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INTRODUCTION — Heparin-induced thrombocytopenia (HIT) is a life-threatening complication of exposure to heparin (ie, unfractionated heparin, low molecular weight [LMW] heparin) that occurs in up to 5 percent of patients exposed, regardless of the dose, schedule, or route of administration. HIT results from an autoantibody directed against platelet factor 4 (PF4) in complex with heparin. HIT antibodies activate platelets and can cause catastrophic arterial and venous thrombosis, with a mortality rate as high as 20 percent, although with improved recognition and early intervention, mortality rates below 2 percent have been reported.
Here we discuss the prevention and management of HIT. The clinical presentation and diagnosis of HIT are discussed separately. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia".)
IMMEDIATE DISCONTINUATION OF HEPARIN
Presumptive diagnosis of HIT — We always consider clinical and laboratory evidence in evaluating patients for heparin-induced thrombocytopenia (HIT). However, definitive laboratory data (ie, immunoassay and/or functional assay for HIT antibodies) may not be available for several days. Thus, we make a presumptive diagnosis of HIT based on clinical findings and immediately available laboratory data.
Clinicians, particularly those who have less familiarity with HIT, should involve the consulting hematologist as early as possible in determining the likelihood of HIT because a presumptive diagnosis of HIT carries management implications (eg, discontinuation of heparin, administration of a non-heparin anticoagulant). Not diagnosing HIT when it is present or mistakenly diagnosing HIT when it is absent are both associated with significant risks (eg, life-threatening thrombosis if a diagnosis is missed; life-threatening bleeding and high cost of presumptive treatment with a non-heparin anticoagulant if an incorrect diagnosis is made).
The 4 T's score (calculator 1) is an easy-to-use score that quantifies the clinical findings associated with HIT (eg, degree of Thrombocytopenia, Timing, Thrombotic events or sequelae, alternative causes of thrombocytopenia). The 4 T's score should be used as a guide for clinicians and should not substitute for clinical judgement .
●In general, if the 4 T's score is intermediate or high probability, we make a presumptive diagnosis of HIT because an intermediate or high probability 4 T's score will capture the vast majority of patients with a reasonable likelihood of HIT regardless of whether they have had a thrombotic event.
●In general, if the 4 T's score is low probability, we generally do not make a presumptive diagnosis of HIT because the risk of HIT is exceedingly low and presumptive treatment carries risks (eg, bleeding) and costs. However, in rare or complex cases, a clinician may suspect HIT despite a low probability 4 T's score, and a presumptive clinical diagnosis of HIT may be made.
The clinical evaluation for suspected HIT is discussed in more detail separately. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia", section on 'Overview of our approach to evaluation'.)
Individuals with a presumptive diagnosis of HIT should be treated for HIT until the diagnosis is confirmed or refuted by laboratory testing (algorithm 1). Presumptive treatment includes the following:
●All forms of heparin should be discontinued (eg, unfractionated heparin, low molecular weight [LMW] heparin, heparin flushes, heparin-bonded catheters, heparin-containing medications [eg, some prothrombin complex concentrates]).
●Anticoagulation with a non-heparin anticoagulant should be initiated in all patients except those with bleeding or at a high risk for bleeding [2-4]. (See 'Initiation of a non-heparin anticoagulant' below.)
●The need to avoid all forms of heparin exposure should be conveyed to all personnel caring for the patient immediately, along with a notation in the patient's medical record and signs posted at the bedside or attached to all intravenous delivery devices .
●Warfarin should not be started until thrombocytopenia resolves, in order to avoid the transient increase in hypercoagulability induced by warfarin and the associated potential risk of limb gangrene. (See 'Transition to warfarin' below.)
If the clinical picture is not suggestive of HIT, we pursue other causes of thrombocytopenia. However, any change in clinical findings (eg, development of a new thrombosis, further drop in platelet count) should prompt reevaluation and recalculation of the 4 T's score, with appropriate HIT antibody testing based on the revised risk. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia", section on 'Differential diagnosis' and "Approach to the adult with unexplained thrombocytopenia" and "Causes of thrombocytopenia in children".)
Confirmed diagnosis of HIT — The final diagnosis of HIT is confirmed (or excluded) once definitive data from HIT antibody testing are available. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia", section on 'Diagnosis'.)
●In some cases, the quantitative result of an immunoassay (eg, ELISA) for anti-platelet factor 4 (PF4) antibodies is sufficiently low (ie, optical density [OD] <0.40) or high (ie, OD >2.00) to exclude or confirm the diagnosis of HIT, respectively. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia", section on 'Immunoassay (eg, ELISA)'.)
●If the results of the immunoassay are indeterminant (eg, OD 0.40 to 2.00), a functional assay may be required to confirm or exclude the diagnosis of HIT. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia", section on 'Functional assays'.)
If a diagnosis of HIT is confirmed, the patient should continue on a non-heparin anticoagulant; the duration of anticoagulation depends on the presence or absence of thrombosis. (See 'Duration of anticoagulation' below.)
The importance of the HIT diagnosis and its implications (eg, lifetime avoidance of all forms of heparin) should be emphasized to the patient and all individuals caring for the patient, and recorded in the medical record. Sources of heparin include unfractionated heparin, LMW heparin, heparin flushes, heparin-bonded catheters, and heparin-containing medications (eg, some prothrombin complex concentrates). (See 'Avoidance of heparin for life' below.)
