FcyIIaRMediated Platelet Activation

Murine monoclonal IgG1 anti-CD9 were among the first studied for their platelet-activating properties. Subsequently, it was determined that monoclonal antibodies to GPIIb IIIa, -microglobulin, GPIV (CD36), and other selected antigens can activate platelets (Rubinstein et al., 1995). In each instance, platelet activation occurs by a consistent mechanism first, the variable region of the antibody binds to its cognate antigen then the Fc portion of the antibody interacts with platelet FcyRIIa....

Vitamin K Antagonists

Although vitamin K antagonists, such as warfarin, phenprocoumon, and other coumarin agents, are an important part of the longer-term management of patients with HIT-associated thrombosis, they are ineffective, and potentially dangerous, when given to patients with acute HIT as single therapy, or in combination with ancrod (a defibrinogenating snake venom that is no longer used as therapy for HIT) (Warkentin et al., 1997 Smythe et al., 2002 Srinivasan et al., 2004) (see Chapter 2). In patients...

Pentasaccharides

Within the scope of developing new carbohydrate-based antithrombotics, fonda-parinux, a fully synthetic, chemically defined pentasaccharide (formerly named Org31540 SR90107A, MW 1728 Da DS 1.6 700 anti-Xa U mg), has been developed, which corresponds to the AT-binding site of heparin (Petitou et al., 1997) (Fig. 5 see also Chapter 17). By its highly specific binding to AT, fondapar-inux selectively inhibits factor Xa and thus prevents thrombin generation (Bauer et al., 2002). Fondaparinux is...

Frequency Of Immune

Tables 2 and 3 list prospective studies of the frequency of HIT that employed in vitro testing for HIT antibodies or were studies in which the likelihood of HIT could be judged based on information provided, especially the timing of the onset of thrombocytopenia. Relevant variables influencing the frequency of HIT include the type of heparin used and the patient population. TABLE 2 The Frequency of HIT Prospective Studies of HIT in Medical Patients Using In Vitro Testing of Patient Serum Plasma...

Classic Coumarinlnduced Skin Necrosis

Classic coumarin-induced skin necrosis (CISN) is a very rare complication of oral anticoagulant therapy (Cole et al., 1988). In its classic form, it is characterized by dermal necrosis, usually in a central (nonacral) location, such as breast, abdomen, thigh, or leg, that begins 3-6 days after starting therapy with warfarin or other coumarin anticoagulants (Fig. 9). Initially, there is localized pain, induration, and erythema that progresses over hours to central purplish-black skin...

Diagnostic Interpretation of Laboratory Results

In patients with a high pretest probability of HIT who have a negative screening test, the test should be repeated and the complementary activation or antigen assay should be performed. The diagnosis of HIT is very unlikely if both activation and antigen assays are negative. In patients with a moderate pretest probability who have one or more positive tests for HIT, the final diagnosis may well rest on the overall clinical picture, rather than on the test result alone. This conclusion results...

Unsuitable Approaches

LMWH is not recommended as an alternative anticoagulant for managing acute HIT. In vitro tests for HIT antibodies show a high degree of cross-reactivity between UFH and LMWH (Greinacher et al., 1992b Vun et al., 1996). Furthermore, in vivo cross-reactivity manifesting as persistent or recurrent thrombocytopenia or thrombosis during LMWH treatment of HIT appears to be common (Greinacher et al., 1992a Horellou et al., 1984 Roussi et al., 1984). Because non-heparin anticoagulants are available,...

Immune Vascular Injury And Monocyte Activation In Hitassociated Thrombosis

The studies described above support the notion that platelet activation and or an inflammatory milieu contribute to EC dysfunction, predisposing to HIT-associated thrombosis. This view of HIT as an inflammatory disorder has gained additional experimental support by recent findings that monocytes are activated as well. HIT plasma or IgG stimulates monocytes to elaborate tissue factor-dependent procoagulant activity in monocytes (Pouplard et al., 2001). This procoagulant effect required small...

Pathogenesis of HIT Treatment Implications

HIT is caused by antibodies that usually recognize multimolecular complexes of platelet factor 4 (PF4) and heparin. HIT can be viewed as a syndrome of in vivo thrombin generation that results from the activation of platelets, endothelium, monocytes, and coagulation pathways (Warkentin and Kelton, 1994 Greinacher, 1995 Warkentin, 2003 Warkentin et al., 1998) (Fig. 1) (see Chapters 4-9). Given this model of pathogenesis, therapy for acute HIT should focus on the following issues (1) rapid...

Management Of Hd In Hit Patients A Discontinuation of Heparin Treatment

As HIT is frequently associated with potentially life-threatening thrombotic events (Warkentin et al., 1995 Warkentin and Kelton, 1996), discontinuation of heparin treatment and initiation of adequate alternative anticoagulation is generally considered mandatory (Warkentin et al., 1998). Thus, heparin must not be added to any flushing solution, and no heparin-coated systems can be used. Indeed, heparin flushes and heparin-coated devices can both initiate and sustain HIT (Moberg et al., 1990...

Info

FIGURE 8 Comparisons of ROC curves among five different assays for anti-PF4 heparin antibodies. (Top) UFH-treated patients (n 192). (Bottom) LMWH-treated patients (n 256). The sensitivity-specificity tradeoffs at different diagnostic cut-offs for clinical HIT are shown. For the SRA, the points represent step-wise 10 changes in percent serotonin release. For the EIA-IgG and EIA-GTI, the points represent step-wise 0.20 units of optical density, except for the point labeled 0.45, which represents...

Prophylaxis of Arterial Thromboembolism

Danaparoid has been used to prevent arterial thromboembolism in patients undergoing various vascular operations, including peripheral artery bypass graft surgery, embolectomy, and endarterectomy. In these patients, it was given as a preoperative iv bolus of 2500 or 2250 U, and in some it was also administered postoperatively. Given as an iv bolus of 2500 or 2250 U immediately before the procedure, danaparoid has also been used to provide antithrombotic cover during percutaneous coronary...

Skin Necrosis in the Absence of Coumarin Therapy

Other patients have developed skin lesions during intravenous heparin therapy, or at locations otherwise distant from subcutaneous injection sites, in the absence of coumarin therapy. Hartman and colleagues (1988) reported a man who received intravenous heparin for saphenous vein thrombosis the platelet count fell from 864 to 44 X 109 L (day 10). On day 7, when the platelet count had fallen by 33 to 575 X 109 L, progressive necrosis of skin in the thigh at the region of the thrombosed vein...

