REVIEW ARTICLE HIT/HITT and alternative anticoagulation: current concepts

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1 British Journal of Anaesthesia 90 (5): 676±85 (2003) DOI: /bja/aeg063 REVIEW ARTICLE HIT/HITT and alternative anticoagulation: current concepts E. Pravinkumar* and N. R. Webster Academic Unit of Anaesthesia and Intensive Care, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, UK *Corresponding author. Br J Anaesth 2003; 90: 676±85 Keywords: blood, coagulation; blood, anticoagulants, heparin Accepted for publication: July 25, 2002 Heparin is a widely used anticoagulant for the treatment and prevention of thromboembolic disorders in medical and surgical patients. Its importance as an anticoagulant has been well established by its effectiveness, rapid onset of action, ease of laboratory monitoring and cost. 18 Heparin is a member of the heterogeneous family of glycosaminoglycans, which range in size from 3000 to Da. The non-branching, negatively charged chain structure of heparin consists of repeating disaccharide units. Heparin is an anticoagulant released by mast cells and basophils in the process of clot formation, as well as a drug that is administered to the same effect. Standard unfractioned heparin is usually derived from porcine intestinal mucosa or bovine lung. 53 Heparin plays many roles in human physiology, such as: (i) binding to antithrombin III and increasing the ef cacy of antithrombin III as an inhibitor of the activation of thrombin and certain clotting factors; (ii) inhibiting platelet formation; (iii) increasing the permeability of vessel walls; (iv) inhibiting the proliferation of vascular smooth muscle cells; and (v) playing a role in the regulation of angiogenesis. In clinical use heparin has numerous activities, but the most important is its anticoagulant property (Table 1). It is also used as a thrombolytic, a fat-clearing anti-atherosclerotic and as a potentially effective anti-in ammatory agent. Heparin inhibits reactions that lead to clotting of blood and formation of brin clots both in vitro and in vivo. It acts at multiple sites in the normal coagulation system. It binds to antithrombin III (heparin cofactor), causing a conformational change in the structure of antithrombin III. This conformational change converts antithrombin III from a slow- to a fast-acting inhibitor of thrombin activation. The complex has a further inhibitory effect on other clotting factors, such as factors IX, X, XI and XII and kallikrein, and on the conversion of prothrombin to thrombin Once active thrombosis has developed, larger amounts of heparin can inhibit further coagulation by inactivating thrombin and preventing the conversion of brinogen to brin. Heparin also prevents the formation of a stable brin clot by inhibiting the activation of the brin-stabilizing factor. Thrombocytopenia and heparin Thrombocytopenia can result from conditions that lead to increased platelet destruction or decreased platelet production (Table 2) Heparin can cause thrombocytopenia via immune and non-immune mediated mechanisms. 41 There are two types of heparin-induced thrombocytopenia that can result from heparin administration: type I, nonimmune-mediated; and type II, immune-mediated In the interest of standardization, the term `non-immune heparin-associated thrombocytopenia' is recommended for type I, a benign condition in which no heparin-dependent antibodies are present. The term `heparin-induced thrombocytopenia' (HIT) is recommended for thrombocytopenia in which pathogenic heparin-dependent antibodies are detectable. This term is the most widely accepted designation for HIT type II. 67 Non-immune-mediated thrombocytopenia, also known as heparin-associated thrombocytopenia (HAT) and heparininduced thrombocytopenia type I (HIT type I), denotes the absence of heparin-dependent antibodies. It is probably caused by direct non-immune platelet activation by heparin. Type I HIT is usually associated with larger doses of heparin in contrast to HIT type II, which can occur with variable doses. HIT type I occurs earlier in the treatment course, Ó The Board of Management and Trustees of the British Journal of Anaesthesia 2003

