Heparin induced thrombocytopenia and thrombosis

Heparin Induced Thrombocytopenia and Thrombosis Karthik Ananthasubramaniam, Mohammed Shurafa, and Anil Prasad

Heparin remains the most commonly used parenteral medication in hospitalized patients. Heparin induced thrombocytopenia (HIT) and heparin induced thrombocytopenia with thrombosis syndrome or the white clot syndrome are important complications of heparin use. This article provides an indepth review of the etiopathogenesis, clinical manifestations, diagnosis, and management options in patients with HIT. Clinical problems associated with HIT such as antiphospholipid antibody syndrome and venous gangrene are described. The management options of HIT patients during cardiac interventional procedures and coronary surgery as well as recent advances in therapeutic options are summarized. Copyright 娀 2000 by W.B. Saunders Company

H

eparin is a mucopolysaccharide with a molecular weight ranging from 3,000-30,000 d and is the most commonly used intravenous medication in hospitalized patients. Because it is widely used in hospitalized patients with venous thromboembolic disease, acute myocardial infarction (MI), as an adjunct to thrombolytic therapy, in unstable angina, or in those predisposed to a thromboembolic state, it is paramount that clinicians are aware of its side effects and potentially devastating complications. Heparin induced thrombocytopenia (HIT) occurs in 5% to 10% of heparin treated patients1-4 but is usually of little clinical impact and resolves once heparin is stopped. Heparin induced thrombocytopenia and thrombosis (HITT) or the white clot syndrome (WCS) is a more serious manifestation of HIT where platelets auto aggregate to form white clots and cause medium to large vessel occlusion leading to widespread thrombosis and gangrene. Although it occurs only in 10% to 20% of patients who develop HIT, its consequences can be severe with mortality as high as 30% and permanent morbidity of approximately 20% to 30%.5 The

true incidence of HITT is difficult to estimate because there have been no comparably designed, prospective, large-scale trials investigating the frequency of HIT. Pooled analysis6,7 indicate that HIT is more common with the intravenous than subcutaneous route, and the frequency of HITT may be between 0% to 30% depending on the patient groups studied, types of heparin used, and the varying definitions of thrombocytopenia.8

Clinical Classification For purposes of clinical differentiation, the more benign form of HIT is referred to as HIT I. HIT I is associated with mild thrombocytopenia (100,000130,000/µL) occurring usually 1 to 4 days after initiation of heparin. It usually has no clinical impact and resolves when heparin is stopped and is not associated with thrombotic complications. This form of thrombocytopenia is said to be caused by direct interaction between heparin and platelets rather than an antibody mediated effect.9 HIT II is the more serious but less common manifestation of HIT. It usually occurs approximately 7 to 10 days after heparin therapy, although previous exposure to heparin may herald an earlier onset. HIT II is associated with more severe thrombocytopenia (⬍100,000/µL) and is caused by an antibody mediated effect on platelets and has increased predilection for venous and arterial thromboembolic events such as venous

From the Divisions of Cardiology, Hematology, and Pathology, Henry Ford Hospital, Detroit, MI. Address reprint requests to: Karthik Ananthasubramaniam, MD, Henry Ford Hospital, Heart and Vascular Institute, K-14, 2799 W Grand Blvd, Detroit, MI 48202; e-mail: [email protected]. Copyright 娀 2000 by W.B. Saunders Company 0033-0620/00/4204-0002$10.00/0

Progress in Cardiovascular Diseases, Vol. 42, No. 4 (January/February), 2000: pp 247-260

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thrombosis, venous gangrene, pulmonary embolism, MI, stroke, visceral infarction, and limb gangrene.9

