HEPARIN INDUCED THROMBOCYTOPENIA: HIT HAPPENS Jerrold H. Levy, MD Professor of Anesthesiology Deputy Chair, Research Emory University School of Medicine Cardiothoracic Anesthesiology and Critical Care Emory Healthcare Atlanta, Georgia

Hemostasis Endothelial cell Subendothelial matrix Hemostatic plug WBC Platelets Fibrin RBC Hemostasis refers to the prevention of blood loss, and is accomplished by vasoconstriction and coagulation by cellular and coagulation factors. Undue bleeding is controlled and the fluidity of the blood is maintained by counterbalances within the coagulation and fibrinolytic systems. Blood vessel injury or disruption, platelet defects, abnormalities of the normally circulating anticoagulants and fibrinolytic mechanisms may upset the balance between fibrinolysis and coagulation. Blood normally circulates through endothelium-lined vessels without coagulation or platelet activation occurring and without appreciable hemorrhage. Injury to the endothelial cells triggers the hemostatic process, which typically begins with the attachment of platelets (“Adhesion”) to the damaged endothelium or exposed subendothelial proteins such as collagen and von Willebrand factor (vWf). The platelets then change form (“Activate”) and release factors that stimulate the clotting process. They also bind together (“Aggregate”). At the same time, plasma proteins may react with elements in the subendothelium, activating the “contact” phase of coagulation. Exposed fibroblasts and macrophages present tissue factor, a membrane protein, to the blood at the injured site, thereby triggering the “Extrinsic “phase of blood coagulation. Under normal conditions, hemostasis protects the individual from massive bleeding secondary to trauma. In abnormal states, life-threatening bleeding can occur or thrombosis can occlude the vascular tree. Hemostasis is influenced by a number of different factors including: (a) vascular extracellular matrix and alterations in endothelial reactivity, (b) platelets, (c) coagulation proteins, (d) inhibitors of coagulation, and (e) fibrinolysis. Cotran RS, Kumar V, Robbins SL, eds. Robbins pathologic basis of disease, 5th ed. Philadelphia: W.B. Saunders, 1994 pp 99-106. Goodnight S. Physiology of coagulation and the role of vitamin K. In: Ansell JE, Oertel LB, Wittkowsky AK, eds. Managing oral anticoagulation therapy, Gaithersburg: Aspen Publishers, 1997 pp 1B-1:1-5.

COMPONENTS OF HEMOSTASIS Vasculature Coagulation proteins Platelets

Stimulation of Platelets Aprotinin PAR-1 (Thrombin receptor) Thrombin PAR-4 ADP ADP GpIIb/IIIa GpIIb/IIIa Aggregation GpIIb/IIIa Aggregation GpIIb/IIIa Aggregation Adhesion Aggregation Platelet GpIb Adrenaline Adrenaline Adhesion vWF Exposed Collagen Endothelium

HEPARIN Polyanion: (-) charge From cow lung/pig intestine Mixture of 3K to 30K MWt Binds ATIII/inhibits thrombin Inhibits Xa, esp LMWH Reversible with protamine Causes HIT

Heparin-induced Thrombocytopenia (HIT) Definition: HIT is a serious immune-mediated syndrome where heparin administration is associated with: Thrombocytopenia The generation of heparin-dependent antibodies (typically IgG) A high risk for thrombosis causing significant morbidity and mortality Heparin has become one of the most commonly used products in the hospital setting; its use is increasing with the number of procedures performed in cardiovascular medicine and orthopedics. Patients receiving heparin in the hospital setting should be frequently monitored for platelet count to identify HIT as early as possible. When HIT is thought to occur, administration of heparin should be stopped immediately and alternative anticoagulants which do not cross-react with heparin-dependent antibodies should be initiated. Antibody testing may be useful in confirming the diagnosis of HIT.