2 HIT/HITT and alternative anticoagulation within a period of 4 days, in 30% of patients receiving heparin. The platelet abnormality is usually mild and reversible even with the continuation of the heparin (Table 3). The condition is self-limiting and there are no major complications associated with it. Heparin should be continued despite the low platelet count The clinical importance of the asymptomatic, self-limiting disease HIT type I lies in the necessity of differentiating it from the more serious HIT type II. Immune-mediated HIT type II exists in three separate diagnosable forms: (i) latent: antibodies without thrombocytopenia; (ii) HIT: antibodies with thrombocytopenia; and (iii) HITT: antibodies with thrombocytopenia and thrombosis. HIT/HITT (heparin-induced thrombocytopenia and heparin-induced thrombocytopenia with thrombosis syndrome) is an immune-mediated adverse reaction to heparin that is often underdiagnosed and can result in venous and arterial thrombosis ±73 79 The alternative name of HITT, white clot syndrome, refers to the gross pathology of the clots. The platelet±platelet adhesion without erythrocyte involvement gives a classic appearance of a white clot. Patients with HITT may suffer from venous thrombosis, most often deep venous thrombosis (DVT), which can be extensive and complicated by pulmonary embolism. Venous limb gangrene has been reported to Table 1 Clinical uses of heparin occur with warfarin treatment of HIT-associated DVT, and is characterized by a high international normalized ratio (INR), resulting from severe reduction in protein C caused by warfarin. Adrenal vein thrombosis and cerebral sinus thrombosis are other unusual venous thromboses that complicate HIT. Arterial thromboses associated with HITT may result in ischaemic limb damage that often requires amputation. Myocardial infarction, ischaemic stroke and end-organ thromboses, such as mesenteric, renal, brachial, splenic and hepatic arterial thromboses, can also occur (Table 4) HIT develops in 3% of patients treated with unfractioned heparin for more than 4 days. 72 Without treatment, mortality in HIT patients with new thromboembolic complications is about 20±30%, with equal morbidity caused by arterial and venous thrombosis The risk of venous thromboembolism from HIT is greater in high-risk surgical patients than in medical patients. Also, 40±50% of HIT patients will have a thrombotic event when heparin is discontinued. Mechanism of heparin±pf4±igg complex Most patients with HIT produce immunoglobulin G (IgG) antibodies, commonly IgG against macromolecular complexes of platelet factor 4 (PF4) and heparin (H±PF4) The high binding af nity between heparin and PF4 is probably attributable to a high concentration of C-terminus lysine residues that interact strongly Vascular Topical Surgery Prophylaxis Support systems Critical care Other (as anticoagulant) Acute-phase myocardial infarction Venous and arterial thromboembolism Pulmonary embolism Peripheral arterial disease Atherosclerosis Atrial brillation with embolization Acute ischaemic stroke Deep vein phlebitis Flap survival/pruritus Leg ulcers Open-heart surgery Vitreoretinal surgery Pulmonary embolism Deep vein thrombosis Extracorporeal circulation Renal replacement therapy Heparin-coated central venous and pulmonary arterial catheters Heparin ushes in arterial and central venous lines Laboratory samples Blood transfusion Table 2 Causes of thrombocytopenia Increased platelet destruction Non-immune Immune Septicaemia/in ammation Disseminated intravascular coagulation (DIC) Thrombotic thrombocytopenic purpura (TTP) Autoimmune: idiopathic or secondary immune thrombocytopenia Alloimmune: post-transfusion purpura Drug-induced: prothrombic (heparin), prohaemorrhagic (quinine, quinidine, gold, sulpha antibiotics, rifampicin, vancomycin, NSAIDs) Decreased platelet production Alcohol, cytotoxic drugs Leukaemia, aplastic anaemia Myelodysplasia Metastatic bone marrow involvement Infections Other causes NSAIDs=non-steroidal anti-in ammatory drugs. Hypersplenism Haemodilution (infusion of blood products, colloids, crystalloids) Table 3 Heparin-induced thrombocytopenia 68 Non-immune-mediated HAT (type I HIT) Immune-mediated HIT (type II HIT) Onset Within 4 days 5±14 days or sooner Platelet count Typically ± ml ±1 Typically ± ml ±1 Incidence 5±30% 1±3% Complications None Thromboembolic lesion Recovery 1±3 days 5±7 days Cause Benign: tiny platelet aggregates IgG-mediated platelet activation 677