Pathophysiology The mechanism of HIT and HITT is believed to be immune as a heparin dependent antiplatelet antibody has been isolated in the sera of a number of such patients.2 Evidence for the involvement of immunoglobulins in HIT was provided as early as 1973 by Rhodes et al10 who showed that purified immunoglobulin G (IgG) from sera of patients with HIT was capable of inducing platelet aggregation in the presence of heparin. Heparin-dependent immunoglobulin M (IgM) and immunoglobulin A (IgA) antibodies have also been described and recent evidence suggest that they also can precipitate HIT.11 Heparin forms a complex with platelet factor 4 (H-PF 4), which is recognized by the heparin induced immunoglobulin IgG leading to aggregation via the Fc receptor (Fc␥R11) on IgG.12,13,14 HIT patients have an increased expression of Fc receptors on their platelet surface. These platelets have a higher tendency to aggregate in the presence of heparin. Recently, genetic polymorphisms of the Fc receptor (Fc␥R11AHis131 allele), have been identified suggesting that patients with this polymorphism may be susceptible to HIT.15 Heparin induced antibodies are powerful platelet activators and cause the release of thromboxane A2 and platelet microparticles.16-21 These microparticles are negatively charged phospholipids with potent procoagulant activity. Nonimmune mediated activation of platelets has also been reported where patients have developed HIT without previous exposure to heparin with resolution of the syndrome despite continuation of heparin. Many patients with nonimmune thrombocytopenia have concomitant conditions such infection, malignancy, MI, and auto-immune disorders such as systemic lupus erythematosus and antiphospholipid antibody syndrome (APLS), which may cause a synergetic effect by releasing bacterial, immune complexes, or other platelet activating factors that may promote platelet aggregation and precipitate HIT. In patients with nonimmune HIT, throm-

bocytopenia does not occur on rechallenge with heparin.2,17,18

Heparin Induced Thrombocytopenia and Thrombosis or the White Clot Syndrome HITT or WCS is a subcategory of HIT where patients progress to develop platelet clots (white clots) leading to widespread venous and arterial thrombotic events. Clinical manifestations vary from mild ischemia of extremities to limb threatening gangrene (Fig 1), MI, stroke, or pulmonary emboli. The most common sites of arterial thrombosis are the distal aorta and the ileo-femoral vessels. Although these platelet thrombi occur in the arterial system, venous thrombosis seems to be much more commonly seen (Fig 2), particularly in the postoperative setting. In one study, pulmonary embolism was found to be the most common venous thrombotic event and the most common cause of death in HITT patients.22 HITT may also present as disseminated intravascular coagulation syndrome.23 Massive adrenal hemorrhage and shock may be yet another uncommon but devastating presentation.24 Earlier and subtle clinical signs may also include skin necrosis because of microvascular thrombi around the area

Fig 1. Extensive necrosis and gangrene of the fingers of a woman secondary caused by heparin induced thrombocytopenia and thrombosis leading to arterial occlusion.

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of injection, if the route of heparin administration is subcutaneous.25-28 Increased resistance to heparin,18,29 or abdominal and limb pain30,31 may be other signs of impending HIT. Clinical conditions that increase the risk of HIT in patients are sepsis, recent surgery, and atherosclerotic vascular disease with or without recent vascular instrumentation, all of which set the stage for endothelial damage. In 1958 Weisman et al32 reported 10 patients who developed arterial embolism when administered heparin and speculated that heparin was the cause. Similarly Roberts et al33 reported 11 patients who had arterial thrombi when administered heparin and suggested that platelet deposition as a result of antigen-antibody reaction may be the causative mechanism. Makhoul et al34 in their series of 25 patients with HITT observed that there was no relation to age, sex, route of heparin administration, or amount of heparin given to the development of this syndrome. Most of their patients had vascular instrumentation in the involved extremity lending weight to the hypothesis that endothelial damage after instrumentation can initiate HITT. This mechanism of endothelial damage precipitating HITT also has been shown in studies by Cines et al.35 In their retrospective review of 23 cases Chang et al36 observed the occurrence of HITT in patients older than 55 years of age predominantly within 10 days after initiation of therapy, which is consis-

Fig 2. A histopathologic section of amputated gangrenous lower extremity of a patient secondary to HITT. Partially occlusive thrombi filling the lumen of artery (left) and vein (right) in different stages of evolution, with associated inflammatory reaction in the adjacent soft tissue (Hematoxylin and eosin stain magnification ⴛ40).