Heparin-induced Thrombocytopenia Clinical Presentation: Following heparin: Thrombocytopenia observed 5 – 14 days later; or may occur sooner with previous heparin exposure Platelet count <100,000/µL or Platelet count 50% of baseline (pre-heparin value) Thrombocytopenia associated with HIT has been observed to occur generally 5 – 14 days following the initiation of heparin therapy1; however, patients previously exposed to heparin may demonstrate an early reaction, which progresses rapidly.2 Relative to other clinical situations the degree of thrombocytopenia may be mild. Therefore it is important to monitor decrease in platelet counts in terms of trend and absolute value. 30 – 50% of patients demonstrating thrombocytopenia from heparin will progress and experience thrombotic complications within 30 days.3 30%–50% of patients with HIT will have a thrombotic complication within 30 days Warkentin TE Am J Med. 1996;101:502–507

HIT: Pathophysiology Presence of IgG antibodies that recognize PF4/heparin complexes on platelet surfaces and vascular walls Binding of IgG to PF4/heparin complexes on platelets Antibody activates platelets via the Fc receptor Activated platelets release microparticles with prothrombotic activity In HIT patients, heparin stimulates an immune response and serum from these patients contains antibodies that recognize platelet factor 4 (PF4) in association with heparin.3–7 IgG was the most common immunoglobulin detected in the serum of patients with HIT6, 7; however, in some cases IgA and IgM have also been reported to be associated with HIT.8 The PF4/heparin complex bound to IgG causes platelet activation through binding to the platelet Fc receptors.9, 10 Platelet activation causes the release of microparticles possessing thrombotic activity. 9, 10 PF4/heparin-binding antibodies cross-react with naturally occurring heparin sulfate/PF4 on endothelial cells and potentially cause damage to vessel walls.10

Pathophysiology of HIT and Thrombosis lecture copy HIT begins as intravenous injection of heparin stimulates the release of PF4 (a), a heparin-binding protein that is normally found on endothelial cells bound to glycosaminoglycans. Heparin and PF4 then combine to form heparin/PF4 complexes (b). In some patients, heparin/PF4 complexes interact with predominantly IgG antibodies to form immune complexes, which in turn bind to platelet Fc receptors (c). These platelets are either removed from circulation by splenic macrophages, resulting in thrombocytopenia, or are activated, resulting in the release of platelet-derived microparticles (d) that accelerate the generation of thrombin and the formation of new thromboses.4,5,7 The combination of heparin-induced thrombocytopenia and thrombotic complications are the hallmark of HIT.8

Laboratory Testing for HIT Test Advantages Disadvantages SRA Sensitivity >85% Technically demanding, radioisotopes; Low predictive value HIPA Rapid, available Variable sensitivity (30% – 80%); Technique-dependent ELISA High sensitivity High cost, low specificity, 10% false-negative tests Three tests are available1: ELISA (enzyme-linked immunosorbent assay) uses immobilized PF4 bound to heparin as a target for the HIT antibody. Two platelet activation assays: SRA (14C-serotonin release assay) HIPA (heparin-induced platelet aggregation) test Both tests detect the ability of serum to activate platelets in the presence of heparin While these tests are helpful in confirming HIT, the diagnosis remains a clinical one since there is wide variability of, access to, and turnaround time for these assays. There is no Gold Standard in diagnostic testing; HIT requires a clinical diagnosis

Frequency of Clinical Sequelae in HIT Sequelae Incidence Thrombosis 30%–50% Amputation 20% (arterial thrombosis) Death 30% HIT is a potentially devastating complication of heparin administration. 30 – 50% of patients presenting with HIT experience a thrombotic event within 30 days.3 Morbidity and mortality are significant in patients with HIT despite discontinuation of heparin therapy.14

4:1 Incidence Ratio Venous to Arterial Sites of Thrombotic Complications in HIT: Warkentin TE Am J Med 1996;101:502–507 30%–50% of untreated patients with thrombocytopenia progress to thrombosis 4:1 Incidence Ratio Venous to Arterial Venous Deep Vein Thrombosis Pulmonary Embolism Cerebral Dural Sinus Thrombosis Adrenal Hemorrhagic Infarction Arterial Aortic/Ileofemoral Thrombosis Acute Thrombotic Stroke Myocardial Infarction Intraventricular Thrombosis Thrombosis in upper limb, mesenteric, renal and spinal arteries Venous complications were observed more frequently than arterial events in a ratio of approximately 4:1.3 The early symptoms of venous thrombosis may not be obvious. The most common venous thrombotic complication was deep vein thrombosis, which was responsible for more than 60% of thrombotic events in one study, followed by pulmonary embolism, which was responsible for 25% of all events.3, 11 Arterial events are generally evidenced by overt clinical symptoms and may be life or limb threatening. In a single patient, significant clot extensions or multiple sites of thrombosis may occur.5, 15

