Critical Care Medicine

HIT Syndrome (heparin-induced thrombocytopenia with thrombosis)

1. Description of the problem

  • Heparin-induced thrombocytopenia (HIT) is a potentially fatal immunologic complication of heparin therapy.

  • The cardinal clinical manifestations are a fall in the platelet count and an increased propensity for thromboembolism in the setting of a proximate heparin exposure.

  • Management involves immediate discontinuation of heparin and initiation of an alternate parenteral anticoagulant to prevent or treat thrombosis.

See Table I: Clinical features that support a diagnosis of HIT.

Table I.

Clinical features that support a diagnosis of HIT
Feature Comments
Fall in platelet count >50%. From highest platelet count after heparin exposure; platelet count fall is 30-50% in 10% of cases.
Fall in platelet count begins 5-14 days after heparin exposure.  
Fall in platelet count begins within 24 hours of heparin exposure. In patients with a previous recent heparin exposure, usually within the last 30 days.
Nadir platelet count >/=20 x 109/L. May be <20 x 109/L in cases associated with DIC. 
Venous or arterial thrombosis.  
Skin necrosis. At subcutaenous heparin injection sites.
Absence of alternative causes of thrombocytopenia. Such as infection, other medications known to cause thrombocytopenia, recent cardiopulmonary bypass, etc. 
Absence of petechiae and other significant bleeding.  

2. Emergency Management

  1. Stop all heparin immediately, including heparin flushes. Remove heparin-coated catheters.

  2. Initiate an alternative parenteral anticoagulant.

  3. Do not start an oral anticoagulant until the platelet count has normalized. If the patient is on warfarin at the time HIT is diagnosed, it should be reversed with vitamin K.

  4. Avoid prophylactic platelet transfusions.

3. Diagnosis

The diagnosis of HIT is based on:

  1. An assessment of clinical probability.

  2. Laboratory testing.

Clinical diagnosis

See Table II: The 4 T's: A clinical probability model.

Table II.

The 4 T's: A clinical probability model
4 T's 2 Points 1 Point 0 Points
Thrombocytopenia Platelet count fall >50% and platelet nadir >20 x 109/L. Platelet count fall 30-50% or platelet nadir 10-19 x 109/L. Platelet count fall <30% or platelet nadir <10 x 109/L.
Timing of platelet count fall Clear onset between days 5-14 or platelet fall <1 day (prior heparin exposure within 30 days). Consistent with days 5-14, but not clear (e.g. missing platelet counts) or onset after day 14 or fall <1 day (prior heparin exposure within 30-100 days). Platelet count fall <5 days without recent prior exposure.
Thrombosis or other sequelae New thrombosis (confirmed); skin necrosis at heparin injection sites; anaphylactoid reaction after IV heparin bolus. Progressive or recurrent thrombosis (confirmed); non-necrotizing (erythematous) skin lesions; suspected thrombosis (not confirmed).  None.
The causes of thrombocytopenia None apparent. Possible. Definite.

Laboratory diagnosis

Laboratory assays for HIT fall into 2 categories - immunologic and functional. (See Table III)

Table III.

Laboratory assays for HIT
Assay category Mechanism Examples Sensitivity Specificity Comments
Immunologic Detects antibodies against PF4/heparin, regardless of their capacity to activate platelets. HIT ELISA >95% 80-90% OD of ELISA directly correlates with clinical probability of HIT.
Functional Detects antibodies that induce heparin-dependent platelet activation. SRA, HIPA >90% >90% Not available at many centers; may require referral to a reference laboratory.

Diagnostic and initial treatment algorithm

I. HIT suspected

A. Low clinical probability ⇒ HIT unlikely; continue heparin; consider alternative diagnoses

B. Intermediate/high clinical probability ⇒ Discontinue heparin; start alternative parenteral anticoagulant; obtain immunologic assay

II. Immunologic assay

A. Negative; intermediate clinical probability ⇒ HIT unlikely; resume heparin; consider alternative diagnoses

B. Negative; high clinical probability ⇒ HIT indeterminate

C. Positive ⇒ Obtain functional assay

III. Functional assay

A. Negative ⇒ HIT indeterminate

B. Positive ⇒ HIT likely

Adapted from Cuker A & Crowther MA, 2009 American Society of Hematology Clinical Practice Guideline on the Evaluation and Management of Heparin-Induced Thrombocytopenia.

Differential diagnosis

The differential diagnosis includes other conditions that cause thrombocytopenia in hospitalized patients:

  1. Non-heparin drugs known to cause thrombocytopenia (e.g. antibiotics, glycoprotein IIb/IIIa antagonists, quinine, etc.).

