Heparin-Induced Thrombocytopenia

Theodore E. Warkentin

Andreas Greinacher

Heparin-induced thrombocytopenia (HIT) is an immune-mediated adverse drug reaction caused by heparin-dependent, platelet-activating immunoglobulin (Ig) G antibodies that recognize complexes of platelet factor 4 (PF4) bound to heparin.¹, ², ³ HIT represents a strong, independent risk factor for venous and arterial thrombosis.⁴

HIT typically causes thrombosis in large veins and arteries; platelet-rich, intra-arterial “white thrombi” were first described in 1958.⁵, ⁶, ⁷ However, HIT is also a risk factor for microvascular thrombosis in certain situations, such as in coumarin treatment of deep vein thrombosis (DVT) (i.e., coumarin-associated venous limb gangrene [see Chapter 109]) or severe HIT-associated disseminated intravascular coagulation (DIC).⁸, ⁹, ¹⁰

Thrombosis typically occurs in anti-PF4/heparin antibodypositive patients who develop significant declines in platelet count,¹¹, ¹², ¹³, ¹⁴ pointing to clinically relevant consequences of in vivo platelet activation induced by these antibodies. A central role for in vivo thrombin generation in HIT⁸ provides a rationale for the use of anticoagulants that inhibit thrombin or its generation.¹⁵

DEFINITION AND TERMINOLOGY

HIT can be defined as any clinical event best explained by platelet-activating anti-PF4/heparin antibodies (“HIT antibodies”) in a patient who is receiving, or who has recently received, heparin (or another polyanion implicated in this syndrome).¹ Thrombocytopenia is the most common event in HIT and occurs in at least 90% of the patients, depending on the definition of thrombocytopenia. A high proportion (50% to 75%) of patients with HIT develop thrombosis.

A consensus report¹⁵ recommended that the term heparin-induced thrombocytopenia should be used to refer to the antibody-mediated disorder. Therefore, HIT can be considered a clinicopathologic syndrome in which the diagnosis can be made accurately when one or more clinical events (e.g., thrombocytopenia, thrombosis, necrotizing skin lesions at heparin injection sites, acute systemic [anaphylactoid] reactions, decompensated DIC) occur together with laboratory detection of the pathologic HIT antibodies. In contrast, it is recommended that the term nonimmune heparin-associated thrombocytopenia (HAT) should be used to describe thrombocytopenia occurring during heparin use that is not associated with HIT antibodies. Often, nonimmune HAT is due to a comorbid disorder (e.g., perioperative hemodilution), although a direct platelet-activating effect of heparin that is not mediated by antibody may occur in some patients.¹⁶ Unlike the situation in HIT, the causative role of heparin in nonimmune HAT in a given patient cannot readily be ascertained.

PATHOGENESIS

FIGURE 108.1 summarizes the pathogenesis of HIT.¹⁷ The central concept is the formation of heparin-dependent IgG that activates platelets via their FcγIIa receptors.¹⁸ It remains controversial—although in our view unlikely—whether IgA and IgM antibodies evince pathogenicity.¹⁹, ²⁰, ²¹, ²² The target antigen is a complex of heparin and the positively charged platelet α-granule protein, PF4,²³, ²⁴, ²⁵, ²⁶ a member of the CXC subfamily of chemokines. HIT antibodies are directed against one or more sites on PF4 that have been conformationally altered by binding to negatively charged heparin.²⁷, ²⁸, ²⁹, ³⁰ This model is consistent with reports that other highly sulfated, nonheparin carbohydrates such as pentosan polysulfate³¹ and polysulfated chondroitin sulfate³² can trigger HIT. This possibly triggered additional adverse effects by oversulfated chondroitin sulfate within “contaminated” heparin.³³ It may also explain why low molecular weight heparin (LMWH) is less likely to trigger HIT,¹¹, ¹² as only heparin molecules of at least 12 saccharides in length bind PF4 in such a way as to induce a large number of neoepitopes required for clinical breakthrough of HIT.³⁴ Rarely, a disorder mimicking HIT on clinical and serologic grounds can occur in the absence of preceding heparin exposure (“spontaneous HIT”); reported cases have featured preceding inflammatory events such as surgery or infection.³⁵, ³⁶, ³⁷ This indicates that the immune reaction to PF4/polyanion complexes can also be induced by endogeneous factors, a feature relevant to understanding the temporal features of antibody formation. Moreover, many HIT-positive sera³⁸, ³⁹—but especially those obtained from patients whose HIT begins⁴⁰ or worsens after stopping heparin—are able to activate platelets in vitro even in the absence of pharmacologic heparin, a phenomenon consistent with “autoimmune-like” features.

