Effective Remedies for Low Platelets

Conquer Low Platelets

Alternative And Natural Therapies For Itp (idiopathic Thrombocytopenia Purpura). Live Free From Itp. Complete Program To Increase Platelets. This Is What You Will Learn With this Guide: The Two Herbs That can help bring up your platelets. The Two Vitamins needed to keep those platelets from dropping. What foods may cause your platelets to drop. How science has confirmed the benefits of these herbs in their use with low platelets. Why your doctor may not know about these natural alternatives and how you can assist him in helping you. Different tests that naturopathic doctors do to determine your real state of health that may reverse the course of your body drastically. Understand some of the reasons why people develop low platelets. Discover how your digestive tract may be the culprit to your low platelet level problems. How you can prevent the most drastic step a splenectomy. How you can restore your health so that you dont need any more dangerous drugs. Get your life back and stop ending up in the hospital all the time. Learn why your immune system is attacking your platelets and how to calm it down. Learn what over the counter medications to stay away from if you have low platelets More here...

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Nonimmune Heparinassociated Thrombocytopenia

Nonimmune Mechanisms in Heparin-Associated Thrombocytopenia Klein and Bell (1974) reported on two patients who developed severe thrombocytopenia, thrombotic complications, and DIC, with hypofibrinogenemia and microangiopathic red cell abnormalities i.e., these patients likely had severe HIT. This experience prompted Bell to perform the first prospective study investigating the frequency of thrombocytopenia complicating therapeutic-dose UFH (Bell et al., 1976). Sixteen of 52 patients (31 ) developed a platelet count fall to less than 100 x 109 L, and some of these patients developed hypofibrinogenemia and elevated fibrin(ogen) degradation products. The authors speculated that a thromboplastic contaminant extracted along with heparin from beef lung could explain the thrombocytopenia. A subsequent randomized controlled trial by Bell and Royall (1980) found the frequency of thrombocytopenia to be higher in patients who received bovine heparin (26 ) compared with heparin of porcine...

Early Versus Lateonset Thrombocytopenia

The distinction between thrombocytopenia that begins early (within 4 days) or late (5 or more days after beginning heparin treatment) is a simple clinical feature that is useful to distinguish nonimmune HAT, which begins early, from (immune) HIT, which begins late. For this assessment, the first day of heparin use is considered day 0. There is an important exception to this rule of timing for HIT a rapid fall in platelet count on starting heparin therapy can represent acute HIT, but only if a patient already has circulating HIT antibodies, usually the result of a recent heparin exposure. HIT antibodies are transient, which could explain why the risk for rapid-onset HIT is restricted to a period of about 100 days following exposure to heparin (Warkentin and Kelton, 2001) (see Chapter 2). Typically, nonimmune HAT begins 1 -2 days after starting heparin administration and resolves during continued heparin therapy (Johnson et al., 1984 Chong and Berndt, 1989 Warkentin and Kelton, 1994...

Variable Frequency Of Hit Implications For Platelet Count Monitoring

Practically, these findings suggest strategies for platelet count monitoring in patients receiving heparin. Some physicians are hesitant to institute regular platelet count monitoring for HIT. One explanation is the almost ubiquitous use of heparin in hospitalized patients. Thus, a requirement that regular, perhaps even daily, platelet count monitoring be performed seems excessive. Additionally, there is no convincing evidence that regular platelet count monitoring can prevent the throm-botic complications of HIT if the physician response is merely to stop the heparin (Wallis et al., 1999). However, a noteworthy consideration is that instituting alternative, parenteral anticoagulation likely will prevent thrombosis in patients recognized as having isolated HIT. These comments notwithstanding, marked differences in risk for HIT are apparent among different patient populations. Thus, it seems prudent to recommend that patients at the highest risk of HIT, and for HIT-associated...

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 al., 1980). The designation associated helps to convey the uncertain role of heparin in causing thrombocytopenia in this setting, and the term nonimmune distinguishes this syndrome from immune-mediated HIT (Warkentin et al., 1998). Nonimmune HAT is typically mild, often transient, and clinically inconsequential (Gollub and Ulin, 1962 Johnson et al., 1984 Chong, 1988 Warkentin and Kelton, 1994). There is debate whether this represents a real in vivo phenomenon or whether the apparent...

Role of Sulfated Polysaccharides in the Pathogenesis of Heparin Induced Thrombocytopenia

Unfractionated heparin (UFH) and low molecular weight heparin (LMWH) are the anticoagulants of choice when parenteral anticoagulation is required. Both can be given subcutaneously or intravenously, and both are effective in a variety of clinical settings (Hirsh and Raschke, 2004). UFH, in particular, has several limitations. These include its poor bioavailability after subcutaneous injection as well as the marked variability in the anticoagulant response to UFH treatment in patients with acute thromboembolism (Hirsh and Raschke, 2004 Young et al., 1992). Another problem is the risk of inducing heparin-induced thrombocytopenia (HIT). These limitations are closely linked (Greinacher, 1995) the underlying cause is the high density of negative charges of the heparin molecule, leading to nonspecific interactions of heparin with cells and plasma proteins other than antithrombin (AT). This results in reduced anticoagulant effects of heparin as well as in conformational changes of the...

Surgical Thrombocytopenia

Pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) increases the platelet count in HIV-infected baboons. Three thrombocytopenic, HIV-infected baboons were treated with three doses of PEG-rHuMGDF (arrows), and the platelet count was measured. (Reproduced with permission from ref. 96.) Fig. 10. Pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) increases the platelet count in HIV-infected baboons. Three thrombocytopenic, HIV-infected baboons were treated with three doses of PEG-rHuMGDF (arrows), and the platelet count was measured. (Reproduced with permission from ref. 96.)

Thrombopoietin Increases Platelet Count in Healthy Humans

PEG-rHuMGDF has been given to healthy volunteers (99) and healthy apheresis donors (100-102). Treatment of apheresis donors with a single dose of PEG-rHuMGDF on d 1 produces a dose-dependent increase in the platelet count that begins on d 5 and peaks after 10-12 d (Fig. 11). A clear dose-response effect is seen. Compared with placebo-treated donors who had platelet counts of 225 x 109 L, donors treated with 1 or 3 g kg of PEG-rHuMGDF had median platelet counts of 336 x 109 L and 599 x 109 L, respectively. The donors experienced no adverse effects. The platelets produced had normal platelet aggregation responses in vitro and, when transfused into thrombocytopenic recipients, produced a dose-dependent increase in platelet count (101).

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. This could reflect the prothrombotic process associated with the patient's primary diagnosis. Alternatively, heparin could exacerbate the platelet count fall by nonimmune proaggregatory effects on platelets (see Chapter 4). If the patient previously received heparin, physicians might consider HIT in the differential diagnosis of the platelet count fall. However, one pseudo-HIT syndrome in particular closely resembles even the typical day 5-10 timing of thrombocytopenia characteristic of HIT...

Thrombocytopenia in Patients with Aplas Receiving Heparin

In retrospective studies, Auger and colleagues (1995) reported that platelet counts typically fell by about 50 in patients with chronic thromboembolic disease and the lupus anticoagulant who were treated with heparin. Neither timing of the onset of thrombocytopenia nor results of specific antigen or activation assays for HIT antibodies were reported so it remains uncertain whether these patients had (immune) HIT. It is possible that nonidiosyncratic platelet activation caused by heparin could increase the thrombocytopenic potential of antiphospholipid antibodies in the absence of HIT antibodies. Alternatively, some patients with APLAS may have low levels of circulating HIT antibodies even in the absence of previous heparin exposure (Lasne et al., 1997 Martinuzzo et al., 1999). We observed a young woman with ischemic stroke who developed thrombocytopenia and lower-limb thrombosis when therapeutic-dose heparin was given pretreatment blood samples contained both antiphospholipid...

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 1-like domains), which is responsible for cleaving ultralarge vWF multimers released from endothelium. Thus, the pathogenesis of idiopathic (primary) TTP likely reflects the formation of arteriolar-occluding complexes of ultralarge vWF multimers and platelets, thereby explaining both the thrombocytopenia and the tissue ischemia. Secondary TTP has been reported to occur in association with pregnancy, certain drugs (e.g., ticlopidine, clopidogrel, quinine, cyclosporine, mitomycin), autoimmune disorders (systemic lupus erythematosus), organ transplantation, and infections (human immunodeficiency virus, bacterial endocarditis). TTP clinically resembles a nephrotropic...

