Treatment 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 Continue reading...

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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...

Table 73 Differential diagnosis of isolated thrombocytopenia

Amegakaryocytic thrombocytopenia Carbamazepine Alcohol Sequestration Post-transfusion purpura Heparin-induced thrombocytopenia Non-immune destruction Rare patients with autoimmune amegakaryocytic thrombocytopenia may present with severe thrombocytopenia but do not respond to steroids or immunoglobulin. On marrow biopsy they have diminished to absent megakaryocytes. The etiology is due to suppressor T-cells repressing platelet production. Therapy is with cyclosporine or anti-thymocyte globulin. In elderly patients, mild thrombocytopenia may be the first indicator of a myelodysplastic syndrome. Patients with myelodysplasia usually have an elevated MCV even if anemia is absent.

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...

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,...

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...

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...

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...

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...

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...

Table 74 Most common drugs implicated in druginduced thrombocytopenia

Who has recently received a red cell or platelet blood product. Treatment consists of steroids. Immunoglobulin is useful in severe cases. Rare patients may require plas-mapheresis. The patient's thrombocytopenia will resolve in a few months. If patients with a history of PTP require further transfusions the red cells should be washed and only PLA1 negative platelets should be given. Heparin-induced thrombocytopenia (HIT) Heparin can induce a unique form of immune thrombocytopenia. Unfortunately, some of these patients will then develop severe thrombosis. HIT is discussed in more detail in Chapter 22.

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

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) (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 probability, should lead to...

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...

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...

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...

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).

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.)

Table 224 Heparin induced thrombocytopenia scoring system

Thrombocytopenia OTher cause for thrombocytopenia Patients with HIT but without evidence of thrombosis are at a high risk of thrombosis (53 in one study) and should be considered for antithrombotic therapy. Patients with HIT should also be carefully screened for any thrombosis, which includes obtaining lower extremity dopplers. It is unknown whether prophylactic doses or therapeutic doses of anticoagulants are needed for thrombosis prevention in patients with HIT but no thrombosis. The duration of such therapy is also controversial. One approach is to give prophylactic doses of antithrombotic agents until the platelet count has returned to normal. In post-surgical patients prolonged prophylaxis for up to six weeks may be of benefit. 8. Warkentin TE. Platelet count monitoring and laboratory testing for heparin-in-duced thrombocytopenia. Arch Pathol Lab Med 2002 126(11) 1413-23. 10. Warkentin TE, Heddle NM. Laboratory diagnosis of immune heparin-induced thrombocytopenia. Curr Hematol...


Thrombocytopenia is a relatively common finding in hospitalized patients. For example, thrombocytopenia is very common in the critical care population, with platelet counts below 100,000 L found in 25-38 of such patients. Finding the etiology is frustrating, as multiple factors may be producing the thrombocytopenia. A rational approach is to consider the differential from a mechanistic point of view. Thus defects in platelet production, increased platelet sequestration, or increased platelet destruction (immune or non-immune) can lead to thrombocytopenia. The mode of presentation can be an important clue to the etiology of the throm-bocytopenia . Patients who present only with severe thrombocytopenia and no other systemic signs or symptoms (outside of bleeding) and a normal blood smear most often will have either idiopathic or drug-induced immune thrombocytopenia. If the patient is in the hospital, the reason for hospitalization is a very important indicator in the evaluation of...

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

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...

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...

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...

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).

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...

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,...

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.

Cross Reactivity of HIT Antibodies with Danaparoid

The in vitro cross-reactivity of the HIT antibodies with danaparoid does not appear to be usually clinically significant. Newman et al. (1998) investigated the clinical significance of in vitro cross-reactivity in 21 patients treated with danapar-oid. The eight patients who tested positive for cross-reactivity by the fluid-phase EIA, but negative by the 14C serotonin-release washed platelet assay, recovered with resolution of their thrombocytopenia and thrombosis, in a fashion similar to the 11 patients who did not manifest in vitro danaparoid cross-reactivity in either assay. Two patients tested positive in both assays in one patient, both thrombocy-topenia and pulmonary embolism resolved during danaparoid treatment. However, in the other patient, thrombocytopenia and extensive thrombosis persisted despite danaparoid therapy, although it was unclear whether this unusual patient course represented a specific danaparoid treatment failure (the patient's subsequent clinical course was...