Anti-PF4/heparin seroconversion has certain atypical features⁴¹, ⁴²: Antibodies are formed relatively quickly—approximately 4 days (median) after even a first-time immunizing heparin exposure, and without evidence for more rapid formation with previous heparin exposure or even with previous HIT.⁴³ Anti-PF4/heparin antibodies of any of the three major Ig classes can develop and in any combination, in the frequency IgG > IgA > IgM.⁴¹, ⁴² Moreover, when IgM antibodies are formed, these are detectable simultaneously with IgG and/or IgA, that is, there is no IgM precedence (as would be expected in a “classic” immune response). This indicates that the immune response induced by heparin is a secondary, rather than a primary, immune response; PF4 complexed to polyanions on bacterial surfaces might be the “preimmunizing” trigger.⁴⁴

Several factors contribute to the prothrombotic nature of HIT (FIGURE 108.1): (a) the potent platelet-activating
properties of the HIT antibodies, which also generate procoagulant, platelet-derived microparticles⁴⁵, ⁴⁶; (b) pancellular activation (either directly or indirectly by HIT antibodies),⁴⁷, ⁴⁸ manifesting as tissue factor expression on endothelium²⁵, ⁴⁸, ⁴⁹ and monocytes,⁵⁰, ⁵¹ and possibly platelet-leukocyte complex formation⁵²; and (c) neutralization of the heparin anticoagulant effects by PF4. Collectively, these factors result in increased thrombin generation in HIT.⁸, ⁵³, ⁵⁴

FIGURE 108.1 Pathogenesis of HIT. Heparin produces mild platelet activation, resulting in the release of PF4 from platelet α-granules and in the formation of immunogenic PF4/heparin complexes. B lymphocytes generate IgG that recognize the PF4/heparin complexes; the Fc “tails” of the IgG bind to platelet FcγII receptors, resulting in Fc receptor clustering and consequent strong platelet activation. Platelet aggregation is mediated by glycoprotein (GP) IIb/IIIa. Platelet-derived microparticles that accelerate thrombin generation are produced. The HIT antibodies also recognize PF4 bound to endothelial heparan sulfate, leading to tissue factor expression on endothelium. HIT antibodies also can activate monocytes. In all, increased thrombin generation results can explain some of the unusual clinical manifestations of HIT (e.g., venous limb gangrene and DIC) and provide a rationale for treatment that reduces thrombin generation. (From Greinacher A, Warkentin TE. Treatment of heparin-induced thrombocytopenia: an overview. In: Warkentin TE, Greinacher A, eds. Heparin-induced thrombocytopenia, 4th ed. New York: Informa Healthcare USA, 2007:283-317.)

Women are more likely than men to develop HIT (˜ two-fold increase by odds ratio).⁵⁵ However, no HLA association or other genetic risk factor has been identified.⁵⁶ Although the platelets bearing FcγIIa receptors of the His131 phenotype (˜70% of the population) are more readily activated by HIT antibodies of IgG1 subclass (the predominant subclass in HIT),⁵⁷, ⁵⁸ no clear association between HIT and Fc receptor genotype has been established.⁵⁹, ⁶⁰ A strong, albeit indirect, argument against a genetic risk factor is the surprising observation that even patients with a previous history of HIT do not usually regenerate HIT antibodies upon repeat heparin exposure.⁴³, ⁶¹