  2. Infection.

  3. Disseminated intravascular coagulation (DIC).

  4. Recent cardiopulmonary bypass.

  5. Presence of an indwelling intra-arterial device (e.g. intra-aortic balloon pump, extracorporeal membrane oxygenation, ventricular assist device).

  6. Post-transfusion purpura.

4. Specific Treatment

Parenteral anticoagulant therapy

Treatment of HIT involves immediate discontinuation of heparin and initiation of a parenteral non-heparin anticoagulant to treat and/or prevent thrombotic complications. Parenteral anticoagulant options, including their initial dosing, monitoring and clearance, are summarized in Table IV.

Table IV.

Parenteral anticoagulants for the treatment of HIT
  Weight <60 kg → 1500 U      
  Weight 60-75 kg → 2250 U      
  Weight 75-90 kg → 3000 U      
  Weight >90 kg → 0 U      
Danaparoid1      
  Accelerated initial infusion: Adjust to anti-Xa level of 0.5-0.8 U/ml. Renal (24 hrs)
  400 U/hr x 4 hrs, then 300 U/hr x 4 hrs    
  Maintenance infusion:    
  Normal renal function → 200 U/hr    
  Renal insufficiency → 150 U/hr    
  Bolus:    
  None    
  Continuous infusion:    
Argatroban   Adjust to APTT of 1.5-3.0 times patient baseline. Monitor APTT every 4 hours during dose titration. Hepatobiliary (40-50 mins)
  Normal organ function → 2 mcg/kg/min    
  Liver dysfunction (total serum bilirubin >1.5 mg/dl), heart failure, post-cardiac surgery, anasarca → 0.5-1.2 mcg/kg/min    
  Bolus:    
  None.    
  Continuous infusion:    
  Bivalirudin3    
  Bivalirudin3 Adjust to APTT of 1.5-2.5 times patient baseline. Enzymatic and renal (25 mins)
  Normal organ function → 0.15 mg/kg/hr    
  Renal or hepatic insufficiency → dose reduction may be necessary    
  <50 kg → 5 mg SC daily    
  50-100 kg → 7.5 mg SC daily None Renal (17-20 hrs)
  >100 kg → 10 mg SC daily    
Fondaparinux4      
  ClCr 30-50 ml/min → use caution      
  ClCr <30 ml/min → contraindicated    

A major risk associated with approved agents is bleeding. The incidence of major hemorrhage with argatroban is ~1%/day. This risk is compounded by lack of an available reversal agent. Therefore, patients receiving these agents should be closely monitored for bleeding.

Platelet transfusion

Prophylactic platelet transfusion in HIT is discouraged because:

  1. There is a theoretical risk of precipitating thrombosis.

  2. The bleeding risk in HIT is low.

Therefore, routine prophylactic platelet transfusion should generally be avoided. Platelet transfusion may be appropriate in situations of diagnostic uncertainty, high bleeding risk or clinically significant bleeding.

Transitioning to oral anticoagulant

Patients with acute HIT treated with warfarin are at risk of venous gangrene, a severe thrombotic complication of the microvasculature that may lead to ischemia and gangrene of the extremities.

The following measures should be employed in all patients with acute HIT to prevent venous gangrene:

  1. For patients on warfarin at the time of HIT diagnosis, warfarin should be immediately discontinued and its effects reversed with vitamin K.

  2. Warfarin should not be initiated until the platelet count reaches a stable plateau.

  3. The initial warfarin dose should be </= 5 mg/day. Larger loading doses should be avoided.

  4. A parenteral non-heparin anticoagulant should be overlapped with warfarin for >/= 5 days and until the INR has reached the intended target.

Because argatroban raises the INR, the following protocol is recommended when transitioning a patient from argatroban to warfarin (See Table V).

Table V.

An algorithm for transitioning from argatroban to warfarin
Argatroban dose (mcg/kg/min)  
</= 2 Stop argatroban when INR is >4 on combined argatroban and warfarin.Repeat INR in 4-6 hrs.If INR is <2, restart argatroban.Repeat procedure daily until INR >/=2 is achieved.
>2 Reduce argatroban dose to 2 mcg/kg/min.Repeat INR in 4-6 hrs.Stop argatroban when INR is >4 on combined argatroban and warfarin.Repeat INR in 4-6 hrs.If INR is <2, restart argatroban.Repeat procedure daily until INR >/=2 is achieved.