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 drugs, although the frequency may be higher with repeat exposures (especially with abciximab) (Curtis et al., 2002). Platelet counts usually recover in 2-5 days after discontinuing the drug. Thrombocytopenia occurring after first exposure to a GPIIb IIIa antagonist is explained by naturally occurring antibodies that recognize GPIIb IIIa in the presence of the provoking drug (Bougie et al., 2002). Delayed onset of thrombocytopenia is explained by persistence of platelet-bound drug for several...

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 thrombocytopenia (nonimmune HAT), this direct proaggregatory effect of heparin occurs predominantly in patients receiving high-dose, intravenous (iv) UFH therapy. Typically, platelet counts decrease within the first 1-2 days of treatment and then recover over the next 3-4 days. There are no data indicating that these patients are at increased risk for adverse outcomes, including thrombosis. Indeed, it is possible that inappropriate discontinuation of heparin for nonimmune HAT could increase the risk for...

Project Title Heparin Induced Thrombocytopenia In Children With Cpb

Summary This study examines the prevalence of anti-heparin PF4 antibodies as well as heparin-induced thrombocytopenia in pediatric patients undergoing cardiopulmonary bypass surgery. Specific Aims - To determine the prevalence of heparin-dependent platelet-reactive antibodies in a pediatric population undergoing cardiopulmonary bypass surgery for congenital heart disease. - To determine the incidence of heparin-induced thrombocytopenia in a pediatric population after exposure to heparin during cardiopulmonary bypass surgery - To examine the role of heparin-induced thrombocytopenia in clinical thrombotic or thromboembolic events occurring in pediatric patients after heparin exposure for cardiovascular procedures Heparin is used frequently as an antithrombotic agent during cardiovascular procedures in patients with congenital heart disease. An increasingly recognized complication of heparin therapy is the development of heparin induced thrombocytopenia (HIT) and related thrombosis....

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 historical control group treated before lepirudin became available. A meta-analysis of HAT-1 and -2 was performed to evaluate patients given lepirudin for treatment of HIT with thrombosis (Greinacher et al., 2000). A second meta-analysis of the HAT-1, -2, and -3 studies was performed to evaluate the effects of lepirudin in patients with HIT and isolated thrombocytopenia (isolated HIT) (Lubenow et al., 2004). In addition, an observational study termed the drug-monitoring program (DMP) was carried out...

Heparininduced Thrombocytopenia In Hemodialysis Patients

Given the major role of unfractionated heparin (UFH) for anticoagulation in hemodialysis (HD), it is important to define the potential impact of immune heparin-induced thrombocytopenia (HIT) in contributing to morbidity and mortality in patients with dialysis-dependent renal failure. To date, there is only one study reporting the incidence of HIT in patients being newly treated with HD. Six of 154 patients (3.9 ) were clinically suspected of having developed HIT because of a fall in the platelet count accompanied by clotting of the dialyzer and extracorporeal circuit (Yamamoto et al., 1996). The clinical diagnosis was confirmed by the detection of HIT antibodies in all but one patient. Only one patient developed organ damage from thrombosis (myocardial infarction and stroke). All six patients were switched to an alternative anticoagulant and did not suffer from thromboembolic events in the follow-up period. Compared with the incidence of HIT of 2.7 found in 332 hip surgery patients...

Recommendations For Platelet Count Monitoring For

Monitoring for typical-onset HIT stratifying the intensity of platelet count monitoring for HIT based upon its risk C. Patients at low risk for HIT (< 0.1 ) (e.g., medical obstetrical patients receiving prophylactic- or therapeutic-dose LMWH, or medical patients receiving only intravascular catheter flushes with UFH) routine platelet count monitoring is not recommendedd 2. Monitoring for rapid-onset HIT for a patient recently exposed to heparin (within the past 100 days), a repeat platelet count within 24 h following reinitiation of heparin A relative (proportional) platelet count fall of 50 or greater that is otherwise clinically unexplained should be considered suspicious for HIT, even if the platelet count nadir remains above 150x109 L. For any patient who develops thrombosis during (day 5 to 14) or within several days after stopping heparin therapy, or who develops an unusual clinical event in association with heparin therapy (e.g., inflammatory or necrotic skin lesions at...

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 another good explanation for thrombocytopenia. (An important caveat is that sometimes a recent heparin exposure is not known to the patient or has not been documented in the medical records.) With a low pretest probability for HIT, either of the sensitive assays for HIT (washed platelet activation assay or antigen assay) can reliably rule out HIT. However, an unexpected negative result in a patient with a high pretest probability, or an unexpected positive result in a patient with a low pretest...

Heparininduced Thrombocytopenia And Paradoxical Thrombosis

Heparin-Induced Thrombocytopenia Routine platelet count measurements were not a feature of hospital laboratory practice until the 1970s, and neither the Dartmouth nor Philadelphia surgeons reported thrombocytopenia in their patients with heparin-induced arterial thrombosis. Ironically, the first report of severe heparin-induced thrombocytopenia (HIT) involved a patient who did not develop paradoxical thrombosis. Natelson and coworkers (1969) reported on a 78-yr-old man with prostate carcinoma and pulmonary embolism, who on day 10 of treatment with therapeutic-dose heparin developed severe thrombocytopenia. Three days after discontinuing the heparin therapy, the patient's fibrinogen fell to 1 g L, attributed to carcinoma-associated disseminated intravascular coagulation (DIC). Heparin treatment was restarted and, although fibrinogen levels normalized, the platelet count fell to 5 X 109 L, rising to 115 X 109 L 6 days after stopping heparin administration. Simultaneously, however,...

Treatment Of Isolated

Isolated HIT refers to HIT diagnosed on the basis of thrombocytopenia alone, rather than because of HIT-associated thrombosis. Often, the initial reason for administering heparin includes routine postoperative prophylaxis or a medical indication such as acute stroke or myocardial infarction. Until the early 2000s, the standard approach upon suspecting HIT in such patients was discontinuation of heparin, sometimes with substitution of oral anticoagulants. In July 1992, the author became aware of a 68-yr-old patient whose platelet count fell from 151 to 51 X 109 L between days 5 and 8 following coronary artery bypass surgery, during routine postoperative heparin antithrombotic prophylaxis. The heparin was stopped, and laboratory testing confirmed HIT. The platelet count recovered, and the patient was discharged to home on postoperative day 12. Three days later, the patient complained of dyspnea, and then died suddenly. Postmortem examination showed massive pulmonary embolism. This...

Clinical Development Of Hematopoietic Growth Factors

Another set of blood factors studied were the factors stimulating the platelet lineage. The development of factors stimulating platelets was impaired by several observations. The first was that the factors available, rHuIL-11 and rHuTPO, act on increasing the number and ploidy of megakaryoctes but do not stimulate platelet shedding. Therefore, the increase in platelet counts is slow. Second, IL-11 was pleiotropic and was associated with significant adverse events. The recombinant thrombopoietins (rHuTPO, PEG-rHuMGDF) tested in the clinic induced antibodies that inhibited their own activity and the activity of TPO, leading to prolonged thrombocytopenia.

Combined Hematopoietic Growth Factor Signaling Deficiencies

- - Thrombocytopenia - - Males lacking yc Perturbed T lymphopoiesis Perturbed B lymphopoiesis G-CSF-deficient mice were interbred with GM-CSF-deficient mice to create mice deficient in both factors (66). G-CSF- -GM-CSF- - mice were more neutropenic than G-CSF- - mice in the early neonatal period, had higher neonatal mortality, and showed a propensity to the development of the amyloidosis evident in G-CSF- - mice. Mice deficient in G-CSF and IL-6 signaling have been generated, both by creating mice deficient in both ligands (43) and by creating G-CSFR- -IL-6- - mice (79). G-CSFR- -IL-6- - mice had an exacerbated neutropenia compared with G-CSFR- - mice (79). Although infection of G-CSF- - mice with C. albicans resulted in a neutrophilia with increased amounts of serum IL-6, indicating that factors other than G-CSF can drive the emergency granulopoietic response, G-CSF- -IL-6- - mice also showed this phenomenon, indicating that IL-6 was not the sole driver of this infection-related...

