Over 12 Million Patients Receive Heparin Annually: 600k new HIT cases each year
HIT Occurs in Up to 5% of Patients Exposed to Heparin for >4 Days
Risk Factors
Dose/Route of Heparin Exposure
HIT Can Occur with Any Heparin Dose, Schedule, or Route of Administration (Subcutaneous or Intravenous)
Therapeutic Heparin Dosing Has a Higher Risk of HIT (0.76% of Cases), as Compared to Prophylactic Heparin Dosing (<0.1% of Cases) (Chest, 2007) [MEDLINE]
However, HIT Can Occur with Any Dose of Heparin: cases of HIT have been reported in patients with heparin-coated catheters
Very High Doses of Heparin May Be Associated with Lower Risk of HIT (As Occurs During Cardiopulmonary Bypass), as Compared to Therapeutic Heparin Dosing
Type of Heparin Exposure
HIT Can Occur with Any Heparin Dose, Schedule, or Route of Administration (Subcutaneous or Intravenous)
Patients treated with low molecular weight heparin can develop HIT with prior exposure to either unfractionated or low molecular weight heparin: frequency of HIT was higher in those previously exposed to heparins of any type (Blood, 2005) [MEDLINE]
Risk of HIT is Less with Low Molecular Weight Heparins in Surgical Patient Populations (But Not in Medical Patient Populations)
HIT occurs in 2.6% % of unfractionated heparin-treated surgical patients [MEDLINE]
HIT occurs in 0.2% of low molecular weight heparin-treated surgical patients [MEDLINE]
Fondaparinux: HIT is less common with Fondaparinux (as a matter of fact, some cases of HIT have been treated with Fondaparinux)
Meta-analyses suggest that the relative risks of HIT with unfractionated vs low molecular weight heparins are comparable in medical patients (Chest, 2007) [MEDLINE]
Sex
Female Sex Carries a 2.37x-Fold Increased Risk of HIT (Blood, 2006) [MEDLINE]: unclear reasons
Female Predominance of HIT is Observed Only in Those Receiving Unfractionated Heparin (as Opposed to low Molecular Weight Heparin): with the highest risk observed in female surgical patients
Age
Unclear if Older Age is a Risk fFactor for HIT: studies are currently lacking
HIT is Very Rare in Children
Surgery
General Comments
Risk of HIT is Higher in Surgical Patients (Likely Related to Vascular Trauma), as Compared to Medical Patients (Blood, 2006) [MEDLINE]
Cardiopulmonary Bypass Patients Have Multiple Exposures to Heparin, Receipt of High Heparin Doses, and/or Receipt of Heparin for Prolonged Periods of Time
Incidence
HIT Occurs in 1% of Cardiopulmonary Bypass Cases (Blood, 2000) [MEDLINE]
Timing of Thrombocytopenia
Thrombocytopenia Which Occurs Between 5-10 Days Post-Cardiac Surgery is Highly Predictive for HIT (J Thromb Haemost, 2010) [MEDLINE]
In Contrast, Early-Onset and Persistent Thrombocytopenia is Usually Caused by Non-HIT Mechanisms (Coinciding with Heparin-Dependent Antibody Seroconversion)
Orthopedic Surgery
Orthopedic Surgery Patiens Have Multiple Exposures to Heparin, Receipt of High Heparin Doses, and/or Receipt of Heparin for Prolonged Periods of Time
Incidence
HIT Occurs in 4.9% of Orthopedic Patients Treated with Unfractionated Heparin (Blood, 2000) [MEDLINE]
HIT Occurs in 0.9% of Orthopedic Patients Treated with Low Molecular Weight Heparin (Blood, 2000) [MEDLINE]
Vascular Surgery
Vascular Surgery Patients Have Multiple Exposures to Heparin, Receipt of High Heparin Doses, and/or Receipt of Heparin for Prolonged Periods of Time
Cardiology/Interventional Cardiology Patients
Cardiology/Interventional Cardiology Patients Have Multiple Exposures to Heparin, Receipt of High Heparin Doses, and/or Receipt of Heparin for Prolonged Periods of Time
Presence of Inherited Hypercoagulable States