Acute Systemic Reactions Following Intravenous Bolus Heparin

An abrupt fall in the platelet count invariably accompanies these reactions. However, the platelet count drop is often transient (Warkentin et al., 2005b). Thus, physicians should determine the platelet count immediately on suspecting the diagnosis and test for HIT antibodies. Heparin must be discontinued, as further use can lead to fatal complications (Ling and Warkentin, 1998). Any inflammatory, cardiopulmonary, or other unexpected acute event that begins 5-30 min after an intravenous heparin bolus should be considered acute HIT unless proved otherwise. The postbolus platelet count should be measured promptly and compared with prebolus levels, because the platelet count fall is abrupt and often transient. Timing onset 5-30 min after intravenous heparin bolus Clinical context recent use of heparin (past 5-100 days) Laboratory features abrupt, reversible fall in the platelet count Signs and symptoms similarities between ASR and the administration of ADP in humans, including acute...

Hemodialysis Hemofiltration and Intensive Care

Danaparoid was first used to anticoagulate non-HIT patients requiring hemodia-lysis in one of several clinical settings stable chronic renal failure (CRF) (ten Cate et al., 1985 Henny et al., 1990, von Bonsdorff et al., 1990) or intensive care unit (ICU) patients who developed postoperative acute renal failure (ARF) (Henny et al., 1983). Danaparoid was then used to treat very ill patients in intensive care settings who developed HIT during CRRT for ARF (Wester et al., 2000 LindhoffLast et al., 2001). Switching from UFH to danaparoid overcame the repeated deposition of fibrin on the hemodialysis filtration membranes, thus restoring the lifespan of the filters and allowing continuation of extracorporeal circuit use without further incident (Burgess and Chong, 1997 van Eps et al., 2000 LindhoffLast et al., 2001). Such fibrin deposition may also be secondary to UFH-induced platelet aggregation and microthrombus formation and, because HIT antibodies are often absent, this may be a...

Other Potential Uses

Bivalirudin has also been studied in a rat model of endotoxemia and found to increase survival rate in one (but not the other) study (Cicala et al., 1995 Itoh et al., 1996). Bivalirudin reduced endotoxin-induced thrombocytopenia, leukope-nia, and fibrinogen consumption, suggesting a possible future therapeutic role in sepsis (Cicala et al., 1995).

We Can Wait for the Test to Come Back

The time just after heparin is stopped may be the most dangerous for the emergence of thromboemboli, because heparin may be exerting some protective anticoagulant effect at the same time it is feeding a prothrombotic maelstrom. The protocol for the lepirudin registration trials in Europe called for heparin to be stopped when HIT is suspected, but lepirudin was initiated only after obtaining positive serologic results a 6 per day thrombosis event rate was observed while physicians awaited the test results (Greinacher et al., 2000). The initial suspicion for HIT depends on clinical features, such as the 4 T's (Thrombocytopenia, Timing, Thrombosis, oTher causes of thrombocytopenia unlikely) (Lo et al., 2006) when HIT is reasonably suspected, an alternative anticoagulant should be initiated, and the results of serologic tests considered later.

Transition to Vitamin K Antagonist Coumarin Therapy

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 parenteral anticoagulant (including at least 2 days in the target-therapeutic range), and the parenteral anticoagulant should not be stopped until the platelet count has reached a stable plateau (Grade 1C).

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).

