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platelet inhibition as a strategy to permit heparinization for CPB, 494-495 with and without CPB, 488-495: argatroban, 492-494; bivalirudin, 491-492; danaparoid sodium,

488-491; r-hirudin, 488-491 Intravenous gammaglobulin, 42,194,302 Intravenous heparin bolus acute systemic reactions (ASRs) following, 49. See also separate entry Isolated HIT, 11-13, 35-37, 87-91, 101, 284, 295-296, 325, 328, 351, 353, 358-364, 449, 453, 523 definition of, 87

natural history of, 11-12, 35, 87-91 Isolated limb perfusion (ILP), 76

Laboratory testing for HIT, 227-260 antigen assays for HIT antibodies, 240-247. See also separate entry classification of, 229 diagnostic interpretation, 249-251 interpretation, 247-251

clinical HIT, definition, 247-249 rapid versus typical onset of thrombocytopenia, 247 platelet activation assays for HIT

antibodies, 227-240 rapid immunoassays, 244-246 in vitro cross-reactivity, 251-253. See also separate entry Lepirudin for HIT treatment, 345-378. See also Hirudin allergic reactions, 365-366 antibody formation, 364-365 approved dose is too high, 292-293,

347-348 characteristics, 292 hirudin and its derivatives,

345-353. See also Hirudin dose adjustments, 351-352: lepirudin and vitamin K antagonists, 351; renal impairment, 351 functional monitoring tests, limitations, 350 in patients with HIT, dosing schedules for, 348 in HIT, clinical studies with, 353-366 heparin-associated thrombocytopenia (HAT)-1, -2, and -3, 353-361 HAT-1 study, 255 HAT-1, -2, and -3, meta-analy-sis of, 356-361 efficacy outcomes, 356, 361 safety outcomes, 358, 361 HAT-1, -2, and -3, synopsis of, 355

HAT-2 study, 355 HAT-3 study, 355 historical control group, 354

comparison with, 356 objectives, 353 patients, 353

[Lepirudin for HIT treatment] in other clinical settings, 366-369 ACS and percutaneous coronary intervention, 366-367 in children, 368-369 CPB and vascular surgery, 367 hemodialysis, 368 in pregnancy, 368 other treatments and, comparison,

362-364 in pediatric HIT, 509-510 postmarketing drug monitoring program, 361-362 reversal/removal of, 292, 352, 369, 473

Livedo Reticularis, 43-44, 48, 268 Low molecular weight heparin (LMWH), 13-14,174 contraindicated for treatment of HIT, 304, 521 Luminography, 229, 233

Medical thrombolysis, 301, 348, 350,

451, 509 Meizothrombin, 349, 353, 489 Meningococcemia, 43,197, 271 Metachromatic granules, 150 Molecular immunopathogenesis of HIT, 149-166. See also Heparin; Platelet factor 4 HIT antibodies, epitopes recognized by, 151-156 implications, 159-161 polyanion, role of, 151-154 protein, role of, 155-156 Monoclonal antibody immobilization of platelet antigens (MAIPA) assay, 251 Monocytes activation, 35, 135, 161, 187, 193, 287

Fc receptors, 189,196 in HIT-associated thrombosis, 217-218

Myocardial infarction and acute coronary syndromes (MI/ACS) argatroban as treatment for, 384

[Myocardial infarction and acute coronary syndromes (MI/ACS)] bivalirudin as treatment for,

422-424 fondaparinux as treatment for,

447-448 frequency of HIT in, 71-72, 74 lepirudin as treatment for, 348, 353, 366-367