DIC and Acquired Anticoagulant Deficiency

Other patients with HIT-associated DIC evince clinical signs of microvascular thrombosis. For example, Figure 13 shows livedo reticularis and patchy foot necrosis (despite palpable foot pulses) in a postoperative cardiac surgery patient with HIT (platelet count nadir, 39 X 109 L) complicated by hypofibrinogenemic DIC. Evidence for acquired natural anticoagulant failure included mildly reduced antithrombin levels (0.76 U mL normal, 0.77-1.30 U mL) and moderately reduced protein C activity (0.50U mL normal, 0.70-1.80U mL) that subsequently resolved. Free protein S levels were normal (1.12 U mL normal, 0.62-1.38 U mL). Evidence for DIC included a fibrinogen of 1.2 g L (normal, 1.5-4.0 g L) that rose to 4.7 g L 1 wk later during therapeutic-dose danaparoid therapy, a strongly positive protamine sulfate paracoagulation assay (4+ reactivity at 15 min normal, no reactivity), a fibrin D-dimer level that was greater than 2000 mg L (normal, < 500 mg L), and the presence of red cell fragments....

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 HIT antibodies, in patients who develop thrombosis of grafts, prostheses, or other devices during heparin treatment.

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

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 occurred, necessitating surgical excision. Thrombosis of veins and capillaries, with arterial sparing, was noted. Balestra et al. (1994) reported a patient who developed thrombocytopenia (75 X 109 L) and skin necrosis of the thigh on day 9 of subcutaneous injections of LMWH given into the lower abdominal wall. A skin biopsy showed small vessel thrombosis with a mild inflammatory reaction. Other clinicians have reported patients with HIT antibodies who developed skin lesions that occurred at...

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. Further, these scoring systems were developed before various features of the timing and severity of platelet count fall in HIT were understood.

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 for HIT Antibodies or Indicating a High Likelihood of HIT Based on Timing of Platelet Count Fall TABLE 2 The Frequency of HIT Prospective Studies of HIT in Medical Patients Using In Vitro Testing of Patient Serum Plasma for HIT Antibodies or Indicating a High Likelihood of HIT Based on Timing of Platelet Count Fall

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 al., 1980) involving porcine and bovine heparins. The study of Bell and Royall (1980) has been excluded from primary analysis because neither laboratory testing for HIT antibodies nor data on the timing of onset of thrombocytopenia were provided.

Frequency of HIT in Medical Patients Treated with Porcine Mucosal UFH

In contrast, HIT may occur more often in prospective studies of acute HD patients receiving porcine UFH (Yamamoto et al., 1996). Whether this is a real difference that reflects increased platelet activation (and PF4 release) during HD or it reflects a more sensitive definition of thrombocytopenia (any platelet count fall associated with line clotting) is unknown. The frequency of clinical HIT in chronic HD patients appears to be less than 2 and may be considerably lower, but up to 18 develop a positive EIA for anti-PF4 heparin antibodies. Whether the incidence of elevated levels of anti-PF4 heparin antibodies and clinical HIT are dependent on the time since the initiation of HD is unclear. Some have suggested that the frequency of anti-PF4 heparin antibody increases with time (Palomo et al., 2005), while others have found no association (Pe a de la Vega et al., 2005). Two studies suggest that the antibodies tend to develop early after initiation of HD, and may disappear after months,...

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 109 L) were observed in 216 patients randomized to receive LMWH (Bergmann and Neuhart, 1996). In another RCT that compared deep-vein thrombosis treatment with LMWH (reviparin) versus UFH, none of 720 patients who received LMWH developed (antibody-positive) HIT, whereas one of 356 (0.3 ) patients treated with UFH manifest this complication (Lindhoff-Last et al., 2002). Interestingly, if the definition of HIT in that study was expanded to include thrombosis and a positive test for anti-PF4 heparin...

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 manufacturer, given by the subcutaneous (sc) route at a dosage of 15,000 U day. Other studies of postorthopedic UFH thromboprophylaxis (using confirmatory in vitro testing) have shown frequencies of HIT of about 2.0 (Leyvraz et al., 1991 Mahlfeld et al., 2002).

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

The strongest evidence that LMWH is indeed associated with a lower frequency of HIT was provided by an RCT that directly compared the frequency of HIT between the two types of heparin (Warkentin et al., 1995, 2003, 2005a). The frequency of HIT in patients treated with the LMWH preparation, enoxaparin (itself derived from porcine mucosal heparin), was lower than that seen in patients treated with porcine UFH, irrespective of whether a standard definition (platelet fall to < 150 x 109 L on or after day 5 of heparin treatment) or a more sensitive definition (> 50 platelet count fall from the postoperative peak) of thrombocyto-penia was used. The frequency of HIT antibody formation also differed between the two patient groups, using either the SRA (Warkentin et al., 1995, 2005a) or a PF4 heparin (or PF4 polyanion) EIA (Warkentin et al., 2000, 2005a). Thrombocytopenia also appeared to be infrequent in other trials of LMWH (Leyvraz et al., 1991 Simonneau et al., 1997 ENOXACAN Study...

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 anticoagulation) is virtually ubiquitous in the ICU, making HIT a frequent diagnostic consideration. There have been several prospective and retrospective studies that have evaluated the frequency of HIT in critically ill patients (Table 4). The two largest prospective studies (Verma et al., 2003 Crowther et al., 2005) found that although HIT was clinically suspected in 12 to 15 of ICU patients, compatible serology supporting the diagnosis (including the washed platelet activation assay, a relatively...

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, 2007) and 28 358 (7.8 ) (Koster et al., 2007) of VAD patients developed apparent HIT. In both studies, the frequency of anti-PF4 heparin antibody formation (by EIA) was over 60 . While these apparent frequencies of clinical HIT ( 8 ) are among the highest reported in any patient population, it remains unclear how to distinguish true clinical HIT from a patient with cardio-genic shock or other non-HIT explanations for thrombocytopenia who coinciden-tally develop heparin-dependent platelet-activating...

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 mimics HIT. These drugs include the semisynthetic five-carbon subunit-based heparinoid pentosan polysulfate (Gouault-Heilman et al., 1985 Vitoux et al., 1985 Follea et al., 1986 Goad et al., 1994 Tardy-Poncet et al., 1994 Rice et al., 1998), polysulfated chondroitin sulfate (Bouvier, 1980 Wolf et al., 1983 Greinacher et al., 1992a), and the anti-angiogenic agent, PI-88 (Rosenthal et al., 2002). The frequency of immune-mediated thrombocytopenia, with or without thrombosis, after exposure to these...

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 receiving postoperative heparin prophylaxis, no patient developed HIT antibodies after day 10, even though many patients received heparin for up to 14 days (Warkentin et al., 1995). These data are consistent with a point exposure model for risk of HIT in this patient population, such as a brief time shortly after surgery, when high circulating PF4 levels coincide with the first few sc heparin injections. However, even if HIT antibody formation occurs during the day 5-10 window period,...

Frequency Of Thrombosis Complicating

It is possible that nonthrombotic mortality may be higher than expected by chance in patients with HIT. This speculation is based on the observation that only a minority of patients who form anti-PF4 heparin antibodies develop HIT (discussed subsequently) a corollary to this statement is that comorbid factors that tend to result in increased pathogenicity of heparin-dependent antibodies may also independently contribute to increased patient morbidity and mortality (i.e., patients with septicemia or multisystem organ failure may be more likely to have platelet activation in the presence of HIT antibodies than well patients). Alternatively, because the patients develop thrombocytopenia they are tested for heparin-dependent antibodies, and non-pathogenic antibodies are detected.

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 attempted to minimize bias. First, the date that the HIT assay was ordered was used as an objective marker of first suspicion of the diagnosis of HIT. Second, patients were excluded from analysis if there was any evidence in the medical records to suggest the possibility of new signs or symptoms of thrombosis that may have caused the physician to suspect HIT. In other words, efforts were made to identify patients in whom HIT was suggested because of thrombocytopenia alone. Finally, only objectively...

Populationbased Studies Of Hit Antibody Seroconversion

Usually, serological investigation for HIT antibodies is performed on patients who develop thrombocytopenia during heparin treatment. Since 1995, however, many studies have systematically assessed heparin-dependent antibody seroconversion 3. Seroconversion occurs frequently without thrombocytopenia or thrombosis. Indeed, most patients who form HIT antibodies do not develop HIT. The proportion who develop HIT, however, is highest among the patients who have a positive SRA. This suggests that HIT antibodies strong enough to activate platelets are more likely to be clinically significant. Patient-dependent factors also must be important, however, because the probability of a positive SRA indicating clinical HIT ranges from about < 10 (cardiac surgery) to approximately 50 (orthopedic surgery patients receiving UFH).