Pharmacologic and Pharmacokinetic Considerations in Anticoagulant Selection

XR with HIT antibodies in vitro XR usually not associated with adverse effects patients should be monitored for in vivo XR (unexplained platelet count fall, progressive new TECs) in vivo XR is estimated to occur in 3 of patients (Magnani and Gallus, 2006) Bleeding complications in compassionate-release study (Ortel and Chong, 1998) fatal (0.9 ), major nonfatal bleeding (6.5 ) no major bleeds in RCT (Chong etal., 2001) Skin hypersensitivity rare Abbreviations ACT, activated clotting time aPTT, activated partial thromboplastin time AT, antithrombin III HCII, heparin cofactor II HIT, heparin-induced thrombocytopenia iv, intravenous PT INR, prothrombin time international normalized ratio RCT, randomized controlled trial sc, subcutaneous TEC, thromboembolic complication t1 2, drug half-life XR, cross-reactivity . Abbreviations aPTT, activated partial thromboplastin time CPB, cardiopulmonary bypass ECA, ecarin chromo-genic assay ECT, ecarin-clotting time EIA, enzyme-immunoassay HIT,...

Viec Antibodies In

The role of EC-reactive antibodies was also explored in an animal model that simulates certain aspects of HIT (Blank et al., 1997). Mice injected with IgG fractions obtained from HIT patients developed anti-idiotypic antibodies that recognized complexes between hPF4 and heparin. Furthermore, the anti-idiotypic antibodies competed with the immunizing antibodies for binding to the antigenic complex. These effects were not noted when antibodies obtained from mice immunized with control IgG were studied. Additionally, mice immunized with HIT-IgG developed thrombocytopenia when exposed to heparin. Affinity-purified anti-PF4-heparin antibodies bound to murine endothelioma cells in the presence of PF4, but not b2GPI. Of interest, immunized mice did not develop overt thrombi on exposure to heparin, possibly because of insufficient circulating PF4, intrinsic differences in the balance between the procoagulant and fibrinolytic systems compared with humans, or differences in signal transduction...

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.

Monocyte FcyRs in HIT

Monocytes and macrophages possess several different classes of FcyR (Table 1), and thus may play a part in influencing the frequency and severity of both thrombocytopenia and thrombosis in HIT. One role, discussed in the previous section, involves their potential to influence the balance between platelet activation and reticuloendothelial-mediated platelet clearance in HIT. Another function recently proposed for monocytes is that of contributing to the procoagulant state in HIT (a role posited previously for endothelial cells) (see Chapter 9). Pouplard and colleagues (2001) found that by adding HIT-IgG and PF4 (or PF4-H) directly to isolated monocytes or to whole blood, the monocytes produced TF, an effect that could be inhibited by high concentrations of heparin. Arepally and Mayer (2001) found that monocytes expressed surface TF when incubated with PF4 in the presence of either HIT-IgG or the HIT-mimicking murine monoclonal antibody, KKO. Because monocytes express sulfated...

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,

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...

Pseudohit Syndromes A Adenocarcinoma

Thrombocytopenia Paraneoplastic

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...

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...

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...

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

Classic HIT ensues 5-10 days (occasionally, a few days later) after the beginning of a course of heparin, but rapid-onset HIT occurs sooner, sometimes within minutes of heparin administration, if the patient has had prior sensitization to heparin within the preceding 3 mo (Warkentin and Kelton, 2001a Mims et al., 2004). While the degree of thrombocytopenia with HIT is often moderate (median platelet count, 60 X 109 L), 10 of patients may experience severe thrombocytopenia (platelet count less than 20 X 109 L) (Warkentin, 2003, 2007) remarkably such patients rarely bleed, even though many are fully anticoagulated, and in fact those patients with the lowest platelet counts have the highest risk for thromboembolic complications and thus the most dire need for alternative anticoagulation. Another 10 of HIT patients may have nadir platelet counts that fall within the normal range, but usually these are patients that had substantially elevated platelet counts a few days earlier (Warkentin...

