American Journal of Kidney Diseases
Volume 54, Issue 2 , Pages 361-374, August 2009

Antibodies to Heparin–Platelet Factor 4 Complex: Pathogenesis, Epidemiology, and Management of Heparin-Induced Thrombocytopenia in Hemodialysis

  • Andrew Davenport, MD

      Affiliations

    • Corresponding Author InformationAddress correspondence to Andrew Davenport, MD, UCL Center for Nephrology, University College London Medical School, Royal Free Campus, Rowland Hill St, London NW3 2PF, UK

UCL Center for Nephrology, University College London Medical School, Royal Free Campus, London, UK

Received 6 January 2009; accepted 24 March 2009. published online 01 June 2009.

Article Outline

Index Words: Heparin-induced thrombocytopenia, hemodialysis, hirudin, argatroban, danaparoid

 

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Case Presentation 

An 83-year-old man treated with continuous ambulatory peritoneal dialysis for 3 years for end-stage renal disease caused by type 2 diabetes and hypertension was admitted with peritonitis. After 3 days, there had been no significant improvement, the peritoneal dialysis catheter was removed, and he was converted to treatment with intermittent hemodialysis using a right internal jugular catheter. His condition improved, and after 10 days, he was scheduled to be discharged home after a hemodialysis session.

That morning, the patient was sent from the inpatient ward to the outpatient hemodialysis facility for his treatment. Within 3 minutes of the start of the hemodialysis session, he reported feeling unwell, dizzy, and short of breath. He rapidly became unconscious, with no recordable blood pressure or pulse, and died despite attempts at resuscitation.

Because this was an unexpected death, the patient's charts and in-patient records were reviewed. In retrospect, it was observed that the peripheral platelet count had decreased since starting hemodialysis therapy (Fig 1); subsequent laboratory testing confirmed a positive result (optical density > 1.0) for an enzyme-linked immunosorbent assay (ELISA) for antibodies to the heparin–platelet factor 4 (PF4) complex, as well as a positive heparin-induced platelet aggregation test result. His pretest probability score was 8 (Table 1).1 An assay for mast cell tryptase was negative. Although the initial hemodialysis sessions had not been performed with heparin, because he had been bed-bound, he had received prophylactic subcutaneous porcine unfractionated heparin (UFH), and the dialysis catheter had been locked with porcine UFH (1,000 IU/mL). He was then given a bolus of porcine UFH (1,000 IU) at the start of subsequent hemodialysis sessions. Review of his dialysis charts showed that although the flows through the catheter initially had been satisfactory, in the sessions before his collapse, arterial and venous pressures had increased, raising the suspicion of catheter-associated thrombus.

Table 1. Pretest Probability Score: Thrombocytopenia, Timing of Heparin Exposure, Thrombosis, and Other Causes (4T scoring system)
Score (points)
210
ThrombocytopeniaNadir of 20-100 × 109/L or >50% ↓Nadir of 10-19 × 109/L or 30%-50% ↓Nadir of <10 × 109/L or <30% ↓
Timing of onset of platelet ↓5-10 d⁎ heparin exposure<10 d or timing not evident<1 d heparin exposure
Thrombosis or acute systemic symptomsProven thrombosis, skin necrosis, or acute systemic reactionProgressive, recurrent, silent thrombosis or erythematous skin lesionsNone
Other cause of thrombocytopeniaNone evidentPossibleProbable

Note: Pretest probability of heparin-induced thrombocytopenia: high, 6 to 8; intermediate, 4 to 5; and low, 0 to 3.

Based on Warkentin and Greinacher.1

⁎In patients previously exposed to heparins, heparin-induced thrombocytopenia type II can occur within 24 hours after reexposure.

Postmortem examination excluded pulmonary embolus and acute myocardial infarction, but showed marked increased interstitial lung edema (Fig 2). This patient was presumed to have died of acute pseudo-pulmonary embolus syndrome associated with heparin-induced thrombocytopenia (HIT).

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  • Figure 2. 