tent with published reports.2,37,38 Regardless of the route, thrombocytopenia occurs earlier within 3 to 4 days of heparin therapy if prior exposure to heparin is present because of immune sensitization.5 Different heparin preparations are associated with varying frequencies of heparin induced thrombocytopenia with bovine heparin having a higher frequency of thrombocytopenia than porcine heparin.2,39

Diagnosis The clinical diagnosis of immune mediated HIT is suspected when (1) the platelet count drops below 150 ⫻ 109/L or is less than 30%-50% of baseline levels after initiation of heparin; (2) absence of other causative factors for thrombocytopenia like drugs, infections, malignancy, and autoimmune disorders; and (3) the platelet count returns to normal after discontinuation of heparin. The detection of heparin dependent platelet aggregating body is yet another diagnostic feature of HIT but is not mandatory for the diagnosis. The first 2 criteria must be satisfied for a diagnosis of HIT. In the absence of thrombocytopenia, the occurrence of new thromboembolic events or skin necrosis while heparin is being administered should raise the suspicion of HIT. A prolonged duration for recovery of platelet count after stopping heparin should prompt investigation for

250 other causes of thrombocytopenia as described earlier. Laboratory confirmation of HIT can be obtained by performing either platelet aggregation tests, serotonin release assays or enzyme linked immunoasorbant assay (ELISA) tests. The principle of the platelet aggregation test involves mixing the patient’s plasma with an adequate size pool of normal donor platelets and testing for platelet aggregation. If aggregation occurs then it is repeated with protamine sulfate. If the patient’s plasma shows no aggregation after protamine then it is concluded that a heparin dependent platelet aggregating factor is present in the plasma. An important prerequisite in performing heparin aggregating tests seems to be in obtaining an adequate pool of normal donors’ platelets because 50% of normal people lack the ability to detect heparin dependent factor.40 Thus an inadequate sample of normal plasma may lead to a false negative tests. This assay is the cheapest, quickest, and the most widely available test for HIT. Although its specificity is approximately 90%, its sensitivity is 30% to 50%,17,41-43 which may limit its clinical usefulness. Using a good donor pool as specified before,40,44 however may raise its sensitivity to approximately 80%. The heparin induced platelet aggregation assay test (HIPA) uses washed platelets instead of platelet rich plasma and has a higher sensitivity and specificity.45 The C-serotonin release assay14 is considered the gold standard for the diagnosis of HIT, and is used in many laboratories.46 The principle of this test is to measure whether the patient’s sera can activate normal donor platelets in the presence of a low and a high concentration of heparin (0.1 and 100U/mL, respectively). A positive test is one in which serotonin release occurs at the lower but not the higher concentration of heparin. This assay is a more sensitive, but more expensive, and less widely available test, and as it involves the use of radioactive serotonin, it may not be available on a daily basis. The ELISA47 test uses microtiter plates coated with heparin and recombinant PF-4. The patient’s sera is added and antibody binding is detected by adding monovalent or polyvalent antiserum against IgG, IgA or IgM. This test is more sensitive than the serotonin assay (90%) and may be of value in determining whether recipients of heparin in whom thrombo-

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cytopenia develops can undergo re-exposure to heparin during surgical procedures. It may also be used for identifying antibodies that are cross reactive with low molecular weight heparin (LMWH) or danaparoid. In patients with arterial thromboembolism, surgical specimens or autopsy material showing platelet clots confirm the diagnosis of WCS. Prospective studies are needed to determine the actual utility of ELISA in the diagnosis of HIT. It is to be emphasized that the diagnosis still depends on high clinical suspicion, and heparin should be withheld in suspected cases even if tests are negative.