Negative test for HIT antibodies

Consider continuing or switching back to (LMW) heparin' (high frequency of subclinical D h ) If HIT, consider anticoagulating until platelet count recovery, even if no thrombosis apparent ( coumarink) a Recent heparin indicates exposure within the past 30 days (2 points) or past 30-100 days (1 point) b ASR, acute systemic (anaphylactoid) reaction following Lv. heparin bolus c Stop all heparin, including low molecular weight heparin, catheter Hushes and, possibly, heparin-coated catheters d...

Graft Prosthetic Device and Extracorporeal Circuit Thrombosis

HIT predisposes to thrombosis of blood in contact with native or prosthetic grafts or vascular fistulae, valve or other intravascular prostheses, as well as extracorpo-real circuits (Towne et al., 1979 Silver et al., 1983 Bernasconi et al., 1988 AbuRahma et al., 1991 Lipton and Gould, 1992 Hall et al., 1992). This presents serious management problems in certain situations, such as renal hemodialysis (see Chapter 18). Clinicians should check for unexpected platelet count declines, and test for...

Adverse Effects

Bleeding is the major adverse effect of bivalirudin and occurs more commonly in patients with renal impairment. Injection site pain has been reported in individuals given sc bivalirudin (Fox et al., 1993). Mild headache, diarrhea, nausea, and abdominal cramps have also been reported (Fox et al., 1993). In the Hirulog Angioplasty Study (HAS) (now known as the Bivalirudin Angioplasty Trial BAT ), the most frequent adverse effects included back pain, nausea, hypotension, pain, and headache....

Clinical Presentation Of Hit In Hd Patients

The diagnosis of HIT and respective management decisions should be primarily based on clinical criteria (Lewis et al., 1997). A further consideration in HD patients is that the procedure of HD itself is associated with a relative decrease in platelet count, even when so-called biocompatible dialyzer membranes are used (Beijering et al., 1997 Schmitt et al., 1987). Furthermore, the fall in platelet count in HD patients developing HIT may be only moderate (Matsuo et al., 1997). The occurrence of...

Interactions with Other Sulfated Carbohydrates

The formation of platelet-activating immune complexes is not limited to heparin (Greinacher et al., 1992, 1993). Various other sulfated polysaccharides, and even polyvinylsulfonate, bind PF4 to form antigen complexes recognized by HIT antibodies. This cross-reaction depends on their structure, especially on their DS and MW (Greinacher et al., 1992, 1995 Kelton et al., 1994 Amiral et al., 1995). In vitro assays demonstrate that pentosan polysulfate, dextran sulfate, as well as a high-sulfated...

V

FIGURE 4 Repeating unit of (-1, 3-glu-can sulfates The primary OH group in position 6(**) is preferentially sulfated. Glycosidic-branched (-1, 3-glucan sulfates are substituted by a glucose, rham-nose, or arabinose unit, respectively, in position 6. An increase in the DS results in improved anticoagulant activity and, after binding to PF4, in increased formation of HIT antibody-binding sites. The MW is a second important structural parameter for anticoagulant potency of a sulfated...

Pediatric Cardiac Surgery Patients

Boshkov et al. (2003a) reported a retrospective case series in pediatric cardiac surgery patients. HIT antibodies were demonstrated by positive functional assay in five of 433 children following open heart surgery (incidence, 1.2 ). Martch-enke and colleagues (2004) found an incidence of HIT with thrombotic complications of 2.5 in pediatric patients after congenital heart surgery. Boning et al. (2005) performed a retrospective analysis to identify the incidences of HIT and of anti-PF4 heparin...

I I

FIGURE 2 (See color insert) Atherosclerotic tissue is invested with PF4. (A) Photomicrograph (H& E stain) demonstrating the appearance of a group of foamy macrophages, which contain bubbly, vacuolated cytoplasm and indistinct nuclei (arrows). A giant cell is indicated by the arrowhead. (B) Photomicrograph of immunohistochemical staining for CD68, which is specific for cells of the macrophage lineage. Foamy macrophages (arrows) and a giant cell (arrowhead) is indicated. (C) Photomicrograph of...

Clinical Use of Danaparoid in Patients with HIT

Danaparoid has been used extensively to treat patients with HIT (Chong and Magnani, 1992 Magnani, 1993, 1997 Magnani and Gallus, 2006). After the diagnosis of HIT and discontinuation of heparin administration, patients often require an alternative anticoagulant for any one of the following indications (1) treatment of a recent or new thrombosis (2) prophylaxis of venous thromboembolism (3) anticoagulation for cardiopulmonary bypass (CPB) surgery or peripheral arterial surgery (4)...

Heparinplatelet Interactions In The Pathogenesis Of

Nonimmune heparin-platelet interactions are central to the pathogenesis of HIT because of the key role of platelet factor 4 (PF4). This cationic chemokine is secreted from activated platelets and binds to GAGs on the surface of platelets and endothelium (Dawes et al., 1982 Rao et al., 1983 O'Brien et al., 1985 Capitanio et al., 1985 Cines et al., 1987 Visentin et al., 1994). PF4 also binds to soluble GAGs, especially highly anionic heparin, leading to a competition between cell-bound and...

Patients with a History of HIT Requiring Acute Anticoagulation

A subgroup analysis of the prospective studies of argatroban in HIT identified 36 patients with a history of serologically confirmed HIT who had fully recovered from their initial episode of HIT, had a normal platelet count, and had no exposure to heparin or other parenteral anticoagulants (except argatroban) during their hospitalization (Matthai et al., 2005). Each patient required acute anticoagulation, most often for venous thromboembolism or acute coronary syndrome, and 12 had previously...

Intravenous Gammaglobulin

In vitro, both intact IgG as well as its Fc fragments inhibit HIT antibody-induced platelet activation, an effect that depends somewhat on the method of immunoglo-bulin preparation (Greinacher et al., 1994a) (see Chapter 8). Case reports describe rapid increase in the platelet counts after high-dose ivIgG (Vender et al., 1986 Frame et al., 1989 Nurden et al., 1991 Grau et al., 1992 Prull et al., 1992 Warkentin and Kelton, 1994). The possibility that ivIgG treatment interrupts platelet...

