Heparin-Induced Thrombocytopenia

Jeanine M. Walenga, PhD
Cardiovascular Institute, Stritch School of Medicine
Loyola University Chicago, Maywood, Illinois 60148 USA

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Heparin-induced thrombocytopenia (HIT) is an important adverse effect of heparin. HIT is reported to occur in 1% of medical, 3% of surgical, and 5% of cardiac surgery or orthopedic surgery patients, and has also been diagnosed in other patient populations (1-8). Progression to overt thrombosis leading to amputation or death is the most serious complication occurring in approximately one-third of patients with HIT (9). Thrombosis can occur anywhere throughout the venous and arterial circulation. Spontaneous bleeding and petechiae have been reported only rarely.

Early diagnosis and treatment are important to improve clinical outcomes. Diagnosis of HIT is based on a comprehensive interpretation of clinical and laboratory information.

Clinical Presentation
In patients being treated or having been recently treated with heparin, HIT should be suspected on the basis of a 30% decrease in platelet count from baseline in the absence of other reasons for thrombocytopenia (10-13). HIT occurs from exposure to unfractionated heparin (UFH) at prophylactic or treatment doses or from exogenous sources (e.g., catheter flush) (1-9). Low molecular weight heparin (LMWH) also causes HIT but at a 3-fold lower frequency than UFH (14).

HIT patients can present without thrombocytopenia, i.e., the platelet count does not fall to <100 x 109/L. An abrupt fall in platelet count in the absence of other etiologies, and unexplained thrombosis, are also characteristics of HIT. Symptoms typically appear 4-14 days after exposure to UFH, or 8-14 days after exposure to LMWH (15). Patients who received heparin within the prior 100 days can have an immediate, rapid-onset HIT when restarting UFH or LMWH. A delayed-onset HIT has also been observed with symptoms appearing several days after discontinuation of UFH (16).

The post-cardiac surgery patient presents the greatest challenge due to the typical 40% platelet count decrease that follows surgery. Two platelet recovery patterns have been observed in the cardiac surgery patient with HIT: a typical post-surgery platelet count recovery with an abrupt decrease on day 7, and a slower than typical platelet count recovery becoming significantly lower than expected on post-surgery day 3 (17-18).

Careful monitoring for thrombocytopenia and thrombosis are the primary means for recognition of HIT. For the first 14 days of treatment, platelet counts should be performed every 2 days in patients treated with LMWH, daily if treated with UFH, and daily if the patient’s risk of developing HIT is high. For medical and obstetric patients treated with LMWH exclusively and no prior exposure to UFH, it is not necessary to monitor the platelet count (19,20).

HIT patients experience a spectrum of thrombotic events including venous and arterial thrombosis, vascular graft occlusion, intracardiac thrombosis, pulmonary embolism, cerebrovascular accident, cavernous sinus thrombosis, mesenteric infarct, renal artery thrombosis, etc.

Patients with co-morbidities, such as sepsis, inflammation, pre-existing vascular pathologies, are at higher risk of poorer clinical outcomes (12). Platelet count nadir, renal impairment, and surgery are associated with more severe thrombotic complications (21). All clinical settings, including the emergency department, need to be aware of a patient’s prior UFH/LMWH exposure and history of HIT.

Pathologic Mechanism
HIT is an immune response in which antibodies are mainly targeted to the complex of heparin and platelet factor 4 (PF4) (22,23). Antibodies to heparin binding proteins other than PF4, such as NAP-2 and IL-8, have also been identified in patients with HIT (24,25). Heparin binding exposes cryptic regions within the protein molecule creating neoepitopes that elicit the formation of HIT antibodies (26,27). Anti-PF4/heparin antibodies are heterogeneous in affinity and specificity (28,29). Immunoglobulin G (IgG) antibodies are the predominant antibody found in symptomatic HIT patients (30,31). However, IgA and IgM have also been identified in patients with symptomatic HIT (32).

Immune complexes of PF4-heparin and HIT antibodies that are IgG bind to platelets via FcgIIa receptors, (33) inducing platelet activation, aggregation, and generation of highly procoagulant platelet microparticles (34,35). In addition, HIT antibodies provoke leukocyte and endothelial cell activation which produces hypercoagulable and inflammatory states through tissue factor, cytokine, and cellular adhesion molecule up regulation (36-42). This combined cellular activation leads to a burst of thrombin generation. The inter-relationships of platelets, leukocytes, endothelium, and the inflammatory state determine the clinical expression of HIT (43).