Nadroparin sodium (Fraxiparin®), 76,

77,174, 476 Nafamostat mesilate, 475 Necrotic skin lesions, 46, 47, 101, 519

Nonidiosyncratic heparin-induced platelet activation, 119-120 Nonimmune heparin-associated thrombocytopenia, 6-7, 286, 329 mechanisms, 6 nonimmune (Type I) versus immune (Type II) HIT, 6-7 Nonimmune heparin-platelet interactions, 117-129 heparin binding to platelets, 117-119 parameters for, 118 implications, 123

nonidiosyncratic heparin-induced platelet activation, 119-120 nonimmune heparin-associated thrombocytopenia, 120-121

platelet-related prohemorrhagic effects, 120 Normiflo®, 174

OPCAB surgery, 424-425 Orgaran®. See Danaparoid (Orgaran®) Orthopedic patients, postoperative, HIT in, 8, 24, 38, 67, 73, 76-77, 86, 89, 92, 94, 97, 173, 248-251

Parnaparin sodium (Fluxum®), 174 Paroxysmal nocturnal hemoglobinuria (PNH), 262, 272, 451 Particle gel immunoassay, 229, 243-245

Particle immunofiltration assay

(PIFA), 229, 245-246 Pediatric HIT

pediatric cardiac surgery patients, 505

pediatric dialysis patients, 506 pediatric intensive care unit patients, 503-505 therapy of, 509-512 argatroban, 510 coumarin, 510 danaparoid, 509 lepirudin, 509-510 Pentasaccharides, 177-178. See also Fondaparinux (Arixtra®) chemical structure of, 178 pentasaccharide sequence of heparin, 169 Percutaneous coronary intervention (PCI), 366-367, 394-397, 421-423 approvals of argatroban and bivalirudin for HIT, 10, 12, 13, 379

argatroban dosing and monitoring during, 392, 396-397 bivalirudin dosing and monitoring during, 413, 415-416 danaparoid dosing during,

323, 328 lepirudin dosing during, 348 Percutaneous transluminal angioplasty (PTA), 416, 418, 424

Percutaneous transluminal coronary angioplasty (PTCA), 10, 13, 409. See also Percutaneous coronary intervention PF4. See Platelet factor 4 Phenprocoumon, 39, 42, 284, 296, 304,

305, 355, 394, 510 Phlegmasia cerulea dolens, 6, 11, 22,

38, 39, 41, 263-264 Plasma IgG concentrations, 194

Plasmapheresis, 11, 43, 273, 302-303,

321, 419, 468, 473 Plasma-soluble FcgRIIa, 194 Platelet activation assays for HIT antibodies, 227-240 using citrate-anticoagulated blood, 238-240

washed platelet assays, 227-238. See also separate entry Platelet aggregation test (PAT), 149, 229

Platelet and leukocyte Fcg receptors (FcgR) in HIT, 187-208 ADP potentiation of platelet activation, 191 Fcg receptor IIa-mediated platelet activation, 190 Fcg receptor RIIa activation in HIT, 192-196

Fcg receptor IIA polymorphisms in disease, 196-200 determining, 196-197 in infectious or autoimmune disease, 197 role of, 197-198 Fcg receptor IIa-Arg/His polymorphism, 194-195 Fcg receptor-mediated signal transduction, 191-192 immunoglobulin G agonists and platelet activation, 190-192 molecular and structural characteristics, 189 plasma IgG concentrations, 194 plasma-soluble Fcg receptor IIa, 194 platelet activation, dynamic model of, 193

platelet Fcg receptor IIa numbers, 194

procoagulant, platelet-derived microparticles, 190-191 structure, distribution, and function, 188-190 tissue distribution, 189 Platelet basic protein (PBP), 150 Platelet count monitoring, for HIT, 32, 47, 85,

100-102, 286, 468 recovery following discontinuation of heparin, 32, 52, 247

Platelet factor 4 (PF4)

amino acid composition of, 154 atherosclerotic tissue invested with, 215

atomic force microscopy of, 172 and the endothelium, 211-216 heparin and, 121-123, 132-136,

150-156, 167-172, 211-216 PF4-heparin complexes, 171-174 PF4-sulfated polysaccharide complexes, 169-170 primary and secondary structure of, 156 structure of, 167-168 sulfated polysaccharides interactions with, 167-170 in vivo, 170 transformed into alloantigens, 132-136 Platelet glycoprotein Ilb/IIIa inhibitors, 299, 303 cardiac surgery and, 488, 494-495 cause of immune thrombocytopenia, 31, 262, 273-274