L HIT and Ventricular Assist Devices

Ventricular assist devices (VADs) are surgically implanted mechanical pumps that have a large foreign surface area in direct contact with flowing blood, thereby creating an inherently prothrombotic environment. In a non-randomized study of patients who received heparin-coated and uncoated VADs, there was no difference in the development of anti-PF4 heparin antibodies and thromboembolism between the groups (Koster et al., 2001). In two more recent studies, 10 113 (8.8 ) (Schenk et al., 2006,...

Clinical Use of Danaparoid in Disorders Other Than HIT

Controlled clinical trials of danaparoid for the routine prophylaxis and treatment of venous thromboembolism in non-HIT patients have confirmed its efficacy as an antithrombotic agent. In eight prospective, randomized, controlled, and assessorblind studies, danaparoid was more effective than other standard antithrombotic agents (e.g., warfarin, dextran, low-dose UFH plus dihydroergotamine) in preventing deep vein thrombosis (DVT) after total hip replacement (Hoek et al., 1992 Leyvraz et al.,...

Safety

Major bleeding occurred in 6.9 (21 304) of argatroban-treated patients, compared with 6.7 (13 193) of historical controls. In each group, there were two fatal bleeding events. One patient experienced a fatal intracranial hemorrhage 4 days after discontinuation of argatroban and following urokinase and warfarin therapy one historical control also experienced a fatal intracranial hemorrhage. Minor bleeding rates were similar between the groups (41 ). The most common adverse events among...

Thrombolytic Therapy

Early-onset thrombocytopenia occurs in about 1 of patients with acute coronary syndrome whether treated by heparin or non-heparin anticoagulants (Eikelboom et al., 2001). The frequency of thrombocytopenia is even higher in patients treated with streptokinase, especially when this thrombolytic agent is combined with heparin (Balduini et al., 1993) (Fig. 6). This could represent a direct, activating stimulus of heparin on platelets that perhaps is exacerbated by procoagulant FIGURE 6 Pseudo-HIT...

Longer Term Anticoagulant Management of the HIT Patient with Thrombosis

Acute HIT by itself is not an indication for longer-term anticoagulation (i.e., 3-6 mo). However, HIT-associated thrombosis, or the underlying disease itself, often is. For longer-term control of thrombosis, oral anticoagulants of the coumarin class (e.g., warfarin or phenprocoumon) are the treatment of choice. However, as discussed subsequently, it is important that coumarin therapy be delayed until there has been substantial recovery in the platelet count. Another option is to avoid coumarin...

Comparison with Other Treatments for HIT

Mortality rates in patients with HIT remained at approximately 20-30 for more than a decade (King and Kelton, 1984 AbuRahma et al., 1991 Warkentin and Kelton, 1996 Nand et al., 1997). Notably, these rates are two to three times higher than those observed in the HAT studies. In addition to lepirudin, other drugs with antithrombin activity (e.g., argatroban) or antifactor Xa activity (e.g., danaparoid) may be appropriate for management of HIT (see Chapters 13 and 15-17). Comparisons of the...

Lepirudin and Vitamin K Antagonists

Long-term treatment of HIT patients often involves a transition from DTI to oral anticoagulation. Initiation of the transition to vitamin K antagonist (coumarin) therapy should begin only after the platelet count has substantially recovered (preferably, > 150 x 109 L), with a minimum of 5 days of overlapping therapy with an alternative anticoagulant, and with the last 2 days stably within the target therapeutic range (Warkentin and Greinacher, 2004). In patients with deep vein thrombosis...

Ivplatelet Factor 4 And The Endothelium

The biochemistry of PF4 and its involvement in HIT is reviewed elsewhere (see Chapter 5). The metabolism of the protein is regulated by its interactions with the endothelium. PF4 is stored in the a-granules of platelets as a tetramer bound to chondroitin sulfate (Barber et al., 1972). The tetramer may dissociate from the GAG as the platelets are activated, but more likely, dissociation occurs subsequent to binding to EC HSPG, which contains a higher charge density. 125I PF4 is cleared from the...

Frequency of HIT in Surgical Patients Treated with Porcine Mucosal UFH

Two large prospective studies suggest that HIT is an important problem in orthopedic patients receiving UFH (Warkentin et al., 1995, 2003, 2005a Greinacher et al., 2005a). When using a proportional fall in platelet count (e.g., 50 or greater) that began on or after day 5 of heparin treatment, and that was confirmed by serologic testing for HIT antibodies, both studies observed a frequency of HIT of about 5 (Table 3). Each study used porcine mucosal heparin, derived from a different...

Management of the Patient with a Low or Intermediate Probability of HIT Pending Results of HIT Antibody Testing

In patients with HIT without thrombosis, the risk of major bleeding with therapeutic-dose DTI therapy per patient day has been reported to be as high as 1.0 for lepirudin (i.e., 14.3 major bleeding over a mean treatment period of 13.9 days) (Lubenow et al., 2004) and for argatroban it was 0.6 and 1.0 (3.1 and 5.3 major bleeding over a mean treatment period of 5.3 and 5.1 days, respectively) (Lewis et al., 2001, 2003). In the large case series of HIT patients treated with danaparoid (Magnani and...

O Variable Duration of Heparin Treatment

As HIT typically begins 5-10 days after starting therapy with heparin, it follows that the length of heparin treatment can influence the risk for HIT, e.g., a 10-14 day course of UFH is far more likely to result in clinical HIT than a 1 day treatment period (> 2 vs. 0.02 , i.e., an OR of 100). Of note, there is evidence that the risk of HIT begins to decline after 10 days of uninterrupted heparin use (see Fig. 1C, Chapter 2). In a large study of postoperative orthopedic surgical patients...

Antibivalirudin Antibodies

Bivalirudin is a relatively small polypeptide and thus is expected to lack significant antigenicity (Fenton et al., 1998). In a study of plasma samples from seven patients, no evidence for antibody formation (IgG, IgM, or IgE) was found (Fox et al., 1993) with plasma samples obtained at 7 and 14 days after iv administration. There was also no evidence for changes in the pharmacokinetics or pharma-codynamics of bivalirudin in their study. One patient exhibited antibody titers of greater than 1...