A direct oral anticoagulant (e.g., dabigatran, rivaroxaban, apixaban, edoxaban) may be used as an alternative warfarin. As with warfarin, the direct oral anticoagulant should not be started until the platelet count has normalized. However, it is not necessary to overlap a parenteral antcoagulant with a direct oral anticoagulant.

5. Disease monitoring, follow-up and disposition

Duration of anticoagulation

  • Duration of anticoagulation depends on whether thrombosis is present.

  • Patients with HIT-associated thrombosis should be anticoagulated for a defined course (typically 3-6 months) as with other thromboses provoked by a transient risk factor.

  • For patients with HIT without thrombosis (isolated HIT), the optimal duration of anticoagulation is unknown. The risk of thrombosis in this population is greatest during the platelet recovery phase. Therefore, anticoagulation should be given at least until the platelet count recovers to a stable plateau.

  • Bilateral lower extremity compression ultrasonography should be considered in all patients with HIT whether or not there is clinical evidence of lower-limb deep vein thrombosis (DVT) because the finding of DVT may influence the recommended duration of anticoagulation.

Heparin re-exposure in patients with a history of HIT

Certain properties of heparin, including its short half-life, ease of monitoring, availability of an antidote and familiarity to clinicians, make its use highly desirable in certain settings, such as cardiac/vascular surgery and cardiac catheterization.

HIT laboratory testing may be used to determine the safety of exposing a patient with a history of HIT to intraoperative heparin in these settings. If pre- or post-operative anticoagulation is indicated, a non-heparin anticoagulant should be used.

Cardiac and vascular surgery

See Table VI and Table VII.

Table VI.

Suggestions for intraoperative anticoagulation in patients with a history of HIT who require cardiovascular surgery
Clinical picture Immunologic assay Functional assay Intraoperative anticoagulation
Remote HIT Negative Negative Use unfractionated heparin.
Subacute HIT Positive Negative Delay surgery, if possible, until immunologic assay becomes negative.If surgery cannot be delayed, consider unfractionated heparin.
Acute HIT Positive Positive Delay surgery, if possible, until immunologic and functional assays become negative.If surgery cannot be delayed, use bivalirudin.

Table VII.

Suggestions for intraprocedural anticoagulation in patients with a history of HIT who require coronary angiography
Clinical picture Immunologic assay Functional assay Intraprocedural anticoagulation
Remote HIT Negative Negative Use a non-heparin anticoagulant such as bivalirudin.if a non-heparin anticoagulant is not available, use unfractionated heparin.
Subacute HIT Positive Negative Use a non-heparin anticoagulant such as bivalirudin.if a non-heparin anticoagulant is not available, use unfractionated heparin.
Acute HIT Positive Positive Use a non-heparin anticoagulant such as bivalirudin.

Cardiac catheterization

See Table VII.

Pathophysiology

  • HIT is an immunologic adverse reaction to heparin therapy.

  • The target antigen in HIT is a novel epitope within platelet factor 4 (PF4).

  • PF4 is a positively charged platelet chemokine that is released by activated platelets onto the platelet surface.

  • In the presence of appropriate concentrations of heparin, PF4 binds to and forms large multimolecular complexes with heparin. As these PF4/heparin complexes form, PF4 undergoes a conformational change that exposes a cryptic PF4 epitope to the immune system.

  • Susceptible hosts make antibodies to this epitope. It is these antibodies that are detected by immunologic assays for HIT, such as the HIT ELISA.

  • A minority of anti-PF4/heparin antibodies, primarily of the IgG class, have the capacity to activate platelets and cause HIT. While the Fab fragment of these antibodies binds to PF4/heparin complexes on the platelet surface, the Fc portion of the molecule engages Fc receptors on the platelet, thereby activating it. It is these antibodies, which have the capacity to activate platelets in the presence of heparin, that are detected by functional assays for HIT such as the serotonin release assay.

  • Activated platelets in turn release more PF4, setting up a vicious cycle of PF4/heparin complex formation, antibody binding and unchecked platelet activation.

  • The end result is a pronounced thrombotic tendency.

Epidemiology

  • The incidence of HIT in patients receiving unfractionated heparin (UFH) for 5 or more consecutive days is 1-5% depending on the patient population.

  • The risk is approximately 10-fold lower in individuals treated with low molecular weight heparin (LMWH) for a similar duration.

In addition to heparin type (UFH vs. LMWH), other risk factors for development of HIT include age, gender and patient type.