3 Pravinkumar and Webster with the highly negatively charged heparin molecule. Neither heparin nor PF4 is normally antigenic, but the formation of an H±PF4 complex induces a conformational change in both molecules. Upon binding to the heparin molecule, PF4 exposes several antigenic epitopes, which trigger the immune reaction and the production of immunoglobulin G These antibodies activate platelets through their FcRIIA receptors, causing platelet destruction and release of prothrombotic platelet-derived microparticles. 12 Microparticles in turn promote thrombin generation and contribute to a hypercoagulable state 77 (Fig. 1). PF4, a small peptide stored within the alpha granules of platelets, binds to heparin and is released into the blood during treatment with it. 3 In vitro, IgG±PF4±heparin complexes can activate platelets. Increased propensity to thrombosis in HIT is therefore probably mediated by thrombin generated as a result of in vivo platelet activation, from interaction between heparin±pf4±igg immune complexes with Fc receptors on platelets. 38 A minimum of 12±14 saccharides is required to form the antigenic complex with PF4. Heparin molecules with a molecular weight >4000 Da have the potential to cause HIT. Hence HIT is less common with low molecular weight heparin (LMWH) than with unfractioned heparin No speci c laboratory or clinical characteristics can predict which patients will have isolated thrombocytopenia or have thrombocytopenia with thrombotic complications. between days 5 and 15 after the introduction of heparin, 72 but can develop earlier in patients exposed to heparin during the previous 3 months. 41 Case reports have shown thrombocytopenia developing within 10.5 h in patients exposed to heparin in the last 100 days. Thus, a patient with a rapid decrease in platelets soon after commencing heparin therapy, who has not been exposed to heparin previously, probably has another aetiology for the thrombocytopenia. During recovery from thrombocytopenia, heparindependent antibodies in the serum decrease to undetectable levels by 50±85 days. 78 Those with undetectable antibody but a previous proven diagnosis of HIT type II may take as long as 5 days to produce IgG antibodies and thrombocytopenia. Laboratory diagnosis There are two main classes of assays for laboratory diagnosis of HIT. Activation (functional) assays include the platelet aggregation assay and the serotonin release assay. The platelet aggregation assay involves the use of washed platelets rather than platelet-rich plasma derived from normal donors. This increases the reliability of activation assays, which are performed in the laboratory Diagnosis of HIT Manifestations of HIT include an otherwise unexplained decrease in platelet count and skin lesions at heparin injection sites, accompanied by HIT antibody formation. The platelet count during HIT can be variable, but only rarely decreases to < litre ±1. The median platelet count nadir in several studies is ~ litre ±1. HIT should also be suspected if the platelet count decreases by 30±50% after 5 days of heparin treatment (Table 3) The occurrence of thromboembolic complications during heparin therapy is another strong marker of HIT. Regardless of the degree of thrombocytopenia, the predominant clinical feature is thrombosis and not bleeding. The decrease in platelet count almost always occurs Table 4 Venous and arterial thromboses associated with heparin-induced thrombocytopenia and thrombosis syndrome (HITT) Venous thrombosis Deep venous thrombosis Pulmonary embolism Venous limb gangrene associated with warfarin Adrenal vein thrombosis/infarction Cerebral sinus thrombosis Arterial thrombosis Lower limb thrombosis Myocardial infarction Acute coronary syndromes Stroke End-organ thromboses (mesenteric, renal, brachial, splenic, hepatic) Fig 1 Mechanism of action of heparin±pf4±igg complex and the vicious circle that leads to thrombus formation and platelet destruction. IgG=immunoglobulin G; PF4=platelet factor 4; GP=glycoprotein. 678

4 HIT/HITT and alternative anticoagulation with a speci city >90%. The disadvantages are low sensitivity (35%) and the fact that assay reactivity varies between donor platelets The serotonin release assay measures the release of serotonin from platelet aggregates. It relies on the aggregation of the platelets from the patient in the presence of heparin. This assay has high sensitivity and speci city and has been validated by blinded assessment of clinical trials. 