Risk of HIT is Not Higher in Patients with Inherited Hypercoagulability (Such as Factor V Leiden and Prothrombin Gene Mutation)
Physiology
Formation of Heparin-Dependent IgG Antibodies to Platelet Factor 4 Complexed with Heparin
Latency of Antibody Formation: formation of heparin-induced antibodies is believed to take at least 4 days of exposure to heparin
However, there are rare cases where the antibodies can form in the absence of heparin exposure: in these cases, an inflammatory stimulus or exposure to non-heparin polyanions may be involved
While heparin-induced IgM and IgA antibodies can also develop, IgG is thought to be the only pathogenic antibody (since the platelet surface Fc receptor only recognizes IgG)
Interestingly, naturally-occurring antibodies against platelet factor 4 complexed to heparin exist in 3-8% of the general population without HIT: these may develop when platelet factor 4 binds to negatively-charged polysaccharides on bacteria, creating an antigen in platelet factor 4 that mimics platelet factor 4 complexed to heparin (and this may explain why some patients have rapid development of heparin-induced antibodies following heparin exposure)
Necessity of Presence of Heparin for Heparin-Induced Antibody Binding: it is believed that the binding of heparin (or other polyanions) induce a conformational change in platelet factor 4 protein, resulting in a neoantigen, to which the heparin-induced antibodies bind
Therefore, heparin-induced antibodies only cause clinical symptoms when heparin is present
Heparin-Induced Antibody Binding to Platelet Factor 4-Heparin Complexes on the Platelet Surface
Fc region of the antibody is captured by the Fc receptor on the surface of the same or adjacent platelets -> platelet activation -> further platelet factor released from platelet alpha granules
Clinical Variability Based Upon Molecular Parameters
Optimal 1:1 Molar Ratio of Platelet Factor 4 Tetramer/Heparin Molecules: results in the formation of more ultralarge complexes (and is more imunogenic) and is related to the severity of clinical sequelae
This may explain why patients treated with high doses of heparin (as are used during cardiopulmonary bypass) are less likely to develop HIT than those exposed to standard doses of heparin
Type of Heparin: heparins vary in their ability to produce the optimal 1:1 ratio of platelet factor 4 tetamer/heparin molecules (this ratio results in formation of more ultralarge complexes)
HIT occurs in 2.6% of unfractionated heparin-treated patients (ultralarge complexes form most efficiently with unfractionated heparin) [MEDLINE]
HIT occurs in 0.2% of low molecular weight heparin-treated patients (ultralarge complex formation is 10x less efficient with low molecular weight heparin, as compared to unfractionated heparin) [MEDLINE]
Fondaparinux (Arixtra) (see Fondaparinux): HIT is less common with fondaparinux (ultralarge complex formation is negligible with fondaparinux, as it has no affinity for platelet factor 4)
Patients with Larger Amounts of Circulating or Platelet Surface-Bound Platelet Factor 4: have a higher risk and severity of HIT
Titer of Heparin-Induced Antibody: high titer antibodies that react with platelet factor 4 bound to non-heparin glycosaminoglycans (such as chondroitin sulfate) may explain the occurrence of HIT in patients who have never been exposed to heparin or in those who develop delayed-onset HIT after heparin withdrawal
Mechanisms of Thrombocytopenia
Removal of IgG-Coated Platelets by Reticuloendothelial System Macrophages in Spleen/Liver/Bone Marrow: similar to other types of drug-induced thrombocytopenia
Platelet Consumption in Thrombi
Mechanisms of Arterial and Venous Thrombosis