Treatment General Principles Immediate cessation of exposure to all routes of heparin is the first step in the treatment of HIT. Particular attention should be paid to eliminating heparin flushes (used in intravenous lines) and substitution with saline flushes should be performed. Confirmation of the diagnosis with available tests should be attempted, but clinical suspicion should prevail if the initial testing is negative. The initiation of coumadin should be avoided in the acute stage of HIT as it can paradoxically elevate thrombosis by depleting proteins C and S.48 Once the thrombocytopenia has resolved, long-term anticoagulation can be initiated with coumadin. If extensive thrombosis is present, consideration of thrombolytic therapy and/or early surgical intervention (discussed later) may be needed if gangrene is present. The hematologist should be involved early in the decision process to facilitate appropriate therapy. Although the use of aspirin and other antiplatelet drugs have been suggested in cases of HITT49 to block thromboxane mediated platelet aggregation, the heparinplatelet antibody continues to promote aggregation showing that there may be other pathways apart from the arachidonic acid pathway through which platelet aggregation is mediated.50 Therefore, aspirin or other antiplatelet therapies are incapable of fully preventing HITT and their role in treatment of this condition is of unclear significance. Prostacyclin analogues51-53 and fibri-

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nolytic54-57 therapy have been tried in anecdotal cases, but there are no controlled studies.

Specific Therapies for HIT Argatroban. Recently, the use of argatroban, a new fast acting parenteral direct thrombin inhibitor, has been shown to be safe in the setting of HIT. Becker et al,58 in their trial with HIT and HITT patients (the ARG-11 trial) administered argatroban (Novastan; SmithKline Beecham, Philadelphia, PA) at a dose of 2.0 ⫾ 0.1 microgram/kg/ min as an infusion. Both in their trial and in the study of Lewis et al,59 patients administered argatroban had 30% to 40% less new thrombosis, deaths and, amputation compared with patients with HIT given conventional therapy. There was significant resolution of thrombocytopenia and no increase in bleeding. Other reports of successful use of argatroban in HIT also have been published.60,61 Major studies using argatroban in HIT patients undergoing cardiopulmonary procedures and percutaneous interventions are nearing completion and more insight into the potential use of this medication for HIT patients will be available once the results of these studies are available. Recombinant-hirudin. The use of recombinant hirudin (r-Hirudin) in the treatment of HIT has been studied by Janssens et al,62 in 29 patients. They showed that it provided safe anticoagulation accompanied by rapid recovery of platelet count and suggested that it could be used as a safe alternative to heparin in the HIT syndrome. Although major studies such as TIMI-9B63 and GUSTO-2B64 have not shown r-Hirudin to be superior to heparin in patients with acute coronary syndromes, these trials have established the antithrombotic efficacy of hirudin as well as its safety. In the absence of cross reactivity with heparin, hirudin seems to be a good alternative for antithrombotic therapy in patients with HIT. r-Hirudin has received FDA approval for use in the treatment of HIT. Danaparoid. A heparin like drug, danaparoid (Orgaran; Organon Inc, West Orange, NJ) has been used in studies to treat patients with HIT/ HITT.65,66 This drug requires the presence of antithrombin III and heparin cofactor II for therapeutic efficacy. Prior laboratory testing is

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needed to rule out cross reactivity with heparin antibodies, which have been observed with certain patients to avoid exacerbating HIT. The degree of cross-reactivity with unfractionated heparin (UFH) is less than that of LMWH. Because this medication has a prolonged half-life (7-25/h) it may be difficult to neutralize once administered because of the lack of an effective antidote (protamine is ineffective). Caution, particularly in patients with renal failure is needed because danaparoid is excreted via the kidneys. In 230 patients who received this drug for HIT,65 93% of patients responded adequately during the treatment period, although in other studies, bleeding problems were significant because of the lack of an effective antidote for quick reversal of effects.66 This is its major limitation in contrast to direct thrombin inhibitors where, although there are no effective antidotes for argatroban and hirudin, the half life of direct thrombin inhibitors is much less (30 minutes), making the control of a hemorrhagic complication easier. Furthermore, argatroban is relatively safe to use in renal failure patients although dosage adjustment is needed in patients with hepatic involvement. Ancrod. In Canada, defibrinating snake venom, ancrod, has been used in the treatment of HIT.67 It is immunologically distinct from heparin and does not cause thrombocytopenia. It acts by cleaving fibrinopepetide A from fibrinogen and is monitored by measuring serum fibrinogen levels. Although successful use of this medication has been reported in HIT patients,68,69 this has not been approved for use in the United States. Fibrinolytic Therapy. In severe cases of HIT/ HITTS with major thrombotic complications, the use of thrombolytic therapy with agents such as urokinase or streptokinase has been reported with good results.54-57 Plasma Exchange. A small series of HIT patients where the thrombocytopenia and thrombotic complications have been managed with repeated plasma exchanges have been reported.70-73 Plasma exchange works on the principle of removing heparin-associated IgG antibodies. When performed repeatedly with the adjunctive use of antiplatelet agents, reversal of HIT has been reported. Surgery. Surgical intervention for limb salvage in severe cases of HITT has also been