If a diagnosis of HIT is excluded based on laboratory testing, the individual can resume heparin therapy (if the original indication persists) and can receive heparin in the future. Alternative causes for thrombocytopenia should be sought, and the medical record should clearly state that the patient does not have HIT. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia", section on 'Differential diagnosis' and "Approach to the adult with unexplained thrombocytopenia" and "Causes of thrombocytopenia in children".)
INITIATION OF A NON-HEPARIN ANTICOAGULANT — For patients with a presumptive clinical diagnosis heparin-induced thrombocytopenia (HIT) or a confirmed diagnosis of HIT based on HIT antibody testing, we recommend immediate anticoagulation with a non-heparin anticoagulant (eg, argatroban, danaparoid, fondaparinux, bivalirudin) rather than discontinuation of heparin alone, unless there is a strong contraindication (eg, bleeding, high bleeding risk). This applies to all patients, regardless of the initial indication for and dose of heparin (eg, full-dose anticoagulation, heparin flushes).
Rationale for starting another anticoagulant — Patients who develop HIT will have an ongoing need for anticoagulation due to the risk of thrombosis associated with HIT, and possibly also for the condition for which heparin was administered originally (algorithm 1). Heparin cessation alone is often not sufficient since patients with HIT remain at risk for subsequent thrombosis, especially during the period when the HIT antibody continues to activate platelets [1,2,6].
The persistent risk of thrombosis is illustrated by the following examples:
●In a retrospective series of 127 patients with HIT, in which half were only diagnosed after they had a complicating thrombotic event , of the 62 patients who presented with HIT without thrombosis, subsequent 30-day thrombosis risk was 53 percent.
●Another study evaluated 113 patients with HIT in whom heparin was stopped early (mean 0.7 days) or late (mean five days) after the onset of thrombocytopenia . The overall incidence of thrombosis was 45 and 34 percent in the early and late groups, respectively, with 61 and 40 percent of the thrombotic events occurring more than 24 hours after cessation of heparin.
Choice and dose of non-heparin anticoagulant — There are a number of alternative anticoagulants that can be used in a patient with HIT. These include parenteral direct thrombin inhibitors (eg, bivalirudin, argatroban); fondaparinux; danaparoid (not available in the United States); or lepirudin (discontinued in May 2012) (table 1) [5,7-12].
Our approach to the choice and dose level of anticoagulant is as follows:
●For patients with normal renal and hepatic function, any of the alternative anticoagulants can be used, and the choice can be based on availability and institutional and/or clinician preference. We generally use intravenous argatroban infusion; fondaparinux can be used if there is a need for a subcutaneous agent.
●We use therapeutic rather than prophylactic dosing, with the exception of patients with combined renal and hepatic impairment.
●We treat patients with renal insufficiency with argatroban at therapeutic doses since argatroban is metabolized hepatically and does not require dose adjustment in this setting.
●We treat patients with hepatic impairment with fondaparinux at therapeutic doses.
Specific dosing of each agent is described in the sections below.
Evidence for the similar efficacy of these anticoagulants in HIT comes from retrospective and single-arm studies; there have been no prospective randomized trials comparing the efficacy and toxicity of the available non-heparin agents. A retrospective cohort study that compared outcomes in 133 patients with HIT who were treated with fondaparinux versus 60 propensity matched controls treated with danaparoid or argatroban found a similar risk of thrombosis (17 percent with fondaparinux versus 21 percent with controls [danaparoid: 19 percent; argatroban: 21 percent]) . The risk of major bleeding was also similar (21 versus 20 percent), although there was a non-significant trend towards greater bleeding with argatroban. Fondaparinux was administered at prophylactic doses in 60 percent of the patients, suggesting that prophylactic fondaparinux dosing might be effective in individuals who have not had a thrombotic event.
In a nonrandomized comparison study that evaluated 126 patients treated with danaparoid and 175 patients treated with lepirudin, the overall risk of a composite endpoint of death, amputation, or new thromboembolic complications did not differ significantly when therapeutic doses were used (22 versus 19 percent) [1,14]. However, among the subgroup who did not have a thromboembolic event before starting the non-heparin anticoagulant, most of whom were treated with prophylactic dosing, there was a greater risk of thrombosis in patients who received danaparoid compared with lepirudin (20 versus 6 percent). The risk of bleeding appeared to be lower in patients treated with danaparoid versus lepirudin (3 versus 10 percent).
Bivalirudin — Bivalirudin (Angiomax, previously called Hirulog), a parenteral direct thrombin inhibitor and hirudin analog, has been successfully used in patients with HIT, with reduced doses safely used in patients with renal failure and patients with combined hepatic and renal failure [5,15-18]. Its effect is monitored by the aPTT. (See "Direct oral anticoagulants: Dosing and adverse effects", section on 'Bivalirudin'.)
The recommended initial dose of bivalirudin for HIT is approximately 0.15 mg/kg per hour, adjusted to achieve an aPTT 1.5 to 2.5 times baseline. Doses of 0.14 mg/kg per hour in patients with hepatic dysfunction; 0.03 to 0.05 mg/kg per hour in patients with renal or combined hepatic and renal dysfunction; and 0.04 to 0.03 mg/kg per hour in those receiving continuous renal replacement therapy, have been successfully used . Bivalirudin is hemodialyzable.
There is a theoretical concern that in patients who were previously exposed to lepirudin and developed anti-lepirudin antibodies, these antibodies might bind to bivalirudin and enhance the anticoagulant effect of bivalirudin . However, those exposed to bivalirudin appear to have a very low incidence of developing drug-induced antibodies.