Laboratory Diagnosis
Two types of laboratory assays for HIT are available: platelet function tests and ELISA tests. Each test provides unique and complementary information (44-47). It is useful to perform a combination of tests and to repeat testing over a period of several days as the HIT antibody titre changes (48).

Platelet function tests include the serotonin release assay (SRA) and platelet aggregation assays (PAAs). The PAAs use platelet rich plasma and detect IgG, IgM, and IgA HIT antibodies. The SRA, which uses washed platelets, only detects HIT IgGs with high affinity. Generally, the SRA is more sensitive than the PAAs. However, HIT patients can respond positive in the PAA but negative in the SRA and vice versa (44,45,47). False negatives occur in both the SRA and the PAAs but false positives are rare. Due to the limitations of sensitivity and specificity, these laboratory tests can confirm a diagnosis of HIT, but negative results do not exclude a diagnosis of HIT.

The current ELISAs detect IgG, IgA, and IgM HIT antibodies but only to the PF4/heparin complex. HIT antibodies targeting IL-8, NAP-2 or other heparin-binding proteins cannot be detected. New ELISAs that only detect IgG-PF4/heparin antibodies have recently become available. Antibody generation is far more common than the development of clinical HIT (46-50). The clinical relevance of HIT antibody titres without clinical symptoms is unclear. Measurable antibody without strong clinical indication should not be considered HIT. Thus, the ELISA should not be used as a screening test since this will over-estimate the incidence of HIT. A positive ELISA should be confirmed with a platelet function test for

HIT since the functional tests are more specific than the ELISAs. On the other hand, since ELISAs can also fail to diagnose HIT a negative result should only rule out HIT if the clinical probabilities are very weak (51).

The current laboratory tests for HIT do not have sufficient sensitivity and specificity to be used as the sole tool to diagnosis HIT. Any laboratory test for HIT should only be performed when there is a strong clinical suspicion of HIT. Initial therapeutic decisions should not be dependent upon a positive laboratory test, but should be based upon clinical findings (i.e., thrombocytopenia and/or new thromboembolic events). Clinical judgement with appropriate use and knowledgeable interpretation of the laboratory test results are important for the diagnosis of HIT.

Patient Management
UFH and LMWH should be stopped when the diagnosis of HIT is suspected (10-13,19,20). It is not sufficient to merely remove the heparin (52). Due to the strong hypercoagulable state and high risk of thrombosis associated with HIT, it is recommended that all HIT patients be treated with a non-heparin anticoagulant that does not cross-react with HIT antibodies such as argatroban, lepirudin, or danaparoid (10-13,19,20,53,54). Certain factors need to be considered when making a clinical treatment decision including patient renal and liver function, patient risk of bleeding, prior exposure of patient to lepirudin, physician’s experience with the drug, and drug availability (55-57). LMWH can cross-react with most HIT antibodies and is contraindicated for use in patients with HIT (10-13,19,20).

Clinical trials have shown the direct thrombin inhibitors (DTIs) argatroban (58,59) and lepirudin (60,61) to be safe and effective for reducing the thrombosis and associated morbidity / mortality in patients with HIT. Argatroban is approved for the prophylaxis and treatment of HIT thrombosis, as well as for anticoagulation of HIT patients undergoing interventional cardiology procedures. Lepirudin is approved for the treatment of HIT thrombosis. Both argatroban and lepirudin can be monitored with the aPTT. A third DTI, bivalirudin, is under development.

The pharmacokinetics and pharmacodynamics of the DTIs differ (11,55,56). Lepirudin is cleared through the kidneys, whereas argatroban is cleared through the liver. Lepirudin has a longer half-life than argatroban. Antibodies to lepirudin can develop in 50% of patients which, upon re-exposure to lepirudin, can result in severe anaphylactic reactions with fatal outcomes (62). All DTIs affect clot-based laboratory assays (e.g., PT/INR, aPTT, factor assays) (63,64). Argatroban has a more pronounced effect on the PT/INR than lepirudin (64,65).

Danaparoid is a non-heparin anticoagulant that has been used to successfully treat HIT patients since the 1980’s (66). Studies have shown danaparoid to have a similar efficacy as lepirudin but with a better safety profile with regard to bleeding, accumulation with renal failure, and immunization (67). It has a sustained effect, can be used either intravenously or subcutaneously, and does not require routine monitoring. Although cross-reactivity of danaparoid with HIT antibodies is uncommon, treatment regimens should include platelet count monitoring (47).