RISK FACTORS FOR HIT

The frequency of HIT is variable and is influenced by the type of patient population (major surgery or trauma > minor surgery > medical > obstetrical), sex (female > male), the type of heparin used (bovine unfractionated heparin [UFH] > porcine UFH > porcine LMWH > fondaparinux), duration of heparin therapy (the risk increases until ˜10 to 14 days of heparin administration), and, possibly, the timing of the first
dose of anticoagulant in relation to surgery (postoperative > preoperative) and body mass index (BMI) (high BMI > low BMI).⁵⁵, ⁶², ⁶³, ⁶⁴ A stoichiometric model of optimally immunizing PF4:heparin ratios has been proposed to explain some of these observations.⁶⁴, ⁶⁵

A relatively high frequency (˜5%) of HIT occurs in postoperative orthopedic surgery patients receiving prophylactic-dose UFH for up to 14 days.¹¹, ¹², ⁶⁶ The frequency is even higher (8% to 10%) in postcardiac surgery patients who receive therapeuticdose UFH after implantation of a ventricular assist device.⁶⁷, ⁶⁸, ⁶⁹ In contrast, HIT was not observed in several large studies in which LMWH was administered for many weeks during pregnancy.⁷⁰, ⁷¹, ⁷² The frequency of HIT occurrence is estimated to be about 1% in patients receiving UFH for treatment of venous thromboembolism⁶² and, perhaps, for prevention of thrombosis in medical patients,⁷³ and approximately 0.1% to 0.5% in postoperative patients receiving LMWH⁶²; case reports suggest a small risk of HIT (probably <0.01%) with fondaparinux thromboprophylaxis after surgery.⁷⁴, ⁷⁵, ⁷⁶ However, it might be that in these cases the antibodies (albeit triggered by fondaparinux) show the autoantibody-like behavior described above. Given the decreasing use of UFH after orthopedic surgery, one common scenario for HIT today is antithrombotic prophylaxis with UFH following cardiac surgery (risk: ˜1% if UFH is given for >1 week).⁷⁷

Patient-dependent risk factors influence the type of HIT-associated thrombotic event. For example, venous thrombosis occurs in at least half of postorthopedic surgery patients who develop HIT, with relatively few arterial thrombi observed.¹¹, ¹², ⁶⁶ In contrast, arterial thrombosis occurs at least as often as venous thrombosis in patients with HIT after cardiac surgery, suggesting a predisposing role for atherosclerosis.⁶², ⁷⁸, ⁷⁹ Risk of limb amputation is greater in patients who develop HIT in the setting of peripheral vascular surgery.⁸⁰ Patients with a central venous catheter who develop HIT have about a 10% chance of developing symptomatic upper limb DVT at the catheter site, reflecting the interaction of localized vessel injury with the systemic hypercoagulability of HIT.⁸¹

CLINICAL PRESENTATION

HIT is a distinct immunohematologic syndrome that usually can be distinguished on clinical grounds from IgG-mediated thrombocytopenia caused by drugs such as quinine/quinidine or sulfa antibiotics.⁸², ⁸³, ⁸⁴

Thrombocytopenia

The thrombocytopenia is usually mild to moderate in severity (median platelet count nadir, ˜50 to 60 × 10⁹/L)¹, ⁹, ⁸², ⁸³, ⁸⁴ (see FIGURE 108.2). The platelet count is <20 × 10⁹/L in only 5% to 10% of patients with HIT; in contrast, severe thrombocytopenia typically occurs in patients with immune thrombocytopenia caused by other drugs.⁸⁴, ⁸⁵, ⁸⁶ Petechiae and ecchymoses are usually absent even in patients with HIT who have severe thrombocytopenia. Thrombosis is common in HIT, irrespective of the severity of the thrombocytopenia, and can occur in patients with a decreased platelet count that may not necessarily be lower than 150 × 10⁹/L¹, ¹² (see FIGURE 108.3), although the risk and severity of thrombosis increase with the degree of thrombocytopenia, whether expressed in absolute or proportional terms.¹², ¹³, ¹⁴, ⁸⁰, ⁸⁷, ⁸⁸ In postoperative patients, a proportional fall in platelet count (≥50%) between postoperative days 4 and 14 is more sensitive (and similarly specific) for HIT than the conventional definition of thrombocytopenia (platelet count fall to <150 × 10⁹/L). Identifying the postoperative platelet count peak as the appropriate “baseline,” together with regular platelet count monitoring (particularly in patients receiving UFH after a major surgery), is important for being able to recognize a HIT-associated decrease in platelet count when a thrombotic event occurs (FIGURE 108.3).¹², ⁸³, ⁸⁷, ⁸⁸

