> Table of Contents > Heparin-Induced Thrombocytopenia
Heparin-Induced Thrombocytopenia
Tipsuda Junsanto-Bahri, MD
Maria A. Pino, PhD, MS, RpH
image BASICS
DESCRIPTION
  • Unexplained decrease in platelet count in a patient treated with heparin
    • Minimum platelet count falls between 30 and 50% from baseline.
  • Antibody-mediated prothrombotic disorder initiated by heparin administration
  • Unlike other thrombocytopenias, heparin-induced thrombocytopenia (HIT) is an idiosyncratic reaction that produces thrombosis rather than bleeding.
  • Two types: nonimmune heparin-associated thrombocytopenia (previously called HIT type I) and HIT (immune induced; previously called HIT type II)
    • Nonimmune heparin-associated thrombocytopenia: more common, onset 1 to 4 days after starting heparin, mild thrombocytopenia (>100,000), few complications
    • HIT: less common, onset 5 to 14 days after primary exposure to heparin, thrombocytopenia often <100,000 but usually >20,000; high risk of thrombosis
      • Presentation of thrombocytopenia can be immediate with recent heparin exposure (within past 100 days).
EPIDEMIOLOGY
Incidence
  • 10-15% of heparin-treated patients will experience decrease in platelet count.
  • 0.3-3% will develop HIT.
ETIOLOGY AND PATHOPHYSIOLOGY
  • Nonimmune heparin-associated thrombocytopenia: potentially a result of direct platelet membrane binding with heparin
  • HIT: Heparin can cause an increase in the blood concentration of platelet factor 4 (PF4), a chemokine. PF4 will form a complex with heparin.
  • Heparin/PF4 complex can, in turn, stimulate the production of specific antiheparin/PF4 complex antibodies. These antibodies cause platelet activation and a prothrombotic state. Ultimately, this hypercoagulable state leads to thromboembolic complications in many patients.
RISK FACTORS
  • Postsurgical > medical > obstetric
    • Postcardiopulmonary bypass is the most significant risk factor.
  • Bovine unfractionated heparin (UFH) > porcine UFH > low-molecular-weight heparin (LMWH)
  • Female > male
  • Heparin duration >4 days
GENERAL PREVENTION
  • Inquire about recent heparin exposure and any history of HIT.
  • Use of LMWH (vs. unfractionated), for a shorter duration, reduce the risk of developing HIT.
  • Properly document past HIT reactions in patient's medical record. Develop a HIT recognition and treatment protocol (1)[A].
  • No form of heparin should be administered once the diagnosis of HIT is confirmed.
COMMONLY ASSOCIATED CONDITIONS
  • Venous thrombosis: deep venous thrombosis (DVT), pulmonary embolism (PE), adrenal vein thrombosis with hemorrhagic infarction
  • Arterial thrombosis
  • Skin lesions (skin necrosis at site of injection)
  • Acute systemic reactions
image DIAGNOSIS
  • Nonimmune heparin-associated thrombocytopenia: asymptomatic drop in platelet count
  • HIT: thrombocytopenia or thrombosis with the presence of heparin-dependent antibodies
    • The foundation for diagnosis is based on both clinical and serologic findings.
PHYSICAL EXAM
  • Signs of venous or arterial thrombosis
  • Skin necrosis (begins with erythema, progresses to ecchymosis and necrosis)
  • Ischemic changes (signs of limb, renal, splenic, mesenteric ischemia)
  • Bleeding (less common)
  • Acute systemic reactions after IV bolus of heparin (e.g., signs of anaphylaxis)
DIFFERENTIAL DIAGNOSIS
Other potential causes of thrombocytopenia include (list is not all-inclusive)
  • Sepsis and other infections
  • Drug reactions
  • Autoimmune
  • Transfusion reactions
  • Physical destruction (e.g., during cardiopulmonary bypass)
DIAGNOSTIC TESTS & INTERPRETATION
  • Serial platelet counts in patients receiving heparin who have a possible risk of HIT >1%: Check platelets at baseline and then every 2 to 3 days from days 4 to 14 of heparin therapy (3)[B]:
    • Withhold platelet monitoring for patients receiving heparin with risk of HIT <1%
  • Confirmatory lab tests needed for a clinical diagnosis can be divided into two major categories:
    • Antigen assay to detect presence of HIT antibodies:
      • ELISA: up to 99% sensitive, poor specificity; thus, has an excellent negative predictive value for HIT
    • Functional assay to detect evidence of platelet activation in the presence of heparin:
      • Serotonin release assay (SRA), gold standard for diagnosis: high specificity and high sensitivity
      • Heparin-induced platelet activation (HIPA): high specificity and low sensitivity
  • Antigenic assay should be the initial test.