Fondaparinux is a heparin-derived, factor Xa inhibitor that is approved for prophylaxis of post-orthopedic surgery venous thrombosis as well as for treatment of deep venous thrombosis and pulmonary embolism. It does not bind PF4 or cross-react with pre-formed HIT antibodies (68,69). Several documented case studies suggest that fondaparinux may provide adequate anticoagulation in HIT patients; however, no studies have been performed to date and it is not approved for this clinical indication.

For special populations of patients with HIT requiring anticoagulation, such as pregnant, pediatric, and hemodialysis, specific drug and dose issues need to be considered. HIT patients requiring cardiac surgery are best anticoagulated with UFH but only if they are HIT antibody negative at time of surgery. For patients wit HIT antibody titre, although lepirudin and bivalirudin have been used dosing and monitoring regimens for cardiac surgery are not optimized. Danaparoid is contraindicated for use in cardiac surgery.

For long-term anticoagulation of patients with HIT thrombosis vitamin K antagonists can be used. It is important that treatment only be initiated after rise of platelet counts to >100 x 109/L or to pre-HIT values to avoid warfarin-induced limb gangrene/skin necrosis (70). Starting doses need to be low (5 mg warfarin, 6 mg phenprocoumon) and given with overlapping administration of argatroban, lepirudin, or danaparoid for at least 5 days (19,20).

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Heparin-Induced Thrombocytopenia: CASE PRESENTATION

Lina Matta, PharmD, BCPS
Clinical Pharmacy Practice Manager
Brigham and Women's Hospital, Boston, MA 02115 USA

DS is a 63-year-old male admitted with chest pain radiating to both arms and accompanied by nausea and weakness.

Upon presentation to the ED his EKG demonstrates ST-elevations in the inferior leads with first degree AV block. Cardiac Catheterization shows occlusion in the proximal LAD artery (100%). A DES was placed to establish TIMI 3 flow. Medications given intra-procedure included heparin and eptifibatide continuous infusion. ECHO reported inferior, apical, and septal akinesis and EF 25%.

Past medical history is significant for CAD s/p three ACS events and s/p CABG in 2002, CHF, chronic renal insufficiency (Cr 1.8-2.1), hypertension, gout, GERD, and AF.

Medications on admission:

Aldactone 50 mg po Daily
Atorvastatin 40mg po Daily
Metoprolol XL 50 mg Daily
Aspirin 81 mg po Daily
Clopidorgrel 75 mg po Daily
Colchicine 0.6 mg po Every Other Day
Warfarin 3 mg po Daily

Admission Labs:

Na 135	WBC 7.40	ALT 84
K 4.8	HgB 11.0	AST 388
CI 103	HCT 32.6	CKMB 258
CO2 22	PLT: 228	Tnl 223
BUN 51
Cr 2.3
Glu 182

Temp 98°; BP 75-110/40-70 mmHg; RR 16-22 breaths/minute; HR 60 beats per minute
JVP 12; Crackles at the base of his lungs

Hospital Course:

Days 1-3:

Following catheterization, patient is admitted to the CCU with cardiogenic shock and worsening respiratory status. He is intubated and an intra-aortic balloon pump (IABP) is placed to maintain adequate perfusion. During the CCU admission, the patient becomes increasingly anuric with worsening renal function. The renal team is consulted and continuous veno-venous hemofiltration (CVVH) is started.

VS: Temp 101 degrees; BP 80-100/50-80; HR 80 bpm,
Rhythm: NSR

Medications on Day 3: Heparin 750 Units/hour, clopidogrel 75 mg po daily, aspirin 325 mg daily, captopril 12.5 mg three times daily, esomperazole 20mg daily, fentanyl 80 mcg/hour, midazolam 2 mg/hour, dobutamine 3 mcg/kg/min, atorvastatin 80mg daily,  Senna 2 tablets twice daily, potassium chloride IV SCALE, magnesium chloride IV SCALE, insulin continuous infusion per ICU protocol.