Endothelial Cell Activation
Endothelial Cell Injury Due to Binding of HIT Antibodies to Endothelial Heparan Sulfate: leads to increased tissue factor and thrombin generation
Endothelial Cell Release of Adhesion Molecules: such as IL-6 and vWF
Heparin-Induced Antibody Activation of Monocytes
Heparin-Induced Antibody Alteration of Other Aspects of the Coagulation Cascade: such as deceased activated protein C generation, etc
Platelet Activation
Release of Platelet Microparticles (Fragments from Platelet Membrane): these catalyze clot formation
Release of Procoagulant Substances from Activated Platelets
Formation of Heparin-Induced Antibodies (Detectable by Laboratory Assays) Without Clinical Thrombocytopenia and HIT (Blood, 2000) [MEDLINE]
Heparin-Induced Antibodies May Occur with Heparin Exposure
Cardiopulmonary Bypass Patients Treated with Unfractionated Heparin (see Cardiopulmonary Bypass,)
Days of Treatment: 5.1 +/- 2.2 days
Frequency of Heparin-Induced Antibodies: 20% (by activation assay) or 50% (by antigen assay)
Frequency of Clinical HIT: 1% of cases
Orthopedic Patients Treated with Unfractionated Heparin
Days of Treatment: 9.2 +/- 2.2 days
Frequency of Heparin-Induced Antibodies: 9.3% (by activation assay) or 14.1% (by antigen assay)
Frequency of Clinical HIT: 4.9% of cases
Orthopedic Patients Treated with Low Molecular Weight Heparin
Days of Treatment: 9.5 +/- 3.0 days
Frequency of Heparin-Induced Antibodies: 3.2% (by activation assay) or 7.5% (by antigen assay)
Frequency of Clinical HIT: 0.9% of cases
Heparin-Induced Antibodies May Occur Without Heparin Exposure
Principle: ELISA assay used to detect the presence of heparin-induced anti-platelet factor 4 antibody in patient’s serum
Solid-Phase ELISA
Most Commonly Used Test for HIT
Principle of Assay: detects presence of anti-platelet factor 4 antibodies in serum
Accuracy
Sensitivity: 91 to >97%
Specificity: low
False-Positive Test Results (Usually with Lower OD Values) Can Occur in the Setting of Anti-Phospholipid Antibody Syndrome and Systemic Lupus Erythematosus (SLE)
ELISA Assay Cut-Off Values and Corresponding Serotonin Release Assay Result (J Thromb Haemost, 2008) [MEDLINE]
OD <0.40: SRA positive in 0.0 to 0.1% of cases
OD 0.40 to <1.00: SRA positive in 1-5% of cases
OD 1.00 to <1.40: SRA positive in 18-30% of cases
OD 1.40 to <2.00: SRA positive in 19-46% of cases
OD >2.00: SRA positive in 89-100% of cases
Impact of Renal Failure on Immunoassays
Heparin-Induced Antibodies are More Frequently Detected in the Setting of Renal Failure: they are found in 20% of patients during the first 90 days after hemodialysis (and by 6 mo, 9% of patiets of patients on hemodialysis or peritoneal dialysis have positive heparin-induced antibodies)
Functional Assays
General Comments
Principle of Assay: assay designed to measure the ability of heparin-induced antibody from patient’s serum to activate test platelets
Serotonin Release Assay (SRA)
Considered the Gold Standard Test
Principle: measures platelet activation by detecting the release of serotonin from test platelets in the presence of patient’s serum and heparin
Interpretation: <20% release -> negative
Accuracy
Positive-Predictive Value: 100%
Negative-Predictive Value: 80%
Heparin-Induced Platelet Aggregation (HIPA)
Principle of Assay: platelets or platelet-rich plasma from healthy donors is added to serum or platelet-poor plasma from a patient with suspected HIT -> platelet aggregation is measured in the absence of heparin and in the presence of low and high heparin concentrations