Targeting Cd33positive Acute Myeloid Leukemia

Multicenter phase II trials were conducted in 142 patients in first relapse with a relatively long first remission duration (median approximately 11 months) and no antecedent hematologic disorder.109 Complete remission, but with incomplete recovery of platelet count to > 100,000, was obtained in 30 of patients. Non-hematologic toxicities were modest and included grade 3 or 4 hyperbilirubinemia in 23 , elevated hepatic transaminases in 17 , and infections in 28 . An hepatic veno-occlusive disease-like

The risks resistance clinical problems AIDS

The sharp increase in viral load that may often occur can present as a retroviral syndrome. The symptoms are similar to acute HIV infection, with lymphadenopa-thy, fever, asthenia and malaise (Colven 2000, Kilby 2000, Zeller 2001, Ruiz 2004). Thrombocytopenia has also been described during interruptions (Ananworanich 2003). The blood count needs to be monitored, especially in patients with a previous history of thrombocytopenia. Finally, attention should also be paid to patients who are co-infected with hepatitis B virus. If the HBV treatment with 3TC, FTC or tenofovir is interrupted, HBV rebound can result in fulminant and life-threatening hepatitis (Sellier 2004). It is therefore advisable to look after these patients very carefully and monitor the liver enzymes at least every two weeks.

Heparinplatelet Interactions In The Pathogenesis Of

Once stimulated by exposure to PF4-heparin, HIT antibodies can bind to PF4 complexed with other GAGs (e.g., heparan sulfate and chondroitin sulfate) on cell membranes. By this mechanism, they could stimulate platelets (Rauova et al., 2006) and also (directly or indirectly) endothelial expression of tissue factor (Cines et al., 1987 Herbert et al., 1998). Such heparin-independent binding of HIT antibodies to platelets and endothelium may explain the appearance or persistence of thrombocytopenia in HIT after heparin exposure has ceased (see Chapter 2). Activation of platelets in the absence of heparin, however, appears to require extensive saturation of the platelet surface with PF4, since antibody binding in vitro is observed only with PF4 concentrations > 300 nM, whereas the Kd for the binding of PF4 to platelets is reported to be about 30 nM (Loscalzo et al., 1985 Rauova et al., 2006). Such concentrations would be rarely, if ever, achieved in vivo. On the other hand, PF4 binds to...

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). However, in some patients, true autoantibodies to PF4 alone can also be observed. In the absence of heparin, these antibodies usually do not demonstrate any clear pathogenicity. However, during heparin therapy, PF4 and other chemo-kines are released into blood from their storage pools. Heparin may further localize these chemokines onto blood cells and endothelium, with deleterious consequences. The amount of chemokine-heparin complexes bound to blood cells and ECs depends on different factors the...

Effects of HIT Antibody Containing Immune Complexes

In addition to platelet and endothelial cell activation, there is concomitant activation of coagulation, as shown by marked elevations in thrombin-AT complex levels (Warkentin et al., 1997 Greinacher et al., 2000). The simultaneous activation of platelets, endothelium, and coagulation factors is in line with the development of thrombocytopenia combined with thrombosis and disseminated intravascular coagulation in patients with HIT (see Chapter 2).

Importance of HIT Antibodies in Clinical HIT

HIT antibodies occur commonly in heparin-treated patients. However, as many patients develop neither thrombocytopenia nor thrombosis (Amiral et al., 1996a Kappers-Klunne et al., 1997 Arepally et al., 1997), it is evident that pathogenicity requires additional factors. Possible factors are number and size of the antigen complexes (Rauova et al., 2005 Greinacher et al., 2006), antibody class (Warkentin et al., 2005b Juhl et al., 2006), and titer of the HIT antibodies (Suh et al., 1997), as well as optimal concentrations of heparin and PF4 in the blood circulation, which enable the formation of macromolecular PF4-heparin antigen complexes (Horne and Alkins, 1996 Horne and Hutchison, 1998). Thus, during low-dose heparin prophylaxis in a setting of minimal platelet activation, clinical HIT may occur less often than in patients with activated platelets receiving high heparin doses (Fondu, 1995). Accordingly, HIT antibodies are most frequently induced by UFH in patients following...

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 chondroitin sulfate, and a highly sulfated polysaccharide (PI-88) developed for anti-tumor treatment (Rosenthal et al., 2002) can substitute for heparin. In contrast, neither dextran, dermatan sulfate, N-desulfated heparin, sulfated glucosamine (Weimann et al., 2001), nor the AT-binding pentasaccharide react in these assays. Accordingly, pentosan polysulfate, high-sulfated chondroitin sulfate, and PI-88 have induced thrombocytopenia and thrombosis in vivo (Greinacher et al., 1993 Tardy et al.,...

In Vivo Expression of Recombinant Adenoviral Encoded Proteins

Systemically administered Ad vectors can also provide high-level temporary expression of a protein that is secreted into the bloodstream. Much of this work has focused on preclinical applications, as in expression of factor VIII for the treatment of hemophilia A (Connelly et al., 1996) or of erythropoietin to stimulate erythro-poiesis (Setoguchi et al., 1994a), but this property can also be useful in understanding the in vivo roles of secreted proteins. For example, rats treated intravenously with a viral vector directing expression of the rat leptin protein exhibited reduced food intake and weight gain, as well as a disappearance of fat deposits (Chen et al., 1996). Intraperitoneal administration of an Ad vector containing the gene encoding HST-l FGF-4 to mice stimulated platelet production (Sakamoto et al., 1994). This group then used the same viral vector in an in vitro study to demonstrate that the increased platelet count was due to FGF-4 stimulation of megakaryocyte maturation...

FcgRMediated Signal Transduction

FIGURE 1 Electron microscopy of negatively stained platelets activated in situ with HIT serum. Platelets were allowed to settle on bovine serum albumin-coated Formvar grids and then incubated with (A) serum testing negative for HIT antibodies or heparin (not shown) or (B) HIT serum in the presence of heparin, 0.1 U mL. Platelets were then fixed with 2 glutaraldehyde and negatively stained with 2 phosphotungstic acid. Whereas unactivated platelets demonstrated round or discoid shapes (see A), platelets activated by HIT serum demonstrated numerous surrounding microparticles ranging in size from < 0.1 to 1.0 mm in diameter. (Original magnification x13,000.) Abbreviation HIT, heparin-induced thrombocytopenia. Source From Hughes et al., 2000.

In Vivo Effects in Animals

When administered to normal animals, TPO increases bone marrow and peripheral blood Meg-CFC, increases bone marrow megakaryocyte number size and ploidy, and increases platelet count. Interestingly, both erythroid and multipotential precursor cells are also increased in the bone marrow and peripheral blood, but not the erythro-cytes or neutrophils. After daily administration of a recombinant form of TPO (PEG-rHuMGDF) to normal baboons (Fig. 2), a predictable response occurs (4,50,51). During the first 4 d of administration, bone marrow megakaryocyte ploidy increases to a maximum without change in platelet count. On d 5, the platelet count begins to increase and does so at a dose-dependent rate. With continued administration of TPO, a dose-dependent plateau platelet count is reached on d 8-12. A log-linear relationship exists between TPO dose and the plateau platelet count, with a maximum sixfold increase in the rate of platelet production (Fig. 2, inset). Upon stopping the growth...

Normal Animal Physiology

Much has been learned about the normal physiology of TPO. First, TPO is the only physiologically relevant regulator of platelet production and acts to amplify the basal production rate of megakaryocytes and platelets. TPO is not necessary for megakaryocyte differentiation. When TPO or its receptor have been knocked out by homologous recombination in mice (56-59), the megakaryocyte and platelet mass are reduced to approx 10 of normal, but the animals are healthy and do not spontaneously bleed (Fig. 3). The neutrophil and erythrocyte counts are normal. In animals in which only one of the TPO genes has been deleted, the platelet count is reduced to approx 65 of normal. If treated with other thrombopoietic growth factors such as IL-6, IL-11, and stem cell factor (SCF), such TPO-deficient mice modestly increase their platelet count (60). Fig. 3. Mice deficient in thrombopoietin (TPO) or its receptor (MPL) are thrombocytopenic. Platelet counts (+ SD) in normal (+ +) mice were compared with...