  1. Age: The incidence of HIT increases with age. HIT is very rare among children and young adults.

  2. Gender: HIT is more common in women than men. In a large meta-analysis, women were approximately twice as likely to develop HIT as men (RR 2.4, 95% CI 1.4-4.1).

  3. Patient type: Surgical patients are at greater risk of HIT then medical patients (RR 3.2, 95% CI 2.0-5.4). HIT is uncommon in medical and surgical intensive care units; one study found an overall incidence of 0.4% in this population. HIT is also very rare among pregnant women receiving heparin.

Prognosis

  • In historical series, approximately half of untreated HIT patients suffered thromboembolism, limb amputation, or death in the month following heparin cessation.

  • Treatment with an alternative parenteral anticoagulant reduces the incidence of these endpoints by approximately 55-60%.

Special considerations for nursing and allied health professionals.

Eliminate patient exposure/contact with heparin, which includes all heparin flushes and any heparin-coated catheters. If a catheter is in place, it should be removed immediately.

What's the evidence?

Linkins, LA, Dans, AL, Moores, LK. "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. vol. 141. 2012. pp. e495S-530S.

(Evidence-based guidelines on the management of HIT.)

Warkentin, TE, Kelton, JG. "Temporal aspects of heparin-induced thrombocytopenia". N Engl J Med. vol. 344. 2001 Apr 26. pp. 1286-92.

(This observational study helped define the timing of the fall in platelet count in relation to heparin exposure in patients with both typical-onset and rapid-onset HIT.)

Warkentin, TE, Roberts, RS, Hirsh, J, Kelton, JG. "An improved definition of immune heparin-induced thrombocytopenia in postoperative orthopedic patients". Arch Intern Med. vol. 163. 2003 Nov 10. pp. 2518-24.

(An analysisof the degree of fall in the platelet count in patients with HIT.)

Warkentin, TE, Kelton, JG. "A 14-year study of heparin-induced thrombocytopenia". Am J Med. vol. 101. 1996 Nov. pp. 502-7.

(A retrospective review of the incidence of venous and arterial thromboembolism in patients with HIT.)

Warkentin, TE. "Heparin-induced skin lesions". Br J Haematol. vol. 92. 1996 Feb. pp. 494-7.

(A description of six patients with HIT-associated skin necrosis and a review of the literature.)

Schindewolf, M, Kroll, H, Ackermann, H, Garbaraviciene, J, Kaufmann, R. "Heparin-induced non-necrotizing skin lesions: rarely associated with heparin-induced thrombocytopenia". J Thromb Haemost.. vol. 8. 2010 Jul. pp. 1486-91.

(An observational study of patients with erythematous non-necrotizing skin lesions at subcutaneous heparin injection sites showing that such lesions are generally due to a delayed type IV hypersensitivity reaction and not to HIT diagnosis.)

Napolitano, LM, Warkentin, TE, Almahameed, A, Nasraway, SA. "Heparin-induced thrombocytopenia in the critical care setting: diagnosis and management". Crit Care Med.. vol. 34. 2006 Dec. pp. 2898-911.

(A thorough review on HIT in the intensive care unit with a focus on diagnosis.)

Lo, GK, Juhl, D, Warkentin, TE, Sigouin, CS, Eichler, P, Greinacher, A. "Evaluation of pretest clinical score (4 T's) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings". J Thromb Haemost.. vol. 4. 2006 Apr. pp. 759-65.

(A prospective study demonstrating the negative predictive value of the 4 T's.)

Cuker, A, Arepally, G, Crowther, MA, Rice, L, Datko, F. "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 Sep 20. pp. 1538-7836.

(Description of an alternative clinical scoring model for HIT that outperformed the 4 T's in a retrospective analysis.)

Warkentin, TE. "Platelet count monitoring and laboratory testing for heparin-induced thrombocytopenia". Arch Pathol Lab Med.. vol. 126. 2002 Nov. pp. 1415-23.

(An authoritative review on the laboratory diagnosis of HIT with evidence-based recommendations.)

Warkentin, TE, Sheppard, JI, Moore, JC, Sigouin, CS, Kelton, JG. "Quantitative interpretation of optical density measurements using PF4-dependent enzyme-immunoassays". J Thromb Haemost.. vol. 6. 2008 Aug. pp. 1304-12.

(Single institution study documenting the relationship between the optical densityvalue of the HIT ELISAand the likelihood of a positive serotonin release assay.)