FIGURE 108.2 Platelet count nadirs in HIT, quinine-induced immune thrombocytopenic purpura (Q-ITP), and thrombotic thrombocytopenic purpura (TTP) with absent ADAMTS-13 activity. The majority of patients with HIT have HIT-associated thrombosis, and the risk of thrombosis is substantial irrespective of the severity of the thrombocytopenia. Data on TTP were kindly provided by James N. George, MD. (From Warkentin TE. Think of HIT. Hematology Am Soc Hematol Educ Program 2006:404-414, with permission.)

Timing

Patients with HIT typically develop a platelet count fall that begins between days 5 and 10 of heparin treatment (1st day of heparin use [especially intraoperative or early postoperative heparin] = day 0).⁹, ⁴³, ⁸⁹ Sometimes, thrombocytopenia can begin earlier in patients who have been exposed previously to heparin. In general, this is observed only in patients whose previous heparin exposure is recent (within the past 3 months), in which case an immediate recurrence of thrombocytopenia can occur on reexposure to heparin.⁴³, ⁸⁹ A true anamnestic immune response, in which previous heparin exposure predisposes to a greater probability of forming more avid (higher-titer, higher-affinity) antibodies, is not a feature of HIT. Sometimes, HIT can begin several days after all heparin has been stopped (delayed-onset HIT) or progress despite stopping heparin.⁴⁰, ⁹⁰, ⁹¹, ⁹², ⁹³ This clinical picture is characterized by high-titer HIT antibodies that can activate platelets even in the absence of heparin.⁴⁰

Prospective studies indicate a characteristic “timeline” of anti-PF4/heparin seroconversion and development of clinically evident HIT: Antibodies first become detectable at day 4, the platelet count begins to fall at day 6, thrombocytopenia (≥50% platelet count fall) is manifest at day 8, and thrombosis occurs at day 10 (days all expressed as median values). However, while the timing of the immune response and the associated platelet
count fall is rather uniform, for thrombotic events, the onset ranges widely, sometimes occurring even before the fall in platelet count is readily apparent, or up to several weeks later.¹⁴, ⁸³, ⁸⁸

FIGURE 108.3 Characteristic timing, severity, and prothrombotic nature of HIT. The shaded area indicates the mean (±2 standard deviation [SD]) platelet count range in the reference population without HIT. There is an immediate postoperative decrease in the platelet count (maximal, days 1 to 3), followed by a rise to levels greater than baseline (maximal, days 11 to 14). Antithrombotic prophylaxis with subcutaneous UFH (7,500 U twice daily) or the LMWH, enoxaparin (30 mg twice daily), was begun usually on postoperative day 1. Eighteen patients developed HIT (50% or greater fall in the platelet count from the postoperative peak), with nine evincing a platelet count nadir <150 × 10⁹/L and nine a platelet count nadir >150 × 10⁹/L. The symbols indicate thrombotic events, 18 of which occurred in 13 of the 18 patients with HIT. One patient who received enoxaparin developed an abrupt platelet count fall when given a 5,000 U bolus of UFH (^†). (Created from figures in Warkentin TE, Levine MN, Hirsh J, et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med 1995;332:1330-1335; Warkentin TE, Roberts RS, Hirsh J, et al. An improved definition of immune heparin-induced thrombocytopenia in postoperative orthopedic patients. Arch Intern Med 2003;163:2518-2524.)