58 The disadvantages are that the assay is technically demanding and involves the use of radioactive materials Of the various activation assays available, those that use washed platelets and platelet serotonin release or heparin-induced platelet activation (HIPA) are the most accurate. The other class of assay is the antigen assay. The heparin±pf4 enzyme-linked immunosorbent assay (ELISA) relies on the speci city of HIT IgG antibodies for the heparin±pf4 complex. This assay is 10 times more sensitive than the serotonin release assay for detecting heparininduced antibodies. However, the heparin±pf4 ELISA is expensive and time-consuming. The assay also responds to clinically insigni cant antibodies more often than activation assays, and hence has a lower speci city. Most of the available laboratory tests for the diagnosis of HIT are expensive, time-consuming, frequently contradictory to the clinical presentation, and vary in sensitivity and speci city. Testing a patient with a history of HIT before expected heparin re-exposure should therefore be done with more than one sensitive test. Hence, the diagnosis of HIT remains clinical. It should be suspected in patients who develop thrombocytopenia with or without associated arterial or venous thrombosis while on heparin. 15 Prevention of HIT Currently there are no tests available to predict which patients are at high risk of developing HIT. Therefore, whenever heparin is clinically indicated, it is necessary to assess the risk± bene t pro le in all patients. The following points should be considered in the prevention of HIT: (i) history of previous sensitization to heparinð requires initiation of alternative anticoagulant therapy; (ii) limit heparin duration to less than 5 days whenever possible; (iii) early use of warfarin in patients requiring long-term anticoagulation, except when HIT is diagnosed; (iv) initiating warfarin at the start of heparin treatment in patients who require long-term anticoagulation; (v) use of LMWHÐa prospective study shows LMWH is less likely to cause HIT and HIT±IgG antibodies; 72 (vi) avoid unnecessary heparin ushes; (vii) use of porcine heparin (frequency of HIT, 1.3±8%) rather than bovine heparin (frequency of HIT, ±30.8%); (viii) regular monitoring of platelet count. Management of HIT After the clinical diagnosis or suspicion of HIT, heparin should be discontinued promptly. The platelet count should be monitored carefully and warfarin should not be used alone in patients with acute HIT. 67 Management of the patient with HIT is aimed at prevention of the thromboembolic complications seen in 50±70% of patients. The mortality associated with isolated thrombocytopenia without thrombosis is 21%. Therefore, the principle of managing HIT is the discontinuation of all forms of heparin exposure and the institution of an alternative anticoagulant The diagnosis should be con rmed as soon as practicable, but treatment should not be delayed for this reason. In the absence of thrombosis, cessation of heparin has been the traditional mode of therapy, 65 but several studies have shown that stopping heparin may be inadequate because of the high risk of overt thrombosis (50%) in the week after its interruption Warfarin in HIT Warfarin should not be used alone to treat acute HIT complicated by DVT because of the paradoxical risk of developing venous limb gangrene, which causes more than half the limb loss attributable to HIT at one centre. 75 Rapid loading with warfarin can cause depletion of the anticoagulant vitamin K-dependent protein C faster than it depletes procoagulant vitamin K-dependent proteins Higher warfarin doses cause a rapid increase in the INR, but this is entirely a result of earlier reduction of factor VII rather than a reduction in factor II, a coagulable protein with a longer half-life. Initiating warfarin therapy with a relatively high loading dose for rapid anticoagulation, which is a common practice, may prove dangerous, particularly in HIT Although other thrombin inhibitors have been introduced for continuing anticoagulation in the place of heparin, warfarin still remains an option for patients with HIT who require anticoagulation. Studies have shown that aiming for modest levels of the INR with warfarin and a smaller loading dose prevents the development of a potential hypercoagulable state caused by a precipitous decrease in the concentration of protein C. It is therefore important to start treatment in all patients with HIT who remain at risk of thrombosis, including postoperative patients and those with sepsis. Thrombin inhibitors (lepirudin or argatroban) should be used in these patients until the platelet count has recovered. Treatment with thrombin inhibitors should also be considered for patients with acute HIT without thrombosis (isolated HIT), because there is a high risk of subsequent clinically evident thrombosis. Warfarin given to patients adequately anticoagulated with lepirudin appears safe in acute HIT, but it is prudent to delay starting warfarin until the platelet count has risen above litre ±