    Computed tomographic (CT) chest scan of a patient in whom the dialyzer circuit clotted, who then collapsed when reconnected after a second bolus of low-molecular-weight heparin. The scan shows intra-alveolar edema, typical of pseudo-pulmonary embolus syndrome.

HIT should be considered in patients newly starting hemodialysis treatment who develop peripheral thrombocytopenia, particularly in association with venous access catheter thrombus.

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Introduction 

Routine laboratory measurement of peripheral platelets was introduced only in the 1970s, and as such, the first published report of HIT complicated by thrombosis dates back to 1969,2 although cases of HIT undoubtedly occurred many years before this report. Heparin is now recognized as the most common cause of drug-induced thrombocytopenia in clinical practice. However, not all patients who develop antibodies to the heparin-PF4 complex develop thrombocytopenia, and similarly, not all patients who develop HIT experience thrombotic consequences, which has led to the concept of an “iceberg” model3 (Fig 3). The frequency of antibody formation depends on a variety of factors, including the chain length of the heparin molecule and degree of sulfation,4 amount and frequency of heparin administration, clinical setting, and degree of nonimmune platelet activation.5 Whether patients then develop thrombocytopenia relates to the clinical setting,6 dose of heparin, platelet Fc receptor expression and also possibly Fc receptor polymorphisms,7 and concurrent inflammatory responses. Similarly, risk of thrombosis is then dependent on patient factors, including immobility, previous limb gangrene, peripheral vascular disease, presence of mutations disrupting levels or activity of natural anticoagulants such as protein C, treatment with coumarins, and degree of thrombocytopenia. Risk of thrombosis also is increased by the use of indwelling central venous catheters.8 Patients who experience multiple thromboses or such severe systemic reactions as pseudo-pulmonary embolus typically have endothelial cell activation by HIT antibodies (Fig 4).

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  • Figure 4. 

    Schematic representation of the development of heparin-induced thrombocytopenia (HIT). Heparin binds to the platelet surface and leads to release of platelet factor 4 (PF4). If a critical stoichiometric ratio of heparin to PF4 is achieved, the heparin-PF4 complex undergoes a conformational change that exposes novel epitopes, leading to antibody (Ab) formation. The heparin-PF4 complex–bound antibody then binds to platelets, leading to activation and microparticle release, which activates the contact coagulation cascade to produce thrombin and further platelet activation. The antibody complex also binds endothelial cells through heparin sulfate and activates endothelial cells, leading to local thrombus and endothelial permeability, which causes the pseudo-pulmonary embolus syndrome. Abbreviation: ADP, adenosine diphosphate.

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Pathogenesis 

Heparins can bind surface-bound PF4, leading to platelet activation with a decrease in peripheral platelet count.3 This usually occurs when patients are first exposed to heparins, such as initiating hemodialysis therapy9; typically is transitory; and is termed HIT type I (Table 2).10

Table 2. General Differences Between HIT Types I and II
HIT Type IHIT Type II
Frequency (%)10-200.1-3
Timing after heparin (d)1-35-10⁎
Peripheral platelet count (× 109/L)10030-50
Antibody mediatedNoYes
Risk of thrombosisNoYes
Risk of hemorrhageNoYes
ManagementObserve, continue heparinWithdraw all heparins

Data from Davenport.9

Abbreviation: HIT, heparin-induced thrombocytopenia.

⁎In patients previously exposed to heparins, HIT type II can occur within 24 hours after reexposure.

When heparin binds to PF4 at a key stoichiometric ratio of 27 IU heparin to 1 mg of PF4, conformational change occurs within the PF4 molecule leading to exposure of novel epitopes, thus allowing the generation of autoantibodies to the heparin-PF4 complex.11 The affinity of heparin for PF4 depends on molecular weight, chain length, and degree of sulfation, thus accounting for the increased antibody formation with bovine to porcine UFH12 and UFH compared with low-molecular-weight heparins. In 80% of cases, heparin-PF4 antibodies are of the immunoglobulin G (IgG) isotype13 because only IgG antibodies can bind to platelet FcγIIa receptors, although occasionally IgM and IgA antibodies have been reported to be pathogenic. The heparin-PF4-IgG complex then activates platelets through their FcγIIa receptors, and there is debate about whether some receptor isoforms predispose to HIT.14 Platelet activation results in the release of platelet microparticles, platelet consumption, and peripheral thrombocytopenia, with generation of thrombin, activation of monocytes and other inflammatory cells, and also endothelial injury and activation (Fig 4).