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

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

Lepirudin in Pregnancy

A pregnant woman with systemic lupus erythematosus who was treated with dalteparin developed HIT at week 25. Her platelet count dropped from 230 to 59 X 10 L, after which she was treated with lepirudin (15 mg sc twice daily), with aPTT and ECT used to monitor her dosage. Following delivery by cesarean section, she experienced no postpartum bleeding complications, and treatment with lepirudin was continued for several weeks thereafter (Huhle et al., 2000b). Another pregnant woman with lupus anticoagulant and HIT was successfully treated for 36 wk with lepirudin.

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...

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.

Danaparoid Cross Reactivity

Danaparoid is a mixture of non-heparin anticoagulant glycosaminoglycans, predominantly (low-sulfated) heparan sulfate, dermatan sulfate, and chondroitin sulfate (see Chapter 13). About 10-40 of HIT patient sera cross-react in vitro with danaparoid, depending on the assay used (lower cross-reactivity rates by platelet aggregometry, higher rates with fluid-phase PF4 heparin immunoassays) (Vun et al., 1996 Warkentin et al., 2005 Magnani and Gallus, 2006). The question arises as to the in vivo relevance (if any) of this phenomenon. In our experience, the majority of patients with detectable in vitro cross-reactivity have favorable clinical courses that do not differ significantly (either in clinical outcomes or in time to platelet count recovery) from patients without cross-reactivity (Warkentin, 1996). Furthermore, it is not possible to distinguish in vivo cross-reactivity from a severe natural history of HIT. For example, the authors are aware of HIT patients with strong antibodies,...

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.

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...

Bivalirudin for PCI in HIT

The ATBAT trial was a prospective, open-label study to evaluate the safety and efficacy of bivalirudin in patients with acute HIT or a past history of HIT undergoing PCI (Campbell et al., 2000b Mahaffey et al., 2003). The primary endpoint was major bleeding within 48 h after completion of the bivalirudin infusion (1.0 mg kg h iv bolus followed by 2.5mg kg h by iv infusion for 4 h). This dose was later changed to a 0.75 mg kg h iv bolus followed by a 1.75 mg kg h infusion for 4 h. Secondary endpoints included event rates for components of the primary endpoint and the ACT, aPTT, and platelet counts (at baseline, pre-PCI post-PCI, Abbreviations HIT, heparin-induced thrombocytopenia INR, international normalized ratio iv, intravenous.

Adequate Anticoagulants for HD in HIT Patients

HIT antibodies potentially cross-react with danaparoid. Although the respective clinical risk has been claimed to be less than 5 (Warkentin et al., 1998 Magnani and Gallus, 2006), individual patients, nevertheless, may be threatened if this condition occurs. As positive in vitro cross-reactivity is of uncertain clinical significance (Warkentin, 1996 Wilde and Markham, 1997 Newman et al., 1998), attention should focus on platelet count monitoring. A further fall in platelet count, or new fibrin deposits and clot formation within the extracorporeal circuit after application of danaparoid, may indicate clinically relevant cross-reactivity. To differentiate in vivo cross-reactivity from under-anticoagulation owing to insufficient dosage, determination of antifactor Xa levels and HIT antibody cross-reactivity studies are needed.

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,...

Therapy Of Pediatric

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

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).

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...

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...

About the fourth edition

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

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...

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...

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 (

Lepirudin in Children

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

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

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...

Use in Children and Pregnant Women

Were the same as those in non-pregnant women for the same indications. In 24 pregnancies (75 ) carried to term, normal babies were delivered either vaginally or by caesarian section, although in some a maternal adverse event (usually associated with a placental abnormality) occurred. In eight pregnancies, danapar-oid was stopped prematurely. In two patients, this was because of successful short-term use (no further follow-up). Early fetal death occurred in three pregnancies, two in association with the maternal antiphospholipid syndrome, the other a therapeutic abortion necessitated by a maternal amputation due to thrombosis extension in the second trimester. In two pregnancies, major bleeds occurred, one due to placental abruption (fatal bleeding followed caesarian section in a Jehovah's Witness) after 24 wk of problem-free danaparoid use, and one due to placenta previa with fatal cardiopulmonary complications after caesarian section. One pregnancy was complicated by the onset of...