5 Pravinkumar and Webster Ancrod in HIT Ancrod, a brin inhibitor derived from the Malayan pit viper venom, is another treatment option for HIT. Ancrod has not been widely used and there is only one small study on 11 patients. 16 Being a foreign protein, Ancrod induces resistance with prolonged use. There has also been increased thrombin generation and warfarin-induced limb gangrene in patients treated with it. Fig 2 Actions of thrombin. NO=nitric oxide; PgI 2 =prostaglandin I 2 ; t-pa=tissue plasminogen activator. Adapted with permission from Fuster and Verstraete. 22 Prostacyclin analogues in HIT Prostacyclin is a natural vasodilator and inhibitor of platelet aggregation. Iloprost has been shown to be effective in suppressing HIT-induced platelet aggregation and in preventing thrombotic complications. Prostacyclin analogues have a short half-life of 15±30 min and have been preferred in cardiac and vascular surgery for anticoagulant coverage in patients with HIT. They are also used in intensive care units for anticoagulation during renal replacement therapy The main side-effects are hypotension and bradycardia. Low molecular weight heparin and HIT Low molecular weight heparin does not bind strongly to plasma proteins and endothelial cells; its bioavailability is much greater than with unfractionated heparin and there is also a more predictable dose response. However, low molecular weight heparins have a high in vitro crossreactivity rate with heparin-dependent antibodies, reaching 100% in some very sensitive assays. Low molecular weight heparins can cause HIT, 72 and when used in its treatment there is a signi cant risk of recurrent or progressive thrombocytopenia with or without thrombosis. Because of these drawbacks, and as there are other effective drugs available, low molecular weight heparins are not recommended for the management of patients with HIT. 67 Danaparoid in HIT Danaparoid sodium (Orgaran â ) does not contain heparin and is a low molecular weight heparinoid. It is a mix of dermatan sulphate, glycosaminoglycans and chondroitin sulphate. The use of danaparoid is associated with a favourable outcome in 90% of patients with HIT. 11 The main activity of danaparoid is against factor Xa, with the anti-xa:anti-iia ratio of 22:1 resulting in inhibition of brin formation. The potential disadvantage is the prolonged halflife of anti-factor Xa activity (around 25 h). This is disadvantageous for patients who are at risk of bleeding and who might need a surgical procedure. There is a 10±20% cross-reactivity rate with HIT antibodies in vitro, although it is less common in vivo Danaparoid does not interfere with INR measurements, and therefore allows concurrent and easy monitoring of warfarin anticoagulation. Thrombin inhibitors in HIT Thrombin plays a central role in HIT-related thromboembolic complications (Fig. 2). Thrombin generation is enhanced in HIT by the concomitant activation of platelets, 13 the generation of platelet microparticles and the alteration of endothelial cells. 80 Thrombin inhibitors such as lepirudin and argatroban have found a greater role in the management of HIT/HITT. 39 Thrombin inhibitors currently available for the management of HIT and HITT are: (i) lepirudin (Re udan â ); (ii) argatroban (Argatroban â, Novastan â ); (iii) hirulog and bivalirudin (Angiomax â ) and (iv) desirudin (ReVase â ). Lepirudin is currently licensed for the treatment of HIT/ HITT in the UK, the USA and Europe. Argatroban has recently been approved for use in the prophylaxis and treatment of thrombosis in HIT in the USA and Canada. Bivalirudin and desirudin are currently not licensed for use in HIT/HITT, although their use in the treatment of this condition has been reported. Hirudin is a direct inhibitor of thrombin and acts independently of cofactors such as antithrombin. 52 Unlike heparin, hirudin is not inactivated by PF4 and may be more effective in the presence of platelet-rich thrombi. 59 Hirudin can also inhibit thrombin bound to brin or brin degradation products Lepirudin (Re udan â ) is a recombinant hirudin derived from yeast cells and is a highly speci c direct and irreversible inhibitor of thrombin. One molecule of lepirudin binds with one molecule of thrombin. The halflife for distribution and elimination is 10 min and 1.3 h respectively. Lepirudin is almost exclusively excreted in the kidneys and hence systemic clearance of lepirudin is 680

