HEPARIN –INDUCEDTHROMBOCYTOPENIA DR. NAHID SHERBINI R3 INTERNAL MEDICINE
Case• A 63-y old man with CAD who has recently undergone bypass surgery presents with dyspnea.• Findings in exam are unremarkable.• Lab tests reveals PLT 86,000 as compared with 225,000 at the time of discharge 9 days earlier.• CXR normal , SPIRAL CT show PE
Cont.• What is the cause of this thrombocytopenia , how you will approach and manage this patient?
WHAT I WILL TALK ABOUT?• Thrombocytopenia: Definition , Mechanism and Causes.• HIT : clinical importance , pathophysiology , incidence , types , clinical features , associated thrombosis , approach , laboratory diagnosis and management.
Thrombocytopenia• Defined as a PLT count of < 140,000• Thrombocytopenia is one of the most common laboratory abnormalities found among hospitalized patients.• Serologically proven HIT occurs in 1.5% to 3% of patients with heparin exposure.
Mechanisms of Thrombocytopenia• Increased Platelet Destruction – Non-immune – Immune• Decreased Platelet Production
HIT• Heparin-induced thrombocytopenia (HIT), was considered a rare disorder in the past • unrecognized by many clinicians • diagnoses can be difficult to confirm – until recently there was no therapeutic options other than discontinuation of heparin.
CLINICAL PROBLEM• HIT is a life threatening disorder that follows exposure to unfractionated or less commonly LMWH .• CLASSICALY : PLT less than 150,000 or decrease of 50% or more from the baseline .• Thrombotic complication develop in 20-50 % of patients.
HIT• An immunoglobulin-mediated adverse drug reaction characterized by: – platelet activation – thrombocytopenia – thrombotic complications
HIT CAUSED BY• Antibodies against complexes of platelet factor 4 (pf4) and heparin.• Nearly in all patients
PATH0PHYSIOLOGY OF HIT
INCIDENCE• According to population at risk and recommendations for monitoring of PLT count.
INCIDENCETherapy Risk Clinc. % of %of PLT pop PF4 ab HIT countHeparin High Ortho 14 3-5 Base & every surg. other day from 4-14 Intermedi Cardic . 25-50 1-2 ate surg ,neuroLMWH Intermedi Med. pt 2-8 0-0.9 Base & ate every 2-4 days from 4-14 Recomm. British committee for standerds in haema and ACCP
HIT-associated Thrombosis ‘HITT’• HIT is prothrombotic – 89% with HIT developed thrombosis – 18% without HIT developed thrombosis “increased risk for thrombosis was seen only in the patients who developed thrombocytopenia, and not in the patients who developed HIT antibodies without thrombocytopenia”
HIT-associated thrombosis• The thrombotic risk is more than 30 times that in control population .• Risk is high for days to weeks after discontinuation of heparin , even after normalizing tha PLT count.
Venous Thromboembolism• Most common complication of HIT• Deep vein thrombosis• Pulmonary embolism• Venous limb gangrene• Adrenal hemorrhagic infarction• Cerebral sinus thrombosis AM J Med 1996;101:502-507
Arterial thrombosis• Venous thrombotic events predominate over arterial events by 4:1 ratio. Usually involving large vessels.• Stroke• Myocardial infarction• Lower limb involvement AM J Med 1996;101:502-507
Other Atypical Manifestation• Heparin –induced skin necrosis• Venous gangrene of limbs• Anaphylactic –type reactions after receipt of iv bolus of heparin.• Acute platelet activation syndrome --Acute inflammatory reactions --Transient global amnesia
Skin lesions associated with HIT LEFT: Heparin-induced erythematous plaques. RIGHT: Heparin-induced skin necrosis
Clinical diagnosis• Dx of HIT in complicated medical conditions can be challenging.• Other causes of thrombocytopenia should be excluded .• Plt count should recover after d/c of heparin .• Dx of HIT in pt. undergone recent cardiac surgery is difficult.
Clinicaly Suspicious for HIT• a rapid drop in platelets in a patient received heparin within the previous 3 months.• a fall in platelet count of >50% that begins after 5 days of heparin therapy, even with platelet count > 150 x 109/L.• Consider other causes if occurs after 2 wks of therapy.
LABORATORY DIAGNOSISSerological assays• Detect circulating IgA ,IgG ,IgM• Sensitivity >97%• Specificity 74-86% limited by that also detect pf4-heparin ab in pt. that don’t have HIT.• The positive predictive value is low but negative predictive value is high >95%.
Functional assays SENSTIVITY SPECIFICITYPAA >90% 77-100%SRA 88-100% 89-100%HIPA >90% >90% •Positive predictive value higher in functional Assay than negative predictive value.