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, (

Observational Studies

The first published case of fondaparinux use in a patient with HIT was by Dr. Elbio D'Amico et al. (2003). A patient with paroxysmal nocturnal hemo-globinuria and Budd-Chiari syndrome developed HIT following administration of LMWH (dalteparin 5000IU sc q12h). The patient experienced spontaneous platelet count recovery, and received thrombolytic therapy. While receiving prophylactic doses of fondaparinux, the platelet count remained unchanged and the patient was transitioned uneventfully to oral anticoagulant therapy. treat HIT (Table 3). The case series involved 38 patients with HIT who were treated with fondaparinux at the Massachusetts General Hospital (MGH) between January 1, 2002, and August 1, 2004 (Table 3). This series represents two cohorts of patients treated either with fondaparinux after initial treatment with a DTI (n 17) or receiving fondaparinux for the initial treatment of HIT (n 21). Platelet count recovery data from the MGH series are presented in Figure 3,...

Prospective Evaluation

FIGURE 3 Twenty-two patients with HIT were treated with fondaparinux at (or near) the platelet count nadir following exposure to UFH or LMWH. Platelet count recovery is illustrated by this graph, which compares mean platelet counts for the population. Platelet data have been normalized by subtracting the individual value of the patient's platelet count at first administration of fondaparinux from each preceding and subsequent measurement. Error bars represent one standard deviation from the mean. Abbreviations UFH, unfractionated heparin LMWH, low molecular weight heparin HIT, heparin-induced thrombocytopenia. FIGURE 3 Twenty-two patients with HIT were treated with fondaparinux at (or near) the platelet count nadir following exposure to UFH or LMWH. Platelet count recovery is illustrated by this graph, which compares mean platelet counts for the population. Platelet data have been normalized by subtracting the individual value of the patient's platelet count at first administration of...

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 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 Group, 1997). A meta-analysis of five surgical thromboprophylaxis prospective cohort studies 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).

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).

Ysine Krich Ctermirius

FIGURE 6.6 Proposed model of pathogenesis in HIT and thrombosis. PF4 is postulated to be both the target for the antibody (when complexed with heparin) and a modulator of T-cell responsiveness (see text for additional details). Abbreviations APC, antigen-presenting cell GAG, glycosami-noglycan HIT, heparin-induced thrombocytopenia MHC, major histocompatibility complex PF4, platelet factor 4 TCR, T-cell receptor Tr, T regulatory TF, tissue factor.

This Cannot Be HIT Because the Patient Is Not on Heparin

The syndrome of delayed-onset HIT was elucidated a few years ago, and is now increasingly recognized around the world (Warkentin and Kelton, 2001b Rice et al., 2002). The patients have been off heparin for a few days or more, often recuperating at home from a benign hospital course that included heparin exposure, then they return to hospital with an arterial or venous thrombotic event. Upon return, the platelet count is often (although not necessarily) low. These people are often given heparin for their presenting thrombosis, which invariably leads to an abrupt fall in platelet count, frequently clinical deterioration, and substantial mortality. Invariably, there are high-titer antibodies against PF4-heparin complexes. The message to emergency room doctors, intensivists, and hospitalists is to consider the possibility of delayed-onset HIT and not to initiate heparin reflex-ively when a recently hospitalized patient returns with thrombosis. Of note, the U.S. Food and Drug...

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.

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.

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.

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).

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...

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.