Argatroban — Argatroban is a parenteral small molecule direct thrombin inhibitor with a half-life of 24 minutes . Its effect is monitored by the aPTT, although dose-dependent increases also occur in the prothrombin time . Steady-state anticoagulation is reached one to three hours after intravenous administration; after discontinuation, the aPTT returns to normal within two hours . (See "Direct oral anticoagulants: Dosing and adverse effects", section on 'Argatroban'.)
In patients with normal hepatic function, the standard starting dose is 2 mcg/kg per minute by continuous intravenous infusion, adjusted to maintain the aPTT at 1.5 to 3 times baseline, not to exceed 100 seconds.
Since argatroban is mostly metabolized by the liver, dose adjustment is required in the presence of hepatic dysfunction. A conservative lower starting dose (eg, 0.5 to 1.2 mcg/kg per minute) is appropriate in patients total serum bilirubin >1.5 mg/dL (25.5 micromol/L) as well as in those with combined hepatic/renal dysfunction, heart failure, severe anasarca, or who are postcardiac surgery [5,23,24]. In such patients it is prudent to check the aPTT at four-hour intervals after drug initiation or dose change. Dose adjustment is not required in the presence of isolated renal impairment .
A small study in 24 patients has suggested that an even lower starting dose of argatroban (0.2 mcg/kg per minute) may be appropriate in critically ill patients with multiple organ dysfunction syndrome and HIT . We generally initiate dosing at 0.5 mcg/kg per minute in these patients.
Since both warfarin and argatroban elevate the PT/INR, institutional guidelines should be reviewed to determine the appropriate INR target during the transition to warfarin in order to achieve an INR in the range of 2.0 to 3.0 when argatroban is discontinued. This target will differ according to the reagents used to determine the PT/INR in each particular institution. (See 'Transition to warfarin' below.)
Three prospective trials of the use of argatroban for the treatment of HIT have been published, representing 1419 patients [27-29]. These studies showed superior efficacy of argatroban compared with historical controls in reducing subsequent thrombotic events and death due to thrombosis, with no increased bleeding risk.
Fondaparinux — Fondaparinux (Arixtra) is a chemically synthesized version of the active pentasaccharide subunit of heparin that does not interact with platelet factor 4 and therefore has a theoretical role in treatment and/or prevention of HIT. It is administered subcutaneously, and monitoring is not used in routine practice, although drug levels can be measured. Patients taking fondaparinux for prolonged periods should have periodic monitoring of renal function. (See "Fondaparinux: Dosing and adverse effects", section on 'Monitoring'.)
We use full therapeutic dosing of fondaparinux (eg, 5 to 10 mg/day).
The 2012 American College of Chest Physicians (ACCP) Guidelines mention the use of fondaparinux for suspected or confirmed HIT, but the evidence for using this agent was considered weak and it is not listed among the suggested treatment choices for most cases of HIT . However, we believe that the available data, as well as its mechanism of action, support the use of this agent if needed. (See 'Choice and dose of non-heparin anticoagulant' above.)
The safety of fondaparinux in HIT is supported by data from a retrospective review of the Matisse trial, which randomized patients with deep vein thrombosis to treatment with fondaparinux versus low molecular weight heparin (LMW) . A retrospective review of the outcome in patients with preexisting HIT antibodies found that fondaparinux did not cause HIT in any of the 10 patients with preexisting HIT antibodies, whereas LMW heparin caused HIT in all of the four patients with pre-existing HIT antibodies. A number of observational reports describe the successful management of patients with confirmed HIT using fondaparinux [32-38].
Although fondaparinux is generally not used in patients with platelet counts <100,000/microL, those with HIT are an exception because the platelet count is expected to rise upon discontinuation of heparin.
Danaparoid — Danaparoid (Orgaran) is a heparinoid (heparan derivative) that consists predominantly of dermatan sulfate and low-sulfated heparan sulfate; it is devoid of heparin. A shortage in drug substance caused the manufacturer (Organon) to discontinue providing this medication in the United States. Danaparoid is available in several other countries, including Canada. Danaparoid is administered subcutaneously or intravenously and monitored by anti-factor Xa activity (four hours after injection if administered subcutaneously). (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Danaparoid'.)
The recommended therapeutic dose of danaparoid in HIT is an initial intravenous (IV) bolus of 2250 units, modified up or down according to body weight, followed by an IV infusion at the rate of 400 units/hour for four hours, 300 units/hour for the next four hours, and 200 units/hour thereafter. Doses are adjusted to achieve anti-factor Xa levels of 0.5 to 0.8 anti-Xa units/mL .
The disadvantages of danaparoid are the need to measure anti-factor Xa levels, which are less readily available in some settings, to monitor its anticoagulant effect; its long half-life (25 ± 10 hours) ; its renal elimination; and the absence of a reversal agent .
Lepirudin — Lepirudin (Refludan) is a recombinant hirudin that is no longer available. The manufacturer of lepirudin (Bayer HealthCare) discontinued marketing this product as of May 31, 2012, and no further product is expected to be shipped to wholesalers in the United States, Canada, and the European Union.
Lepirudin was shown to be effective in preventing new thromboses in patients with isolated HIT and no clinically evident thromboembolic complications .
Other agents — We do not use agents other than those described above due to lack of data on clinical efficacy and safety in patients with HIT.
A preliminary report of three patients suggests that a glycoprotein IIb/IIIa inhibitor in combination with a direct thrombin inhibitor may be effective when a thrombin inhibitor alone fails to relieve acute thrombosis .