HIT Has Occurred with All Types of Heparin Risk Factor Highest Risk Moderate Risk Route/Dose IV use SC use High dose Low dose Type UFH LMWH Source Bovine heparin Porcine heparin Patient type Surgical Medical CABG Orthopedic Although various factors have been associated with a high risk for the development of HIT, HIT has occurred with: all types of heparin, all routes of heparin administration, and all heparin dose levels.1, 11

Clinical Diagnosis of HIT Platelet count drop occurs during or after heparin therapy Platelet count drops to <50% of baseline Platelet count <100,000/L or No other cause of thrombocytopenia identified Clinical diagnosis of HIT HIT remains a clinical diagnosis based on a drop in platelet counts after initiation of heparin therapy and elimination of other causes of thrombocytopenia. Drop to <50% of baseline Drop to <100,000/mL Once a clinical diagnosis has been made, discontinue all heparin and initiate alternative anticoagulant therapy.14 Discontinue all types of heparin Assess the risk of thrombosis If indicated, initiate alternative anticoagulant therapy

THROMBOCYTOPENIA AND HIT: KEY POINTS 50% decrease in platelets is significant Appears day 5-8 of treatment, but earlier suggestes pre-existing heparin antibodies (three months). Consider other causes: sepsis, DIC, autoimmune, and other medications. MOA: PF4/heparin epitope

IV ANTITHROMBINS Antithrombin Hirudin: r-lepirudin, Refludan™ Bivalirudin (Angiomax) Argatroban Other agents Levy JH: Novel intravenous antithrombins. Am Heart J 2001;141:1043

RECOMBINANT HIRUDIN (LEPIRUDIN, REFLUDAN) 65 amino acid peptide with potential antigenicity Direct, IRREVERSIBLE thrombin inhibitor, most potent. Rapid onset IV bolus; efficacy in HIT; short half life (PK) but accumulates in renal failure, NOT reversible, and can cause anaphylaxis. Approved in US 1998

ARGATROBAN Direct thrombin inhibitor Rapid anticoagulation following IV bolus; efficacy in HIT suggested; short half-life; does not accumulate in renal failure Accumulates in hepatic failure; effect on INR complicates monitoring during overlap with warfarin; no antidote FDA approved 2002

Bivalirudin 20-amino acid peptide with an active site-directed peptide, D-Phe-Pro-Arg-Pro, linked via a tetraglycine spacer to a dodecapeptide analogue of the carboxy-terminal of hirudin. Binds directly/reversibly to both the active catalytic site and anion-binding exosite 1 of both circulating and clot-bound thrombin. Thrombin slowly cleaves the bivalirudin - Arg3-Pro4 bond, resulting in recovery of thrombin active site function.

Bivalirudin: 20 amino acid peptide Gly-Pro-Arg-Pro (active site binding region) C-terminal dodecapeptide (exosite 1-binding region) (Gly)4 The active substance of bivalirudin is a synthetic, 20-amino acid peptide comprised of an active site-directed peptide, D-Phe-Pro-Arg-Pro, linked via a tetraglycine spacer to a dodecapeptide analogue of the carboxy-terminal of hirudin. Bivalirudin has little secondary structure. That which does exist is comprised of randomly-folded and beta-sheet structures. Unlike heparin, bivalirudin binds specifically to both clot bound and circulating thrombin.

Specific, reversible binding (Gly)4 C-terminal dodecapeptide (Exosite 1-binding portion) 2 1 Thrombin Bivalirudin Gly-Pro-Arg-Pro (active-site-binding portion) Bivalirudin binds directly to both the active catalytic site and the anion-binding exosite 1 of both circulating and clot-bound thrombin. The binding of bivalirudin to thrombin is considered reversible as thrombin slowly cleaves the bivalirudin - Arg3-Pro4 bond, resulting in recovery of thrombin active site function.