Animal Models of HIT

When platelet-activating (anti-CD9) IgG was administered to FcyRIIa trans-genic mice, more severe thrombocytopenia resulted, compared with a previously studied anti-mouse platelet (nonactivating) IgG (Taylor et al., 2000). Severe thrombosis, shock, and death developed in FcyRIIa transgenic mice crossed with FcRy-chain knockout mice. Moreover, splenectomy facilitated anti-CD9-mediated shock in FcyRIIa transgenic mice. The authors concluded that the clearance of antibody-sensitized platelets by phagocytic cells in the spleen may play a protective role in preventing thrombosis. 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...

The Endothelium In Hemostasis

The existence of an optimal concentration range of PF4 for hemostasis mirrors the binding of HIT antibody to complexes formed at various molar ratios of PF4 to heparin (Bock et al., 1980 Greinacher et al., 1994 Rauova et al., 2005). PF4 and heparin form ultra-large complexes (ULCs, MW > 670 kDa) over a narrow range of molar ratios, approximating 1 mole of PF4 tetramer to 1 mole of unfractionated heparin, the ratio at which HIT antibody binding is optimal (Rauova et al., 2005) (see Chapter 5). These ULCs are preferentially recognized by KKO, a murine HIT-like antibody. Recent in vivo studies affirmed the importance of these findings. When KKO is administered to double transgenic mice expressing platelet hFcgRIIA and varying levels of hPF4 (hPF4high hFcgRIIA, hPF4mid hFcgRIIA, or hPF4low hFcgRIIA), the severity of thrombocytopenia is proportionate

Overexpression in Animal Models

In a third model, normal mice and syngeneic mice with variable degrees of immune dysfunction (nude, SCID, NOD SCID) were infected with adenovectors carrying human TPO cDNA. All mice had an increase in platelet count, but the increase was much higher in the SCID (T- and B-cell defect, minimal Ab response) and NOD SCID (T- and B-cell defect, minimal Ab response, mononuclear phagocytes diminished in number and function) mice than in BALB c (control) or nude mice (T-cell defect, impaired Ab production). The platelet count increase was proportional to the concentration of circulating TPO. The control mice subsequently developed Abs to human TPO that crossreacted with murine TPO, and the mice became thrombocy-topenic. The SCID and NOD SCID continued to express high concentration of TPO and did not develop Abs. They both developed hypercellular bone marrows however, only the SCID mice developed osteosclerosis, myelofibrosis, and extramedullary hematopoiesis (86).

Immune Vascular Injury And Monocyte Activation In Hitassociated Thrombosis

FIGURE 3 (See color insert) Model of HIT antibody interactions with endothelial cells. (1) HIT antibodies bind to antigen (multimolecular PF4 heparin complexes) localized to platelets. (2) Platelet activation occurs after Fc receptor binding, leading to platelet granule release. (3) Released PF4 binds to platelets and endothelial cell HS displacing AT from endothelial cells. (4) Antigenic complexes on endothelial cells bind HIT antibodies. (5) HIT antibody binding to endothelial cells leads to endothelial cell activation and further platelet activation. Abbreviations ADP, adenosine diphosphate AT, antithrombin HIT, heparin-induced thrombocytopenia HS, heparan sulfate PF4, platelet factor 4. FIGURE 3 (See color insert) Model of HIT antibody interactions with endothelial cells. (1) HIT antibodies bind to antigen (multimolecular PF4 heparin complexes) localized to platelets. (2) Platelet activation occurs after Fc receptor binding, leading to platelet granule release. (3) Released PF4...

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, specificity, and affinity for portions of the PF4 molecule, may provide some of the answers. However, it is also likely that part of the propensity for thrombosis, and the localization of clotting observed in HIT, relate to antigen expression and response to injury at the level of the vessel wall itself

Bone Marrow Transplantation

In several animal models, recombinant TPO was administered after bone marrow infusion with no significant effect on the recovery of any lineage. These unexpected results led to further investigations in mice in which the donor animals were treated with recombinant TPO, and the TPO-stimulated marrow was transplanted into recipient animals (Fig. 9). This TPO-stimulated marrow transplantation reduced the duration of thrombocytopenia and allowed earlier recovery of erythrocytes (93). It may be more important to use TPO to treat the stem cell donor than to treat the stem cell recipient, a conclusion also reached in human trials (94).

Iiplatelet Activation Assays For Hit Antibodies A Washed Platelet Assays

Heparin-induced thrombocytopenia bPhosphatidylserine is located in the inner leaflet of platelet membranes thus, antiphospholipid antibodies with antiphosphatidylserine activity could be relatively more important in the pathogenesis of thrombocytopenia. Abbreviations EIA, enzyme immunoassay 2-GPI, beta2-glycoprotein I LMWH, low molecular weight heparin PF4-H, platelet factor 4-heparin HIT, heparin-induced thrombocytopenia. Comment. Following resuspension, the platelets should rest for 45 min at 37 C (Greifswald). The final resuspension buffer (Tyrode's buffer at physiological pH) contains calcium (2 mmol L) and magnesium (1 mmol L Hamilton 2 mmol L Greifswald). The platelet count is adjusted to a minimum of 300 x 109 L thus, after addition of washed platelets (75 mL) to the microtiter wells containing test serum (20 mL) and heparin-buffer (5 mL in Hamilton, 10 mL in Greifswald), the final platelet concentration will be at least 215 X 109 L. Apyrase must not be included in this buffer,...

Stem Cell Expansion Ex Vivo

The thrombocytopenia of three HIV-infected nonhuman primates was rapidly reversed by infusion of PEG-rHuMGDF (Fig. 10) (96). In these animals, the expanded megakaryocyte mass was presumably not producing adequate amounts of platelets owing to premature megakaryocyte apoptosis. Addition of TPO was felt to prevent premature megakaryocyte apoptosis and stimulate effective platelet production. Approximately 40 of all platelet transfusions are used in surgical settings (97). Preoperative and postoperative thrombocytopenia complicates surgical procedures and mandates platelet transfusions. Although no clinical studies have targeted this important area, one animal model is of interest. The administration of PEG-rHuMGDF to dogs 4 d before surgery decreased thrombocytopenia after cardiopulmonary bypass (98). Despite its 5-d lag time before platelet increase, judicial administration of TPO before surgery may ameliorate preoperative and postoperative thrombocytopenia and reduce the need for...

Stimulation of Thrombocytosis and Thrombosis

In none of the closely followed animal or human studies with TPO has there been any evidence for increased thrombotic events, but three potentially prothrombotic attributes of TPO deserve attention. These molecules are extremely potent growth factors and can markedly increase the platelet count in a short period. The deposition of platelets in an extravascular shunt in baboons is directly related to the platelet count after PEG-rHuMGDF administration (50,51). Since the extravascular shunt mimics an ulcerated atheroma in humans, these results show that except for its ability to increase the platelet count, PEG-rHuMGDF does not synergize with or exacerbate platelet deposition. Nonetheless, increasing the platelet count in individuals with active arterial thrombotic disease may exacerbate the cardiovascular disease.

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

There are at least two potential explanations for strong platelet activation in the absence of added heparin. First, there may be residual heparin in the sample (White et al., 1992 Potzsch et al., 1996). However, this phenomenon can persist despite attempts to remove heparin using binding resins. Further, heparin-independent platelet activation can be a feature of serum obtained from patients with delayed-onset HIT, in which the presence of residual heparin is unlikely because onset of thrombocytopenia and thrombosis begins several days after the patient's last exposure to heparin (Warkentin and Kelton, 2001) (see Chapter 2). A second explanation is that some HIT antibodies recognize platelet-bound PF4 in the absence of an exogenous source of heparin, perhaps by PF4 bound to platelet glycosaminoglycans such as chondroitin sulfate (Rauova et al., 2006). Alternatively, as HIT antibodies are heterogeneous, there may be pathogenic antibody subpopulations that bind relatively well to PF4...

Antigen Assays For Hit Antibodies A Solid Phase PF4H Enzyme Immunoassay

FIGURE 2 Schematic figure of solid-phase PF4-heparin-EIA. Abbreviations EIA, enzyme immunoassay HIT, heparin-induced thrombocytopenia PF4, platelet factor 4. FIGURE 2 Schematic figure of solid-phase PF4-heparin-EIA. Abbreviations EIA, enzyme immunoassay HIT, heparin-induced thrombocytopenia PF4, platelet factor 4.