Criteria for Positive HIPA: minimal platelet aggregation in the absence of heparin and in the presence of high heparin concentrations (10 to 100 units/mL) and strong aggregation in the presence of low heparin concentrations (0.1 to 0.3 units/mL)
Accuracy
Sensitivity: low
Specificity: >90%
Clinical Subtypes of Heparin-Induced Thrombocytopenia (HIT)
Heparin-Induced Thrombocytopenia-Type I
Epidemiology: occurs in 10-20% of patients
Mechanism: non-antibody-mediated, non-immune type of HIT (due to platelet activation and sequestration)
Latency: thrombocytopenia occurs 1-4 days after starting heparin
Clinical Severity: less severe (platelet count rarely falls <100k)
One should consider the diagnosis of HIT in any patient with a decrease in platelet count >50% from baseline
Thromboembolic Events: absent
Hemorrhagic Events: absent
Treatment: observation (without discontinuation of heparin)
Prognosis: self-limited -> platelet counts generally recover, despite continuation of heparin
Heparin-Induced Thrombocytopenia-Type II (aka Heparin-Induced Thrombocytopenia and Thrombosis, HITT)
Epidemiology: occurs in 1-3% of patients
Reaction is idiosyncratic, not dose-dependent
Mechanism: antibody-mediated, immune type of HIT (due to antibody against platelet factor 4 complexed to heparin)
Latency: thrombocytopenia usually occurs around 4-7 days after starting heparin (may appear sooner in cases where patient has been exposed to heparin within the last 3 mo)
Clinical Severity: more severe (platelet counts may fall to around 60k)
One should consider the diagnosis of HIT in any patient with a decrease in platelet count >50% from baseline
Thromboembolic Events: 30-80% of cases
Arterial Thrombosis
Venous Thrombosis
Hemorrhagic events: rare
Treatment: cessation of heparin and use of alternative anticoagulation agent (see below)
Clinical Scoring Systems
4 T’s Scoring System (Am J Hematol, 2008) [MEDLINE]
Scoring System
General Comments
4 T’s
Thrombocytopenia
Timing of Thrombocytopenia
Thrombosis
Absence of Other Causes of Thrombocytopenia
4 T’s Scoring System Has Been Clinically Validated with Unfractionated Heparin: although it has not been validated with low molecular weight heparin, it can also be used for these patients
Thrombocytopenia
Platelet Count fall <30% or Nadir <10k: 0 points
Platelet Count fall 30-50% or Nadir 10-19k: 1 points
Platelet Count fall >50% and Nadir ≥20k: 2 points
Timing of Platelet Count Fall
Platelet Count Fall at <4 days Without Recent Exposure: 0 points
Consistent with Fall at 5-10 Days but Unclear (eg: Missing Platelet Counts), Onset After Day 10, or Fall ≤1 Day with Prior Heparin Exposure Within 30-100 Days: 1 point
Clear Onset Between Days 5-10 or Platelet Count fFall at ≤1 day if Prior Heparin Exposure Within the last 30 Days: 2 points
Thrombosis or Other Sequelae
None: 0 points
Progressive or Recurrent Thrombosis, Non-Necrotizing (Erythematous) Skin Lesions, or Suspected Thrombosis That Has Not Been Proven: 1 point
Confirmed New Thrombosis, Skin Necrosis, or Acute Systemic Reaction After Intravenous Unfractionated Heparin Bolus: 2 points
Other Causes of Thrombocytopenia
Definite: 0 points
Possible: 1 point
None Apparent: 2 points
Interpretation
Low Probability: 0-3 pts
Intermediate Probability: 4-5 pts
High Probability: 6-8 pts
Clinical Efficacy
Evaluation of 4T’s Scoring for Heparin-Induced Trombocytopenia (J Oncol Pharm Pract, 2010) [MEDLINE]
Using the 4T’s Scoring System, Patients at Low Risk Were More Likely to Receive Initial Inappropriate Therapy and Were More Likely to Have a Negative ELISA Test Result
Lillo-Le Louet Model
Used exclusively for assessment of thrombocytopenia in the post-cardiopulmonary bypass setting (has not been clinically validated)
HIT Expert Probability (HEP) Score