Relation Between the Anticoagulant Activity of 1 3Glucan Sulfates and Their Cross Reaction with HITAssociated Antibodies

To establish the structural requirements for the anticoagulant activity of sulfated carbohydrates, as well as for the development of platelet-activating immune complexes in the presence of HIT antibodies, we synthesized structurally well-defined sulfated polysaccharides (Greinacher et al., 1995). The resulting (-1,3-glucan sulfates (GluS) varied in their DS, MW, sulfation pattern, and chemically introduced glycosidic side chains (Fig. 4). Although these compounds differ structurally from...

FcgRMediated Signal Transduction

FcgRIIa activation, as a result of IgG binding and by action of phosphatidylinositol 3-kinase (PI 3-kinase) and phospholipase C-g2 (PLCg2), leads to release of diacylglycerol (DAG) and inositol triphosphate (IP3), mobilization of internal calcium stores, and, subsequently, platelet aggregation (Anderson and Anderson, 1990). Initially, IgG binding leads to FcgRIIa clustering, resulting in the phosphorylation of FcgRIIa ITAMs by Src family protein tyrosine kinases (Chacko et al., 1994 FIGURE 1...

Iinonimmune Heparinassociated Thrombocytopenia

In some patients, especially those with comorbid conditions associated with platelet activation (burns and anorexia nervosa), heparin treatment can result in a transient decrease in platelet count (Burgess and Chong, 1997 Reininger et al., 1996) (see Chapter 4). Unfractionated heparin (UFH) activates platelets directly (Salzman et al., 1980), an effect observed less frequently with low molecular weight heparin (LMWH) (Brace and Fareed, 1990). Known as nonimmune heparin-associated...

Nonidiosyncratic Heparininduced Platelet Activation

The functional consequence of heparin binding to platelets is subtle cell stimulation. Antibody-independent activation of platelets by heparin in vitro has been reported from many laboratories. However, the results of these studies have varied, presumably because of differences in experimental conditions. In plasma, for example, heparin alone causes slight platelet aggregation, whereas platelets suspended in laboratory buffers are reported to aggregate either briskly or not at all in response...

Effects of HIT Antibody Containing Immune Complexes

HIT antibodies bind to PF4-heparin complexes by their F(ab')2 domains (Horne and Alkins, 1996 Newman and Chong, 2000). The predominant immunoglobulin isotype in clinical HIT is IgG (Amiral et al., 1996b Warkentin et al., 2005b Juhl et al., 2006). Thus, divalent IgG binding to multimolecular PF4-heparin complexes, leads to the formation of large immune complexes containing HIT-IgG on the platelet surface. The interaction of the HIT-IgG Fc with the platelet FcyIIa receptors leads to cross-linking...

Antigen Assays For Hit Antibodies A Solid Phase PF4H Enzyme Immunoassay

The solid-phase enzyme immunoassay (EIA) has been described in detail (Amiral et al., 1992 Visentin et al., 1994 Greinacher et al., 1994a Amiral et al., 1995 Horsewood et al., 1996 Juhl et al., 2006). Methods differ in the way that PF4-H complexes are coated on the microtiter wells. A general scheme is shown in Figure 2. In this assay, stoichiometric concentrations of PF4 and heparin (e.g., 50 mL each of 20 mg mL PF4 and 1 U mL UFH) dissolved in phosphate buffer are added Add alkaline...

Use Of Heparin For Cpb In Patients With A Previous History Of

An intriguing option for patients with a history of HIT, but in whom HIT antibodies can no longer be detected, is to consider reexposure to UFH for CPB, and to avoid heparin completely both before surgery (e.g., at heart catheterization) and in the postoperative period. This approach has been used successfully (Makhoul et al., 1987 Potzsch et al., 2000 Selleng et al., 2001 Warkentin and Kelton, 2001), and is based on the following rationale. First, HIT antibodies are transient, and are usually...

Congenital Hypercoagulability and HITAssociated Thrombosis

Gardyn and associates (1995) reported a patient with fatal HIT and widespread microvascular thrombosis. The investigators identified heterozygous factor V Leiden (G1691A mutation) in this patient, and they speculated that this contributed to the severe clinical course. However, the complications may also have been related to the treatment with LMWH and warfarin. The interaction between factor V Leiden and thrombotic sequelae of HIT was formally investigated in a study of 165 patients with HIT,...

Specifically Designed Oligosaccharides

Pentasaccharides such as fondaparinux or the long-acting idraparinux (Herbert et al., 1998) have minimal, if any, undesirable interactions with blood and vessel components, but their anticoagulant activity is limited to AT-mediated factor Xa inhibition. Additional thrombin inhibitory properties might further improve the anticoagulant efficacy of heparin-related oligosaccharides. Unfortunately, as with heparin, lengthening the sulfated oligosaccharide chain increases nonspecific binding that...

Posttransfusion Purpura

Posttransfusion purpura (PTP) is a rare syndrome characterized by severe throm-bocytopenia and mucocutaneous bleeding that begins 5-10 days after blood transfusion, usually red cell concentrates. More than 95 of affected patients are older women, in keeping with its pathogenesis of an anamnestic recurrence of platelet-specific alloantibodies in women previously sensitized by pregnancy. Destruction of autologous platelets is believed to result from the pseudospecificity of the alloimmune...

Renal Impairment

Lepirudin has been studied in patients with varying degrees of renal impairment. It can be used safely and effectively if started at a very low dose of 0.005-0.01 mg kg h, if there is evidence for renal compromise. If renal function is normal, the starting dose should be 0.05-0.10 mg kg h. In both situations the initial lepirudin bolus should be omitted (Table 2). In case of transient renal failure close monitoring of aPTT is mandatory. Even when renal function appears normal, the potential for...

Recognition And Treatment Of Pseudohit

Many patients with pseudo-HIT can be distinguished from HIT because of the early onset of thrombocytopenia (Table 1). Unless the patient received heparin within the past 30, and at most 100, days, the early platelet count fall is the strong evidence against HIT (Warkentin and Kelton, 2001 Lubenow et al., 2002) (see Chapter 2). However, for patients with adenocarcinoma-associated DIC, or postoperative pulmonary embolism, in whom the platelet count fall can occur after 5 days of heparin...

Cerebral Venous Dural Sinus Thrombosis

Thrombosis of the dural venous sinuses is an unusual cause of stroke in HIT patients that was first reported by Stevenson (1976). Often, there is a second hypercoagulable state, such as pregnancy (Van der Weyden et al., 1983 Calhoun and Hesser, 1987) or myeloproliferative disease (Kyritsis et al., 1990), that may have interacted with HIT to cause this complication. Platelet-rich white clots were identified in the superior sagittal venous sinus in one necropsy study (Meyer-Lindenberg et al.,...