Comparison of Activation and Antigen Assays

Detecting HIT antibodies not associated with thrombocytopenia or other clinical events (Amiral et al., 1995 Arepally et al., 1995 Bauer et al., 1997 Warkentin et al., 2000, 2005a Juhl et al., 2006 Schenk et al., 2006, 2007) (Fig. 6). Stated another way, the SRA is more specific for clinical HIT than the antigen assay. The biological explanation for greater specificity of a sensitive activation assay for clinical HIT, compared with an antigen assay, could relate to the functional heterogeneity of HIT antibodies against antigenic determinants on PF4, only some of which activate platelets strongly (Amiral et al., 2000). Data reported by Visentin and colleagues (1994) also support a higher sensitivity of antigen assays for detecting platelet-activating anti-PF4 H antibodies. These workers studied 12 HIT plasmas that tested positive in both SRA and PF4-heparin-EIA. However, at a 1 100 sample dilution, only 2 of the 12 samples still tested positive in the activation assay. In contrast, even...

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 results (Greinacher et al., 1994a Pouplard et al., 1997 Warkentin, 2003a Warkentin and Heddle, 2003 Lo et al., 2006). Some include assessing the platelet count recovery upon stopping heparin, and so may be more useful when reviewing a case after its clinical evolution. Chapter 2 provides an example of one scoring system to estimate the pretest probability of HIT that can be applied at the time of initial diagnostic assessment.

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 from two clinical realities (1) sensitive HIT assays frequently detect clinically insignificant anti-PF4-H antibodies in patients who have received heparin for more than 5 days, and (2) thrombocytopenia, whether caused by HIT or not, is common in clinical practice. There is evidence that positive washed platelet activation assays for HIT have greater diagnostic specificity for clinical HIT (Warkentin et al., 2000, 2005a), especially when strong, rapid platelet activation is produced by patient...

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 resemble HIT (Fig. 1). Typically, a patient presents with idiopathic deep vein thrombosis (DVT), sometimes with mild to moderate thrombocytopenia. During treatment with therapeutic-dose unfractionated or low molecular weight heparin (LMWH), the platelet count rises, FIGURE 1 Pseudo-HIT adenocarcinoma with thrombocytopenia and phlegmasia cerulea dolens after stopping administration of UFH. The late presentation of thrombocytopenia suggested HIT, prompting use of an alternative anticoagulant...

Haematological effects of splenectomy and hyposplenism

The spleen normally pools up to a third of the circulating platelets. In the immediate period after a splenectomy, the platelet count rise steeply to levels of 600-1000 X 109 l. This thrombocytosis is usually temporary and fall to a level one-third higher than in normal subjects over the following 1-2 months. Occasional large and bizarre platelets can be seen in blood films.

Venous Limb Gangrene Complicating Adenocarcinoma

The venous thrombotic events complicating adenocarcinoma include DVT, phleg-masia cerulea dolens, and even venous limb gangrene (Everett and Jones, 1986 Adamson and Currie, 1993). Clinical and laboratory parallels between HIT and adenocarcinoma suggest that, paradoxically, coumarin treatment could contribute to the pathogenesis of venous gangrene in these patients through a disturbance in procoagulant-anticoagulant balance (Warkentin, 1996, 2001 Klein et al., 2004 Ng and Crowther, 2006). Figure 2 summarizes the proposed pathogenesis of this syndrome from the perspective of the characteristic clinical triad of venous limb gangrene (1) thrombocytopenia caused by HIT or adenocarcinoma-associated DIC Venous limb gangrene appears to result from failure of the protein C anticoagulant pathway to down-regulate thrombin generation within the microvascu-lature (Warkentin 1996 Warkentin et al., 1997 see Chapter 2). Here, the elevated INR represents a surrogate marker for marked reduction in...

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 activation of coagulation includes elevated fibrin degradation products and reduced antithrombin (Paton, 1981). Figure 5 illustrates a patient with white clots in the femoral artery, leading to amputation, who was initially thought to have HIT. However, HIT antibody testing and subsequent clinical events proved that the patient did not have HIT as the initial explanation for this dramatic clinical presentation of thrombocytopenia and thrombosis complicating DKA (although HIT occurred later in the...

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 antibodies were not detectable (day 12), either by SRA, (< 5 release) or PF4-heparin-EIA (optical density, 0.149 negative, < 0.450). (B) A platelet count profile similar to that seen in (A) also occurred in a patient who developed a platelet count fall from 378 to 161 x 109 L (57 fall) that began on day 7 after cardiac surgery in which UFH was given for CPB. The platelet count recovered on therapeutic-dose danaparoid. Only one clinical clue pointed to the diagnosis of HIT erythematous skin...

Parallels Between APLAS and HIT

Table 2 lists some common features of APLAS and HIT. Both clinicopathologic disorders are characterized by thrombocytopenia, a paradoxical risk for venous and arterial thrombosis, and associated antibodies that can be detected by either functional or antigen assays (see Chapter 10). Moreover, for both APLAS and HIT, positive functional assays are more strongly associated with thrombosis than positive antigen assays (Ginsberg et al., 1995 Warkentin et al., 2000 Galli et al., 2003). The parallels between these disorders led Arnout (1996) to hypothesize that IgG-mediated platelet activation could explain thrombosis in APLAS. Supportive experimental data include the observations that antiphospholipid antibodies enhance platelet activation induced by other agonists (Martinuzzo et al., 1993). Furthermore, Arvieux et al. (1993) observed murine monoclonal antibodies reactive against b2GPI induced platelet activation in the presence of subthreshold concentrations of ADP and epinephrine, an...

Clinical spectrum and systemic manifestations

And thyroiditis (Hogg et al., 1981 Engel et al., 1986 Gupta et al., 1992 Knowles et al., 1999 Sekine et al., 2001 Fujino et al., 2002). Clinical hematological involvement is observed in lymphadenopathy and hepatosplenomegaly. Biological hemato-logical abnormalities include hypereosinophilia, atypical lymphocytes, neutropenia, thrombocytopenia, hemolytic anemia, pancytopenia, and hemophagocytic syndrome.

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 associated with thrombolytic therapy. A 72-yr-old man developed moderate thrombocytopenia shortly after receiving streptokinase and heparin, which resolved following discontinuation of heparin. The early onset of thrombocytopenia, as well as the negative testing for HIT-IgG using the platelet serotonin-release assay, was consistent with pseudo-HIT. Abbreviations HIT, heparin-induced thrombocytopenia i.v., intravenous p.o., per os s.c., subcutaneous. Source From Warkentin and Kelton, 1994. FIGURE...

Septicemia Associated Purpura Fulminans

Only a small minority of septic patients develop acral limb ischemia or necrosis. Many, however, develop thrombocytopenia, with or without laboratory evidence for DIC. The predominant explanation for increased platelet destruction in sepsis is uncertain, but appears to involve the underlying inflammatory host response (Aird, 2003a,b). Since hospitalized septic patients frequently are exposed to heparin, diagnostic confusion with HIT can result. Low protein C levels correlate with poor outcomes in sepsis (Yan et al., 2001), and recombinant human activated protein C (drotrecogin, Xigris) has been shown to reduce mortality in septic patients (Bernard et al., 2001). It is possible that this therapy might reduce risk of limb ischemia from microvascular thrombosis in this patient population. A potential dilemma is that septic patients with severe thrombocytopenia (< 30 X 109 L) were excluded in the clinical trials because of the bleeding potential of drotrecogin however, as relative and...

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). Micro-embolization leading to multiple small infarcts or microabscesses, in such organs as muscles, adrenal glands, and spleen, is an additional feature of endocarditis (Ting et al., 1990) that is not seen in HIT. When endocarditis-associated thrombocytope-nia is unusually severe, potential explanations include platelet-reactive autoantibo-dies (Arnold et al., 2004) or procoagulant monocyte-stimulating factors secreted by microorganisms from within large vegetations (Selleng et al., 2006).

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 complement-mediated hemolysis. Some patients have thrombocytope-nia, and an increased risk for unusual, life-threatening venous thrombotic events, such as hepatic vein thrombosis, occurs in some patients. Thus, the clinical profile of HIT potentially can be mimicked. The thrombocytopenia could be related either to decreased platelet production or to complement-mediated formation of procoagulant platelet-derived microparticles (Wiedmer et al., 1993).