252 performed when extensive occlusion leading to gangrene becomes a major complication.51,74,75 Inferior vena cava filter placement as a temporary measure to prevent pulmonary embolism in HIT patients with lower extremity thrombosis has been attempted but has been complicated by caval thrombosis.51 Abxicimab. Fareed et al,76 have shown that plasma of patients with HIT when treated with platelet IIb/IIIa inhibitor abxicimab (Reopro; Eli Lilly, Indianapolis, IN) did not show any aggregation, and that both the luminescence aggregometry method and the serotonin release method used for evaluating heparin induced platelet aggregation were inhibited by abxicimab. Also, by flow cytometry they showed P-selectin and microparticle inhibition by abxicimab. This and other in-vitro studies,77,78 have raised the interesting possibility of the role of platelet glycoprotein IIb/IIIa inhibitors in treatment of HIT although further investigation in treating HIT patients are needed before drawing any conclusions. Because profound thrombocytopenia is an uncommon but serious side effect of abxicimab63,64 its exact role in the setting of coronary angioplasty in HIT patients requires further study. The Low Molecular Weight Heparins LMWH. These agents deserve special mention as they are rapidly moving into the front-line as an alternative therapy to heparin in venous thromboembolic disease.79-81 LMWH is derived from repeating disaccharide subunits of uronate glucosamine and has a much higher Factor Xa/antithrombin 111 activity ratio than UFH. It also binds less to platelet factor 4 and has a much more predictable anticoagulant effect than heparin.82-84 Several studies have reported that LMWH administered in HIT patients after ruling out cross reactivity (by platelet aggregation assay or ELISA) results in a favorable outcome. If cross reactivity is present, thrombotic events may be significantly increased.83,84 Because the cross reactivity in studies have been close to 100%,41,85 we feel that LMWH should not be used in HITT and either r-Hirudin or argatroban should be the alternative therapy. If LMWH is to be used in HITT, it should be only after a negative cross reactivity test with UFH. Close monitoring of thrombotic events and platelet counts are mandatory when LMWH is substituted for heparin in HIT patients.

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Special Issues in Patients With Heparin Induced Thrombocytopenia HIT and the Antiphospholipid Antibody Syndrome Characteristic of both syndromes, thrombosis may occur in virtually all arterial and venous sites. In general, venous events are more common than arterial ones. Arnout et al86 have described the similarities in pathogenic mechanisms between HIT and APLS. Because not all patients with HIT or APLS develop thrombosis, a second insult may serve as a trigger to initiate the thrombotic cascade in both these entities. An example of such triggers would be vascular instrumentation predisposing to endothelial damage as alluded to earlier. Both syndromes can be associated with arterial and venous thrombotic episodes. HIT patients with cardiovascular risk factors have a tendency for arterial thrombosis whereas postoperative patients have a predilection for venous thrombosis.87 Arterial and less commonly venous thrombotic events can occur also in APLS in the same scenario described for HIT before.87,88 In APLS the antibodies are directed against protein bound phospholipid rather than the phospholipid itself, similar to HIT where the antibody is not directed toward heparin but to the heparin-PF4 complex. In both syndromes the cellular Fc␥ receptor plays a role in the initiation of the thrombotic cascade.18,87,88 Furthermore, there have been few case reports of successful treatment of HIT89,90 and APLS91-97 with high dose intravenous immunoglobulin. This response to the same modality of treatment suggests that the pathogenic pathways in the thrombotic cascade involve a Fc␥ receptor mediated mechanism, although a possible role for anti-idiotypic antibodies have been suggested.96 The similarities mentioned before suggest that use of heparin in patients with APLS should be cautious with close monitoring of platelet counts because a double hit on the platelet may be a potential mechanism for interaction of these 2 disease processes.