There are theoretical reasons why the direct oral anticoagulants (DOACs) such as apixaban, edoxaban, rivaroxaban, or dabigatran should be effective for patients with established HIT, although clinical experience with these agents in this off-label setting is very limited [47-50]. A systematic review identified 54 patients with HIT who were treated with a DOAC . In most cases, the oral anticoagulant was preceded by a parenteral agent. There was one thrombotic complication (extension of a catheter-associated thrombus), three cases of clinically relevant bleeding, and no deaths. More data are needed before DOACs are used routinely for patients with HIT.
Other approaches, including fibrinogen-depleting agents (eg, ancrod), thrombolysis, plasmapheresis, dextran, or intravenous immune globulin, are not effective for the initial treatment of HIT and should not be used.
TRANSITION TO WARFARIN — Warfarin should not be used as the initial anticoagulant in patients with heparin-induced thrombocytopenia (HIT) since warfarin therapy may increase the risk of venous limb gangrene in patients with deep vein thrombosis through its rapid lowering of protein C levels [52,53]. However, once initial anticoagulation has been started, warfarin can be used for continued oral anticoagulation. (See 'Duration of anticoagulation' below.)
●The patient has been stably anticoagulated with an alternative anticoagulant, and
●The platelet count has increased to at least 150,000/microL
There should be a minimum of five days of overlapping therapy before the alternative anticoagulant is discontinued.
The starting dose of warfarin should be a low maintenance dose of ≤5 mg/day (or phenprocoumon ≤6 mg/day) rather than a high initial or loading dose (eg, ≥10 mg/day), to minimize the transient hypercoagulable state induced by the rapid decline in protein C levels [5,54]. (See "Warfarin and other VKAs: Dosing and adverse effects", section on 'Initial dosing' and "Warfarin and other VKAs: Dosing and adverse effects", section on 'Establishing a maintenance dose'.)
Warfarin must be monitored by the prothrombin time (PT) with international normalized ratio (INR). The target range for anticoagulation should be an INR in the range of 2.0 to 3.0. If the patient is being transitioned from argatroban to warfarin, institutional guidelines regarding the appropriate INR target should be followed, because both warfarin and argatroban elevate the INR. (See 'Argatroban' above.)
DURATION OF ANTICOAGULATION — The length of treatment with warfarin or other anticoagulants following an episode of heparin-induced thrombocytopenia (HIT) has not been defined in any prospective study. In view of the high risk of thrombosis following the diagnosis of HIT, we suggest that patients with HIT continue anticoagulation with a non-heparin anticoagulant for at least two to three months, and for at least three to six months if a thrombotic event has occurred [55,56].
The high risk of thrombosis without continued anticoagulation is illustrated by a review of 127 patients with HIT, in which half were only diagnosed after they had a complicating thrombotic event, and those diagnosed with HIT without thrombosis had a subsequent 30-day thrombosis risk of 53 percent .
EXPECTED RESOLUTION — The resolution of thrombocytopenia following withdrawal of heparin typically occurs within seven days. Clinicians should maintain a high suspicion for continued heparin exposure or other potential causes of thrombocytopenia for patients who do not show a trend toward improving platelet count within three to four days of heparin withdrawal. Other possible diagnoses and evaluations are described separately. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia", section on 'Differential diagnosis' and "Approach to the adult with unexplained thrombocytopenia" and "Drug-induced immune thrombocytopenia" and "Drug-induced thrombotic microangiopathy" and "Warfarin and other VKAs: Dosing and adverse effects", section on 'Skin necrosis'.)
Despite the rapid normalization of platelet counts and resolution of clinical HIT, HIT antibodies can persist for two to three months, depending on the assay used to detect them . This provides the rational for administering a non-heparin anticoagulant for at least two to three months. (See 'Duration of anticoagulation' above.)
AVOIDANCE OF HEPARIN FOR LIFE — Patients diagnosed with heparin-induced thrombocytopenia (HIT) based on clinical and laboratory data should avoid heparin (including low molecular weight [LMW] heparin) for life. This information should be conveyed to the patient, family members, and all individuals caring for the patient; and emphasized in the medical record, through the inclusion of "heparin allergy."
Sources of heparin include the following:
●Heparin flushes (eg, for arterial lines or heparin locks)
●Heparin-containing medications (eg, some forms of prothrombin complex concentrates [PCCs])
USE OF HEPARIN DURING CARDIOPULMONARY BYPASS — Patients may require cardiopulmonary bypass (CPB), with accompanying anticoagulation, following or during an episode of heparin-induced thrombocytopenia (HIT). Our approach to the management of procedures requiring anticoagulation depends on whether a functional assay for HIT antibodies is positive. The importance of using a functional assay rather than an immunoassay was demonstrated in a case report in which only a functional assay (and not an immunoassay) was sensitive to removal of HIT antibodies . (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia", section on 'HIT antibody testing'.)
CPB after history of HIT (HIT antibodies absent) — Patients with a history of HIT who require CPB have been successfully anticoagulated with a brief course of unfractionated heparin without complications. This approach is based on the observation that HIT antibodies are short-lived and do not often result in anamnestic responses when subsequently re-challenged.
This approach was applied in 10 patients with a history of HIT who required CPB . At the time of surgery, all patients were negative for HIT antibodies according to a PF4 solid phase immunoassay (ELISA). There were no complications of surgery, no prolonged thrombocytopenia, and no increase in the serum concentration of HIT antibodies during a 10-day post-operative period.
●Prove, using a sensitive assay for PF4-heparin antibodies, that these antibodies are no longer detectable. These antibodies usually disappear at a median time of 50 to 90 days following the last exposure to heparin, but a safer interval is >100 days . (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia", section on 'Timing'.)