PCI and, 392, 396, 397, 409, 418, 422, 424, 430 Platelet inhibition as a strategy to permit heparinization for CPB, 494-495 Platelet microparticles, 35, 50, 132, 135, 138, 160, 190-192, 287, 303

laboratory assay for HIT, 229, 230, 233

Platelet transfusions for HIT, 284, 305, 520

Platelet-related prohemorrhagic effects, 120 Porcine mucosal UFH and risk of

HIT, 6, 8, 69, 70-77, 85, 93-96 Posttransfusion purpura (PTP), 53, 262, 274

Preexisting antibodies. See also Rapid onset of HIT against CXC chemokines, 132, 139, 141 Pregnancy argatroban in, 399 bivalirudin in, 425

[Pregnancy] cerebral dural sinus thrombosis, 42, 50-51

cutaneous hypersensitivity reactions, 48 danaparoid in, 300-301,330-331, 336 deep vein thrombosis in, 38 fondaparinux in, 300-301, 444 HIT during, 50, 67, 69, 300-301

frequency, 79 lepirudin in, 300-301, 368 Pretest probability of HIT, estimating, 52-53, 247, 249-251 Four Ts, 52-53, 81, 247, 298, 522, 523

scoring systems for HIT, 52 clinical use, 52-53 Prochlorperazine edisylate, 418 Procoagulant, platelet-derived microparticles, 190-191. See also Platelet microparticles Prohemorrhagic disorders, 120, 262 Prophylaxis. See also Isolated HIT of arterial thromboembolism, 328 dosing of anticoagulation during acute HIT, 12-13, 284, 298, 323, 327-328, 348, 391-393, 509

of venous thromboembolism, 328 Prostacyclin, 299, 475, 494 Prosthetic device, 45, 464 Prothrombotic nature of HIT (odds ratios), 35 Pseudo-HIT, 261-282 complicated by HIT, 275-276 concept of, 261-262 disorders/syndromes, 262 adenocarcinoma, 262-265 antiphospholipid antibody syndrome, 262, 266-270. See also separate entry diabetic ketoacidosis, 262, 266, 268

glycoprotein IIb/IIIa antagonist-induced thrombocytopenia, 273-274 pulmonary embolism, 262 septicemia-associated purpura fulminans, 262 thrombolytic therapy, 262

[Pseudo-HIT] infective endocarditis, 272 paroxysmal nocturnal hemoglobinuria (PNH), 272 recognition and treatment of,

274-276 septicemia-associated purpura fulminans, 271-272 thrombolytic therapy, 270-271 Pseudo-pulmonary embolism,

49, 465 Pulmonary embolism.

91, 295, 354, 504 indication for medical thrombolysis, 301 IVC filters and, 284, 306 pseudo-HIT and, 262, 265-266 treatment with enoxaparin or fondaparinux, 14, 446-447

Rapid assays, 229, 243-245 Rapid onset of HIT, 25-27, 30, 49, 68,

101, 521 Raynaud's phenomenon, 42 Razaxaban, 454 Reexposure of heparin to HIT patient,

28-29, 284, 298-299, 390, 495-497 with acute or recent HIT,

298-299 with a history of remote HIT, 299

Regional citrate anticoagulation, 475 Reteplase, 418

Reviparin sodium (Clivarin®), 75, 77, 174, 231

r-hirudin, 9-10, 488-491. See also

Lepirudin for HIT treatment; Hirudin characteristics, 292 Risk of HIT. See also Frequency of HIT factors influencing, 50, 79, 82 low molecular weight heparin

(LMWH), 13-14 reducing, 13-15 Rivaroxaban, 442, 453, 454

Scoring systems for HIT, 52 Septicemia-associated purpura fulminans, 262, 271-272 Serotonin release assay (SRA), 227-233 history, 7

operating characteristics, 250 Silver, Donald, 4 Skin lesions heparin-induced in the absence of coumarin therapy, 48 at subcutaneous injection sites,