Low Molecular Weight Heparin

LMWH is less likely than UFH to cause HIT antibody formation as well as clinical HIT (Warkentin et al., 1995, 2003). Furthermore, LMWH binds less avidly to platelets than does UFH (Greinacher et al., 1993b). With functional assays employing platelet-rich plasma, several investigators reported a reduced cross-reactivity of HIT antibodies with LMWH compared with UFH (Ramakrishna et al., 1995 Slocum et al., 1996 Vun et al., 1996) however, with sensitive washed platelet functional assays, the...

Scoring Systems for HIT

Various scoring systems to estimate the probability of HIT based upon clinical information have been published, usually for the purpose of evaluating new laboratory tests for HIT (Greinacher et al., 1994 Pouplard et al., 1999 Alberio et al., 2003). These systems have included the platelet count recovery following heparin cessation, which limits their applicability for judging the clinical likelihood of HIT in real time when a thrombocytopenic patient receiving heparin is first evaluated....

Drug Drug Interactions

No pharmacokinetic or pharmacodynamic drug interactions have been demonstrated between argatroban and aspirin (Clark et al., 1991), erythromycin (Tran et al., 1999), acetaminophen, digoxin, or lidocaine (Inglis et al., 2002). In practice, argatroban coadministered with these frequently used medications should require no dosage adjustments. No pharmacokinetic interactions have been demonstrated between argatro-ban and warfarin (Brown and Hursting, 2002). DTIs as a class variably prolong the PT...

Frequency Of Thrombosis Complicating

Ironically, although thrombosis was the first manifestation of the HIT syndrome, first recognized almost 50 yr ago (Weismann and Tobin, 1958), widespread recognition that thrombosis was a common complication of HIT did not occur until recently. Indeed, until 1995 no study of HIT had compared the frequency of thrombosis with a matched control population (Warkentin et al., 1995). This study quantitated the strength of the association between HIT and thrombosis and further noted that the more...

Platelet Transfusions

Usually there is no need to treat thrombocytopenia with platelet transfusions, as patients with HIT rarely bleed spontaneously. Indeed, platelet transfusions should be avoided because the transfused platelets can be activated by the same immune mechanisms as the patient's own platelets. Anecdotal experience describes throm-botic events soon after platelet transfusions given to patients with acute HIT (Babcock et al., 1976 Cimo et al., 1979). Several consensus conferences (Contreras, 1998 Hirsh...

This Cannot Be HIT Because the Patient Is Not on Heparin

The syndrome of delayed-onset HIT was elucidated a few years ago, and is now increasingly recognized around the world (Warkentin and Kelton, 2001b Rice et al., 2002). The patients have been off heparin for a few days or more, often recuperating at home from a benign hospital course that included heparin exposure, then they return to hospital with an arterial or venous thrombotic event. Upon return, the platelet count is often (although not necessarily) low. These people are often given heparin...

Ysine Krich Ctermirius

EAEEDQOLCCLCVKTTSQVRPR HITSLE VI K AG HCPTAQLtATLKNQRKICLDLQAPLY FIGURE 6.4 Primary and secondary structure of PF4 in relation to HIT neoepitopes. (Top) 3D representation of the PF4 tetramer, indicating two neoepitope sites (per monomer). The ring of positive charge is formed by lysine residues in the C-terminus (light blue) and other lysine and arginine residues (dark blue). (Bottom) The linear sequence of the 70-amino acid polypeptide of a single PF4 molecule is shown. Abbreviation PF4,...

Recommendations For Platelet Count Monitoring For

Monitoring for typical-onset HIT stratifying the intensity of platelet count monitoring for HIT based upon its risk A. Patients at highest risk for HIT (1-5 ) (e.g., postoperative patients receiving prophylactic-dose UFH after major surgery, patients receiving therapeutic-dose UFH) monitoring during heparin therapy, at least every second day from day 4 to day 14a,b B. Patients at intermediate risk for HIT (0.1-1 ) (e.g., medical obstetrical patients receiving prophylactic-dose UFH, or...

Acetylsalicylic Acid Dipyridamole and Clopidogrel

Both acetylsalicylic acid (aspirin, ASA) and dipyridamole have been used in HIT patients with variable success (Janson et al., 1983 Makhoul et al., 1986 Kappa et al., 1987, 1989 Laster et al., 1989 Gruel et al., 1991 Hall et al., 1992 Almeida et al., 1998). Sometimes the platelet count appeared to rise promptly with the application of antiplatelet therapy (Warkentin, 1997). However, HIT antibodies are potent platelet activators, and their effect cannot always be blocked in vitro by ASA or...

Infective Endocarditis

Infective endocarditis is frequently complicated by thrombocytopenia. These patients are also at risk for septic emboli manifesting as thrombotic or hemorrhagic stroke, myocardial infarction, renal infarction, or even acute limb ischemia (de Gennes et al., 1990). Thus, the profile of macrovascular thrombosis and thrombocy-topenia characteristic of HIT can be mimicked, especially as heparin is often used to anticoagulate patients with septic endocarditis (Delahaye et al., 1990)....

EHIT Is Less Frequent in Surgical Patients Receiving LMWH Compared with UFH Prophylaxis

Anecdotal reports indicate that HIT can occur during treatment with LMWH (Ball et al., 1989 Tardy et al., 1990 de Raucourt et al., 1996 Plath et al., 1997 Elalamy et al., 1996 Warkentin, 1998 Gruel et al., 2003 Ng and Lee, 2003). Clinical trial data suggest that the frequency is low, however. Using a sensitive definition for HIT (> 50 fall on or after day 5 and confirmed by positive HIT antibodies), two studies in Hamilton found an overall frequency of only 4 439 (0.9 95 CI 0.252.32 ) for HIT...

Pf4

Division Medium (A) Div. 43.43 0.6 FIGURE 5 PF4 induces proliferation of CD4+CD25+ Tr cells and impairs their ability to suppress the response of CD4+CD25 T cells to anti-CD3. CFSE labeled CD4+CD25 T cells were cultured alone (A-B) or with an equal number of unlabeled CD4+CD25+ Tr cells (C-D). In the converse experiment, CFSE labeled CD4+CD25+ Tr cells were cultured alone (E-F) or with an equal number of unlabeled CD4+CD25 T cells (G-H). Dashed lines (shown only on panel A) indicate the...