●Restrict the use of unfractionated heparin to the operative procedure itself. Use alternative anticoagulants pre- and post-operatively if needed (eg, warfarin). Bivalirudin has been approved by the US Food and Drug Administration (FDA) for patients with, or at risk of, HIT who are undergoing percutaneous coronary intervention. However, there are concerns about how best to monitor use of this agent and that its use may be associated with a high incidence of bleeding in patients undergoing CPB . (See 'Bivalirudin' above.)
Of note, the use of low molecular weight (LMW) heparin is not recommended in patients with a history of HIT undergoing CPB, due to its longer half-life compared with unfractionated heparin as well as the inability to fully reverse its effect with protamine. (See "Heparin and LMW heparin: Dosing and adverse effects".)
CPB during an acute or subacute episode of HIT (HIT antibodies present) — Management is complex when CPB or other surgery requiring an anticoagulant is urgently required in a patient with acute HIT or subacute HIT (ie, in whom the platelet count has recovered but HIT antibodies are still present).
In a report of three patients with subacute HIT requiring urgent heart transplantation, re-exposure to unfractionated heparin was uneventful when it was shown that the patients tested negative for HIT by a sensitive functional assay using washed platelets (eg, heparin-induced platelet aggregation [HIPA]) . Heparin was discontinued and a direct thrombin inhibitor (argatroban or lepirudin) was used a few hours post-operatively in all three cases to prevent recurrence of thrombosis due to a longer exposure to heparin. Another case report demonstrated that exposure to heparin during CPB did not cause recurrence of HIT when a functional assay was negative after serial plasma exchange, despite a persistently positive immunoassay . (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia", section on 'HIT antibody testing'.)
Experience with intraoperative anticoagulation when cardiac or vascular surgery is urgently required in a patient with active HIT is similarly limited, and we manage these patients on a case-by-case basis. The following observations illustrate the range of potential scenarios:
●For urgent cardiac surgery, the 2012 American College of Chest Physician (ACCP) Guidelines suggest the use of bivalirudin over other non-heparin anticoagulants and over heparin plus antiplatelet agents .
●For urgent percutaneous coronary interventions, the 2012 ACCP Guidelines suggest the use of bivalirudin or argatroban over other non-heparin anticoagulants. (See "General principles of the use of intracoronary stents".)
●When CPB is urgently required, HIT antibodies are present, a sensitive functional assay is not available, and heparin is chosen as the anticoagulant, the use of intraoperative plasma exchange has been undertaken in order to reduce the titer of the HIT antibodies [65,66]. Additional experience will be required before a recommendation can be made for such treatment .
●Some patients have successfully undergone successful vascular procedures (eg, thrombectomy, embolectomy) with brief heparin anticoagulation or use of alternative anticoagulants .
PREVENTION — The best way to prevent heparin-induced thrombocytopenia (HIT) is to limit heparin exposure. Discussions of strategies to limit the duration of heparin exposure and the lower risk of HIT with low molecular weight (LMW) rather than unfractionated heparin in different clinical scenarios (eg, hip surgery) are presented separately. (See "Heparin and LMW heparin: Dosing and adverse effects" and "Clinical presentation and diagnosis of heparin-induced thrombocytopenia", section on 'Incidence and risk factors'.)
A baseline platelet count and periodic platelet count monitoring are used in most patients receiving heparin for more than four days. Details of monitoring are discussed separately. (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Platelet count monitoring'.)
HIT WITH BLEEDING — Bleeding is rare in patients with heparin-induced thrombocytopenia (HIT) because platelet counts are usually >20,000/microL. However, if bleeding occurs, platelet transfusion is appropriate. Platelet transfusions may also be appropriate for some patients who require an invasive procedure. This decision is individualized based on the patient's clinical status, platelet count, and expected bleeding risk. Further information regarding platelet transfusions is presented separately. (See "Clinical and laboratory aspects of platelet transfusion therapy", section on 'Indications for platelet transfusion' and "Clinical and laboratory aspects of platelet transfusion therapy", section on 'TTP or HIT'.)
Additional interventions for bleeding include the use of a reversal agent if the patient is still anticoagulated, and correction of surgical/anatomic defects. (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Bleeding'.)
In contrast to the treatment of bleeding, platelet transfusions and reversal agents generally are not used prophylactically (ie, for the routine prevention of bleeding) in patients with HIT, due to the low risk of bleeding in this syndrome and the possibility, although small, that additional platelets might precipitate thrombotic events (ie, "add fuel to the fire").
Support for the use of platelet transfusions in patients with bleeding in the setting of HIT comes from two reports (41 patients in total) that showed appropriate 24-hour post-transfusion platelet count increments in the majority, with cessation of bleeding in two-thirds of the bleeding patients [69,70].
Our approach is also supported by a large retrospective review that included 6332 patients with HIT, approximately 7 percent of whom received a platelet transfusion . There was a slight increase in the rate of arterial thrombosis in patients with HIT who received platelets compared with those who did not (6.9 versus 3.1 percent; absolute increase, 3.8 percent; adjusted OR, 3.4; 95% CI, 1.2-9.5). The rate of venous thrombosis was not different in those who received platelets and those who did not (adjusted OR 0.8; 95% CI 0.4-1.7). Of note, sicker patients were more likely to have received platelets, and the temporal relationship between platelet transfusion and thrombosis was not assessed. An earlier review of the literature revealed no case of a complication clearly attributable to platelet transfusion .
Our approach is consistent with the 2012 American College of Chest Physician (ACCP) Guidelines, which concluded that platelet transfusions can be considered in patients with HIT and overt bleeding or during the performance of an invasive procedure with a high bleeding risk, particularly if heparin has been stopped for at least several hours .