22, 45-47 cutaneous type IV

hypersensitivity reactions, 48 livedo reticularis, 47 urticaria, 48 non-HIT versus HIT-associated, 48-49

Solid-phase enzyme immunoassay

(EIA), 240-242 Spontaneous HIT, 85 Streptokinase, 121, 190, 270, 301, 347, 418, 423

Stroke, argatroban anticoagulation for, 398

Sulfated polysaccharides. See also

Carbohydrate-based heparin alternatives HIT antibodies, cross-reactivity with, 174-176 LMWHs, interactions with, 174-175 HIT caused by, 84-85 PF4 interactions with, 167-170. See also Platelet factor 4 (PF4) role in HIT, 167-186

Therapeutic-dose anticoagulation. See also Prophylaxis for isolated HIT, 12-13 Thrombin Inhibition in Myocardial

Infarction (TIMI), 423 Thrombocytopenia, 21-32

day of onset of thrombocytopenia, determining, 33 definition of, 8, 30-31

[Thrombocytopenia] early- versus late-onset, 68-69 HIT-associated thrombosis without, 32

in patients with APLAS receiving heparin, 269 severity of, 4-6, 30-32 timing, 21-30

delayed onset of HIT, 29-30 diminishing risk of HIT after Day 10, 24

HIT-associated thrombosis, 35, 36 hypothesis to explain, 27-28 rapid onset of HIT, 25-26: temporal profile of, 25 typical onset of HIT, 22-24 Thromboembolism prophylaxis of, 328 Thrombolytic therapy, 262, 270-271 Thrombosis, 32-45

arterial thrombosis, 44-45

angiographic appearance, 45 complicating HIT, frequency of, 86-91 treatment, 9-11: danaparoid sodium, 9; direct thrombin inhibitors, U.S. approvals for, 10-11; recombinant hirudin (lepirudin), 9-10 congenital hypercoagulability and, 44

graft, prosthetic device, and extracorporeal circuit thrombosis, 45 HIT paradox, 32-34 HIT-associated thrombosis, pathogenesis, 36-37 paradoxical, 4-6

thrombotic complications, timing of, 34-36 venous limb gangrene, 6, 10-11,

39-42, 263-265, 275 venous thrombosis, 37-44. See also separate entry Thrombotic and hemorrhagic manifestations, of HIT, 4-5 Thrombotic thrombocytopenic purpura (TTP), 305 platelet-activating effects, 230 post-surgical, 262, 272-273

Tinzaparin sodium (Innohep®), 14,174 Treatment of HIT, 283-317. See also individual treatments caveats for, 304-306 in children, 301 disclaimer, 285 drugs that reduce thrombin generation, 294 nonimmune heparin-associated thrombocytopenia, 286 special clinical situations, 299-301 cardiac or vascular surgery, 299-300

therapy of (immune) HIT, 286-299 anticoagulation of HIT patients with thrombosis, 288-294 discontinuation of heparin, 288 treatment implications, 286-287 treatment paradoxes of HIT Management, 284

Urokinasetype plasminogen activator

Vancomycin hydrochloride, 418 Vascular surgery, 301-302, 323, 348, 367, 488, 491, 494, 497 frequency of HIT, 95 heparin reexposure for previous HIT, 299-300 Venous limb gangrene, 6, 10-11, 39-42, 263-265, 275 and HIT, association between, 40

frequency of, 41 warfarin-induced venous limb gangrene, 6, 10-11, 38-42, 38-42

Venous thromboembolism (VTE), 74, 445

treatment of, 446-447 Venous thrombosis, 37-44

adrenal hemorrhagic infarction

(adrenal vein thrombosis), 42 cerebral venous (dural sinus)