Thrombocytopoietic Growth Factors Tpo Pegmgdf Il11 And Promegapoietin

Clearly, the growth factor with the greatest potential for the treatment of thrombo-cytopenia is TPO. The thrombopoietic potential of the two mpl ligands (recombinant human rHu TPO, the full-length glycosylated molecule and megakaryocyte growth and development factor, a nonglycosylated, polyethylene glycol-derived and truncated form of the full-length molecule PEG-rHuMGDF ) being evaluated in clinical trials was evident early from the consistent and substantial amount of preclinical in vitro and in vivo data in both rodent and nonhuman primate models of myelosuppression (13-18,36-41). Evaluation of the mpl ligands (PEG-rHuMGDF, rHuTPO) in nonhuman primate models of radiation-induced myelosuppression showed that it significantly lessened the degree and duration of thrombocytopenia and also improved myelopoietic and erythropoietic recovery (17,18). Farese et al. (17) first reported the therapeutic efficacy of PEG-rHuMGDF both alone and in combination with rHuG-CSF in a rhesus macaque...

Posttransfusion Purpura

Because both PTP and HIT typically occur about a week after surgery managed with perioperative blood transfusions and postoperative heparin prophylaxis, a diagnostic dilemma can arise (Lubenow et al., 2000). A useful clinical clue is the presence or absence of petechiae PTP almost invariably is characterized by this hallmark of severe thrombocytopenia, whereas patients with HIT generally do not develop petechiae, even if they have very severe thrombocytopenia. The presence of high titers of platelet-reactive alloantibodies suggests PTP.

Chimeric Growth Factor Receptor Agonist Promegapoietin

PMP showed significant therapeutic efficacy for restoration of platelets in preclinical models of irradiation-induced myelosuppression in a manner comparable to that noted for PEG-rHuMGDF and rHuTPO. It was shown that, similar to PEG-rHuMGDF or rHuTPO, a single dose of PMP administered within 1-2 h after exposure was comparable in therapeutic efficacy to the conventional daily administration of PMP in enhancing thrombopoietic recovery from severe radiation-induced myelosuppression (Fig. 6) (22). PMP was evaluated in four administration schedules daily for 18 d 9 doses every other day for 3 wk a single high dose at 20 h or a single high dose 2 h after 600-cGy total body irradiation in the rhesus macaque. PMP, irrespective of administration schedule, significantly improved all platelet-related parameters, thrombocytopenia was eliminated, severity of platelet nadirs was significantly improved, and duration of thrombocytopenia was significantly reduced relative to the control-treated...

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 treatment, the diagnosis initially could be uncertain. As alternative anticoagulants (danaparoid, lepirudin, or argatroban) are available in most countries, treatment with one of these agents before obtaining results of HIT antibody testing may be appropriate. For patients with adenocarcinoma without HIT antibodies, management is more successful with LMWH or UFH than with warfarin (Prandoni, 1997 Lee et al., 2003). FIGURE 7 Pseudo-HIT complicated by HIT A 78-yr-old man, with right proximal lower-limb DVT...

Pathogenesis of HIT Treatment Implications

An increasingly recognized treatment issue involves patients with detectable anti-PF4 heparin antibodies but no platelet count reduction or other clinical evidence of HIT. With increased testing for HIT antibodies, it is now clear that many patients develop anti-PF4 heparin antibodies without developing clinical HIT (see Chapters 3 and 10). In these patients, it seems acceptable to continue heparin treatment but to monitor the platelet counts carefully (watch-and-wait strategy).

Discontinuation of Heparin for Clinically Suspected HIT

Numerous case reports describe the occurrence of new, progressive, or recurrent thromboembolic events during continued or repeated use of heparin in patients with acute HIT. Moreover, the thrombocytopenia usually persists if the administration of heparin is not stopped. Thus, all heparin treatment should be discontinued in patients strongly suspected of having HIT and usually substituted by another anticoagulant (discussed subsequently), while awaiting results of HIT antibody testing. The rationale behind substituting heparin with another anticoagulant is that the potential benefit of stopping heparin (e.g., less antibody-induced heparin-dependent platelet activation) might be outweighed in some patients by a rebound in thrombin generation following loss of heparin's anticoagulant action. Moreover, as discussed later, HIT antibodies sometimes can cause platelet activation even in the absence of pharmacologic heparin. Not infrequently, patients in whom heparin administration has been...

The Need for Anticoagulation of HITAssociated Thrombosis

HIT is a strong, independent risk factor for venous and arterial thrombosis (Warkentin et al., 1995, 2003). HIT can be complicated by thrombosis in several ways (1) a preceding thrombosis, leading to the heparin treatment that caused HIT (this is usually not considered to be HIT-associated thrombosis) (2) new, progressive, or recurrent thrombosis resulting from HIT itself or (3) both reasons. The relationship between thrombocytopenia and thrombosis in HIT is variable thrombosis can both precede (or coincide with) the onset of thrombocytopenia or thrombosis can occur several days (or even a few weeks) later (Warkentin and Kelton, 1996 Greinacher et al., 2005).

Whats New Ligand Receptor Associated Peptides and Ligand Mimetics

These investigators have recently synthesized another peptide that binds to a portion of the extracellular domain of the human TPO receptor, c-mpl (Dr. Lennart Olsson, personal communication). As noted with the EPO receptor peptide, this peptide binds to c-mpl elsewhere than at the TPO binding site therefore peptide and growth factor may act together for additive or synergistic activity. Preclinical experiments in rodent models of chemotherapy-induced thrombocytopenia have shown the TPO receptor peptide to be as efficient as recombinant TPO in enhancing platelet recovery. It was also conveyed that the TPO receptor peptide can act in synergy with administered TPO or with the endogenous TPO released in situ during periods of thrombocytopenia.

Anticoagulants Evaluated for Treatment of HIT

FIGURE 2 Thrombin generation and fibrin formation in acute HIT. (A) Thrombin generation, as assessed by TAT complexes, is markedly increased in acute HIT (mean, 55 ng mL normal, < 4.1 ng mL). Whereas danaparoid reduces thrombin generation in these patients, the defibrinogen-ating snake venom, ancrod, does not. (B) Levels of cross-linked fibrin degradation products (D-dimer) are increased in patients with acute HIT (mean, 4-5mg mL normal, < 0.5mg mL). Whereas danaparoid reduces D-dimer levels, ancrod increases their levels. Baseline (B) samples were obtained at diagnosis of HIT and before treatment with danaparoid or ancrod subsequent values are shown for day 1 (D1, 1-24 h postinitiation of treatment), day 2 (D2, 25-48 h), and day 3 (D3, 49-72 h). *p < 0.001, **p < 0.002. Abbreviations HIT, heparin-induced thrombocytopenia TAT, thrombin-antithrombin. Source From Warkentin, 1998. FIGURE 2 Thrombin generation and fibrin formation in acute HIT. (A) Thrombin generation, as assessed...

Blood and blood vessels

In time, activation of platelets leads to aggregation and coalescence around bubbles with entrapment of other blood constituents. Cellular blood elements - such as red blood cells - may become entangled in the growing fibrin web. This thickening of the bubble skin may reduce diffusion producing a mechanism for bubble stabilization and survival 62. General platelet adhesiveness also increases in response to bubbles. Some studies have reported platelet depletion following decompression, even in the absence of symptoms 63. However, thrombocytopenia or anti-platelet therapies do not appear to protect against DI. Also aggressive anticoagulation runs the risk of precipitating hemorrhage in DI affecting the spinal cord and inner ear 61> 62> 64> 65. On the other hand, DI does induce a hypercoagulable state with a high risk of thromboembolism aggravated by paralysis. This should be actively prevented.

Anticoagulation of the HIT Patient Without Thrombosis

For venous thrombosis without anticoagulation in a patient at very high bleeding risk. Thrombocytopenia itself should not be considered a contraindication to anticoagulation in patients with HIT, as petechiae and other spontaneous hemor-rhagic manifestations are not usually seen in these patients (see Chapter 2). However, if the platelet count is less than 20 X 109 L and bleeding signs, but not thrombosis, are observed, then alternative diagnoses such as posttransfusion purpura or other drug-dependent immune thrombocytopenic disorders should be considered (Kiefel, 2004). Recommendation. Alternative therapeutic-dose anticoagulation with an appropriate anticoagulant, such as danaparoid, lepirudin, or argatroban, should be considered in patients strongly suspected (or confirmed) to have HIT even in the absence of symptomatic thrombosis. Anticoagulation should be continued at least until recovery of the platelet counts to a stable plateau (grade 1C). It is uncertain whether...