Zwicker, JI, Uhl, L, Huang, WY, Shaz, BH, Bauer, KA. "Thrombosis and ELISA optical density values in hospitalized patients with heparin-induced thrombocytopenia". J Thromb Haemost.. vol. 2. 2004 Dec. pp. 2133-7.

(Retrospective cohort study showing the relationship between the HIT ELISA optical density value and the risk of thrombosis in patients with suspected HIT.)

Sheridan, D, Carter, C, Kelton, JG. "A diagnostic test for heparin-induced thrombocytopenia". Blood. vol. 67. 1986 Jan. pp. 27-30.

(The initial description and performance evaluation of the serotonin release assay.)

Arepally, GM, Ortel, TL. "Clinical practice. Heparin-induced thrombocytopenia". N Engl J Med. vol. 355. 2006 Aug 24. pp. 809-17.

(Excellent review of HIT with useful recommendations for diagnosis and initial management.)

Cuker, A, Crowther, MA. 2009 clinical practice guideline on the evaluation and management of heparin-induced thrombocytopenia (HIT). http://www.hematology.org/Practice/Guidelines/2934.aspx.

(Evidence-based guidelines on the diagnosis and treatment of HIT.)

Cuker, A, Gimotty, PA, Crowther, MA, Warkentin, TE. "Predictive value of the 4Ts scoring systems for heparin-induced thrombocytopenia: a systematic review and meta-analysis". Blood. vol. 120. 2012. pp. 4160-7.

(A meta-analysis on the predictive value of the 4Ts score.)

Crowther, M, Cook, D, Guyatt, G. "Heparin-induced thrombocytopenia in the critically ill: interpreting the 4Ts test in a randomized trial". J Crit Care. vol. 29. 2014. pp. 470.e7-15.

(A study of the diagnostic accuracy of the 4Ts score in critically ill patients.)

Nagler, M, Bachmann, LM, Ten Cate, H, Ten Cate-Hoek, A. "Diagnostic value of immunoassays for heparin-induced thrombocytopenia: a systematic review and meta-analysis". Blood. vol. 127. 2016. pp. 546-557.

(A meta-analysis on the diagnostic accuracy of immunoassays for HIT.)

Chong, BH, Gallus, AS, Cade, JF, Magnani, H, Manoharan, A. "Australian HIT Study Group. Prospective randomised open-label comparison of danaparoid with dextran 70 in thetreatment of heparin-induced thrombocytopaenia with thrombosis: a clinical outcome study". Thromb Haemost. vol. 86. 2001 Nov. pp. 1170-5.

(A randomized controlled trial demonstrating the efficacy of danaparoid in the management of HIT.)

Lewis, BE, Wallis, DE, Hursting, MJ, Levine, RL, Leya, F. "Effects of argatroban therapy, demographic variables, and platelet count on thrombotic risks in heparin-induced thrombocytopenia". Chest.. vol. 129. 2006 Jun. pp. 1407-16.

(A pooled analysis of two prospective studies of argatroban for the treatment of HIT.)

Kiser, TH, Fish, DN. "Evaluation of bivalirudin treatment for heparin-induced thrombocytopenia in critically ill patients with hepatic and/or renal dysfunction". Pharmacotherapy.. vol. 26. 2006 Apr. pp. 452-60.

Joseph, L, Casanegra, AI, Dhariwal, M. "Bivalirudin for the treatment of patients with confirmed or suspected heparin-induced thrombocytopenia". J Thromb Haemost. vol. 12. 2014. pp. 1044-53.

(Single center series demonstrating feasibility of treatment with bivalirudin including patients with critical illness and organ dysfunction.)

Warkentin, TE, Pai, M, Sheppard, JI. "Fondaparinux treatment of acute heparin-induced thrombocytopenia confirmed by the serotonin release assay: a 30-month, 16-patient case series". J Thromb Haemost. vol. 9. 2011. pp. 2389-96.

Schindewolf, M, Steindl, J, Beyer-Westendorf, J. "Frequent off-label use of fondaparinux in patients with suspected acute heparin-induced thrombocytopenia (HIT) - findings from the GerHIT multi-centre registry study". Thromb Res. vol. 134. 2014. pp. 29-35.

(Observational studies supporting the efficacy and safety of fondaparinux for HIT.)

Hopkins, CK, Goldfinger, D. "Platelet transfusions in heparin-induced thrombocytopenia: a report of four cases and review of the literature". Transfusion. vol. 48. 2008 Oct. pp. 2128-32.

(A case series and review on the role of platelet transfusion inthe managementof HIT.)