    • Either a functional assay or an antigenic assay alone may not be adequate for clinical diagnosis; their use in combination is usually recommended.
  • The diagnostic interpretation of these laboratory tests must be made in the context of the clinical estimation of the pretest probability because HIT is a clinicopathologic syndrome. Patients may form heparin-dependent antibodies and still not develop HIT.
image TREATMENT
Treatment is by prompt withdrawal of heparin and replacement with a suitable alternative anticoagulant.
GENERAL MEASURES
  • Discontinue all heparin products, including flushes and heparin-coated catheters.
  • All patients with a diagnosis of HIT should receive alternative anticoagulation as they are of high thrombotic risk.
  • Nonimmune heparin-associated thrombocytopenia generally resolves when heparin is stopped:
    • Consider a nonheparin alternative such as fondaparinux if pharmacologic DVT prophylaxis is warranted (3)[C].
  • Platelet transfusions can increase thrombosis. Give platelet transfusions only if bleeding or during an invasive procedure with a high risk of bleeding.
  • Warfarin should not be administered until platelet recovery. If warfarin has been administered, vitamin K should be given (reference, Warkentin TE).
  • Adverse reaction to heparin should be clearly documented in the medical record with instruction to avoid all heparin products.
  • For patients with a documented history of HIT, under special circumstances only (such as the need for cardiopulmonary bypass), the use of heparin for a short duration may be acceptable if the absence of heparin/PF4 complex antibodies can be documented. Patients who develop antibodies to the heparin/PF4 complex have a significantly higher rate of postoperative thrombotic events than patients who lack these antibodies (4)[B].
MEDICATION
  • Most patients require anticoagulation because of
    • Preexisting thrombosis or
    • Risk of thrombosis during 30 days after HIT diagnosis (consider anticoagulation for 30 days)
  • Dosing of anticoagulant depends on indication (prophylaxis vs. treatment):
    • In cases with a clinically low suspicion/pretest probability of HIT and laboratory confirmation is pending, it may be appropriate to continue antithrombotic prophylaxis using nonheparin anticoagulants.
    • In cases with high suspicion/pretest probability of HIT and laboratory confirmation is pending, it is appropriate to begin anticoagulation treatment with a nonheparin product (5)[B].
  • P.463

  • Direct thrombin inhibitors (DTIs) (argatroban and bivalirudin)
    • Reduce relative risk of thrombosis by 30% and are associated with a 5-10% risk of important bleeding.
    • Can produce misleading elevation in international normalized ratio (INR) (most likely an in vitro reaction)
      • Argatroban > bivalirudin (3)[B]
    • Argatroban
      • Initial dose, 2 &mgr;g/kg/min by continuous IV infusion; decrease dose with reduced hepatic function or with critical illness.
      • Dose adjustments based to achieve activated partial thromboplastin time (aPTT) 1.5 to 3 times the baseline.
    • Bivalirudin
      • Favorable pharmacologic profile; however, evidence for use is insufficient compared to argatroban (limited to case series).
      • Reduced risk of bleeding in patients undergoing percutaneous artery interventions (PCIs) and other cardiac procedures
      • Initial dose of 0.15 mg/kg/hr followed by adjustments to keep aPTT 1.5 to 2.5 times the baseline. Reduced dose with renal insufficiency (creatinine clearance [CrCl] <30 mL/min)
      • Dose adjustments based on aPTT
  • Factor Xa inhibitor (fondaparinux)
    • Reports of its use are theorized to be useful; however, minimal data support its efficacy for HIT, and an ideal dose has yet to be determined.
    • Association with the development of HIT has been reported.
    • Optional agent for thromboembolic prophylaxis when practitioner wants to avoid heparin
    • Contraindicated in patients with renal dysfunction (CrCl <30 mL/min) (5)[C]
  • Warfarin
    • Must anticoagulate with an immediate-acting agent before starting warfarin
    • Use of warfarin without other anticoagulants should be avoided because it can cause thrombosis.
    • Begin warfarin after platelet count is >150,000.
    • Discontinue other anticoagulant and continue only warfarin after INR is therapeutic (2 to 3) for at least 5 days. This management differs from the normal heparin-to-warfarin transition in other conditions requiring anticoagulation (5,6)[C].
  • LMWH
    • Although LMWH has a lower risk of initiating a HIT reaction, it should not be used when antibodies are already present. These antibodies can cross-react with LMWH and induce thrombosis and thrombocytopenia.
INPATIENT CONSIDERATIONS
Nursing
  • Avoid heparin flushes.