SUMMARY AND RECOMMENDATIONS
●We make a presumptive diagnosis of heparin-induced thrombocytopenia (HIT) based on clinical findings and immediately available laboratory data. The 4 T's score (calculator 1) is an easy-to-use score that quantifies the clinical findings associated with HIT (eg, degree of Thrombocytopenia, Timing, Thrombotic events or sequelae, alternative causes of thrombocytopenia). This score should be used as a guide but should not substitute for clinical judgement. (See 'Presumptive diagnosis of HIT' above and "Clinical presentation and diagnosis of heparin-induced thrombocytopenia", section on '4 T's score'.)
●We confirm or exclude the diagnosis of HIT using definitive data from HIT antibody testing. (See 'Confirmed diagnosis of HIT' above and "Clinical presentation and diagnosis of heparin-induced thrombocytopenia", section on 'Diagnosis'.)
●For all patients with a presumptive diagnosis of HIT and/or a confirmed diagnosis of HIT (eg, immunologic assay/ELISA with optical density >2.00 or positive functional assay), all forms of heparin should be discontinued. This includes unfractionated heparin, low molecular weight (LMW) heparin, heparin flushes, heparin-bonded catheters, and heparin-containing medications. (See 'Immediate discontinuation of heparin' above.)
●For all patients with a presumptive and/or confirmed diagnosis of HIT, we recommend immediate anticoagulation with a non-heparin anticoagulant (eg, argatroban, danaparoid, fondaparinux, bivalirudin, as available) rather than discontinuation of heparin alone, unless there is a strong contraindication to anticoagulation (eg, bleeding, high bleeding risk) (algorithm 1 and table 1) (Grade 1B). (See 'Initiation of a non-heparin anticoagulant' above.)
●A choice among these alternative non-heparin anticoagulants is largely made based upon the patient's renal and hepatic function (see 'Choice and dose of non-heparin anticoagulant' above):
•Any of these agents can be used in patients whose renal and hepatic functions are both normal.
●Warfarin can be started once the patient has been stably anticoagulated with a non-heparin anticoagulant and the platelet count has recovered to ≥150,000/microL. For patients transitioning to warfarin, low initial doses, rather than high "loading" doses, should be used. The non-heparin anticoagulant should be continued for at least five days along with warfarin and until the INR has reached the intended target range of 2.0 to 3.0. (See 'Transition to warfarin' above.)
●The duration of anticoagulation depends on the absence or presence of thrombosis. We suggest that patients with HIT be anticoagulated for at least two to three months in the absence of a thrombotic event, and for three to six months if a thrombotic event has occurred (Grade 2C). (See 'Duration of anticoagulation' above.)
●The importance of lifetime avoidance of heparin in an individual with HIT should be conveyed to the patient, family members, and all clinicians caring for the patient; it should also be emphasized in the medical record, through the inclusion of "heparin allergy." (See 'Avoidance of heparin for life' above.)
●One exception to lifetime avoidance of heparin is a patient with a history of HIT who requires cardiopulmonary bypass. Such individuals can sometimes be anticoagulated with heparin, provided that HIT antibodies are absent and the heparin exposure is limited to the operative procedure only. If HIT antibodies are present (eg, during an acute or subacute episode of HIT), management options include non-heparin anticoagulants and/or intraoperative plasma exchange. (See 'Use of heparin during cardiopulmonary bypass' above.)
- Warkentin TE. Heparin-induced thrombocytopenia: yet another treatment paradox? Thromb Haemost 2001; 85:947.
- Lubenow N, Eichler P, Lietz T, et al. Lepirudin for prophylaxis of thrombosis in patients with acute isolated heparin-induced thrombocytopenia: an analysis of 3 prospective studies. Blood 2004; 104:3072.
- Warkentin TE, Kelton JG. A 14-year study of heparin-induced thrombocytopenia. Am J Med 1996; 101:502.
- Wallis DE, Workman DL, Lewis BE, et al. Failure of early heparin cessation as treatment for heparin-induced thrombocytopenia. Am J Med 1999; 106:629.
- Warkentin TE, Greinacher A, Koster A, et al. Treatment and prevention of heparin-induced thrombocytopenia: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133:340S.
- Greinacher A. CLINICAL PRACTICE. Heparin-Induced Thrombocytopenia. N Engl J Med 2015; 373:252.
- Danhof M, de Boer A, Magnani HN, Stiekema JC. Pharmacokinetic considerations on Orgaran (Org 10172) therapy. Haemostasis 1992; 22:73.
- Kelton JG. The clinical management of heparin-induced thrombocytopenia. Semin Hematol 1999; 36:17.
- Warkentin TE. Heparin-induced thrombocytopenia: pathogenesis and management. Br J Haematol 2003; 121:535.
- www.hematology.org/Practice/Guidelines/11747.aspx (Accessed on January 07, 2014).
- Linkins LA. Heparin induced thrombocytopenia. BMJ 2015; 350:g7566.
- Scully M, Gates C, Neave L. How we manage patients with heparin induced thrombocytopenia. Br J Haematol 2016; 174:9.
- Kang M, Alahmadi M, Sawh S, et al. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood 2015; 125:924.
- Farner B, Eichler P, Kroll H, Greinacher A. A comparison of danaparoid and lepirudin in heparin-induced thrombocytopenia. Thromb Haemost 2001; 85:950.