Scoring system based on broad expert opinion (has not been clinically validated)
Epidemiology: most common manifestation (occurs in 85-90% of cases)
Severity of Thrombocytopenia
Decrease in Platelet Count of >50% From Baseline: common
Approximately 5% of Cases Lack True Thrombocytopenia (with Platelet Count Remaining >150k), But Demonstrate a 30-50% Decrease in the Platelet Count from Baseline (Chest, 2012) [MEDLINE]
Mean Nadir in Platelet Count: 60k
Platelet Count <20k: rare
Therefore, Bleeding is Rare
Latency of Onset of Thrombocytopenia
Typical Onset of Thrombocytopenia: 5-10 days after heparin initiation (heparin antibodies usually develop between 5-8 days after heparin exposure, rarely develop later)
Early Onset of Thrombocytopenia: may occur within 24 hrs (mean: 10.5 hrs after initiation) in patients previously exposed to heparin in the prior 100 days (and have circulating heparin-induced antibodies)
Delayed Onset of Thrombocytopenia Following Heparin Withdrawal: incidence is unknown
Onset of HIT may occur as long as 40 days after stopping heparin (Ann Intern Med, 2002) [MEDLINE]
In one study, patients had high-titer heparin-induced antibodies (which manifested increased heparin-dependent as well as heparin-independent platelet activation) [MEDLINE]: may explain why HIT occurred in the absence of heparin
Timing of Thrombocytopenia in Relation to Thrombotic Events: thrombocytopenia often precedes onset of thrombotic events
Other Manifestations
Thrombosis
General Comments
Thrombosis occurs in 50% of HIT cases
Thrombosis is the presenting finding in 25% of HIT cases
Venous Thrombosis: 20-50% of HIT cases manifest venous thrombosis
Adrenal Hemorrhage (see Adrenal Hemorrhage): due to adrenal vein involvement
Cardiac Vein Thrombosis: due to cardiac vein involvement
Deep Venous Thrombosis (DVT) (see Deep Venous Thrombosis): due to lower extremity vein involvement
Limb Ischemia/Gangrene with Associated Skin Necrosis (see Limb Ischemia): reported with coumadin monotherapy of HIT-related DVT [MEDLINE]
Skin Necrosis (see Heparin): due to involvement of skin veins
Thrombocytopenia (see Thrombocytopenia): may be absent in some cases (despite clinical and laboratory evidence of HIT)
Prognosis: may be fatal
Clinical: Spontaneous HIT (Autoimmune HIT)
Definition: HIT-like, transient prothrombotic thrombocytopenic disorder without proximate heparin exposure -> considered controversial
Epidemiology: most cases had preceding infectious or inflammatory event (gram-negative bacteremia, orthopedic surgery)
Diagnosis: serologically indistinguishable from HIT
Cases described manifested tested strongly positive for anti-platelet factor 4/heparin immunoglobulin IgG in 2 different immunoassays and in the serotonin-release assay [MEDLINE]
Sera from the two cases also caused strong (>80%) serotonin release in the absence of heparin, a serologic feature characteristic of delayed-onset HIT (where heparin use precedes HIT but is not required for subsequent development or worsening of the thrombocytopenia) [MEDLINE]
Treatment
HIT Type I
Cessation and Avoidance of Heparins + Use of Non-Heparin Anticoagulation
Chest 2012 Antithrombotic Therapy and Prevention of Thrombosis Guidelines (9th ed) [MEDLINE]: stop heparin and use non-heparin anticoagulant, as described below (grade 1C)
HIT Type II (aka Heparin-Induced Thrombocytopenia and Thrombosis, HITT)
Cessation and Avoidance of Heparins For Life
Cross-Reactivity of Low Molecular Weight Heparin with Unfractionated Heparin: 80-90% cross-reactivity
Heparin Cessation Alone is Insufficient
Anticoagulation with a non-heparin anticoagulant is recommended