  • Avoid platelet transfusion.
  • Clearly document reaction in all medical records to control the future use of heparin.
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
  • The transition period of anticoagulation with a DTI and warfarin in patients with HIT can be problematic.
  • The INR while administering both a DTI and warfarin should be therapeutic (2 to 3) for at least 5 days before discontinuing the DTI.
  • Warfarin therapy should not be commenced until the platelet count has stabilized within a normal range.
  • Warfarin therapy should continue for a minimum of 3 months.
  • DTIs can prolong INR; therefore, if INR is <4 while on both warfarin and a DTI, temporarily hold the DTI for 4 to 6 hours and recheck INR; this second INR will represent only the anticoagulant effect of warfarin.
  • Monitor use of concurrent drugs with warfarin.
Patient Monitoring
  • Serial platelet counts
  • Monitor PTT or INR as determined by the anticoagulation agent.
PATIENT EDUCATION
  • Patient should inform all health care providers of any previous adverse reaction to heparin.
  • HIT information available at: http://medlibrary.org/medwiki/Heparin-induced_thrombocytopenia
PROGNOSIS
  • Thrombosis in HIT has 20-30% mortality, with additional morbidity from stroke and limb ischemia.
  • Platelet counts normalize within weeks after stopping heparin.
  • Risk of delayed thrombosis, especially in the first 30 days
REFERENCES
1. Smythe MA, Mehta TP, Koerber JM, et al. Development and implementation of a comprehensive heparin-induced thrombocytopenia recognition and management protocol. Am J Health Syst Pharm. 2012;69(3):241-248.
2. Cuker A, Arepally G, Crowther MA, et al. The HIT Expert Probability (HEP) Score: a novel pre-test probability model for heparin-induced thrombocytopenia based on broad expert opinion. J Thromb Haemost. 2010;8(12):2642-2650.
3. Bakchoul T, Greinacher A. Recent advances in the diagnosis and treatment of heparin-induced thrombocytopenia. Ther Adv Hematol. 2012;3(4):237-251.
4. Zhang R, Huang Y, Zhang M, et al. Serum antibodies to the heparin/platelet factor 4 complex are an independent predictor of thrombotic complications following pediatric fontan surgery. Clin Appl Thromb Hemost. 2012;18(5):448-452.
5. 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(2 Suppl):e495S-e530S.
6. Shantsila E, Lip GY, Chong BH. Heparin-induced thrombocytopenia: a contemporary clinical approach to diagnosis and management. Chest. 2009;135(6):1651-1664.
Additional Reading
&NA;
  • Dager WE, Dougherty JA, Nguyen PH, et al. Heparin-induced thrombocytopenia: treatment options and special considerations. Pharmacotherapy. 2007;27(4):564-587.
  • Lo GK, Juhl D, Warkentin TE, et al. Evaluation of pretest clinical score (4 T's) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost. 2006;4(4):759-765.
  • Stone GW, Ware JH, Bertrand ME, et al. Antithrombotic strategies in patients with acute coronary syndromes undergoing early invasive management: one-year results from the ACUITY trial. JAMA. 2007;298(21):2497-2506.
  • Warkentin TE. Heparin-induced thrombocytopenia: diagnosis and management. Circulation. 2004;110(18):e454-e458.
  • Warkentin TE, Greinacher A, Craven S, et al. Differences in the clinically effective molar concentrations of four direct thrombin inhibitors explain their variable prothrombin time prolongation. Thromb Haemost. 2005;94(5):958-964.
  • Warkentin TE, Maurer BT, Aster RH. Heparin-induced thrombocytopenia associated with fondaparinux. N Engl J Med. 2007;356(25):2653-2655.
Codes
&NA;
ICD10
D75.82 Heparin induced thrombocytopenia (HIT)
Clinical Pearls
&NA;
  • Heparin exposure through virtually any preparation (including LMWH), any dose, or any route can cause HIT, a life-threatening condition which is associated with severe and extensive thromboembolism.
  • LMWH is contraindicated in HIT; although LMWH is less likely to cause HIT. Once HIT is present, the antibodies will cross-react and continue to cause a HIT reaction.
  • If a patient is suspected of HIT (with or without confirmatory testing), immediately discontinue all forms of heparin.
  • Patients will require anticoagulation either because of preexisting thrombosis or the risk of thrombosis in first 30 days after HIT.
  • A direct thrombin inhibitor (DTI) should be used until a patient's INR is therapeutic (2 to 3) on warfarin for at least 5 days.
  • The key to avoiding sequelae from HIT is awareness, vigilance, and a high degree of suspicion.