- Mann MJ, Tseng E, Ratcliffe M, et al. Use of bivalirudin, a direct thrombin inhibitor, and its reversal with modified ultrafiltration during heart transplantation in a patient with heparin-induced thrombocytopenia. J Heart Lung Transplant 2005; 24:222.
- Nikolsky E, Dangas GD. Percutaneous interventions in patients with immune-mediated heparin-induced thrombocytopenia. Semin Thromb Hemost 2004; 30:305.
- Wisler JW, Washam JB, Becker RC. Evaluation of dose requirements for prolonged bivalirudin administration in patients with renal insufficiency and suspected heparin-induced thrombocytopenia. J Thromb Thrombolysis 2012; 33:287.
- Kiser TH, Fish DN. Evaluation of bivalirudin treatment for heparin-induced thrombocytopenia in critically ill patients with hepatic and/or renal dysfunction. Pharmacotherapy 2006; 26:452.
- Eichler P, Lubenow N, Strobel U, Greinacher A. Antibodies against lepirudin are polyspecific and recognize epitopes on bivalirudin. Blood 2004; 103:613.
- Clarke RJ, Mayo G, FitzGerald GA, Fitzgerald DJ. Combined administration of aspirin and a specific thrombin inhibitor in man. Circulation 1991; 83:1510.
- Sheth SB, DiCicco RA, Hursting MJ, et al. Interpreting the International Normalized Ratio (INR) in individuals receiving argatroban and warfarin. Thromb Haemost 2001; 85:435.
- Argatroban for treatment of heparin-induced thrombocytopenia. Med Lett Drugs Ther 2001; 43:11.
- Kodityal S, Nguyen PH, Kodityal A, et al. Argatroban for suspected heparin-induced thrombocytopenia: contemporary experience at a large teaching hospital. J Intensive Care Med 2006; 21:86.
- Levine RL, Hursting MJ, McCollum D. Argatroban therapy in heparin-induced thrombocytopenia with hepatic dysfunction. Chest 2006; 129:1167.
- Swan SK, Hursting MJ. The pharmacokinetics and pharmacodynamics of argatroban: effects of age, gender, and hepatic or renal dysfunction. Pharmacotherapy 2000; 20:318.
- Beiderlinden M, Treschan TA, Görlinger K, Peters J. Argatroban anticoagulation in critically ill patients. Ann Pharmacother 2007; 41:749.
- Lewis BE, Wallis DE, Leya F, et al. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Arch Intern Med 2003; 163:1849.
- Lewis BE, Wallis DE, Berkowitz SD, et al. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation 2001; 103:1838.
- Lewis BE, Wallis DE, Hursting MJ, et al. Effects of argatroban therapy, demographic variables, and platelet count on thrombotic risks in heparin-induced thrombocytopenia. Chest 2006; 129:1407.
- Linkins LA, Dans AL, Moores LK, et al. Treatment and prevention of heparin-induced thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e495S.
- Warkentin TE, Davidson BL, Büller HR, et al. Prevalence and risk of preexisting heparin-induced thrombocytopenia antibodies in patients with acute VTE. Chest 2011; 140:366.
- Blackmer AB, Oertel MD, Valgus JM. Fondaparinux and the management of heparin-induced thrombocytopenia: the journey continues. Ann Pharmacother 2009; 43:1636.
- Baroletti S, Labreche M, Niles M, et al. Prescription of fondaparinux in hospitalised patients. Thromb Haemost 2009; 101:1091.
- Warkentin TE, Pai M, Sheppard JI, et al. Fondaparinux treatment of acute heparin-induced thrombocytopenia confirmed by the serotonin-release assay: a 30-month, 16-patient case series. J Thromb Haemost 2011; 9:2389.
- Goldfarb MJ, Blostein MD. Fondaparinux in acute heparin-induced thrombocytopenia: a case series. J Thromb Haemost 2011; 9:2501.
- Lobo B, Finch C, Howard A, Minhas S. Fondaparinux for the treatment of patients with acute heparin-induced thrombocytopenia. Thromb Haemost 2008; 99:208.
- Grouzi E, Kyriakou E, Panagou I, Spiliotopoulou I. Fondaparinux for the treatment of acute heparin-induced thrombocytopenia: a single-center experience. Clin Appl Thromb Hemost 2010; 16:663.
- Cegarra-Sanmartín V, González-Rodríguez R, Paniagua-Iglesias P, et al. Fondaparinux as a safe alternative for managing heparin-induced thrombocytopenia in postoperative cardiac surgery patients. J Cardiothorac Vasc Anesth 2014; 28:1008.
- Selleng K, Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia in intensive care patients. Crit Care Med 2007; 35:1165.
- Magnani HN. Heparin-induced thrombocytopenia (HIT): an overview of 230 patients treated with orgaran (Org 10172). Thromb Haemost 1993; 70:554.
- Chong BH, Ismail F, Cade J, et al. Heparin-induced thrombocytopenia: studies with a new low molecular weight heparinoid, Org 10172. Blood 1989; 73:1592.
- Wilhelm MJ, Schmid C, Kececioglu D, et al. Cardiopulmonary bypass in patients with heparin-induced thrombocytopenia using Org 10172. Ann Thorac Surg 1996; 61:920.
- Sodian R, Loebe M, Gorman KF, et al. Heparin induced thrombocytopenia. Experiences in 12 heart surgery patients. ASAIO J 1997; 43:M430.
- Gillis S, Merin G, Zahger D, et al. Danaparoid for cardiopulmonary bypass in patients with previous heparin-induced thrombocytopenia. Br J Haematol 1997; 98:657.