[Venous thrombosis] coumarin-induced necrosis, 22, 3842, 47, 263-264, 284, 296-297, 302, 304-305, 352, 454, 510 DIC and acquired anticoagulant deficiency, 42-44 lower limb DVT, 38 recurrence of, 39 upper limb DVT, 22, 37-39 Ventricular assist devices (VADs)

HIT and, 84, 95-96 Vitamin K antagonist (coumarin) therapy. See Coumarin

Warfarin anticoagulation. See

Coumarin Warfarin-induced venous limb gangrene, 6,10-11, 38-42 Washed platelet assays, 227-238 advantages and disadvantages of, 238

aggregation of washed platelets, 233

biological basis for high sensitivity of, 234

citrated platelet-rich plasma versus, 234, 240

heat inactivation of patient serum or plasma, 233 heparin-independent platelet activation, 237 hierarchical versus idiosyncratic platelet activation, 235 high heparin concentrations, inhibition by, 237 interpretation, 237-238 luminography, 233 obtained test and control data, interpretation, 231 platelet activation endpoints, 231 platelets, preparation, 227 quality control in, 235 test conditions, 229 Weismann Rodger Elmer, 1-3, 5 White clot syndrome, 6

Ximelagatran, 442, 455

FIGURE 2.10 Warfarin-associated venous limb gangrene. Progression of deep vein thrombosis to acral necrosis (leading to below-the-knee amputation) occurred despite the presence of palpable arterial foot pulses in this 49-yr-old woman with HIT treated with warfarin (international normalized ratio = 7.2 at the onset of limb gangrene).

FIGURE 2.10 Warfarin-associated venous limb gangrene. Progression of deep vein thrombosis to acral necrosis (leading to below-the-knee amputation) occurred despite the presence of palpable arterial foot pulses in this 49-yr-old woman with HIT treated with warfarin (international normalized ratio = 7.2 at the onset of limb gangrene).

FIGURE 2.12 Warfarin-associated multiple digital necrosis of the right hand in a 61-yr-old woman with paraneoplastic Raynaud's phenomenon and adenocarcinoma-associated thrombotic endocarditis who developed HIT following aortic valve replacement surgery (see text for additional clinical details).

FIGURE 2.13 Clinical manifestations of DIC. (A) Livedo reticularis. (B) Patchy ischemic necrosis of right foot. This 70-yr-old woman developed HIT-associated DIC with hypofibrinogenemia, elevated INR, and reduced antithrombin and protein C activity levels 9 days after emergency cardiac surgery for cardiac catheterization-associated dissection of the left main coronary artery (see text for additional clinical information).

FIGURE 2.13 Clinical manifestations of DIC. (A) Livedo reticularis. (B) Patchy ischemic necrosis of right foot. This 70-yr-old woman developed HIT-associated DIC with hypofibrinogenemia, elevated INR, and reduced antithrombin and protein C activity levels 9 days after emergency cardiac surgery for cardiac catheterization-associated dissection of the left main coronary artery (see text for additional clinical information).

FIGURE 2.14 Heparin-induced skin lesions. (A) Heparin-induced erythematous plaques: UFH injections into the lower abdomen resulted in painful erythematous plaques beginning on day 7 of sc UFH treatment; at this time, the platelet count fell only by 9% from 340 to 311 x 109/L. HIT antibody seroconversion from a negative baseline was shown using the serotonin release assay (from 0% to 84% serotonin release). (B) Heparin-induced skin necrosis: UFH injections into the right anterior thigh led to skin necrosis: a large black eschar with irregular borders is surrounded by a narrow band of erythema. The platelet count fell to 32 x 109/L; despite stopping heparin, the patient developed symptomatic proximal deep vein thrombosis 10 days later. Abbreviations: HIT, heparin-induced thrombocytopenia; UFH, unfractionated heparin.