Because heparin can nonspecifically bind to plasma proteins, some patients can occasionally develop antibodies to heparin-chemokine complexes, resulting in HIT without typical heparin-PF4 antibodies.15

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Clinical Presentation in Hemodialysis Patients 

HIT typically occurs in incident hemodialysis patients, although late cases have been reported, particularly when heparin dosages and/or frequency have been increased.16, 17 Clotting in the extracorporeal circuit18 followed by catheter-associated thrombi are the most common clinical manifestations,19 particularly when patients with acute kidney injury are being dialyzed.20 In routine outpatient hemodialysis, other commonly reported manifestations include access thrombosis (arteriovenous fistulas and grafts) and central venous stenoses in patients undergoing dialysis with central venous catheters. In 1 survey, less than 10% of patients with HIT developed deep venous thrombosis and 4% developed pulmonary emboli. In addition, retroperitoneal hemorrhage was reported in 4%.16 Fortunately, myocardial infarction, multiple thromboses, and pseudo-pulmonary embolus syndrome occur in 1% or less of patients.21, 22, 23

There is debate about whether hemodialysis patients with heparin-PF4 antibodies, but without thrombocytopenia, are at increased risk of thrombosis, in particular, access thrombosis. Because these antibodies cause platelet activation, increased access thrombosis would be expected.24 Although the majority of studies have reported an increased incidence of heparin-PF4 antibodies in patients with recurrent thrombosed accesses,16, 25, 26 this has not been universal.27, 28 Three studies reported increased mortality in hemodialysis patients with anti–heparin-PF4 antibodies without thrombocytopenia.29, 30, 31 In these studies, there was an excess of thrombotic events, not only pulmonary emboli and mesenteric ischemia, but also cardiovascular deaths. However, a recent multicenter report28 did not show excess overall mortality or cardiovascular death in patients with antibodies to heparin-PF4.

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Diagnosis 

The diagnosis of HIT remains a clinical one supported by confirmatory laboratory testing. In the intensive care unit setting, there are many potential causes of thrombocytopenia,32 and similarly, several drugs prescribed to outpatient hemodialysis patients, including such antibiotics as vancomycin, proton pump inhibitors, histamine2 blockers, and antidepressants, also can cause thrombocytopenia. Thus, to provide guidance, Warkentin and Greinacher1 proposed a scoring system to assess the potential risk of patients having HIT, colloquially referred to as the 4Ts (Table 1). If HIT is suspected, all heparin exposure should be withdrawn while awaiting laboratory testing, and unless clinically contraindicated, the patient starts on an alternative systemic anticoagulant therapy.21, 33

Laboratory Testing 

Heparin-PF4 antibodies can be detected by means of either laboratory functional tests or immunoassays. Functional tests assess platelet activation in the presence of both heparin and the patient's serum. These include heparin-induced platelet aggregation, serotonin release assay (SRA), and flow cytometric assays that detect platelet microparticle release.34 Activation assays should be confirmed by using heparin neutralization because at high concentrations of heparin, the test result should be negative because excess heparin leads to different heparin-PF4 binding so that the novel epitopes are not expressed. These activation assays also allow in vitro cross-reactivity to low-molecular-weight heparins and heparinoids to be assessed. Although the SRA is 95% sensitive and specific, when washed platelets are used, it is laborious and available in only a few laboratories worldwide. Thus, the heparin-induced platelet aggregation test, with variable sensitivity of 35% to 85%, is more commonly performed. During the last decade, a number of immunoenzymatic tests (solid-phase enzyme immunoassay, PF4-polyvinylsulfonate antigen assay, fluid-phase enzyme immunoassay, and gel particle immunoassay) have been developed to detect antibodies directed against the heparin-PF4 complex and have become readily available. These ELISAs have high sensitivity of 80% to 100%, but have low specificity because they detect a range of IgA and IgM antibodies that are not pathogenic. More recently, IgG isotype ELISAs have been introduced.