Complications

Table 108.1 lists various complications of HIT by frequency. The strong association between HIT and thrombosis means that this diagnosis should be considered when a patient develops thrombosis or other potential HIT-associated sequelae in association with a falling platelet count during, or shortly after stopping, heparin therapy (FIGURE 108.3).

Venous thrombosis is the most common complication of HIT and includes DVT and pulmonary embolism.¹, ¹¹, ¹², ¹³, ⁹⁴ Abdominal or flank pain suggests adrenal hemorrhagic necrosis, which can lead to shock secondary to acute adrenal failure if bilateral. This complication results from adrenal vein thrombosis.⁹ Headache and acute neurologic sequelae suggest dural sinus (cerebral venous) thrombosis.⁹¹, ⁹² Splanchnic vein thrombosis (e.g., mesenteric vein thrombosis) is a rare complication of HIT.

Arterial thrombosis is relatively common in HIT and most often involves large limb arteries, resulting in acute arterial occlusion with absent pulses.⁸, ⁹⁴, ⁹⁵ Thrombotic stroke, myocardial infarction, or mesenteric artery thrombosis occurs less often.⁹, ⁹⁴

Limb ischemia or gangrene can be categorized as limb ischemia with and without palpable or Doppler-identifiable pulses (see FIGURE 108.4).⁵, ⁸, ⁹⁵ Absent pulses suggests that the acute limb ischemia is caused by large artery occlusion by platelet-rich “white clots.” In contrast, severe limb ischemia with pulses present indicates microvascular thrombosis in HIT and is most commonly caused by treatment of DVT using warfarin (coumarin) (see Chapter 109).⁸, ⁹⁶, ⁹⁷, ⁹⁸ The laboratory hallmark of coumarin-associated venous limb ischemia is a supratherapeutic international normalized ratio (INR) (usually >3.5), which is a surrogate marker for severe protein C depletion (in parallel with a severe reduction of factor VII) complicating coumarin therapy for HIT-associated DVT (see Chapter 109). Rarely, venous limb ischemia or necrosis is associated with decompensated DIC in HIT in the absence of coumarin therapy, with or without associated DVT,⁹, ¹⁰ possibly because of acquired natural anticoagulant depletion.

Classic (nonacral) coumarin-induced skin necrosis has been reported in patients with HIT,⁸, ⁹⁸, ⁹⁹ but this is less common than venous limb gangrene (see Chapter 109).

Table 108.1 Complications of HIT

Venous Thrombosis	Arterial Thrombosis	Miscellaneous
DVT (50%)	Aortoiliac thrombosis (acute limb ischemia) (5%-15%)	Heparin-induced necrotizing skin lesions (small minority of sensitized patients receiving subcutaneous heparin injections)
Pulmonary embolism (25%)	Acute thrombotic cerebrovascular accident (5%-10%)	Acute systemic reactions postintravenous heparin bolus (≈25% of sensitized patients who receive a heparin bolus)
Warfarin-induced venous limb gangrene (≈10% of HIT patients with DVT treated with warfarin)	Myocardial infarction (3%-5%)	Adrenal hemorrhagic infarction (1%-3%)—manifestation of adrenal vein thrombosis
Rare: cerebral sinus thrombosis (<3%); splanchnic vein thrombosis (e.g., mesenteric or portal vein thrombosis) (<3%)	Rare: thrombosis of upper limb, renal, mesenteric, spinal, other arteries (<3%)	Rare: DIC with hypofibrinogenemia and microvascular thrombosis (<3%)
Estimated frequencies of the various complications of HIT are taken from several series of patients with serologic support of the diagnosis of HIT. HIT, heparin-induced thrombocytopenia; DVT, deep vein thrombosis; DIC, disseminated intravascular coagulation.