Heparin and Venous Limb Gangrene Although heparin has been known to cause arterial thrombosis, recently it was shown to be causative in venous limb gangrene without con-

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comitant warfarin in the presence of thrombocytopenia. Warkentin et al48 suggested that in the presence of HIT, when warfarin therapy is initiated, the chances of venous limb gangrene increases. The prothrombotic state created by the HIT is aggravated by the initiation of warfarin resulting in accelerated thrombosis because of quicker depletion of protein C secondary to warfarin. (compared with the other vitamin K dependent clotting factors). Important factors in their series that may have contributed to this may have been the larger doses of warfarin given to some of these patients, presence of low protein C in one patient that may have been exacerbated by the larger doses of warfarin, and the fact that heparin itself has been associated with venous limb gangrene. Venous limb gangrene can occur in the presence of HIT alone, or with warfarin (particularly when large initial loading doses are used), and in the presence of a existing thrombotic state such as deep vein thrombosis.98 Clinicians should be aware of this entity that may be clinically indistinguishable from warfarin induced skin necrosis and HITT. Warfarin skin necrosis usually involves breasts, thighs, buttocks, and less commonly limbs. It usually occurs in patients with concomitant protein C deficiency and/or protein S deficiency, whereas HITT involves veins and/or arteries and is composed predominantly of platelets. The use of large initiating doses of warfarin should be avoided because there is no data to support such practice. If HIT is recognized, alternate modes of anticoagulation such as direct acting antithrombins hirudin,99 danaparoid,66 or argatroban59 should be used. Although LMWH has been used in cases of HIT, cross reactivity (up to 80-100%) with UFH causing acceleration of thrombocytopenia and thrombosis is a potential problem. Danaparoid also has approximately 20% cross reactivity to heparin but is much less cross reactive than LMWH because it has one less sulfate group per saccharide, with a molecular weight of 4 to 10 kilodaltons, in contrast to heparin that has an additional sulfate group per saccharide. We feel that laboratory testing with platelet aggregation assay testing for cross reactivity should be performed and LMWH or danaparoid should be initiated only if the tests are negative for cross-

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reactivity. It should be noted that a positive in-vitro cross-reactivity test does not automatically lead to in vivo complications. Recently Warkentin et al100 have reported a 0% incidence of HITT in patients treated with LMWH as an alternative for UFH. The phenomenon of venous limb gangrene occurring in HIT patients treated with warfarin reiterates the issue that sufficient overlap between heparin therapy and initiation of warfarin is probably needed in this subgroup of patients to overcome the procoagulant mileu created by early initiation of warfarin caused by depletion of protein C.

Cardiac Catheterization and Percutaneous Transluminal Coronary Angioplasty in Patients With HIT Patients undergoing percutaneous cardiovascular procedures such as cardiac catheterization and percutaneous transluminal coronary angioplasty (PTCA) require use of heparin. Reports of acute MI occurring during PTCA because of HIT have been documented.101,102 Precipitation of HIT by arterial or venous puncture or intra-aortic balloon pump insertion have also been reported.34 Therefore these procedures, which normally require heparin, need to be planned carefully to avoid serious adverse effects in HIT patients. If heparin is avoided, then diligent attention to frequent catheter flushing is needed to eliminate the small clots, which can form during these procedures. In patients who require angioplasty, the situation is even more difficult as adequate activated clotting time (ACT) in the range of 250-300 seconds is usually preferred. This is to ensure prevention of complications, such as acute closure, and is usually achieved with frequent boluses of heparin. The use of hirudin62,99 or argatroban61 to maintain an adequate ACT are the safest alternatives but information is limited to case reports. Consultation with a hematologist is crucial. Argatroban has been successfully used in the clinical setting of coronary stent placement in a patient with HITT.60 The ARG 310 multicenter open labeled trial is studying the use of argatroban in approximately 30 HIT/HITT patients undergoing various cardiac interventional procedures with study endpoints of procedural success, and ability