Without appropriate treatment, HIT patients have a 52.8% risk of developing new thrombosis within 30 days after stopping heparin [MEDLINE]
Risk of thrombosis is 5-10% per day within the first week following discontinuation of heparin [MEDLINE]
Additionally, the risk of thrombosis persists even after platelet count returns to normal
Chest 2012 Antithrombotic Therapy and Prevention of Thrombosis Guidelines (9th ed) [MEDLINE]: one of the recommended agents for HIT (although it is not FDA approved for HIT)
Coumadin (see Coumadin): per Chest 2012 Antithrombotic Therapy and Prevention of Thrombosis Guidelines (9th ed) [MEDLINE]
Avoid coumadin monotherapy in HIT, as it may precipitate skin necrosis or venous gangrene of limbs (grade 1C)
After anticoagulation with non-heparin anticoagulant is therapeutic, start coumadin (at low dose, max: 5 mg) only after after the platelet count recovers to >150k (grade 1C)
If coumadin is present at time of HIT diagnosis, vitamin K should be given (grade 2C)
Overlap between non-heparin anticoagulant and coumadin should be at least 5 days and until INR is within the target range (grade 1C)
Additionally, INR should be rechecked after non-heparin anticoagulant has been discontinued: this is due to the fact that 21% of patients with INR >3 while on argatroban + coumadin had a subtherapeutic INR 4 hrs after stopping argatroban
An alternative strategy: once platelets have recovered to >150k, switch argatroban to fondaparinux, then start transition to coumadin (as fondaparinux does not influence the INR or PTT)
Use of Platelet Transfusions in Heparin-Induced Thrombocytopenia
Chest 2012 Antithrombotic Therapy and Prevention of Thrombosis Guidelines (9th ed) [MEDLINE]: platelet transfusion is only recommended to treat active bleeding or to facilitate an invasive procedure with a high-risk of bleeding (grade 2C)
Resolution of Thrombocytopenia and Heparin-Induced Antibodies
Platelet count usually recovers within 7 days after stopping heparin
However, heparin-induced antibodies may persist for 2-3 mo
Special Clinical Situations (per Chest 2012 Antithrombotic Therapy and Prevention of Thrombosis Guidelines (9th ed) [MEDLINE])
Need for Cardiac Surgery or Percutaneous Coronary Intervention
Acute HIT (Thrombocytopenic + Heparin Antibody-Positive)/Subacute HIT (Not Thrombocytopenic, But Heparin Antibody-Positive) with Urgent Need for Cardiac Surgery: use bivalirudin (grade 2C)
Acute HIT (Thrombocytopenic + Heparin Antibody-Positive) with Non-Urgent Need for Cardiac Surgery: delay surgery until HIT has resolved and heparin antibodies are negative (grade 2C)
History of HIT (with Negative Heparin Antibodies) with Need for Cardiac Surgery: use heparin (short-term only), as heparin-induced antibodies are short-lived and do not frequently result in anamnestic responses when the patient is subsequently re-challenged
History of HIT (with Positive Heparin Antibodies) with Need for Cardiac Surgery: use non-heparin anticoagulant
Acute HIT (Thrombocytopenic + Heparin Antibody-Positive)/Subacute HIT (Not Thrombocytopenic, But Still Heparin Antibody-Positive)/History of HIT with Need for Percutaneous Coronary Intervention: use bivalirudin or argatroban (grade 2C)
Other Clinical Scenarios
Acute HIT (Thrombocytopenic + Heparin Antibody-Positive)/Subacute HIT (Not Thrombocytopenic, But Still Heparin Antibody-Positive) with Need for Continuous Veno-Venous Hemodiaylsis (Continuous Renal Replacement Therapy, CRRT): use danaparoid or argatroban (grade 2C)
History of HIT with Acute Thrombosis (Not Related to HIT) and Normal Renal Function: use fondaparinux until transition to coumadin can be achieved (grade 2C)
Pregnancy