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 therapy completely, e.g., a patient can be anticoagulated with danaparoid (e.g. 1500 U sc t.i.d. for 4 wk, followed by 1500 U sc b.i.d.). Some physicians have transitioned patients from DTI therapy to sc fondaparinux following platelet count recovery.

Transition to Vitamin K Antagonist Coumarin Therapy

These are the circumstances predisposing to the disturbed procoagulant-anticoagulant balance characteristic of the coumarin necrosis syndromes in HIT. Thus, it is important to postpone starting administration of coumarin anticoagulants until therapeutic anticoagulation is achieved with danaparoid, lepirudin, or arga-troban and until there has been substantial platelet count recovery (usually to at least 150 X 109 L, indicating that the platelet-activating effects of the HIT antibodies have largely resolved). Recommendation. To minimize the risk of coumarin necrosis in a patient with acute HIT, vitamin K antagonist (coumarin) therapy should be delayed until the patient is adequately anticoagulated with a rapidly acting parenteral anticoagulant, and not until there has been substantial platelet count recovery (at least > 150 x 109 L). The vitamin K antagonist should be started in low maintenance doses (e.g., < 5 mg warfarin), with at least 5 days of overlap with the...

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

In a patient with an intermediate probability for HIT (e.g., 4T's score of 4 or 5), who has an alternative explanation for thrombocytopenia and who does not require therapeutic-dose anticoagulation for other reasons, we suggest alternative anticoagulation in prophylactic, rather than in therapeutic, doses (Grade 2C).

Medical Thrombolysis

Thrombocytopenia is not a contraindication to thrombolytic therapy in patients with HIT. Streptokinase (Fiessinger et al., 1984 Cohen et al., 1985 Bounameaux et al., 1986 Cummings et al., 1986 Mehta et al., 1991), urokinase (Leroy et al., 1985 Krueger et al., 1985 Clifton and Smith, 1986), and tissue plasminogen activator (t-PA) (Dieck et al., 1990 Schiffman et al., 1997) have been used both systemically and by local infusion (Quinones-Baldrich et al., 1989). In patients at high bleeding risk, an ultra-low-dose t-PA (2 mg h over 12 h) was successfully applied without bleeding complications (Olbrich et al., 1998). As thrombin generation is not inhibited by thrombolysis, concomitant non-heparin anticoagulation should be given, in reduced dose, until the fibrinolytic effects have waned.

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 antibodies still present), the intensity of anticoagulation depends on the perceived risk of vessel (or graft) occlusion. In patients at high risk of occlusion (e.g., surgery involving below-knee vessels), the patient should be therapeutically anticoagulated before vessel clamping (in addition to receiving intraoperative flushes with anticoagulant), with therapeutic anticoagulation maintained for several days after Recommendation. Surgical thromboembolectomy is an appropriate adjunctive treatment for...

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 activation by HIT antibodies provides a rationale for its use as an adjunct to anticoagulant therapy in certain life- or limb-threatening situations. The dose should be 1 g kg body weight per day for two consecutive days. Recommendation. ivIgG is a possible adjunctive treatment in selected patients requiring rapid blockade of the Fc receptor-dependent platelet-activating effects of HIT antibodies (e.g., management of patients with cerebral venous thrombosis, severe limb ischemia, or very severe...

Bacteria And Other Unexpected White Cell Changes

Platelet satellitism has been discussed in a case study in a previous chapter. However, it represents a phenomenon that must be recognized as an unexpected event in a peripheral smear. The blood of some patients will react with EDTA, causing platelets to form a ring around neutrophils. This is described as platelet satel-litism (Fig. 10.18). This event will produce a falsely low platelet count and can be corrected only once the patient sample is collected in a sodium citrate tube for an accurate platelet count (Fig. 10.19). An additional peripheral cell change that may occur in segmented neutrophils is pyknosis, or pyknotic changes. This is

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 dipyridamole indeed, HIT has occurred in patients who receive dual antiplate-let therapy with ASA and clopidogrel) (Selleng et al., 2005). These antiplatelet agents may be used as adjunctive therapy (to anticoagulant therapy), particularly in patients with arteriopathy. A potential drawback is increased bleeding (especially when combined with other antithrombotic agents).

Low Molecular Weight Heparin

Treatment of HIT with LMWH is frequently unsuccessful. Of eight consecutive HIT patients who received LMWH, thrombocytopenia persisted in all, and new thromboembolic events occurred in two patients (Greinacher et al., 1992). After LMWH became available in North America, a similar experience was observed in seven HIT patients treated with LMWH (Warkentin, 1997). Another study has also shown a relatively high risk of adverse outcomes of treating HIT with LMWH (Ranze et al., 2000).

Vitamin K Antagonists

To progress to involve even the microvasculature, leading to coumarin-induced venous limb gangrene. This syndrome appears to result from a transient disturbance in procoagulant-anticoagulant balance increased thrombin generation associated with HIT remains high during early warfarin treatment, while simultaneously there is severe, acquired deficiency in the natural anticoagulant protein C. Although high doses of oral anticoagulants may be more likely to cause this syndrome, even relatively low doses that produce a rise in the INR (especially to > 4.0) can cause limb gangrene in some patients, particularly in patients with severe HIT-associated hypercoagulability and overt (decompensated) DIC. Thus, warfarin and phenpro-coumon should always be given in combination with an agent that reduces thrombin generation in patients with acute HIT, and must only be started once the acute HIT has largely subsided, as judged by substantial recovery of the platelet count (in general, > 150 X 109...

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 et al., 2001 British Committee for Standards in Haematology, 2003 Warkentin and Greinacher, 2004) stated that thrombotic thrombocytopenic purpura (TTP) and HIT are two disorders in which prophylactic platelet transfusions are not recommended because of the risk of precipitating thrombosis.

Comparing Acute And Chronic Leukemia

Because leukemia is a disease of the bone marrow that causes normal bone marrow cell production to be crowded out as the abnormal, neoplastic cells take over, the CBC results will commonly show a decreased red cell count or anemia, as well as a decrease in platelets or thrombocytopenia. The level of anemia and thrombocytopenia tends to be more severe in acute leukemia. Leukocytosis is a hallmark feature of chronic leukemia, and because the spleen also becomes a site of extramedullary (outside of the bone marrow) hematopoiesis, prominent hepatosplenomegaly is most often associated with chronic leukemia.

Clinical Use of Danaparoid in Patients with HIT

By the manufacturer (Magnani, 1993, 1997). From 1981 to 1997, over 750 patients were treated under this program for the various indications listed earlier (Ortel and Chong, 1998). The duration of treatment ranged from 1 day to 3.5 yr, and the post-treatment follow-up was 3 mo. Interim, updated reports of this program have been published (Chong and Magnani, 1992 Magnani, 1993, 1997). The overall success rate, defined as platelet count recovery without new, progressive, or recurrent thrombosis during the danaparoid treatment period, or thrombotic death during 3 mo follow-up, and the absence of any adverse effect necessitating treatment cessation, has been over 90 , as judged by the local physician-investigators. However, as this definition does not include non-thrombotic death, the overall mortality observed in the program was 18 , including deaths during the post-treatment follow-up. Most patients in this program received danaparoid for the treatment of acute thromboembolism, often in...

Overlapping Oral Anticoagulants with Danaparoid

Many danaparoid-treated HIT patients also receive overlapping warfarin treatment, since oral anticoagulants are usually preferred when at least 3-6 mo of further anticoagulation is indicated because of venous or arterial thromboembolism. However, it generally takes at least 5 days for warfarin to achieve a therapeutic effect (Harrison et al., 1997). Although warfarin likely can be started safely at the beginning of danaparoid treatment in most patients with HIT-associated thrombosis, it is prudent to delay start of warfarin until the thrombotic process is controlled and substantial resolution of the thrombocytopenia has occurred (usually, to a platelet count > 150 X 109 L). This caveat is based on the observation that warfarin can aggravate the thrombotic process during the first few days of its administration by reducing levels of the natural anticoagulant protein C, particularly when thrombin generation is high (Warkentin, 1996a Warkentin et al., 1997 Potzsch et al., 1996) (see...

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