Transition to Vitamin K Antagonist Coumarin Therapy

Generally, it takes at least 5 days of oral anticoagulant therapy before therapeutic functional hypoprothrombinemia is achieved (Harrison et al., 1997). It is important that thrombin generation be controlled in patients with acute HIT before and during initiation of coumarin treatment, particularly in patients with severe HIT-associated DVT, because otherwise coumarin-induced necrosis (venous limb gangrene and skin necrosis syndromes) can be induced (Warkentin et al., 1997 Srinivasan et al.,...

K HIT and Heparin Coated Devices

Heparin can be bonded to artificial surfaces (Larsson et al., 1987), either through ionic attachment, as used for pulmonary artery catheters (Eldh and Jacobsson, 1974), or by end-linked covalent bonding (e.g., Carmeda BioActive Surface CBAS ) (Larm et al., 1983). CBAS has been used for CPB circuits and filters (Borowiec et al., 1992a,b, 1993), extracorporeal membrane oxygenation (ECMO) devices (Koul et al., 1992), and coronary stents (Serruys et al., 1996). During use in patients, ionically...

Introduction

The most important complication of heparin-induced thrombocytopenia (HIT) is thrombosis. Clinically overt arterial or venous thrombi have been observed in 50 or more patients with HIT in some series (see Chapters 2 and 3), a frequency that far exceeds any other drug-induced immune platelet disorder. The propensity for thrombosis is in part attributable to platelet activation through FcgIIa receptors by IgG-containing complexes comprised of platelet factor 4 (PF4) and heparin (see Chapter 8)....

Miscellaneous Complications Of Hit A Heparin Induced Skin Lesions at Subcutaneous Injection Sites

Skin lesions that occur at the site(s) of subcutaneous heparin injection are a manifestation of the HIT syndrome. For unknown reasons, only 10-20 of patients who form HIT antibodies during subcutaneous UFH or LMWH treatment develop these lesions (Warkentin et al., 2005b). Furthermore, about 50 to 75 of patients who develop heparin-induced skin lesions do not develop thrombocytopenia, even though heparin-dependent, platelet-activating HIT antibodies are readily detectable (Warkentin, 1996a, 1997...

Perspective And Future Directions

HIT continues to pose several enigmas including the fundamental issue of how heparin induces the formation of self-reactive antibodies to a native protein in such a high proportion of immunologically competent individuals (Visentin et al., 1996 Bauer et al., 1997). It also remains unclear why only a subset of patients with anti-PF4-heparin antibodies develops thrombocytopenia, and fewer still develop thrombosis. It is possible that characteristics of HIT antibodies, such as their subtype,...

References

Agnelli G, Iorio A, De Angelis V, Nenci GG. Dermatan sulphate in heparin-induced thrombocytopenia letter . Lancet 344 1295-1296,1994. Akizawa T, Koshikawa S, Ota K, Kazama M, Mimura N, Hirasawa Y. Nafamostat mesilate a regional anticoagulant for hemodialysis in patients at high risk for bleeding. Nephron 64 376-381,1993. Amb hl PM, W thrich RP, Korte W, Schmid L, Krapf R. Plasma hypercoagulability in haemodialysis patients impact of dialysis and anticoagulation. Nephrol Dial Transplant 12...

This Cannot Be HIT Because It Is Too Early Too Late or the Platelets Are Not Low Enough or They Are Too

Classic HIT ensues 5-10 days (occasionally, a few days later) after the beginning of a course of heparin, but rapid-onset HIT occurs sooner, sometimes within minutes of heparin administration, if the patient has had prior sensitization to heparin within the preceding 3 mo (Warkentin and Kelton, 2001a Mims et al., 2004). While the degree of thrombocytopenia with HIT is often moderate (median platelet count, 60 X 109 L), 10 of patients may experience severe thrombocytopenia (platelet count less...

M HIT Caused by Other Sulfated Polysaccharides

The cryptic HIT autoantigen is comprised of conformationally altered PF4 when it forms a multimolecular complex with heparin. Other negatively charged polysac-charides can interact with PF4 to produce the HIT antigen (Wolf et al., 1983 Greinacher et al., 1992a,b,c Anderson, 1992) (see Chapter 7). These considerations explain why a number of high-sulfated polysaccharides, 10 or more subunits in length, have been reported to cause a syndrome of thrombocytopenia and thrombosis that essentially...

Diabetic Ketoacidosis

Diabetic ketoacidosis (DKA) can be associated with acute thromboembolic complications. In vitro studies indicate that high glucose levels enhance platelet activation by adenosine diphosphate (ADP) and other platelet agonists (Sudic et al., 2006). Evidence for in vivo platelet activation was observed in one study of 10 patients who had elevated plasma levels of platelet factor 4 (PF4) and b-thromboglobulin during DKA that resolved following recovery (Campbell et al., 1985). Evidence for...