6 HIT/HITT and alternative anticoagulation Table 5 Comparison between lepirudin and argatroban 7 Lepirudin Argatroban Mechanism Direct thrombin inhibitor Direct thrombin inhibitor Irreversible inhibition Reversible inhibition Dosing 0.4 mg kg ±1 bolus i.v. followed by infusion of 0.15 mg kg ±1 h ±1. Dose adjustment required in renal insuf ciency Monitoring aptt, ecarin clotting time aptt Half-life (min) 40±120 24±50 Reversal agent None None Start at 2 mg kg ±1. Dose can be increased up to a maximum of 10 mg kg ±1 min ±1. Dose adjustment required in hepatic insuf ciency Table 6 Dosing adjustment for lepirudin 7 Creatinine clearance Serum creatinine concentration Adjusted infusion rate (ml min ±1 ) (mmol l ±1 ) (% of standard initial infusion rate) (mg kg ±1 h ±1 ) 45±60 140±176 50% ± ±264 30% ± ±528 15% <15 >528 Avoid or stop infusion Haemodialysis patients Give 0.1 mg kg ±1 every other day only if the aptt falls below the lower therapeutic limit of 1.5 dependent on the glomerular ltration rate. It should therefore be used cautiously in patients with chronic renal failure and should be avoided in patients with acute renal failure (Table 5). There is an increased risk of bleeding with other anticoagulants, thrombolytics and antiplatelet drugs. The usual adult dose is 0.4 mg kg ±1 as a bolus over 15±20 s, followed by 0.15 mg kg ±1 h ±1 initially; adjustments are then made on the basis of the activated partial thromboplastin time (aptt) (Table 5). However, the dose should not exceed an infusion rate of 0.21 mg kg ±1 h ±1 without checking for coagulation abnormalities. In haemodialysis patients and patients with acute renal failure with creatinine clearance <15 ml min ±1 (normally 120 ml min ±1 ) or serum creatinine >528 mmol litre ±1, the drug should be avoided. The infusion rate should be adjusted in patients with renal impairment (Table 6). Ecarin clotting time (ECT) is a suitable assay for bedside real-time monitoring of lepirudin anticoagulation. Ecarin is a metalloproteinase from snake venom (Echis carinatum) that activates prothrombin to meizothrombin. Hirudin forms a 1:1 complex with meizothrombin, thus preventing the conversion of brinogen to brin and the formation of thrombin. Therefore, the clotting time is prolonged with increasing amounts of hirudin. The precision of the ECT assay is directly related to the prothrombin and brinogen concentration, but does not seem to be affected by the presence of heparin or oral anticoagulants. 54 The speci city of the ECT-determined lepirudin concentration is not in uenced by treatment with oral anticoagulants. ECT is a rapid, sensitive clotting assay suitable for precise measurement of plasma concentrations of lepirudin in nonprothrombin-de cient states without interference from heparin or aprotinin or from treatment with oral anticoagulants. 54 Published clinical data regarding the use of this monitoring tool come mainly from case reports. Ecarin clotting time values showed good correlation with plasma concentrations of lepirudin. In these reports, an ECT of 350±400 s corresponds to lepirudin concentrations of 3.5± 4 mg ml ±1. 42 The Heparin-Associated Thrombocytopenia Trials (HAT-1 and HAT-2) are prospective clinical trials of lepirudin. The clinical outcomes of patients were compared with those of a historical control group. A meta-analysis of these trial results 29 represents the largest population of patients with HIT and thromboembolic complications treated with lepirudin. Overall, 198 patients (82 in HAT-1, 116 in HAT-2) were treated with lepirudin and 182 historical control patients were given other treatments. All except ve (one in HAT-1, four in HAT-2 group) prospective patients and all historical control patients were diagnosed with HIT using the heparin-induced platelet activation assay or equivalent assays for testing. In total, 113 (54 in HAT-1, 59 in HAT-2) prospective patients (lepirudin) and 91 historical control patients presented with thromboembolic complications at baseline (day of positive test result) and quali ed for direct comparison of clinical endpoints. In the meta-analysis, the pooled lepirudin patients of the HAT-1 and HAT-2 studies who presented with thromboembolic complications at baseline were compared with the respective historical control patients. Seven and 35 days after the start of treatment, the cumulative risks of death 681