• In cross-sectional studies in humans thrombotic manifestation correlates with biochemical markers of PLT activation and increased thrombin generation .• Retrospective studies in humans thrombotic risk greater with higher level of PF4- heparin antibodies or with a drop of PLT count >70% , or both
Diagnostic algorithm to confirm or rule out HIT in patients who have notundergone bypass surgery
Thrombocytopenia in patients receiving heparin or LMWH High or intermediate Low clinical suspicion of HIT clinical suspicion of HIT Heparin or LMWH therapy D/C heparin or LMWH –initiate may be continued alternative anticoagulant therapy Consider alternative diagnosis Results of immunoassay +ve -ve +intermed susp.+ve +high susp. -ve +high susp. intermed susp. Consider alternative dx Consider alternative HIT confirmed dx , can restart heparin
Positive immunoassay with intermediate susp. Results of functional assayPositive Negative HITHIT likely INTERMEDIATE
Platelet count monitoring of patients recently treated with heparin• Rapid-onset HIT =a large platelet count fall due to presence of HIT antibodies within 24 h of starting heparin.• Has already-circulating HIT antibodies resulted from a recent heparin exposure’ Within 100 days’.
MANAGEMENT• Goals1. Reduce the thrombotic risk by reduce plt activation and thrombin generation.2. All sources of heparin should be stopped.3. Alternative anticoagulant should be started.4. Pt with HIT shouldn’t be treated with LMWH BECAUSE OF HIGH CROSS-REACTIVITY WITH ANTIBODIES.
Lepirudin• A direct thrombin inhibitor – recombinant form of the leech anticoagulant hirudin, the most potent direct thrombin inhibitors yet identified• Rapid anticoagulant effect with IV bolus• Relatively short half-life (1.3 hours)• Relatively contraindicated in renal failure• Anticoagulant effect readily monitored with aPTT (target range 1.5-3.0 times normal)
Lepirudin• The only direct thrombin inhibitor approved for use and for treatment of HIT in the U.S.• German trial of 200 patients with HIT – 75% to 81% effectively anticoagulated – significant reduction in composite endpoints (death, limb amputation, new thrombotic complications) compared with historical control 7 day 10% vs 23% 35 day 25% vs 52%
LepirudinLepirudin for Parental Anticoagulation in Patient with Heparin-induced Thrombocytopenia – a prospective, historically controlled trial – by five weeks after laboratory diagnosis of HIT, the incidence of death, limb amputation, or new thromboembolic events was 52.1% in the historical controls and 30.9% in the Lepirudin- treated group
Argatroban• a small synthetic non-polypeptide molecule• a direct thrombin inhibitor• FDA approved June30, 2000• has the same theoretical advantages of lepirudin – short half-life (< 1hr) – lack of cross-reactivity for HIT antibodies – potent antithrombin activity• metabolized predominantly by the liver, may require dose adjustment• excreted normally even in severe renal failure
Danaparoid• a low-molecular-weight heparinoid – mixture of anticoagulant glycosaminoglycans (heparin sulfate, dermatan sulfate, and chondroitin sulfate) with predominant anti- factor Xa activity• rapid anticoagulant effect with IV bolus• long half-life (~25 hours) for anti-Xa activity• in vitro cross-reactivity with the HIT antibody (10% to 40% ) does not predict development of thrombocytopenia or thrombosis
Alternatives to heparin for the treatment of HIT Direct thrombin Lepirudin inhibitors (renal) ,ptt Argatroban (hepatic) ,ptt Bivalirudin (enzymatic) act. Clotting time Anti-factor Xa Danaparoid therapy (renal) , level of anti-factor Xa 0.5-0.8U/ml
Approach inManagement of Patient withSuspected HIT
Duration of Therapy & Use of Oral Anticoagulants1. For pt with isolated thrombocytopeniaalternative anticoagulants until PLT count recover high risk for thrombosis anticoagulate for 4 weeks.2. HIT and thrombosis alternative anticoagulants after PLT recover oral 5 days of overlapINR therapeutic for 48h as indicated.
Adjunctive Therapies for HIT• Plasmapheresis – can reduce the concentration of HIT antibodies – replace deficient plasma anticoagulant factors• Warfarin is contraindicated in active HIT• ASA and IVC filter are not considered
Steps to Prevent HIT• Porcine heparin preferred over bovine heparin.• LMWH preferred over unfractionated heparin.• Oral anticoagulation should be started as early as possible to reduce the duration of heparin exposure.• IV adapters should not be flush with heparin.• Monitoring of plt count.
FINALY• Answer of the case: New thrombocytopenia and throboembolic event several days after heparin exposure during cardiac surgery suggestive of HIT.• Other causes should be ruled out.• Measure PF4-Ab• Treat with a direct thrombin inhibitorPLT recoveroverlap with warfarin3-6 months, Avoid future heparin exposure.
References• Clinical practice. Heparin-induced thrombocytopenia. N. Engl. J. Med., August 24, 2006; 355(8): 809 - 817• Uptodate 13.4• www.thrombosite.com
References• Heparin-Induced Thrombocytopenia: Recognition, Treatment, and PreventionThe Seventh ACCP Conference on Antithrombotic and Thrombolytic TherapyTheodore E. Warkentin, MD, Chair and Andreas Greinacher, MDChest. 2004;126:311S-337S