Pseudohit Syndromes A Adenocarcinoma

Mucin-producing adenocarcinoma is an important cause of venous and arterial thrombosis that occurs in association with thrombocytopenia. In these patients, DIC is often the predominant explanation for the thrombocytopenia. The diagnosis is suggested by reduced fibrinogen levels (or prolonged thrombin time), elevated prothrombin time, and elevated cross-linked (D-dimer) fibrin degradation products (or a positive protamine sulfate paracoagulation test). Adenocarcinoma-associated DIC can strongly...

Surgical Thromboembolectomy and Fasciotomies

Vascular surgery is often needed to salvage an ischemic limb threatened by HIT-associated acute arterial thromboembolism involving large arteries (Sobel et al., 1988). When performing vascular surgery during acute HIT, it is appropriate to maintain anticoagulation at least in the lower therapeutic range, if possible, before, during, and after surgery, until platelet count recovery. In patients with latent HIT (i.e., no longer thrombocytopenic, but with clinically significant levels of HIT...

Info

Note Repeat aPTT determinations should be made 4-6 h after any dose adjustment. aA maximum body weight of 100 kg should be used for dose calculations. bAdjust for renal insufficiency. cThe ratio is based on comparison with the normal laboratory mean aPTT. If Actin FS or Neothromtin reagents are used, the aPTT target range is usually 1.5-3.0. dThis is the author's recommended starting dose in all HIT patients, unless life-or limb-threatening thrombosis is present eUsed in the HAT-1, -2, and -3...

DIC and Acquired Anticoagulant Deficiency

Although increased thrombin generation occurs in virtually all patients with HIT, overt decompensated DIC, defined as reduced fibrinogen levels or an otherwise unexplained increase in the INR, is relatively uncommon, occurring in about 510 of patients (Natelson et al., 1969 Klein and Bell, 1974 Zalcberg et al., 1983 Castaman et al., 1992 Betrosian et al., 2003). Protein C consumption is also well compensated, as protein C levels are usually within the normal range when HIT is diagnosed...

Platelet Inhibition as a Strategy to Permit Heparinization for CPB

Another approach for managing CPB in a patient with acute or previous HIT is to combine full heparinization with one or more antiplatelet agents. Following surgery, an alternative non-heparin anticoagulant e.g., a DTI or danaparoid is initiated as soon as deemed safe. Several groups of investigators have used iloprost for this situation Kappa et al., 1985 Long, 1985 Palmer Smith et al., 1985 Addonizio et al., 1987 Kraenzler and Starr, 1988 , following the original observation by Olinger et al....

Argatroban

Argatroban is a synthetic, small-molecule 532 Da DTI derived from L-arginine that binds reversibly to thrombin. Its half-life is about 40-50 min. The potential of argatroban to be an effective anticoagulant in patients with HIT has been documented by the studies of Lewis et al. 1997a,b, 2001, 2003 see Chapter 15 . Its feasibility for anticoagulation of HIT patients is after cardiac surgery, with dosing reduced to 0.5-1 mg kg min Koster et al., 2006 . However, only limited information lt 20...

The Discovery Of Heparin And Its First Clinical

The following account of the discovery and first clinical development of heparin was recorded by the physiologist Best 1959 , a codiscoverer of insulin as well as a pioneer in studies of heparin. Incidentally, in 1916, while working at Johns Hopkins University to characterize procoagulant substances, McLean 1916 identified a natural anticoagulant substance. Further studies of this material were performed by his supervisor, Dr. Howell, who coined the term, heparin to indicate its first...

Monocyte FcyRs in HIT

Monocytes and macrophages possess several different classes of FcyR Table 1 , and thus may play a part in influencing the frequency and severity of both thrombocytopenia and thrombosis in HIT. One role, discussed in the previous section, involves their potential to influence the balance between platelet activation and reticuloendothelial-mediated platelet clearance in HIT. Another function recently proposed for monocytes is that of contributing to the procoagulant state in HIT a role posited...

Hit

Patients with central lineb Hong et al., 2003 Medicala Girolami et al., 2003 8 18 44.4 26 647 4.0 2 18 11.1 4 647 0.6 19.1 5.9-58.3 lt 0.001 20.1 1.7-150 0.01 Proximal DVT Bilateral proximal DVT Pulmonary embolism Any thrombosis 13 18 72.2 112 647 17.3 12.4 4.0-45.2 lt 0.001 Upper-limb 14 145 9.7 3 484 0.6 17.1 4.9-60.5 lt 0.001 DVT 2 18 11.1 2 647 0.3 40.3 2.7-572 0.004 21 593 3.5 40.8 5.2-163 lt 0.001 aHIT defined as gt 50 platelet count fall. bHIT defined as any abnormal platelet count fall...