Heparin-induced skin lesions are dermal reactions noted within 24 hours of subcutaneous heparin injection that begin 5 or more days after heparin initiation.¹⁰⁰, ¹⁰¹ These lesions are associated with HIT antibodies. Interestingly, only about one-fourth of patients who develop skin lesions together with HIT antibodies develop thrombocytopenia, but those with heparin-induced skin lesions and thrombocytopenia are at particularly high risk for arterial limb thrombosis.¹⁰² The antibodies found in patients with necrotizing skin lesions are indistinguishable from those associated with other manifestations of HIT.

FIGURE 108.4 Three ischemic limb syndromes in HIT. The two most common causes of limb loss in HIT are coumarin-induced venous limb gangrene (microvascular thrombosis in a limb affected by DVT) and white clot syndrome (occlusion of large limb arteries by platelet-rich white clots). Rarely, microvascular thrombosis (with or without associated DVT) is associated with limb ischemia in the absence of coumarin use. DIC, disseminated intravascular coagulation. (Modified from Warkentin TE. Heparin-induced thrombocytopenia: IgG-mediated platelet activation, platelet microparticle generation, and altered procoagulant/anticoagulant balance in the pathogenesis of thrombosis and venous limb gangrene complicating heparin-induced thrombocytopenia. Transfus Med Rev 1996;10:249-258.)

FIGURE 108.5 Heparin-induced skin necrosis.

Two types of skin lesions are described: painful, red plaques and frank skin necrosis (see FIGURE 108.5). Whereas the former can represent delayed-type hypersensitivity reactions with coincidental anti-PF4/heparin seroconversion,¹⁰³, ¹⁰⁴ the latter (necrotizing) reactions appear to be specific for HIT. Close clinical observation and monitoring of platelet count should be performed for several days after stopping heparin injections in patients with skin lesions because thrombocytopenia and thrombosis can begin several days later.¹⁰²

Acute anaphylactoid reactions (acute systemic reactions) refer to a variety of systemic symptoms and signs that begin within 5 to 30 minutes of receiving an intravenous heparin bolus—or less often, following subcutaneous injection— and are accompanied by an abrupt decrease in platelet count.⁹, ¹⁰⁵, ¹⁰⁶, ¹⁰⁷ Clinical features are inflammatory (i.e., fever, chills, and flushing), cardiopulmonary (i.e., hypertension, tachycardia, dyspnea or tachypnea, and cardiac or respiratory arrest), neurologic (i.e., transient global amnesia and pounding headache), and gastrointestinal (i.e., watery diarrhea). These differ from the anaphylactic reactions induced by heparin contaminants such as oversulfated chondroitin sulfate.³³, ¹⁰⁷

Decompensated DIC refers to an elevated INR and/or activated partial thromboplastin time (aPTT); reduced concentration of fibrinogen; presence of red cell fragments and/or circulating normoblasts; or other laboratory features of severe DIC. Although increased thrombin generation is a universal feature of HIT (as shown by increased levels of thrombin-antithrombin complexes),⁸ only 10% to 15% of the patients evince one or more of these features of decompensated DIC. These patients are at an unusually high risk for developing multiple thrombi and/or microvascular thrombosis.

SCORING SYSTEMS

Scoring systems have been developed for use in diagnosis of HIT, to evaluate new laboratory tests for HIT antibodies, or to estimate the pretest probability of HIT.¹⁰⁸, ¹⁰⁹, ¹¹⁰, ¹¹¹, ¹¹², ¹¹³ Table 108.2 shows the 4Ts scoring system; depending on the clinical setting in which the 4Ts is used, the likelihood of HIT ranges from <2% (low score), to 10% to 30% (intermediate score), to 50% to 70% (high score).¹¹¹ Thus, the main utility of the 4Ts is in predicting a low likelihood of HIT when the score is low (≤3 points), that is, a high negative predictive value.¹¹¹ A recent scoring system developed using broad expert opinion, the HIT Expert Probability Score, exhibited favorable operating characteristics but requires prospective validation.¹¹³

LABORATORY TESTING

Both platelet activation and PF4-dependent antigen assays are useful to support the diagnosis of HIT.¹¹⁴, ¹¹⁵, ¹¹⁶ In general, the more abnormal the test result, for example, higher optical density (OD) in the enzyme (-linked) immuno(sorbent) assay (EIA or ELISA), the greater the likelihood that the patient has HIT.¹¹⁷, ¹¹⁸, ¹¹⁹ HIT antibodies are usually detectable in patient serum or plasma only for a few weeks or months,⁴³ and therefore, acute serum or plasma should be tested.