Argatroban Indications and Usage Argatroban is a synthetic direct thrombin inhibitor indicated as an anticoagulant for prophylaxis or treatment of thrombosis in patients with heparin-induced thrombocytopenia (HIT) Argatroban is a synthetic direct thrombin inhibitor. Bearing no resemblance to heparin, Argatroban does not induce an antibody response that may lead to heparin-induced thrombocytopenia (HIT).16 Argatroban is the first and only agent FDA-approved as anticoagulant therapy for both the prophylaxis and treatment of thrombosis associated with HIT. Argatroban is contraindicated in patients with overt bleeding or in patients hypersensitive to this product or any of its components. 16

Mechanism of Action for Argatroban Directly inhibits all procoagulant and prothrombotic actions of thrombin Reversibly binds to the thrombin catalytic site Active against both free and clot- bound thrombin Argatroban has a unique pharmacologic profile that is distinct from heparin and other indirect thrombin inhibitors. Argatroban directly inhibits all procoagulant and prothrombotic actions of thrombin and reversibly binds to the thrombin catalytic site. Unlike UFH and LMWH, Argatroban inhibits both free- and clot-bound thrombin.

Argatroban Is Distinct from Indirect Thrombin Inhibitors (UFH, LMWH, and Heparinoids) Does not interact with or induce heparin-dependent antibodies Does not require a cofactor for thrombin inhibitory activity Active against both free and clot-bound thrombin Unlike UFH and LMWH, Argatroban is not recognized by heparin-dependent antibodies.16 Unlike lepirudin, Argatroban does not cause the production of antibodies to itself. Antibodies to Argatroban have not been observed with repeat administration.17

Pharmacokinetics of Argatroban Infusion in Healthy Volunteers Rapid Onset of Action Anticoagulant effects are produced immediately upon infusion Steady-state levels are reached within 1 – 3 hours Steady-state levels are maintained until dosage is adjusted or infusion is discontinued Argatroban has a fast onset of action with anticoagulant effects immediately upon infusion. Steady-state drug levels and anticoagulant effects (aPTT) are reached within 1 – 3 hours.16 Rapid elimination occurs with a mean half-life of 39 – 51 minutes.16

Pharmacokinetics of Argatroban Infusion in Healthy Volunteers Short Half-Life T1/2 = 39 – 51 minutes Upon discontinuation of therapy, anticoagulant parameters return to baseline within 2 – 4 hours Argatroban has a fast onset of action with anticoagulant effects immediately upon infusion. Steady-state drug levels and anticoagulant effects (aPTT) are reached within 1 – 3 hours.16 Rapid elimination occurs with a mean half-life of 39 – 51 minutes.16

Plasma Argatroban (µg/mL) Infusion dose (µg/kg/min) Relationship at Steady-State Between Argatroban Dose, Plasma Argatroban Concentration, and aPTT Plasma Argatroban (µg/mL) 0.8 1.6 1.2 0.4 2.0 100 75 50 Mean aPTT (±secs) This graph shows the relationship between the dose of Argatroban (X-axis) and the effect on aPTT (Y-axis). In addition, the levels of plasma Argatroban are shown on the top axis.16 Therapy is monitored using aPTT. A predictable dose-dependent response is produced by Argatroban infusion. When Argatroban is administered to healthy subjects by continuous infusion, anticoagulant effects and plasma concentrations follow similar, predictable response profiles, with low intersubject variability. 25 4 8 6 2 10 Infusion dose (µg/kg/min)

Special Populations In healthy subjects, the pharmacokinetics and pharmacodynamics of Argatroban were NOT affected by renal impairment, age, or gender Dosage adjustment is NOT necessary in renally impaired patients Hepatic impairment decreases Argatroban clearance; therefore, the dosage must be reduced for hepatically impaired patients The effect of renal disease on the pharmacokinetics of Argatroban was evaluated in 24 subjects including normal subjects (n=6), and subjects with mild (n=6), moderate (n=6), or severe (n=6) renal impairment. The pharmacokinetics of Argatroban were not significantly affected by renal dysfunction; thus, the dose of Argatroban does not need to be decreased.16 In patients with hepatic impairment (Child-Pugh score of >6), Argatroban therapy results in decreased clearance (to 1.9 mL/kg/min) and increased half-life (181 minutes). It is recommended that patients with impairment should receive a lower dose of Argatroban (0.5 g/kg/min). Additional time should be allowed for reversal of effects upon discontinuation of infusion.