Acute HIT (Thrombocytopenic + Heparin Antibody-Positive)/Subacute HIT (Not Thrombocytopenic, But Still Heparin Antibody-Positive) during Pregnancy: use danaparoid (grade 2C)
Alternative agents (either may be used if danaparoid is not available): lepirudin or fondaparinux
References
Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med 1995; 332:1330-1335
A 14-year study of heparin-induced thrombocytopenia. Am J Med. 1996 Nov;101(5):502-7 [MEDLINE]
The pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopenia. Ann Intern Med. 1997 Nov 1;127(9):804-12 [MEDLINE]
Impact of the patient population on the risk for heparin-induced thrombocytopenia. Blood 2000; 96:1703 [MEDLINE]
Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest 2001; 119:64S-94S
Delayed-onset heparin-induced thrombocytopenia and thrombosis. Ann Intern Med. 2001 Oct 2;135(7):502-6 [MEDLINE]
Delayed-onset heparin-induced thrombocytopenia. Ann Intern Med. 2002 Feb 5;136(3):210-5 [MEDLINE]
Heparin-induced thrombocytopenia: pathogenesis and management. Br J Haematol 2003; 121:535-555
Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Arch Intern Med 2003; 163:1849-1856
Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis. Blood. 2005 Oct 15;106(8):2710-5. Epub 2005 Jun 28 [MEDLINE]
The incidence of heparin-induced thrombocytopenia in medical patients treated with low-molecular-weight heparin: a prospective cohort study. Blood. 2005 Nov 1;106(9):3049-54. Epub 2005 Jul 19 [MEDLINE]
Gender imbalance and risk factor interactions in heparin-induced thrombocytopenia. Blood. 2006 Nov 1;108(9):2937-41. Epub 2006 Jul 20 [MEDLINE]
No difference in risk for thrombocytopenia during treatment of pulmonary embolism and deep venous thrombosis with either low-molecular-weight heparin or unfractionated heparin: a metaanalysis. Chest. 2007 Oct;132(4):1131-9. Epub 2007 Jul 23 [MEDLINE]
The incidence of recognized heparin-induced thrombocytopenia in a large, tertiary care teaching hospital. Chest. 2007 Jun;131(6):1644-9. Epub 2007 Mar 30 [MEDLINE]
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Quantitative interpretation of optical density measurements using PF4-dependent enzyme-immunoassays. J Thromb Haemost. 2008 Aug;6(8):1304-12. doi: 10.1111/j.1538-7836.2008.03025.x. Epub 2008 May 17 [MEDLINE]
Treatment and prevention of heparin-induced thrombocytopenia: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133:340S-380S
Utility of consecutive repeat HIT ELISA testing for heparin-induced thrombocytopenia. Am J Hematol. 2008 Mar;83(3):212-7 [MEDLINE]
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Early-onset and persisting thrombocytopenia in post-cardiac surgery patients is rarely due to heparin-induced thrombocytopenia, even when antibody tests are positive. J Thromb Haemost. 2010 Jan;8(1):30-6. doi: 10.1111/j.1538-7836.2009.03626.x. Epub 2009 Sep 28 [MEDLINE]
Fondaparinux treatment of acute heparin-induced thrombocytopenia confirmed by the serotonin-release assay: a 30-month, 16-patient case series. J Thromb Haemost. 2011 Dec;9(12):2389-96. doi: 10.1111/j.1538-7836.2011.04487 [MEDLINE]
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 Feb;141(2 Suppl):e495S-530S. doi: 10.1378/chest.11-2303 [MEDLINE]
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Argatroban in the management of heparin-induced thrombocytopenia: a multicenter clinical trial. Crit Care. 2015 Nov 11;19:396. doi: 10.1186/s13054-015-1109-0 [MEDLINE]
Severe and persistent heparin-induced thrombocytopenia despite fondaparinux treatment. Am J Hematol. 2015 Jul;90(7):675-8. doi: 10.1002/ajh.23971. Epub 2015 Feb 27 [MEDLINE]
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