Heparin Reexposure of the Patient with Acute or Recent HIT

Deliberate reexposure to heparin of a patient with acute or recent HIT for diagnostic purposes is not recommended. Rather, the diagnosis should first be excluded or confirmed in most situations by testing acute patient serum or plasma for HIT antibodies using a sensitive activation or antigen assay Grade 1C . Heparin Reexposure of the Patient with a History of Remote HIT Recommendation. Heparin should not be used for antithrombotic prophylaxis or therapy in a patient with a...

Frequency of HIT in Medical Patients and Normal Volunteers Comparison of UFH of Bovine Versus Porcine Origin

Five randomized controlled trials RCTs Bell and Royall, 1980 Green et al., 1984 Powers et al., 1984 Ansell et al., 1985 Bailey et al., 1986 and one nonrandomized study Cipolle et al., 1983 Ramirez-Lassepas et al., 1984 compared the frequency of HIT during treatment with UFH that was derived from either bovine lung or porcine intestinal mucosa. In addition, the frequency of HIT was evaluated in normal volunteers in one RCT Schwartz et al., 1985 and one nonrandomized prospective study Saffle et...

The Concept of Pseudo HeparinInduced Thrombocytopenia

Heparin-induced thrombocytopenia HIT is strongly associated with life- and limb-threatening venous and arterial thrombosis, including pulmonary embolism, venous limb gangrene, and large vessel arterial occlusion. However, HIT is by no means a unique explanation for the combination of thrombocytopenia and thrombosis Table 1 . In these pseudo-HIT disorders so named because they strongly mimic HIT on clinical grounds thrombocytopenia usually occurs early during the course of heparin treatment....

How Does Heparin Transform Pf4 Into An Alloantigen

PF4 is a 7.8 kDa CXC chemokine protein present in platelet a-granules as a tetramer of about 30 kDa. Upon platelet activation or lysis, PF4 is released into blood as a high molecular weight complex 350 kDa consisting of a proteoglycan dimer carrying eight PF4 tetramers. PF4 is rapidly cleared from blood through binding to EC glycosaminoglycans GAGs , for which it has a greater affinity than for the platelet proteoglycan dimer. During heparin therapy UFH or LMWH , PF4 tetramers are displaced...

Viec Antibodies In

There are limited experimental data to indicate that EC-reactive antibodies or immune complexes contribute to the development of thrombosis in patients with HIT. Over 10 yr ago, one group reported that sera from essentially all patients with HIT deposit increased amounts of IgG, IgM, or IgA on HUVEC Cines et al., 1987 . Binding was reduced when the cells were pretreated with enzymes that degrade heparin or heparan sulfate, whereas addition of chondroitinase was without effect. HIT sera induced...

Quality Control in Washed Platelet Assays for HIT

The variable reactivity of donor platelets to HIT sera is an important issue in activation assays for HIT. It has long been recognized that inconsistent results can be obtained using these assays Salem and van der Weyden, 1983 Pfueller and David, 1986 Warkentin et al., 1992 . TABLE 5 Reactivities of 10 HIT Sera with Platelets from 10 Normal Donors Normal platelet donors strongest P-i to weakest P10 TABLE 5 Reactivities of 10 HIT Sera with Platelets from 10 Normal Donors Normal platelet donors...

Solid Phase PF4Polyvinylsulfonate Antigen Assay

Several negatively charged substances can cause the cryptic autoepitope within PF4 to become recognizable to HIT antibodies see Chapters 5-7 . Indeed, a commercial assay for HIT using PF4 complexed with polyvinylsulfonate has been developed Collins et al., 1997 Visentin et al., 2001 . Sensitivity and reproducibility were high using polyvinylsulfonate that had been fractionated to a relatively uniform MW 5000 500 Da . Some technical advantages of this assay include the observation that the ratio...

Rapid Assay Particle Gel Immunoassay IDHPF4 Test

Figure 4 illustrates a rapid assay for anti-PF4-H antibodies, the particle gel immunoassay PaGIA , H PF4-PaGIA DiaMed, Cressier sur Morat, Switzerland . This assay utilizes PF4-H complexes bound to red, high-density polystyrene particles after addition of patient serum or plasma, the anti-PF4-H antibodies bind to the antigen-coated beads Meyer et al., 1999 Eichler et al., 2001 . However, IgG class antibodies do not agglutinate the polystyrene beads well, and therefore a secondary antihuman...

Pharmacologic and Pharmacokinetic Considerations in Anticoagulant Selection

The lack of prospective comparative studies between danaparoid, lepirudin, and argatroban precludes definitive conclusions about relative efficacy and safety. However, there are several pharmacological and pharmacokinetic differences that physicians should consider when determining which drug might be preferred in TABLE 3 Main Characteristics of Danaparoid Sodium Mechanism of action, pharmacokinetics Catalyzes the inactivation of factor Xa by AT, and of thrombin IIa by AT and HCII...