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

An intriguing option for patients with a history of HIT, but in whom HIT antibodies can no longer be detected, is to consider reexposure to UFH for CPB, and to avoid heparin completely both before surgery (e.g., at heart catheterization) and in the postoperative period. This approach has been used successfully (Makhoul et al., 1987 Potzsch et al., 2000 Selleng et al., 2001 Warkentin and Kelton, 2001), and is based on the following rationale. First, HIT antibodies are transient, and are usually not detectable after several weeks or a few months following an episode of HIT (see Chapter 2). Thus, no immediate problems would be expected in a patient without residual HIT antibodies. Second, it appears that a minimum of 5 days are required before clinically significant levels of HIT antibodies are generated following any episode of heparin treatment (Warkentin and Kelton, 2001). In the event that a recurrent immune response to PF4-heparin is induced by reexposure to heparin during CPB, it...

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.

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).

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

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, thrombocytopenia...

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).

Ivplatelet Factor 4 And The Endothelium

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

Lepirudin and Vitamin K Antagonists

Long-term treatment of HIT patients often involves a transition from DTI to oral anticoagulation. Initiation of the transition to vitamin K antagonist (coumarin) therapy should begin only after the platelet count has substantially recovered (preferably, 150 x 109 L), with a minimum of 5 days of overlapping therapy with an alternative anticoagulant, and with the last 2 days stably within the target therapeutic range (Warkentin and Greinacher, 2004). In patients with deep vein thrombosis (DVT) associated with acute HIT, the use of vitamin K antagonist can be associated with venous limb gangrene, which typically occurs when this anticoagulant is used alone for treatment of HIT, or when overlapping therapy with DTIs is not managed appropriately, e.g., early initiation of coumarin and premature discontinuation of the DTI.

Comparison with Other Treatments for HIT

Because of the often critical condition of the patient population under study, the rate of deaths observed for both DTIs is not likely to be solely attributable to treatment failure and may vary considerably with different patient populations. As the argatroban trials included many patients who most likely did not have HIT, the death rate associated with HIT might have been overestimated, as non-HIT patients with a decrease of platelet count are often very sick (e.g., septicemia, DIC). Death rates were 14.3 (meta-analysis) and 12.3 (DMP) for patients with isolated HIT treated with lepirudin, but 18.1 and 23.1 in those treated in the two argatroban trials. In patients with HIT complicated by thrombosis, death rates with lepirudin were 11.9 (meta-analysis) and 10.9 (DMP), compared with 18.0 and 23.1 in the argatroban trials. The major conclusions of these comparisons are (1) HIT patients seem to benefit from a longer treatment period with an alternative anticoagulant, with 10 days...

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.

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...

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...

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...

Patients with a History of HIT Requiring Acute Anticoagulation

A subgroup analysis of the prospective studies of argatroban in HIT identified 36 patients with a history of serologically confirmed HIT who had fully recovered from their initial episode of HIT, had a normal platelet count, and had no exposure to heparin or other parenteral anticoagulants (except argatroban) during their hospitalization (Matthai et al., 2005). Each patient required acute anticoagulation, most often for venous thromboembolism or acute coronary syndrome, and 12 had previously received argatroban. All evaluable patients were successfully anticoagulated. No one had a major bleeding or a new thromboembolic event. There were no adverse events related to reexposure.

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...

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...

Pediatric Cardiac Surgery Patients

Skouri et al. (2006) performed a prospective study in the pediatric hemodialysis unit, evaluating 38 children between 1 and 16 yr of age (mean, 10.45 yr) undergoing chronic hemodialysis thrice weekly. Patients received i.v. UFH as a single bolus (70 IU kg body weight). Plasma samples were tested for antibodies by PF4 heparin-EIA and by a functional assay utilizing washed platelets, the heparin-induced platelet activation assay (HIPA). Of 38 patients, nine patients (21 ) tested positive by EIA and or HIPA, but none had thrombocytopenia or clinical thrombosis. Sequential EIAs performed every 3 mo in seven of the eight patients with antibodies detected by EIA showed gradual reductions in antibody levels in six children, with a persistently positive EIA seen in only one patient at 1-yr follow-up.

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.,...

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