Laboratory Values on Day 3

Na 139	WBC 8.50	ALT 84
K 4.9	HgB 10.0	AST 112
Cl 106	HCT 31.6	CKMB 7.1
CO2 26	PLT 180	Tnl 27
BUN 36	PTT 1.5 x Control
Cr 1.8	INR 1.4
Glu 105

Days 4-6:
Patient’s cardiac and renal function improving and IABP and CVVH are stopped. Patient has been transferred out of the CCU and to the Step-Down Unit for continued medical management. His EKG demonstrates resolution of ST-elevations and atrial fibrillation.
Of note, platelet count on Day 6 was noted to be 110. An ELISA PF4 test returns POS on Day 6. 

VS: Temp 98 degrees; BP 120-140/70-90; HR 90 beats per minute
Rhythm: atrial fibrillation, again

Medications on Day 6:
Heparin 900 Units/hour, clopidogrel 75 mg po daily, aspirin 325 mg daily, captopril 12.5 mg three times daily, esomperazole 20mg daily, amiodarone 400mg po three times daily, atorvastatin 80mg daily, potassium chloride IV SCALE, magnesium chloride IV SCALE, warfarin 3 mg po daily

Laboratory Values on Day 6

Na 142	WBC 8.0	ALT 50
K 5.1	HgB 10.0	AST 95
Cl 110	HCT 31.6	CKMB < assay
CO2 28	PLT 110	Tnl 1.2
BUN 34	PTT 1.5 x Control	Tnl 1.2
Cr 2.1	INR 1.8
Glu 110

Heparin-Induced Thrombocytopenia: CASE QUESTIONS

Lina Matta, PharmD, BCPS

1. What are the first steps that should be taken in this patient’s medication regimen?  Answer: Stop heparin and warfarin. Make sure no heparin flushes are being administered.
2. What are the criteria that the patient demonstrates for HIT?  Answer: Thrombocytopenia (drop by > 50%), use of heparin for > 4 days, positive ELISA test.
3. What are some of the weaknesses of the ELISA test?  Answer (directly from Dr. Walenga’s article): “The clinical relevance of HIT antibody titres is unclear. Measurable antibody without strong clinical indication should not be considered HIT.”
4. What anticoagulants would you consider for this patient?  Answer: Argatroban may be preferred since it is not cleared via the kidneys. Warfarin may be started following overlap with argatroban for at least 5 days AND once platelet function has returned to baseline values.            
5. What is the therapeutic marker of argartoban therapy?  Answer: PTT. The INR is often “falsely” elevated.

INTERNATIONAL SUMMIT ON GENERIC ANTITHROMBOTIC DRUGS

FRIDAY, OCTOBER 12, 2007 – Taj Mahal Hotel, New Delhi, India

This program is held under the Auspices of International Union of Angiology (IUA), International Academy of Clinical and Applied Thrombosis (ICATH), Working Group on LMWH Generics of the SSC on Anticoagulation of the ISTH , North American Thrombosis Forum (NATF) and South Asian Society of Atherosclerosis and Thrombosis (SASAT).

CONFERENCE SCOPE: This international summit is organized to recognize the timely issues related to the evolution of guidelines for the objective and ethical development of generic antithrombotic drugs with particular reference to Low Molecular Weight Heparins (LMWHs).  Current guidelines for the generic conversion of branded antithrombotic drugs, in particular heparins, are inadequate at this time.  Moreover, in the case of LMWHs these guidelines are invalid.  Very little has been done by various organizations to address these issues. This has led to the development and introduction of several generic antithrombotic drugs globally, some of which were withdrawn after the initial approval, to avoid patient care adverse-related issues.  The IUA, SASAT and ICATH have addressed these issues periodically. More recently, the EMEA and other peer groups have also addressed concerns related to the current status of this problem.  This summit is organized to brief the distinguished panel on the problems and issues, generate scientific input for objective guidelines for the development of antithrombotic drugs, in particular the LMWHs. The deliberations of these meetings will be published as a white paper in International Angiology and JCATH.  The listed experts are being contacted for their participation in this meeting.  Those experts who are unable to attend this meeting will provide their input to the respective chairs via e-mail or phone conferences, which will be incorporated in the final document.

Click here to view the Program Brochure

Join WikiDoc.org – Online Medical Community

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FUTURE LEADERS: Thrombosis Journal Review - September 2007

In an effort to promote talented young individuals in the field of thrombosis research, the Future Leaders: Thrombosis Journal Review section will post 4 journal article reviews monthly on recent thrombosis publications from Fellows and other junior health care professionals interested in thrombosis treatment and research. All professional health care disciplines are encouraged to submit a review for consideration.

Please click here for submission guidelines.