Prospective Evaluation

The results of retrospective studies must be interpreted with caution because the reports are subject to publication bias (studies with positive outcomes are more likely to be submitted and accepted for publication than studies with negative outcomes). There also was marked heterogeneity among the studies regarding patient eligibility, the methods used to diagnose HIT, the treatment regimens employed, and the monitoring of the response to treatment. For these reasons, a prospective evaluation...

Observational Studies

The first published case of fondaparinux use in a patient with HIT was by Dr. Elbio D'Amico et al. (2003). A patient with paroxysmal nocturnal hemo-globinuria and Budd-Chiari syndrome developed HIT following administration of LMWH (dalteparin 5000IU sc q12h). The patient experienced spontaneous platelet count recovery, and received thrombolytic therapy. While receiving prophylactic doses of fondaparinux, the platelet count remained unchanged and the patient was transitioned uneventfully to oral...

B 10 12 14 16 18 20 22 24 Days after surgery

FIGURE 4 Pseudo-HIT associated with PE versus HIT (A) A patient developed a platelet count fall from 387 to 159x 109 L (59 fall) that began on day 7 of UFH prophylaxis following orthopedic surgery. PE was diagnosed by pulmonary angiography on postoperative day 11. The platelet count fell during initial intravenous heparin therapy, rising only when sufficient UFH was given (2360 U h) to overcome heparin resistance (as shown by subtherapeutic activated partial thromboplastin times, aPTTs). HIT...

Reversal of Argatroban

Argatroban has a gentle dose-response relationship that offers a wide margin of safety during dose titration (Fig. 3). However, as with any anticoagulant, bleeding is a major safety concern. Excessive anticoagulation, with or without bleeding, may be controlled by discontinuing argatroban or decreasing its infusion dose. Anticoagulant parameters generally return to baseline within 2-4 h after discontinuation of argatroban (Swan et al., 2000 Swan and Hursting, 2000). This reversal takes longer...

Variable Frequency Of Hit Implications For Platelet Count Monitoring

Until recently, studies of HIT frequency have yielded seemingly confusing and inconsistent results. However, as argued in this chapter, by taking into consideration (1) type of heparin used, (2) patient population treated, and (3) laboratory and clinical evidence to distinguish (immune) HIT from nonimmune HAT, distinct profiles for HIT antibody seroconversion, HIT itself, and HIT-associated thrombosis can be discerned (Fig. 3). New research questions will be generated in the search for the...

Use in Children and Pregnant Women

Danaparoid has been used in a small number of pediatric patients (Saxon et al., 1999 Bidlingmaier et al., 2005 see Chapter 20). For 33 of 34 children aged between 2 wk and 17 yr, danaparoid was used for the treatment of HIT. Sixteen children were treated with danaparoid for various indications, including maintenance of catheter patency, renal failure, cardiac surgery, and thrombosis. In general, it was noted that children, particularly infants, often required higher doses of danaparoid than...

Frequency of HIT in Critically Ill Patients

Thrombocytopenia is common in critically-ilL patients, occurring in up to half of all patients in the intensive care unit (ICU). In this population, the presence of thrombo-cytopenia is associated with increased mortality, and depending on severity and etiology, is associated with increased hemorrhagic risk as well. ICU patients often have several potential causes of thrombocytopenia, making evaluation challenging. Heparin exposure (in the form of line flushes, prophylaxis, or therapeutic...

Hemodialysis

Hirudin was the first anticoagulant to be used for hemodialysis, as performed by Haas (1924) in Germany. Because native hirudin preparations were crude and supply of leeches insufficient, hirudin was replaced by heparin to prevent clotting during dialysis. Management of these patients requires careful dosing and frequent monitoring. HIT patients with transient renal failure are difficult to manage with lepir-udin, because substantial dose adjustments are necessary, depending on the extent of...

Frequency of HIT in Medical Patients Treated with LMWH

Although there have been several RCTs evaluating the efficacy of LMWH for prophylaxis in medical patients, published descriptions of secondary safety endpoints such as HIT are usually brief and often inadequate to judge whether the occurrences of thrombocytopenia were due to HIT or not (Samama et al., 1999 Turpie, 2000 Leizorovicz et al., 2004). In one RCT of prophylactic-dose LMWH (enoxaparin) versus UFH in medical patients, no cases of new onset of thrombocy-topenia (platelet count < 100 x...

Lepirudin in Children

Although rare in children, HIT is important in the differential diagnosis of thrombocytopenia or unexplained thrombosis in the presence of heparin administration (Ranze et al., 1999 Klenner et al., 2004). Because of the rarity of HIT and its clinical heterogeneity in pediatric patients, it is difficult to design a standardized dosage protocol for lepirudin. Accordingly, current therapeutic recommendations are based on anecdotal experience. Given that children usually have normal renal function,...

Septicemia Associated Purpura Fulminans

Septicemia complicated by DIC occasionally results in progressive ischemia and necrosis of fingers or hands and toes or feet, producing a syndrome of symmetrical peripheral gangrene also known as purpura fulminans (Knight et al., 2000). The association with DIC suggests that increased thrombin generation in vivo, together with severe consumption and depletion of natural anticoagulant factors (e.g., protein C, protein S, antithrombin), leads to dysregulated fibrin deposition in the...

Anticoagulation of the HIT Patient Without Thrombosis

Approximately 50 of patients with HIT do not have a new HIT-associated thrombosis at the time HIT is first clinically suspected on the basis of thrombocy-topenia alone (Warkentin and Kelton, 1996 Greinacher et al., 1999a,b, 2005). In a retrospective cohort study of 62 such patients with isolated HIT, the subsequent 30-day cumulative thrombotic event rate was high (52.8 ) (see Fig. 2 in Chapter 3). The rate of thrombosis was similar in the two largest patient subgroups patients treated with...

Natural History of Isolated HIT

Isolated HIT is defined as the initial recognition of HIT because of thrombocytopenia alone, rather than because symptoms or signs of thrombosis draw attention to the possibility of underlying HIT. A large retrospective cohort study (Warkentin and Kelton, 1996) suggests that the subsequent frequency of new, progressive, or recurrent thrombosis is relatively high in such a patient population with serologically confirmed HIT (Fig. 2). Although these data are retrospective, the investigators...