- Doherty DC, Ortel TL, de Bruijn N, et al. "Heparin-free" cardiopulmonary bypass: first reported use of heparinoid (Org 10172) to provide anticoagulation for cardiopulmonary bypass. Anesthesiology 1990; 73:562.
- Walenga JM, Jeske WP, Wallis DE, et al. Clinical experience with combined treatment of thrombin inhibitors and GPIIb/IIIa inhibitors in patients with HIT. Semin Thromb Hemost 1999; 25 Suppl 1:77.
- Walenga JM, Prechel M, Jeske WP, et al. Rivaroxaban--an oral, direct Factor Xa inhibitor--has potential for the management of patients with heparin-induced thrombocytopenia. Br J Haematol 2008; 143:92.
- Krauel K, Hackbarth C, Fürll B, Greinacher A. Heparin-induced thrombocytopenia: in vitro studies on the interaction of dabigatran, rivaroxaban, and low-sulfated heparin, with platelet factor 4 and anti-PF4/heparin antibodies. Blood 2012; 119:1248.
- Fieland D, Taylor M. Dabigatran use in a postoperative coronary artery bypass surgery patient with nonvalvular atrial fibrillation and heparin-PF4 antibodies. Ann Pharmacother 2012; 46:e3.
- Tardy-Poncet B, Piot M, Montmartin A, et al. Delayed-onset heparin-induced thrombocytopenia without thrombosis in a patient receiving postoperative thromboprophylaxis with rivaroxaban. Thromb Haemost 2015; 114:652.
- Shatzel JJ, Crapster-Pregont M, Deloughery TG. Non-vitamin K antagonist oral anticoagulants for heparin-induced thrombocytopenia. A systematic review of 54 reported cases. Thromb Haemost 2016; 116:397.
- Warkentin TE, Elavathil LJ, Hayward CP, et al. The pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopenia. Ann Intern Med 1997; 127:804.
- Srinivasan AF, Rice L, Bartholomew JR, et al. Warfarin-induced skin necrosis and venous limb gangrene in the setting of heparin-induced thrombocytopenia. Arch Intern Med 2004; 164:66.
- Potzsch B, Unkrig C, Madlener K, et al. APC resistance and early onset of oral anticoagulation are high thrombotic risk factors in patients with heparin-associated thrombocytopenia (HAT). Ann Hematol 1996; 72 (Suppl I):A6.
- Alving BM. How I treat heparin-induced thrombocytopenia and thrombosis. Blood 2003; 101:31.
- Watson HG, Keeling DM, BCSH Taskforce in Haemostasis and Thrombosis. The management of heparin-induced thrombocytopenia. Br J Haematol 2006; 135:269.
- Warkentin TE, Kelton JG. Temporal aspects of heparin-induced thrombocytopenia. N Engl J Med 2001; 344:1286.
- Warkentin TE, Sheppard JA, Chu FV, et al. Plasma exchange to remove HIT antibodies: dissociation between enzyme-immunoassay and platelet activation test reactivities. Blood 2015; 125:195.
- Pötzsch B, Klövekorn WP, Madlener K. Use of heparin during cardiopulmonary bypass in patients with a history of heparin-induced thrombocytopenia. N Engl J Med 2000; 343:515.
- Warkentin TE. Heparin-induced thrombocytopenia: a clinicopathologic syndrome. Thromb Haemost 1999; 82:439.
- Follis F, Schmidt CA. Cardiopulmonary bypass in patients with heparin-induced thrombocytopenia and thrombosis. Ann Thorac Surg 2000; 70:2173.
- Wanaka K, Matsuo T, Matsuo M, et al. Re-exposure to heparin in uremic patients requiring hemodialysis with heparin-induced thrombocytopenia. J Thromb Haemost 2010; 8:616.
- Dyke CM, Smedira NG, Koster A, et al. A comparison of bivalirudin to heparin with protamine reversal in patients undergoing cardiac surgery with cardiopulmonary bypass: the EVOLUTION-ON study. J Thorac Cardiovasc Surg 2006; 131:533.
- Selleng S, Haneya A, Hirt S, et al. Management of anticoagulation in patients with subacute heparin-induced thrombocytopenia scheduled for heart transplantation. Blood 2008; 112:4024.
- Kajitani M, Aguinaga M, Johnson CE, et al. Use of plasma exchange and heparin during cardiopulmonary bypass for a patient with heparin induced thrombocytopenia: a case report. J Card Surg 2001; 16:313.
- Welsby IJ, Um J, Milano CA, et al. Plasmapheresis and heparin reexposure as a management strategy for cardiac surgical patients with heparin-induced thrombocytopenia. Anesth Analg 2010; 110:30.
- Despotis GJ, Avidan MS. Plasma exchange for heparin-induced thrombocytopenia: is there enough evidence? Anesth Analg 2010; 110:7.
- Warkentin TE, Pai M, Cook RJ. Intraoperative anticoagulation and limb amputations in patients with immune heparin-induced thrombocytopenia who require vascular surgery. J Thromb Haemost 2012; 10:148.
- Hopkins CK, Goldfinger D. Platelet transfusions in heparin-induced thrombocytopenia: a report of four cases and review of the literature. Transfusion 2008; 48:2128.
- Refaai MA, Chuang C, Menegus M, et al. Outcomes after platelet transfusion in patients with heparin-induced thrombocytopenia. J Thromb Haemost 2010; 8:1419.
- Goel R, Ness PM, Takemoto CM, et al. Platelet transfusions in platelet consumptive disorders are associated with arterial thrombosis and in-hospital mortality. Blood 2015; 125:1470.