPB patients, and it has not been validated in prospective studies. A third scoring system, the HIT Expert Probability (HEP) score, was developed from expert opinion of 26 HIT experts, and assesses 8 factors in detail to generate a risk score: magnitude of fall in platelet count, timing of fall in platelet count, platelet nadir, thrombosis, skin necrosis, acute systemic reaction, bleeding, and other causes of thrombocytopenia.10 This model was found to be 100% sensitive and 60% specific for diagnosing HIT; however, it has yet to be evaluated in a large prospective trial.10 At this time, the 4 T's score is the only pretest probability score recommended by ASH guidelines.
Once a pretest probability score is calculated, nursing can play a critical role in expediting treatment decisions with the provider. If the patient is determined to be low risk for HIT, nursing can help facilitate continuation of heparin anticoagulation, if appropriate, and advocate against drawing unnecessary HIT antibody laboratory tests. These often take considerable time to return and result in inappropriate pauses in anticoagulation. If the patient is found to be intermediate or high risk, nursing can initiate urgent conversation with the health care team and advocate for heparin agent discontinuation, sending appropriate laboratories, and initiation of a nonheparin anticoagulant.
Proper interpretation of laboratory results is critical to ensure timely management of HIT. HIT laboratory tests typically consist of 2 laboratory values, a heparin-PF4 antibody enzyme immunoassay, and a platelet serotonin release assay (SRA) or functional assay. First, the heparin-PF4 antibody test detects the presence of antibodies to the heparin-PF4 complex formed. This test has been found to be greater than 90% sensitive, but 50% to 93% specific for typical HIT presentation.6 Given the variable specificity of the heparin-PF4 test, this test is typically used only to rule out HIT diagnosis and is not used to confirm diagnosis. The SRA is accepted as the gold standard for HIT diagnosis and has a sensitivity and specificity of more than 95%.1 The SRA is typically sent after the heparin-PF4 test returns positive to confirm diagnosis of HIT, to avoid time waiting for test results and higher costs associated with this functional assay. A positive SRA would indicate diagnosis of HIT, and caregivers should ensure that proper treatment has been initiated upon receiving this result. Of note, many institutions may not have capability to analyze HIT laboratory tests within their institution and thus these would need to be sent to an outside laboratory. Time for test results to return may vary from 2 to 7 days, which further emphasizes the importance of guideline-directed management of suspected HIT and use of pretest probability scoring to avoid inappropriate management while awaiting laboratory results.
Management of HIT
When HIT is suspected or confirmed by SRA, guidelines recommend cessation of all heparin agents as the first step of treatment.6,7 As a caregiver, it is important to note that heparin may be present in other therapies including dialysate fluids, heparin flushes, and purge solutions for cardiac devices. Although continued heparin therapy may precipitate the risk of thrombosis, discontinuing heparin alone will not prevent thrombosis, and initiation of nonheparin anticoagulation is imperative to prevent thrombotic complications, as thrombosis rates as high as 50% have been observed in patients who were not treated.11
The most common no-heparin anticoagulant used is the direct thrombin inhibitor argatroban, approved for use for prevention of thrombosis in HIT and as an anticoagulant for patients with suspected HIT undergoing percutaneous coronary intervention (PCI).12 Similar to heparin, argatroban is administered as a bolus, followed by a continuous infusion, and anticoagulant effects are seen almost immediately.7 Argatroban therapy is initiated at 2 μg/kg/min in patients with normal hepatic function, and dose adjustments may be made off partial thromboplastin time (PTT), with a typical PTT goal of 1.5 to 3 times the upper limit of normal.7 Argatroban does not require renal dose adjustment, however; dose adjustments may be necessary for serious hepatic impairment or multisystem organ failure.7 Like argatroban, bivalirudin is a direct thrombin inhibitor that may be used when HIT is suspected, specifically in patients undergoing PCI.13 Bivalirudin is typically administered as a bolus followed by an infusion, and PTT is monitored to make dose adjustments. Bivalirudin is cleared by the kidneys, and dose adjustment is required when creatinine clearance is less than 30 mL/min.7 Fondaparinux is the last injectable medication recommended by the ASH guidelines and approved for use in the United States. This medication works by inhibition of factor Xa to prevent generation of thrombin and is administered by subcutaneous injection once daily based on weight. Although this therapy is recommended by ASH guidelines, it has not yet been approved by the Food and Drug Administration for use in this indication.6
Based on the most recent ASH guidelines updated in 2018, direct oral anticoagulants (DOACs) are now recommended as a potential option for anticoagulation in patients with HIT.6 Rivaroxaban is recommended as the preferred DOAC as it has been studied most frequently in this population, but other DOACs such as apixaban and dabigatran are also recommended.6 The duration of treatment with DOACs varies based on whether the patient has had a thrombosis or not, typically ranging from 1 to 3 months of treatment if no thrombosis, to 3 to 6 months of treatment If thrombosis occurred. In practice, a patient may be started on a DOAC when HIT is suspected, or transitioned from parenteral nonheparin anticoagulation.
Unlike DOACs, the use of warfarin is not recommended during the acute stages of HIT.6 If a patient is on warfarin at the time of HIT suspicion or diagnosis, it should be discontinued, and alternative anticoagulation should be used instead. Warfarin is not recommended due to the association of skin necrosis and gangrene with use in HIT. Patients treated with warfarin in the acute phases of HIT commonly developed thrombosis.6 If absolutely needed, warfarin should not be initiated until thrombocytopenia has resolved.6
Heparin-induced thrombocytopenia is a life-threatening condition that requires quick action to avoid severe morbidity and mortality. As a nurse, it is important to monitor patients frequently who are on heparin-containing therapies, and to be familiar with pretest probability scores to help determine a patient's risk of HIT. Nurses play a vital role in advocating for the patient to ensure that guideline-based management consisting of heparin discontinuation and initiation of nonheparin anticoagulation is implemented appropriately when HIT is suspected or confirmed.
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