About the fourth edition

Although first reported in 1973, immune heparin-induced thrombocytopenia (HIT) remains one of the most potentially devastating and frequent adverse drug reactions encountered by physicians. This Fourth Edition reinforces its standing as the leading guide to the accurate diagnosis and management of HIT by identifying key signs and symptoms of this disorder and providing clear intervention strategies, including detailed information on the use of alternative anticoagulants to manage these critical...

Role of Incidental UFH Flushes in the Frequency of HIT

There are two ways that incidental exposure to heparin by flushing of intra-vascular catheters can affect the frequency or clinical effect of HIT. First, such minor heparin exposures can trigger formation of HIT antibodies (Ling and Warkentin, 1998 Warkentin et al., 1998b). And second, in patients who have already formed potent HIT antibodies for any reason, any ongoing or recurrent heparin exposure including small-dose exposure could lead to recurrence or exacerbation of thrombocytopenia or...

Disadvantages of cPRP Aggregation Assays

Problems with these assays include (1) potential for false-positive interpretation if heparin produces nonspecific aggregation of donor platelets, an effect that could be enhanced nonspecifically by proaggregatory factors in the patient serum or plasma, and (2) risk of false-negative interpretation if HIT serum-induced platelet aggregation begins even before addition of heparin. Nonspecific activation of platelets by heparin occurs with some normal donor c-PRP (Chong et al., 1993a), rendering...

Clinical Studies With Lepirudin In Hit A Three Prospective Clinical Trials Heparin Associated Thrombocytopenias 2 and

Three prospective studies with lepirudin for HIT were designated heparin-asso-ciated thrombocytopenia (HAT)-l, -2, and -3 (Greinacher et al., 1999a,b, 2000 Lubenow and Greinacher, 2002 Lubenow et al., 2005). There was no approved non-heparin alternative anticoagulant during the 3 yr in which the HAT studies were conducted (March 1994-April 1996), and thus for ethical reasons, a placebo control was not appropriate. The HAT studies therefore included comparisons of clinical outcomes with a...

Rapid Versus Typical Onset of Thrombocytopenia

We will discuss the diagnostic approach to HIT based on the timing of onset of thrombocytopenia, either rapid (< 5 days) or typical (> 5 days) (see Chapter 2). In general, there are two broad pretest probabilities for patients with rapid thrombocytopenia low and high. Patients with low pretest probability for HIT are those who have not recently been exposed to heparin (thus, they would not be expected to have circulating HIT antibodies, or to have generated them so quickly), or who have...

Interpretation of Platelet Activation by HIT Serum in the Absence of Added Heparin

With activation assays, it is not uncommon for HIT serum or plasma to cause platelet activation, even in the absence of added heparin (Warkentin and Kelton, 2001 Prechel et al., 2005). However, even greater platelet activation occurs in the presence of added heparin. When strong serum-dependent platelet activation occurs with buffer and at a 0.1-0.3 U mL heparin concentration, it is important to ensure that the other reactions (at 100 U mL heparin, and 0.1-0.3 U mL heparin together with Fc...

Role Of Preexisting Antibodies To Cxc Chemokines

Preexisting antibodies to chemokines, such as IL-8 or NAP-2, or possibly even to PF4 itself, may be present in some patients before heparin therapy (Sylvester et al., 1992 Bendtzen et al., 1995 Warkentin et al., 2006b). These antibodies may occur naturally or be induced in pathologic states, where they might have a regulatory role in inflammation (Reitamo et al., 1993). In some diseases, they are present at high concentrations. Antibodies to IL-8 are the most common (Reitamo et al., 1993)....

Glycoprotein IIbIIIa Antagonist Induced Thrombocytopenia

Glycoprotein (GP) IIb IIIa antagonists (abciximab, tirofiban, eptifibatide) are used during coronary angioplasty to reduce platelet-mediated thrombosis. However, in a few patients ( 1 ), acute thrombocytopenia begins within hours of GPIIb IIIa antagonist use (Aster et al., 2006 Warkentin, 2007). The thrombocytopenia is typically severe (usually < 20 X 109 L) and life-threatening bleeding can sometimes occur. Interestingly, most reported cases have occurred after first exposure to one of these...

Platelet Activation Endpoints

14C Serotonin release was the first activation endpoint described using washed platelets (Sheridan et al., 1986). In this method, the washed platelets are incubated with test and control serum or plasma and heparin-buffer in flat-bottomed polystyrene microtiter wells (in duplicate or triplicate), performed on a platelet shaker (shaken, not stirred). After 1 h, the reaction is halted with 100 mL of 0.5 EDTA in phosphated-buffered saline (PBS). The microliter plates are centrifuged at 1000 g...

Paroxysmal Nocturnal Hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal myeloid disorder characterized by an acquired defect in the X-linked phosphatidylinositol glycan class A (PIG-A) gene, leading to loss of cell surface glycosylphosphatidylinositol-anchored proteins (for review see Rosse, 1997). Loss of the complement-regulating glycosylphosphatidylinositol-linked surface proteins, decay-accelerating factor and membrane attack complex inhibitory factor, causes the red cells to be exquisitely sensitive to...

The Immune Response To Heparin

The finding that anti-PF4-heparin antibodies can be of the IgM, IgG, or IgA isotype (Visentin et al., 1994 Greinacher et al., 1994 Kelton et al., 1994 Amiral et al., 1995, 1996b Arepally et al., 1997 Suh et al., 1997) indicates that class switching, likely requiring helper T cells, may occur in patients mounting a humoral immune response to PF4-heparin. Although HIT is a drug-induced disorder, parallels for the role of T cells in HIT may be drawn from studies of autoimmune

Therapy Of Pediatric

Numerous case reports describe the occurrence of new or recurrent thromboem-bolic events during continued or repeated use of heparin in adult patients with acute HIT. Further, thrombocytopenia usually persists if heparin is not stopped. Thus, all heparin should be discontinued in patients strongly suspected of having HIT, including heparin flushes, heparin-coated catheters, and heparin-containing blood products (Severn et al., 2002b) (see Chapter 12). As in adults, low molecular weight heparin...