No single assay has 100% sensitivity and specificity.29, 35 Therefore, most laboratories use a combination of tests. However, it must be remembered that HIT predominantly is a clinical diagnosis29, 36 supported by laboratory testing,33 and there is value in repeated testing in clinically suspected cases.37

Differential Diagnoses 

Mild thrombocytopenia can occur when patients first start dialysis therapy (Table 2) and are exposed to heparins. In addition to infections and alloantibodies, a substantial number of drugs have been reported to cause thrombocytopenia, ranging from antibiotics, including vancomycin and penicillins, to proton pump inhibitors, monoclonal immunosuppressants, and chemotherapeutic agents to antipsychotics.32, 38

HIT can cause an acute collapse shortly after starting hemodialysis caused by heparin exposure by either priming the dialysis circuit with heparin, injection of the remaining heparin lock, and bolus administration.21 However, there are other causes of anaphylactoid-like reactions that can occur shortly after starting dialysis,39 including air embolus, reactions to the dialyzer,40 sterilization agents,41 and anticoagulants. Some patients develop allergies to heparin as part of an allergy to porcine or bovine products or the stabilizing agents used in sodium and calcium heparin preparations. Mast cell tryptase and specific radioallergosorbent test assays for sterilization agents, plasticizers, and adhesives, including methacrylates, may be helpful in investigating such reactions. More recently, a series of fatal reactions have been reported with heparin preparations contaminated with oversulfated chondroitin sulfate.42 Heparin is negatively charged, which can cause activation of the contact coagulation cascade,43 leading to kalikrein and bradykinin generation with complement activation and increased production of both nitric oxide and the anaphylatoxins C3a and C5a, potentially leading to profound hypotension. Contamination of heparin with oversulfated chondroitin sulfate increases the number of negative charges, thus increasing the potential to generate bradykinin and complement activation,44 leading to profound hypotension.45 Increased heparin sulfation also increases the risk of developing HIT.

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Epidemiology of HIT in Hemodialysis Patients 

Very few studies have prospectively measured antibodies to the heparin-PF4 complex in patients initiating hemodialysis. However, a UK survey on HIT reported an incidence of 1.6%.16 Most reports have been cross-sectional in nature, typically reporting positive heparin-PF4 ELISA results, with prevalence rates ranging from 0% to 10.6%.46, 47, 48, 49, 50, 51 Differences between these reports can be explained by the differing assays used (functional versus antigen) and timing, in that the prevalence of antibodies is greater within the first 3 months after starting dialysis therapy (20%) and then decreases with dialysis vintage to 6% after 6 months.27 Similarly, centers have used a different optical density cutoff value to determine a positive test result (for example, 0.6 versus 1.0),26, 29, 46, 47, 48, 49, 50, 51 and a recent study comparing ELISAs and the SRA have suggested that an ELISA optical density of 1.0 or greater is more likely to have a positive SRA result.52

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Management 

When HIT is suspected, all exposure to heparins should cease,33 including heparin catheter locks,53 heparin flushes, heparin priming of extracorporeal circuits, and exposure to heparin-coated catheters, tubing, and dialyzers, while awaiting laboratory testing.

However, despite discontinuation of heparin therapy, a risk of thrombosis of 5% to 10% per day during the first 48 hours persists, with a cumulative risk of 50% during the first month.54, 55 Thus, patients suspected of having HIT should undergo systemic anticoagulation while awaiting laboratory confirmation unless there is a strong clinical contraindication33, 55 because studies have shown a significant risk of thrombosis while awaiting laboratory confirmation of HIT.56 Risk of thrombosis is increased with increasing thrombocytopenia, delayed recovery of thrombocytopenia after heparin therapy discontinuation (median, 4 days), and in cases of acquired anticoagulant deficiency.