Recommended Dosing Guidelines for Argatroban HIT Patients HIT Patients with Renal Impairment HIT Patients with Hepatic Impairment Initiate at 2 µg/kg/min Titrate until steady-state aPTT is 1.5–3.0 times baseline value* Initiate at 0.5 µg/kg/min† Titrate until steady-state aPTT is 1.5–3.0 times baseline value* No dosage adjustment required Dosing for Argatroban is relatively straightforward.17 The initial dose of Argatroban is 2 mg/kg/min; the mean dose during clinical studies was 2 mg/kg/min, indicating dose titration for many patients may not be necessary to achieve adequate anticoagulation. No dosage adjustment is necessary in patients with renal impairment. For patients with hepatic impairment, the dose should be reduced to 0.5 mg/kg/min. * Not to exceed a dose of 10 µg/kg/min or aPTT of 100 seconds † Due to approximate 4-fold decrease in Argatroban clearance relative to those with normal hepatic function

Safety Results for Argatroban Argatroban Historical Control† Studies 1 & 2 (n=568) (n=193) Major Hemorrhagic Events* Overall Bleeding 5.3% 6.7% Gastrointestinal 2.3% 1.6% Genitourinary and hematuria 0.9% 0.5% Decrease in Hb/Hct 0.7% 0% Multisystem hemorrhage and 0.5% 1% DIC Limb and BKA 0.5% 0% Intracranial hemorrhage 0% 0.5% As the table shows, Argatroban benefits on the composite endpoint occur without an increase in bleeding risk, as compared with historical controls.16 The incidence of major bleeding was not significantly (p > 0.05) different between the Argatroban group and historical control group. For the historical control group, adverse events were obtained by a retrospective chart review. Patients in Studies 1 and 2 were observed and/or solicited for the occurrence of adverse events. NOTE: Patients may have experienced more than one adverse event * Defined as overt with a hemoglobin decrease 2 g/dL, that led to a transfusion of 2 units, or that was intracranial, retroperitoneal, or into a major prosthetic joint. Other overt bleeding was considered minor † Typical therapy for patients in the historical control group was heparin discontinuation and/or warfarin therapy

Safety Results for Argatroban Intracranial bleeding was not observed in ANY of the 568 HIT patients treated with Argatroban One patient experienced intracranial bleeding 4 days after discontinuation of Argatroban and following therapy with urokinase and oral anticoagulation Intracranial bleeding was not observed in any of the 568 HIT patients treated with Argatroban.16 However, one patient experienced intracranial bleeding 4 days after discontinuation of Argatroban and following therapy with urokinase and oral anticoagulation The investigator considered the incidence to be unrelated to study medication In the historical control group, two fatal bleeding events, including 1 intracranial hemorrhage, occurred 3 days and 16 days following heparin cessation and in the absence of additional anticoagulants or thrombolytics.

Re-exposure and Lack of Antibody Formation Plasma from 12 healthy volunteers treated with Argatroban over 6 days showed no evidence of neutralizing antibodies Repeated administration of Argatroban to more than 40 patients was tolerated with no loss of anticoagulant activity No change in the dose was required upon re-exposure for safe/effective anticoagulation Given that HIT is a drug-induced, immune-mediated disease, the development of antibodies to therapy is of particular concern.17 Argatroban does not induce neutralizing antibodies to itself Repeat administration of Argatroban does not diminish or potentiate the anticoagulant activity No change in dose is required upon re-exposure to Argatroban

Guidelines for Conversion to Oral Anticoagulant Therapy All direct thrombin inhibitors, including Argatroban, may increase prothrombin time (PT); this must be taken into consideration when converting to warfarin therapy Coadministration of Argatroban and warfarin does produce a combined effect on the laboratory measurement of the International Normalized Ratio (INR) Once the decision is made to initiate oral anticoagulant therapy, it is important to recognize that: Co-administration of Argatroban and warfarin does produce a combined effect on the laboratory measurement of the International Normalized Ratio (INR) Concurrent therapy with Argatroban and warfarin does not exert an additive effect on the warfarin mechanism of action (eg, factor Xa activity) The previously established relationship between INR and bleeding risk is altered during combination therapy (for example, an INR of 4 on co-therapy does not have the same bleeding risk as an INR of 4 on warfarin monotherapy