Prophylaxis of Venous Thromboembolism

Patients with a previous history of HIT may require an alternative anticoagulant to prevent venous thromboembolism if they require prolonged bed rest and or surgery or become pregnant. UFH cannot be used, particularly during the first 1 or 2 mo after the onset of HIT when HIT antibodies still circulate. Thereafter, although HIT antibodies are usually undetectable, and the risk of recurrent HIT is possibly relatively low (Warkentin and Kelton, 2001), most physicians are understandably reluctant...

Argatroban Reexposure

Across the prospective studies of HIT, 55 patients underwent therapy with argatroban on more than one occasion. The argatroban dosing and duration were similar between these patients (repeat group) and patients upon their first exposure (initial group, n 754). Event rates in the repeat group were less than with those in the initial group for the composite endpoint (20 vs. 34 ), new thrombosis (3.6 vs. 11.1 ), and major bleeding (3.6 vs. 6.6 ). The patients reexposed to argatroban had no...

Arterial Thrombosis

Lower limb artery thrombosis was the first recognized complication of HIT (Weismann and Tobin, 1958 Roberts et al., 1964 Rhodes et al., 1973, 1977). Arterial thrombosis most commonly involves the distal aorta (e.g., saddle embolism) or the large arteries of the lower limbs, leading to acute limb ischemia with absent pulses. Sometimes, platelet-rich thromboemboli from the left heart or proximal aorta explain acute lower limb arterial ischemia (Vignon et al., 1996). Other arterial thrombotic...

Frequency of HIT in Medical Patients Treated with Porcine Mucosal UFH

Table 2 also lists the frequency of HIT observed in several prospective studies that have evaluated medical patients receiving intravenous, therapeutic-dose porcine UFH, usually for venous thromboembolism (VTE), myocardial infarction and acute coronary syndromes (MI ACS), or hemodialysis (HD). Excluding studies of HD, an overall frequency of HIT of slightly less than 1 is suggested. This is a relatively low number, particularly when one considers that, paradoxically, the frequency appears to be...

Vnonimmune Heparinassociated Thrombocytopenia

Nonimmune heparin-associated thrombocytopenia (HAT) describes the common clinical situation in which a patient develops a fall in platelet count within the first few days of receiving heparin. Often, there are concomitant clinical factors to explain the thrombocytopenia (e.g., hemodilution, bacteremia, or disseminated intravascular coagulation DIC ). In some patients, however, it is possible that a direct proaggregatory effect of heparin is responsible for the drop in platelet count (Salzman et...

C1c2c3c4

FIGURE 4 (See color insert) Primary and secondary structure of PF4 in relation to HIT neoepitopes. (Top) 3D representation of the PF4 tetramer, indicating two neoepitope sites (per monomer). The ring of positive charge is formed by lysine residues in the C-terminus (light blue) and other lysine and arginine residues (dark blue). (Bottom) The linear sequence of the 70-amino acid polypeptide of a single PF4 molecule is shown. Abbreviation PF4, platelet factor 4. Source From Li et al., 2002....

Iintroduction

Heparin-induced thrombocytopenia (HIT) is caused by heparin-dependent antibodies that usually recognize multimolecular complexes of platelet factor 4-heparin (PF4-H). HIT can be viewed as a clinicopathologic syndrome (Warkentin et al., 1998). Thus, a diagnosis of HIT should be based on two criteria (1) clinically evident abnormalities, most commonly thrombocytopenia with or without thrombosis (see Chapter 2), and (2) detection of HIT antibodies. In some ways, HIT resembles another...

Post Surgical Thrombocytopenic Thrombocytopenia Purpura

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder characterized by thrombocytopenia and microangiopathic hemolytic anemia (Coombs-negative hemolysis with prominent red cell fragmentation). Ischemic necrosis of brain, kidneys, heart, pancreas, and other tissues can result from disseminated arteriolar occlusions by platelet-von Willebrand factor (vWF) microthrombi. In many patients, there is evidence for autoantibodies that inhibit or clear the enzyme, ADAMTS13 (a...

Treatment of VTE

The treatment of VTE was assessed in two large, international studies (Buller et al., 2003, 2004). The primary outcome measure for both non-inferiority studies was the incidence of symptomatic VTE during a total treatment period of 3 mo. TABLE 2 Indications for the Use of Fondaparinux Venous thromboembolism prevention Hip fracture 2.5 mg d sc o.d. for up to 32 days 2.5 mg d sc o.d. for up to 11 days 2.5 mg d sc o.d. for up to 10 days 2.5 mg d sc o.d. Venous thromboembolism treatment Acute...

Prevention of Venous Thrombosis in Other Clinical Settings

Additional clinical studies have examined the utility of fondaparinux in the prevention of VTE following general surgery and in the medical patient. In general surgery patients, the PEGASUS study compared the efficacy of 2.5 mg fondapar-inux versus dalteparin administered preoperatively and then once daily at a dose of 5000 IU (Agnelli et al., 2005). The primary endpoint was venographically evident DVT and symptomatic VTE to day 10. The objective of this non-inferiority study was met, without a...

Thrombosis

The HIT Paradox Thrombosis but not Hemorrhage Table 1 summarizes the clinical spectrum and approximate frequency of clinical sequelae associated with HIT. Spontaneous hemorrhage is not characteristic of HIT, and petechiae are not typically observed, even in those occasional patients whose platelet count is less than 10 X 109 L. Bleeding complications were not increased over controls in two prospective studies of HIT (Cipolle et al., 1983 Warkentin et al., 1995). Petechiae and other signs of...

Adequate Anticoagulants for HD in HIT Patients

Patients with renal failure show plasma hypercoagulability as well as uremic platelet defects, both of which can be worsened by HD (Ambuhl et al., 1997 Sreedhara et al., 1995 Vecino et al., 1998). Therefore, selection of an appropriate anticoagulant in HD patients who also suffer from HIT is difficult. Reports on specific anticoagulant strategies in HIT are anecdotal. Large studies, especially those comparing different anticoagulant regimens, are lacking. Therefore, no treatment recommendations...

Regional Citrate Anticoagulation

Anticoagulation by regional citrate is based on the concept of inhibition of clotting by chelation of ionized calcium, and it was first developed as an alternative anticoagulant regimen in HD patients at risk of bleeding (Pinnick et al., 1983). Metabolic alkalosis, hypernatremia, alterations in calcium homeostasis, and hyperalbuminemia are reported side effects that are generally manageable (Ward and Mehta, 1993 Flanigan et al., 1996 Janssen et al., 1996). Regional citrate anticoagulation is a...