FIGURE 2.14 Heparin-induced skin lesions. (A) Heparin-induced erythematous plaques: UFH injections into the lower abdomen resulted in painful erythematous plaques beginning on day 7 of sc UFH treatment; at this time, the platelet count fell only by 9% from 340 to 311 x 109/L. HIT antibody seroconversion from a negative baseline was shown using the serotonin release assay (from 0% to 84% serotonin release). (B) Heparin-induced skin necrosis: UFH injections into the right anterior thigh led to skin necrosis: a large black eschar with irregular borders is surrounded by a narrow band of erythema. The platelet count fell to 32 x 109/L; despite stopping heparin, the patient developed symptomatic proximal deep vein thrombosis 10 days later. Abbreviations: HIT, heparin-induced thrombocytopenia; UFH, unfractionated heparin.

FIGURE 5.1 Release of PF4 from platelets as a high molecular weight complex of eight tetramers with a proteoglycan dimer; PF4 binds to endothelial cell GAGs, for which it has a greater affinity, but it is displaced by heparin, which exhibits a higher affinity for PF4. Abbreviations: GAGs, glycosaminoglycans; PF4, platelet factor 4; PF4-H, PF4 complexed to heparin.

FIGURE 5.1 Release of PF4 from platelets as a high molecular weight complex of eight tetramers with a proteoglycan dimer; PF4 binds to endothelial cell GAGs, for which it has a greater affinity, but it is displaced by heparin, which exhibits a higher affinity for PF4. Abbreviations: GAGs, glycosaminoglycans; PF4, platelet factor 4; PF4-H, PF4 complexed to heparin.

PF4 excess Stoichiometric PF4-Heparin Heparin excess

(B) (No complexes) (Formation of multimolecular complexes) (No complexes)

FIGURE 5.2 Schema showing the "modifications" of the PF4 tetramer following its tight binding with heparin at stoichiometry and exposure of neoepitopes (A) and depicting the formation of heparin and PF4 complexes at different concentrations of heparin and PF4 (B). In the presence of stoichiometric concentrations of both substances, multimolecular complexes are formed. Heparin then wraps around the PF4 tetramer, altering its structure and rendering it antigenic. Abbreviation: PF4, platelet factor 4.

PF4 excess Stoichiometric PF4-Heparin Heparin excess

(B) (No complexes) (Formation of multimolecular complexes) (No complexes)

FIGURE 5.2 Schema showing the "modifications" of the PF4 tetramer following its tight binding with heparin at stoichiometry and exposure of neoepitopes (A) and depicting the formation of heparin and PF4 complexes at different concentrations of heparin and PF4 (B). In the presence of stoichiometric concentrations of both substances, multimolecular complexes are formed. Heparin then wraps around the PF4 tetramer, altering its structure and rendering it antigenic. Abbreviation: PF4, platelet factor 4.

Endothelial cells

Endothelial cells

Prolonged immobilization inducing neutrophil (Neutr) and platelet (Plt) activation

FIGURE 5.3 Cell-cell interactions in the neighborhood of blood activation or inflammation sites: Presence of heparin-dependent antibodies increases the amount of cells available at these sites, amplifies cell-cell interactions and cellular activation, and can lead to blood clotting or release of circulating cell aggregates. The procoagulant effect is enhanced by release of tissue factor (from endothelial cells and monocytes) and generation of microparticles. Abbreviations: IL-8, interleukin-8; PF4, platelet factor 4; PF4-H, heparin-platelet factor 4; TF, tissue factor.

Prolonged immobilization inducing neutrophil (Neutr) and platelet (Plt) activation

FIGURE 5.3 Cell-cell interactions in the neighborhood of blood activation or inflammation sites: Presence of heparin-dependent antibodies increases the amount of cells available at these sites, amplifies cell-cell interactions and cellular activation, and can lead to blood clotting or release of circulating cell aggregates. The procoagulant effect is enhanced by release of tissue factor (from endothelial cells and monocytes) and generation of microparticles. Abbreviations: IL-8, interleukin-8; PF4, platelet factor 4; PF4-H, heparin-platelet factor 4; TF, tissue factor.

Heparin binding sites

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