254 to achieve appropriate anticoagulation during the procedure. Abxicimab (ReoPro), a platelet glycoprotein IIb/IIIa inhibitor, has been shown in in-vitro studies to inhibit heparin mediated platelet aggregation and in-vitro generation of thrombin.76-78 The safety of this medication during cardiac interventional procedures in HIT patients is unknown. Ticlopidine and clopidogrel (antiplatelet agents) that work by inhibiting adenosine phosphate (ADP) mediated platelet activation are agents, which are now routinely used along with aspirin to prevent subacute stent thrombosis. The use of these agents in patients with HIT is not well studied but preliminary experimental data103 using experimental ADP receptor antagonists show inhibition of platelet activation/aggregation in the sera of HIT patients. These data suggest a potential role for ADP receptor antagonist use in HIT patients and needs further study.

Coronary Artery Bypass Surgery in Patients With HIT In patients who undergo coronary artery bypass surgery (CABG) for coronary artery disease, large doses of heparin are used during cardiopulmonary bypass. Retrospective studies have quoted a frequency of 0.5 to 1.9% of HIT in these patients.104-106 Planning of these procedures involves a multidisciplinary approach involving the cardiologist, hematologist, and surgeon. Two prospective studies using ELISA methods have detected heparin-induced antibodies both before and after cardiopulmonary bypass.107,108 These studies did not show any correlation between antibody positivity, thrombocytopenia, and adverse thrombotic events. A possible explanation for this could be rapid discontinuation and reversal of heparin after bypass. In HIT patients requiring urgent open heart surgery the use of aspirin and dipyridamole along with intraoperative heparin has been reported.6,49,109 Platelet levels should be monitored and the clinical course of the patient followed closely. Although thromboembolic complications were prevented in these patients, thrombocytopenia is still a major problem,109 as only one pathway of platelet aggregation is inhibited by these antiplatelet agents. Iloprost, a prostacyclin analogue, has been success-

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fully administered along with heparin in HIT patients undergoing vascular and cardiac surgical procedures without any major thrombotic complications.51-53 Hypotension needing vasopressor support is a side effect of this medication at higher doses. This agent is not available for use in HIT in the United States. LMWH in conjunction with repeated plasmapheresis has been used in the author’s personal experience in 2 cases with HIT to decrease heparin antibody levels safely at our institution during cardiopulmonary bypass, but there is approximately an 80% chance of cross reactivity with UFH with a potential for accelerated thrombocytopenia. We do not recommend this as an alternative without formal testing to rule out cross reactivity. Danaparoid (Orgaran), a heparin like substance has also been used effectively in HIT patients undergoing cardiac surgery.66,110,111 Its anticoagulant activity has been monitored successfully with aPTT110 and also with activated clotting time.111 Danaparoid cannot be neutralized with protamine sulfate and bleeding is a significant problem. Of 47 HIT patients who underwent bypass with danaparoid as anticoagulant, 17 returned to the operating room for excessive bleeding.66 If it is used the dosing should not exceed 232U/kg body weight.66 Although this agent has not been extensively studied in the United States, it is considered the agent of choice in treating HIT patients in countries such Australia and Canada.8 r-Hirudin, a direct thrombin inhibitor that has been safely used in HIT, is now considered a potential alternative in the cardiopulmonary bypass setting in HIT patients. r-Hirudin does not interact with platelets or heparin antibodies, has a short elimination half-life, and lacks any fibrinolytic activity making it a safe agent in the surgical setting of HIT patients. Information regarding its use in the cardiopulmonary bypass setting is now increasingly available.112-115 Because the cardiopulmonary bypass setting requires precise monitoring of anticoagulant levels, questions regarding the accuracy of aPTT in monitoring r-Hirudin levels have recently been raised,116-117 although several trials have tested the efficacy of aPTT in monitoring the effect of r-Hirudin.118,119 Currently, ACT still is the test used to measure the efficacy of r-Hirudin, although the use of whole blood escarin time may

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be a novel and better way of monitoring rHirudin, because of more linear correlation between this test and serum r-Hirudin levels.120 Argatroban, another direct thrombin inhibitor, is also a good alternative to use in HIT patients in

the bypass setting, because of its efficacy in HIT.58-60 Studies are ongoing to define the exact role of direct antithrombotic agents in HIT patients undergoing major cardiac surgery, as these may be the first line alternative therapy for HIT.