Systemic Anticoagulation 

Because of the potential risk of thrombosis, systemic anticoagulants are the preferred choice for managing patients with HIT.1, 33 Low-molecular-weight heparins should not be used because of the risk of cross-reactivity.35 Therefore, the choice of alternative systemic anticoagulants currently is limited to the heparinoids or direct thrombin inhibitors. Licensing of these drugs varies from country to country, and even within countries, 1 agent may be licensed for treating HIT but not as an anticoagulant for hemodialysis.

Heparinoids 

A number of proteoglycans have been developed as anticoagulants. Danaparoid is a mixture of glycosaminoglycans derived from porcine intestinal mucosa and comprises 84% heparan sulfate, 12% dermatan sulfate, and 4% chondroitin sulfate. It exerts its anticoagulant effect predominantly by activating antithrombin, primarily against activated factor X, but also against thrombin. Because danaparoid has a minimal effect on platelets, it has been used successfully in the management of patients with HIT, although there is potential in vitro cross-reactivity caused by the dermatan sulfate component, which has weak affinity for both platelets and PF4.55

In Europe, danaparoid has been the anticoagulant of choice for treating patients with HIT.55 Before starting danaparoid therapy, laboratory testing should be undertaken to exclude cross-reactivity. The main disadvantage of danaparoid is the prolonged half-life of around 30 hours in patients with renal failure, which affects dosing schedules when danaparoid is used as an anticoagulant for hemodialysis, and also when patients with renal failure require formal systemic anticoagulation when treating thrombosis.

When treating patients with thrombus, formal systemic anticoagulation is required. After a loading dose (as described), an infusion is required, starting at 400 IU/h for 4 hours, reduced to 300 IU/h for an additional 4 hours, then decreased to 100 IU/h, which is adjusted to maintain systemic anti–factor Xa (anti-Xa) activity of 0.5 to 0.8 IU/mL.57, 58 Danaparoid at therapeutic doses uniquely interferes with the pathogenesis of HIT by reducing PF4 binding to platelets, disrupting PF4-containing immune complexes, and preventing activation of platelets by HIT antibodies, whereas the direct thrombin inhibitors have none of these actions, and fondaparinux, only at supratherapeutic concentrations.59

Fondaparinux is a synthetic pentasaccharide that binds to the key heparin-binding site on antithrombin. The half-life is markedly increased in patients with end-stage renal failure, such that 2.5 mg administered on alternate days provides adequate systemic anticoagulation for intermittent hemodialysis,60 although other studies have suggested that greater doses may be required when using high-flux hemodialysis61 or hemodiafiltration. Anti-Xa activity is required for monitoring, aiming for anti-Xa activity of 0.4 to 0.6 IU/mL. As with danaparoid, in vitro cross-reactivity may occur on laboratory testing, and clinical thrombotic sequelae may occur, particularly when low doses are used, as in dialysis-dependent patients.62 Fondaparinux currently is not licensed in the United States for either treatment of HIT or hemodialysis.

Direct Thrombin Inhibitors 

Unlike danaparoid, none of the direct thrombin inhibitors reduce PF4 binding to platelets, disrupt PF4-containing immune complexes, or prevent activation of platelets by HIT antibodies59 and therefore may not be as effective in preventing additional thrombosis in cases of HIT and thrombosis.