Guidelines for Conversion to Oral Anticoagulant Therapy Concurrent therapy with Argatroban and warfarin does not exert an additive effect on the warfarin mechanism of action (e.g., factor Xa activity) The previously established relationship between INR and bleeding risk is altered during combination therapy For example, an INR of 4 on cotherapy may not have the same bleeding risk as an INR of 4 on warfarin monotherapy Once the decision is made to initiate oral anticoagulant therapy, it is important to recognize that: Co-administration of Argatroban and warfarin does produce a combined effect on the laboratory measurement of the International Normalized Ratio (INR) Concurrent therapy with Argatroban and warfarin does not exert an additive effect on the warfarin mechanism of action (eg, factor Xa activity) The previously established relationship between INR and bleeding risk is altered during combination therapy (for example, an INR of 4 on co-therapy does not have the same bleeding risk as an INR of 4 on warfarin monotherapy

Guidelines for Conversion to Oral Anticoagulant Therapy Initiate warfarin therapy using the expected daily dose of warfarin while maintaining Argatroban infusion.* A loading dose of warfarin should not be used Measure INR daily† If INR is 4.0, continue concomitant therapy If INR is >4.0, stop Argatroban infusion Repeat INR 4-6 hours later This slide reflects the outcome of a study designed to develop guidelines for the transition from Argatroban to warfarin therapy.17 Co-administration of Argatroban and warfarin does produce a combined effect on the laboratory measurement of INR; the previously established relationship between INR and bleeding risk is altered during combination therapy. INR should be measured daily while Argatroban and warfarin are co-administered. Initiate warfarin with Argatroban using the expected daily dose of warfarin while maintaining Argatroban infusion. A loading dose of warfarin should not be used. In patients receiving Argatroban at doses of 2 g/kg/min: If INR is 4.0, continue concomitant warfarin until INR is >4.0 If INR is >4.0, stop Argatroban infusion and repeat INR 4 – 6 hours later If INR is below the therapeutic range for warfarin alone, resume Argatroban therapy at previous dose If INR is within therapeutic range on warfarin alone, continue warfarin monotherapy If INR is within therapeutic range on warfarin alone, continue warfarin monotherapy If INR is below the therapeutic range for warfarin alone, resume Argatroban therapy * For Argatroban infusion at 2 µg/kg/min, the INR on monotherapy may be estimated from the INR on cotherapy. If the dose of Argatroban >2 g/kg/min, temporarily reduce to a dose of 2 g/kg/min 4-6 hours prior to measuring the INR.  

Additional Benefits of Argatroban Effective anticoagulation, lowering mortality from thrombosis and preventing new thrombosis in patients with HIT An acceptable bleeding risk, comparable with control No dose modification with renal impairment No formation of antibodies to itself Does not interact with or induce heparin-dependent antibodies To summarize, additional benefits of Argatroban include: Lower mortality from thrombosis as well as preventing new thrombosis An acceptable bleeding risk, comparable with control Safe therapy without dose modification with renal impairment Anticoagulation without the formation of antibodies to itself No interaction with or induction of heparin-dependent antibodies

SYNTHETIC AGENTS Danaparoid (Orgaran): Anti-Xa activity, studied extensively in HIT. For patients with strongly suspected (or confirmed) HIT, whether or not complicated by thrombosis, has Grade 1B recommendation based on ACCP Guidelines (CHEST 2004; 126:311S–337S). Pentasaccharide (Fondaparinux) a highly selective, indirect inhibitor of activated factor X, is the first of a new class of synthetic antithrombotic agents HIT WEB 2 SLIDE 37

Fondaparinux: Targeted mechanism of action Intrinsic pathway Extrinsic pathway 1 2 3 ATIII ATIII Xa Xa ATIII Fondaparinux II IIa Fibrinogen Fibrin clot The first selective inhibitor of Factor Xa Catalytic activity at low doses Olson ST, et al. J Biol Chem. 1992; 267:12528-12538. High potency through action at an early stage of the coagulation cascade

THROMBOCYTOPENIA AND HIT: KEY POINTS 50% decrease in platelets is significant Appears day 5-8 of treatment, but earlier suggests pre-existing heparin antibodies (three months). Consider other causes: sepsis, DIC, IABP, autoimmune, other medications. MOA: PF4/heparin epitope

Summary HIT is a relatively common, often under-recognized, potentially devastating complication of heparin therapy Diagnosis of HIT is based upon clinical suspicion Treatment of HIT should not rely on laboratory confirmation Untreated patients with HIT are at a high risk of a thromboembolic complication

Management of HIT Summary Discontinue all types of heparin R/O other potential causes of thrombocytopenia Assess risk of thrombosis If indicated, initiate alternative anticoagulant therapy

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