Fluid Phase EIA

The fluid-phase EIA for HIT antibodies Newman et al., 1998 is an adaptation of a staphylococcal protein A antibody-capture EIA method Nagi et al., 1993 . By permitting antibody-antigen interactions to occur in a fluid phase, problems of protein antigen denaturation inherent in solid-phase assays are avoided. with biotinylated all IgG with quantitates biotin-PF4- PF4-heparin protein G agarose heparin complexes that with biotinylated all IgG with quantitates biotin-PF4- PF4-heparin protein G...

Vimmune Ec Injury

EC-reactive antibodies have been found in patients suffering from disorders characterized by vasculitis or thrombosis for review see Praprotnik et al., 2001a Meroni et al., 2005 . The best-studied example is allograft rejection, a setting in which there is extensive evidence for AECA, in part directed at carbohydrate antigens that regulate procoagulant activity in vitro Saadi and Platt, 1995 Diujvestijn et al., 2000 . AECA have also been identified in patients with hyper-acute and acute graft...

Hemodialysis Hemofiltration and Intensive Care

Danaparoid was first used to anticoagulate non-HIT patients requiring hemodia-lysis in one of several clinical settings stable chronic renal failure CRF ten Cate et al., 1985 Henny et al., 1990, von Bonsdorff et al., 1990 or intensive care unit ICU patients who developed postoperative acute renal failure ARF Henny et al., 1983 . Danaparoid was then used to treat very ill patients in intensive care settings who developed HIT during CRRT for ARF Wester et al., 2000 LindhoffLast et al., 2001 ....

Acute Systemic Reactions Following Intravenous Bolus Heparin

ASR refers to a variety of symptoms and signs that characteristically begin 5-30 min after an intravenous heparin bolus is given to a patient with circulating HIT antibodies Nelson et al., 1978 Warkentin et al., 1992, 1994 Popov et al., 1997 Ling and Warkentin, 1998 Warkentin, 2002b Mims et al., 2004 Table 5 Fig. 3 . Only about one quarter of at-risk patients who receive a heparin bolus develop such a reaction. The most common signs and symptoms are fever and chills, hypertension, and...

Interpretation Of Hit Test Results

It is important to incorporate clinical information into the interpretation of any laboratory result for HIT. This is because thrombocytopenia, whether or not caused by HIT, is common in hospitalized patients receiving heparin, and because nonpathogenic HIT antibodies are often detected by sensitive assays in patients who have received heparin for 5 or more days. Several clinical scoring methods have been described to help estimate the probability of HIT independently of the HIT antibody test...

Anticoagulants Evaluated for Treatment of HIT

Hit Fibrin

Current treatment of HIT focuses on agents that rapidly control thrombin generation Fig. 2 see Chapters 13-17 . Table 2 lists the available evidence on efficacy for three such agents danaparoid, lepirudin, and argatroban listed in the order the drugs became available , which are approved for use in HIT in various countries. Danaparoid is an indirect antithrombin-dependent inhibitor of factor Xa and, to a lesser extent, thrombin, whereas lepirudin and argatroban inhibit thrombin directly and...

Iiplatelet Activation Assays For Hit Antibodies A Washed Platelet Assays

The classic washed platelet assay for HIT is the serotonin release assay SRA Sheridan et al., 1986 Warkentin et al., 1992 . This assay was a modification of platelet-washing techniques in use at McMaster University that resuspended washed platelets in buffer containing physiological concentrations of calcium. The purpose was to avoid platelet activation artifacts associated with low calcium concentrations Mustard et al., 1972 Kinlough-Rathbone et al., 1983 see Chapter 1 . The use of washed...

Rapid Assay Particle Immunofiltration Assay

Heparin Binding Platelet Factor

More recently, another rapid immunoassay for anti-PF4-H antibodies, the HealthTEST Heparin Platelet factor 4 Antibody Assay Akers Laboratories, Inc., Thorofare, NJ received approval by the U.S. Food and Drug Administration Fig. 5 . This assay utilizes a system known as particle immunofiltration assay PIFA , wherein patient serum fresh not frozen thawed is added to a reaction well containing dyed particles coated with PF4 not PF4 heparin . The lack of requirement for heparin presumably reflects...

I I I I I I111 I I I I I I111 I I I I I I

5 10 20 50 100 200 500 1000 Nadir Platelet Counts x10-9 L Shownon aLog10 Scale FIGURE 6 Platelet count nadirs and clinical profile of classic drug-induced immune-mediated thrombocytopenia versus serologically confirmed HIT. Classic drug-induced immune-mediated thrombocytopenia e.g., caused by quinine, vancomycin, or glycoprotein IIb IIIa antagonists, among other drugs typically produces severe thrombocytopenia median platelet count nadir, approximately 10 x 109 L and associated mucocutaneous...