TABLE 1. Common Clinical Manifestations of HIT-HITT Syndrome With Suggested Management Strategies

Prevention of HIT/WCS

Adverse Event

Actions to be Considered

Thrombocytopenia only

1. Discontinue all heparin 2. Quickly rule out other causes 3. Substitute another anticoagulant if the original thromboembolic risk requires it 4. Assess for thrombosis including leg veins now and for 3-5 days 5. Order heparin-induced platelet antibody testing for HIT 6. Follow the platelet counts every 12 hours until recovery is apparent, then daily until it is normal 7. Retest for HIT antibodies if the first test was negative 8. Consult with a hematologist

Thrombosis with or without thrombocytopenia

1. Discontinue all heparin 2. Consult with a hematologist and cardiovascular or vascular specialist 3. Use antithrombotic therapy as needed or as recommended by consultants 4. Use thrombolytic drugs with surgery as recommended by consultants 5. Test for HIT antibodies.

Hemorrhage with thrombocytopenia

1. Resuscitate with packed red blood cells for massive hemorrhage 2. Stop heparin and give protamine sulfate if bleeding is massive and heparin is still circulating 3. Test for evidence of disseminated intravascular coagulation 4. Give blood products to resuscitate only if massive bleeding continues 5. Platelet transfusions are not advised unless critical bleeding is present and the heparin effect is gone

Reprinted with permission from Wehrmacher WH, Messmore HL, Jr, Lewis B: Thrombcytopenia and thrombosis due to heparin. Cardiovasc Rev Rep 19(4):38-48, 1998.

In patients receiving heparin by any route it is important to obtain a baseline complete blood count (CBC), aPTT and platelet level before initiation of therapy. If baseline thrombocytopenia is present other causes such as infection, drugs, malignancy, and autoimmune diseases should be looked into and heparin should be used very cautiously or not at all. Once heparin therapy is initiated, platelet counts must be checked every 2 to 3 days while the patient is being administered heparin. If a precipitous fall in platelet count is seen heparin should be stopped, which usually results in normalization of platelet count (HIT I). Testing for heparin dependent antibodies should be performed by any of the tests outlined earlier and clear documentation regarding adverse response to heparin should be made to avoid any future exposure. The occurrence of thrombotic events while receiving heparin (onset of HIT II) may masquerade as inadequate heparinization and awareness of this entity is essential to avoid further escalating heparin dosage. Regular monitoring of platelet counts and early recognition of the syndrome complex can lead to effective prevention of HIT/HITT, which if unrecognized can lead to significant morbidity and mortality.5 The principles of management of the spectrum of HIT is shown in Table 1.

Conclusion Since its first clinical use in 1937, heparin remains one of the most frequently used parenteral medications in the field of medicine. Despite its potential limitations and adverse effects, it is still one of the most effective modalities to date for therapeutic and prophylactic anticoagulation. Understanding the pathophysiologic basis of its action and adverse reactions will help the clinician in safe and effective use of this medication.

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Knowledge of HIT/HITT will help prevent potentially disastrous consequences to the patient. Newer treatment options like hirudin and argatroban will most probably be shown in larger trials in the future to be the agents of choice of the HIT/HITT syndrome complex, in various clinical settings. The role of platelet 11b/111a inhibitors and antiplatelet agents need to be defined more in patients with HIT. Also, further research is needed to develop more rapid yet sensitive and specific assays for the confirmation of the diagnosis of this entity to facilitate early initiation of therapy.

14.

15.

16.

17.

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