7 Pravinkumar and Webster Table 7 Results of argatroban study: categorical ef cacy analysis. 44 Values are n (%). a All-cause death, all-cause amputation or new thrombosis within 37- day study period; b severity ranking: all-cause death > all-cause amputation > new thrombosis; patients with multiple outcomes counted once; c patients counted only once if multiple events occurred. (Adapted with permission from Lewis et al.) 44 HIT arm HITTS arm Control Argatroban Control Argatroban Variable (n=147) (n=160) P-value (n=46) (n=144) P-value Primary ef cacy end-point Composite end-point a 57 (38.8) 41 (25.6) (56.5) 63 (43.8) (OR=0.54, 95% CI 0.33±0.88) (OR=0.60, 95% CI 0.31±1.17) Secondary ef cacy end-point Components by severity b Death (all causes) 31 (21.8) 27 (16.9) (28.3) 26 (18.1) Amputation (all causes) 3 (2.0) 3 (1.9) (8.7) 16 (11.1) New thrombosis 22 (15.0) 11 (6.9) (19.6) 21 (14.6) Death caused by thrombosis 7 (4.8) 0 (0.0) (15.2) 1 (0.7) <0.001 Any new thrombosis c 3 33 (22.4) 13 (8.1) < (34.8) 28 (19.4) OR=odds ratio; CI=con dence interval. were 4.4 and 8.9% respectively in the lepirudin group, compared with 1.4 and 17.6% in the historical control group. The cumulative risks of limb amputation were 2.7 and 6.5% in the lepirudin group compared with 2.6 and 10.4% in the historical control group. Most importantly, the cumulative risks of new thromboembolic complications were 6.3 and 10.1% in the lepirudin group and 22.2 and 27.2% in the historical control group. The differences in the cumulative risk of death, limb amputation or new thromboembolic complications between the groups were statistically signi cant in favour of lepirudin in the analysis of time to event (P=0.004). Bivalirudin (Angiomax â ) is a direct thrombin inhibitor and an analogue of the peptide fragment hirugen, a compound derived from hirudin. Unlike lepirudin, the binding of bivalirudin to thrombin is reversible. Bivalirudin binds speci cally to the catalytic site and substrate-binding site of thrombin. Bivalirudin has been approved by the US Food and Drug Administration (FDA) for use in patients undergoing coronary angioplasty with unstable angina who are also on aspirin therapy. Argatroban (Argatroban â, Novastan â ) is a direct competitive synthetic inhibitor of thrombin derived from L- arginine, with a molecular weight of 526. It binds reversibly to the thrombin catalytic site and thus inhibits reactions that are catalysed or induced by the presence of soluble and clotbound thrombin. Actions inhibited by the presence of argatroban include brin formation and activation of coagulation factors V, VIII and XIII and the natural anticoagulant protein C It is 100% bioavailable when given i.v. and is metabolized in the liver by cytochrome P450 enzymes. Unchanged drug is excreted in the urine (16%) and faeces (14%). The primary metabolite exerts an anticoagulant effect that is three to ve times less potent than that of the parent drug. It is eliminated as its metabolite in the faeces (65%), presumably through biliary secretion, and in the urine (22%). Argatroban is contraindicated in patients with active bleeding or known hypersensitivity to the agent. Bleeding is the major adverse effect of argatroban, occurring in 2.3±14.4% of patients in clinical trials. The effective dose is titrated against the aptt and activated clotting time (ACT). The drug has a predictable pharmacokinetic and pharmacodynamic pro le, and there is dose-dependent response in aptt and ACT. Argatroban is given as an initial bolus of 2 mgkg ±1 min ±1 in adult patients without hepatic impairment. The infusion rate is titrated according to the desired level of anticoagulation. An aptt ratio of 1.5±3.0 is usually achieved within 4 h of i.v. administration. A study with argatroban enrolled 304 patients into two armsð160 patients in the HIT arm and 144 in the HITT arm (Table 7). They were compared with 193 historical control subjects with HIT (n=147) or HITT (n=46). 