Srinivasan, AF, Rice, L, Bartholomew, JR, Rangaswamy, C, La Perna, L. "Warfarin-induced skin necrosis and venous limb gangrene in the setting of heparin-induced thrombocytopenia". Arch Intern Med. vol. 164. 2004 Jan 12. pp. 66-70.

(A case series of warfarin-induced venous gangrene in patients with acute HIT.)

Sheth, SB, DiCicco, RA, Hursting, MJ, Montague, T, Jorkasky, DK. "Interpreting the international normalized ratio (INR) in individuals receiving argatroban and warfarin". Thromb Haemost.. vol. 85. 2001 Mar. pp. 435-40.

(Prospective assessment of the effect of argatroban on INR in patients co-treated with argatroban and warfarin.)

Watson, HG, Keeling, DM. "The management of heparin-induced thrombocytopenia". Br J Haematol. vol. 135. 2006. pp. 269.

(Expert recommendations on the treatment of HIT, including duration of anticoagulation.

Potzsch, B, Klovekorn, WP, Madlener, K. "Use of heparin during cardiopulmonary bypass in patients with a history of heparin-induced thrombocytopenia [letter]". N Engl. Med. vol. 343. 2000. pp. 515.

(A case series of 10 patients with a history of remote HITwho received intraoperative heparin for cardiac surgery without clinical or laboratory evidence of recurrent HIT.)

Selleng, S, Haneya, A, Hirt, S, Selleng, K, Schmid, C. "Management of anticoagulation in patients with subacute heparin-induced thrombocytopenia scheduled for heart transplantation". Blood.. vol. 112. 2008. pp. 4024-7.

(A case report of 3 patients with subacute HIT, who were treated with intraoperative heparin for cardiac surgery without evidence of recurrent HIT.)

Visentin, GP, Ford, SE, Scott, JP, Aster, RH. "Antibodies from patients with heparin-induced thrombocytopenia/thrombosis are specific for platelet factor 4 complexed with heparin or bound to endothelial cells". J Clin Invest. vol. 93. 1994 Jan. pp. 81-8.

(In this study of plasma samples from patients with HIT,PF4 complexed withheparin is identified as the target antigenof the HIT immuneresponse.)

Rauova, L, Poncz, M, McKenzie, SE, Reilly, MP, Arepally, G. "Ultralarge complexes of PF4 and heparin are central to the pathogenesis of heparin-induced thrombocytopenia". Blood. vol. 105. 2005 Jan 1. pp. 131-8.

(This study shows that ultra-large multimolecular complexes of PF4/heparin underlie HIT pathogenesis and that these complexes form over a relatively narrow concentration ofPF4 and heparin.)

Newman, PM, Chong, BH. "Heparin-induced thrombocytopenia: new evidence for the dynamic binding of purified anti-PF4-heparin antibodies to platelets and the resultant platelet activation". Blood. vol. 96. 2000 Jul 1. pp. 182-7.

(In vitro studies demonstrating the capacity of anti-PF4/heparin IgG in patients with HIT to induce platelet activation and promote further PF4 release.)

Martel, N, Lee, J, Wells, PS. "Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis". Blood. vol. 106. 2005 Oct 15. pp. 2710-5.

(Large meta-analysis on the incidence of HIT among medical and surgical patients treated with unfractionated heparin and low molecular weight heparin.)

Warkentin, TE, Levine, MN, Hirsh, J, Horsewood, P, Roberts, RS. "Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin". N Engl J Med. vol. 332. 1995 May 18. pp. 1330-5.

(A comparison of the incidence of HIT in a randomized controlled trial of unfractionated heparin vs. low molecular weight heparin for thromboprophylaxis following hip surgery.)

Warkentin, TE, Sheppard, JA, Sigouin, CS, Kohlmann, T, Eichler, P. "Gender imbalance and risk factor interactions in heparin-induced thrombocytopenia". Blood. vol. 108. 2006 Nov 1. pp. 2937-41.

(A pooled analysis of seven prospective studies demonstratinga greater incidence of HIT in females than in males and a greater risk of HIT associated with use of unfractionated heparin than with lowmolecular weight heparin.)

Crowther, MA, Cook, DJ, Albert, M, Williamson, D, Meade, M. "The 4Ts scoring system for heparin-induced thrombocytopenia in medical-surgical intensive care unit patients". J Crit Care.. vol. 25. 2010 Jun. pp. 287-93.

(A prospectiveanalysisin critically ill patientsdemonstrating the low incidence of HIT and the potential utility of a pre-testprobability scoring system for ruling out HITin this population.)
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