Table 108.2 Estimating the pretest probability of HIT: 4Ts scoring system

	Points (0, 1, or 2 for Each of 4 Categories: Maximum Possible Score = 8)^a
	2	1	0
Thrombocytopenia (acute)	>50% platelet fall (nadir ≥ 20 × 10⁹/L)	30%-50% platelet fall (or >50% fall due to surgery) or nadir 10-19 × 10⁹/L	<30% platelet fall or nadir <10 × 10⁹/L
Timing^b of platelet count fall, thrombosis, or other sequelae (1st day of immunizing heparin course = day 0)	Clear onset between days 5 and 10 or ≤1 d (if heparin exposure within the past 30 d)	Consistent with day 5-10 fall, but not clear (e.g., missing platelet counts) or ≤1 d (heparin exposure within the past 31-100 d) or platelet fall after day 10	Platelet count fall ≤4 d without recent preceding heparin exposure
Thrombosis or other sequelae (e.g., skin lesions, ASR)	New thrombosis; skin necrosis^c; ASR after IV heparin bolus	Progressive or recurrent thrombosis; suspected thrombosis (not yet proven); asymptomatic upper limb DVT)	None
oTher causes of thrombocytopenia not evident	No explanation (besides HIT) for platelet count fall is evident.	Possible other cause is evident.	Definite other cause is present.
Note: The score can increase or decrease as additional information is obtained and as the thrombocytopenia evolves.
^aPretest probability score: 6-8 = high; 4-5 = intermediate; 0-3 = low. ^bFirst day of immunizing heparin exposure is considered day 0; the day the platelet count begins to fall for any given episode of thrombocytopenia is considered the day of onset of thrombocytopenia (it generally takes 1-3 more days until an arbitrary threshold that defines thrombocytopenia is passed). In general, giving heparin during or soon after surgery is most likely to induce immunization, and this scenario (when applicable) should be primarily evaluated. ^cAt site(s) of heparin injections.
ASR, acute systemic reaction (i.e., anaphylactoid reaction); DVT, deep vein thrombosis; HIT, heparin-induced thrombocytopenia; IV, intravenous.
Modified from Warkentin TE. Clinical picture of heparin-induced thrombocytopenia. In: Warkentin TE, Greinacher A, eds. Heparin-induced thrombocytopenia. New York: Informa Healthcare USA, 2007:21-66.

Activation Assays

Activation assays exploit the platelet-activating properties of the HIT-IgG antibodies. The characteristic profile of HIT sera is the activation of normal donor platelets using therapeutic heparin concentrations (optimal at 0.1 to 0.3 U/mL) and the inhibition of activation of normal donor platelets at supratherapeutic heparin concentrations (10 to 100 U/mL).¹²⁰, ¹²¹ As noted earlier, many HIT sera also induce considerable platelet activation in the absence of heparin (i.e., buffer control), a feature associated with delayed-onset or worsening of HIT despite stopping heparin.⁴⁰ Washed platelets that have been resuspended in divalent cation-containing buffer—with “washing” performed in the presence of apyrase (an enzyme that preserves platelet reactivity to adenosine diphosphate—an important potentiator of HIT antibody-induced platelet activation¹²²)—respond optimally to HIT antibodies. These features have been incorporated into two “gold standard” assays, the platelet serotonin release assay (SRA)¹²⁰, ¹²³ and the heparin-induced platelet activation (HIPA) test.¹²⁴ In one study, a positive SRA was strongly associated with thrombocytopenia that began on day 5 or later of heparin treatment (odds ratio 78, 95% CI 12 to 819, P < 0.001).¹¹

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