44 Outcomes of these patients were compared with those of the historical controls for a period of 37 days after administration of argatroban in the treatment group and after diagnosis of HIT or HITT in the control group. The primary ef cacy endpoint was a composite of all-cause death, all-cause amputation and new thrombosis within 37 days of baseline. The secondary ef cacy end-point included the individual components of the composite end-point together with death caused by thrombosis, any new thrombosis, achievement of adequate anticoagulation, and resolution of thrombocytopenia. Argatroban was initiated at 2 mg kg ±1 min ±1 and titrated to maintain aptt at 1.5±3 times baseline for 14 days. Treatment continued for an average of 5.3 days in the HIT group and 5.9 days in the HITT group. In patients with HIT, argatroban therapy signi cantly reduced new thrombosis when compared with control subjects (8.1 vs 22.4%, P<0.001). However, the reduction in new thromboses in patients with HITT on argatroban therapy was more modest when compared with the reduction in the controls (19.4 vs 34.8%, P=0.044). There was no decrease in death or amputation caused by all causes in the HIT and HITT groups, but a signi cant reduction was seen in death caused by thrombosis in both groups (P=0.005 and P<

8 HIT/HITT and alternative anticoagulation respectively). Argatroban was associated with more rapid resolution of thrombocytopenia and no increase in bleeding. Argatroban has also been shown to be more effective than heparin for coronary reperfusion after the use of recombinant tissue plasminogen activator (r-tpa) in acute myocardial infarction. 36 The use of warfarin with argatroban results in prolongation of the INR beyond that produced by warfarin alone. For doses up to 2 mgkg ±1 min ±1, the equivalent INR on warfarin alone (INR W ) can be calculated from the INR for cotherapy of warfarin and argatroban (INR WA ) according to a published graph. 48 The error associated with this prediction is 60.4 units. For argatroban doses >2 mg kg ±1 min ±1, the relationship is less predictable and the error of prediction is 61 units. The equivalent INR on warfarin alone (INR W ) cannot be predicted reliably from the INR WA at doses greater than 2 mg kg ±1 min ±1. 48 Other alternatives in HIT There are no convincing data available for the use of the following alternatives. However, they may have a role as an adjunct with other anticoagulants: (i) intravenous immunoglobulins (IgG class); (ii) platelet transfusionðcan increase new thromboembolic complications and is not indicated currently even as an adjunct in the treatment of HIT; (iii) plasma exchangeðits effectiveness is in doubt; (iv) fresh frozen plasmaðsome use in HIT complicated by warfarin therapy; (v) glycoprotein IIb/IIIa inhibitor. Post-heparin thrombosis Studies have shown that HIT antibodies are capable of activating platelets in a non-heparin-dependent manner, as a result of the generation of `superactive' HIT antibody. 1 Using serum of patients with HITT, peripheral blood monocytes and monoclonal antibodies speci c for H±PF4, researchers have shown that monoclonal antibodies and antibodies from patients with HITT induce monocyte activation with secretion of interleukin 8 and cell-surface procoagulant activity. The time-dependence of these changes in vitro (>6 h) far exceeds the short incubation period (<1 h) required for platelet activation by H±PF4 antibodies. Hence, it is suggested that these changes in the monocyte could amount to the pathogenesis of thrombi after the discontinuation of heparin. 5 Summary It is important to have a high index of clinical suspicion in a patient with a falling platelet count who is receiving heparin. It is imperative to discontinue all sources of heparin even before the laboratory con rmation of HIT. Platelet transfusion is contraindicated as this can exacerbate the serious thrombotic complications. Circulating antibodies bind to the transfused platelets and release platelet microparticles, leading to a thrombotic state. Treatment is intended to reduce the thromboembolic complications. There are several pharmaceutical agents available for the treatment of HIT. Before starting any of these agents, the clinician should decide which of them is safe and effective for the individual patient. Lepirudin is an irreversible, direct thrombin inhibitor that has shown effectiveness in treating patients with HIT type II. It does not cross-react with heparin and can be readily monitored with the aptt and ECT. Disadvantages include a prolonged half-life, prolongation of the prothrombin time, possible antibody formation, and the requirement for dose adjustments in patients with renal impairment. 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