Recombinant hirudin (lepirudin) was the first direct thrombin inhibitor to be licensed for treating patients with HIT. Hirudin is an irreversible thrombin inhibitor binding to 2 sites. Because it is renally excreted, the biological half-life is increased to more than 35 hours in patients with renal failure and has been reported to be even longer in anephric patients. Lepirudin is a 7-kDa molecule and is cleared by high-flux dialyzers and during hemodiafiltration.63, 64 Because of the prolonged half-life, intermittent dosing before dialysis can maintain systemic anticoagulation. Depending on baseline clotting testing, dialyzer flux, and whether convection is added to diffusion, predialysis bolus doses of 0.1 to 0.2 mg/kg (to a maximum of 40 mg) are adjusted to maintain an activated partial thromboplastin time ratio (aPTTr) of 1.5 to 2.5.33 However, the relationship between plasma hirudin concentration is not linear with aPTT values greater than 70 seconds (Fig 5). Therefore, to prevent the risk of overanticoagulation and bleeding, other monitoring tests based on a viper venom assay of thrombin activation, the ecarin clotting time and, more recently, the ecarin chromogenic assay have been developed. The latter has the advantage of being independent of prothrombin and fibrinogen levels. An enzyme immunoassay for hirudin plasma concentration has also been developed.65

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  • Figure 5. 

    Schematic representation of nonlinear relationship between activated partial thromboplastin time (aPTT) and plasma hirudin concentration compared with ecarin clotting time.

IgG1 antibodies to hirudin have been reported to develop in 44% to 74% of patients after 5 days, with a peak around 8 to 9 days. Although in 2% to 3% of cases these antibodies decrease the biological activity of hirudin, the main problem is reduced clearance and therefore enhanced biological activity.66, 67

Thus, aPPTr or plasma hirudin concentration should be checked before dialysis sessions during the first 2 weeks of therapy to detect hirudin accumulation caused by antibody formation, with an appropriate decrease in bolus dosage because there is no specific antedote to hemorrhage in cases of hirudin overdosage. Plasma hirudin concentrations can be decreased by using high-flux dialyzers in combination with hemodiafiltration, although plasma exchange is required in cases of antibody formation.67 However, if hirudin therapy is stopped in patients with HIT caused by overcoagulation, they then may be at risk of a possible hypercoagulable state and additional thrombosis.

Occasionally, anaphylaxis has been reported with lepirudin, often related to the dose and rapidity of injection, particularly in patients with high antibody levels. In such cases, hirudin therapy should be withdrawn and patients should not be rechallenged.65 In addition, anaphylaxis can occur on reexposure. Thus, if patients have been previously treated with hirudin, the American Food and Drug Administration recommends that a second course be given only if there is no alternative therapy available.

Bivalirudin, which is used in cardiology practice, is a synthetic reversible direct thrombin inhibitor with a much shorter half-life compared with hirudin because only 20% is renally excreted, and is a potential alternative for patients with HIT, although it has not been licensed for hemodialysis.68 For dialysis patients, systemic anticoagulation can be achieved with a bolus dose of 1 mg/kg, followed by an infusion starting at 0.25 mg/kg/h and then adjusting the infusion to achieve an aPPTr of 1.5 to 2.5 or an ecarin clotting time of 80 to 120 seconds (Fig 6). However, because bivalirudin shares 12 amino acids with lepirudin, there is potential cross-reactivity (up to 40%) with lepirudin antibodies and a 70% risk of anaphylaxis in patients with a history of reactions to lepirudin. Therefore, it should be avoided in patients with a history of allergy to hirudin.69

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  • Figure 6. 

    Schematic representation of relationship between plasma concentration of 2 direct reversible thrombin inhibitors, argatroban and bivalirudin, and ecarin clotting time.

Argatroban is a synthetic arginine derivative that is predominantly hepatically metabolized and has reversible binding to the active thrombin binding site. The half-life is increased in dialysis patients, but even so, is much shorter than that of lepirudin, and as such, the risk of overanticoagulation and bleeding is much less than that for hirudin. Thus, argatroban has become the treatment of choice for HIT in North America and recently has been licensed in some European countries.

The primary metabolite (M1) usually occurs in concentrations of only 0% to 20% of the parent argatroban plasma concentration and exerts a weaker anticoagulation effect. Because of protein binding, argatroban is not significantly cleared during dialysis. Initial reports suggested that hemodialysis patients be given a bolus dose of 250 μg/kg or 20 mg, followed by an infusion of 2 μg/kg/min or 10 to 15 mg/h, adjusted to achieve a target aPPTr of 2.0 to 2.5.70, 71 Much lower doses certainly are required in patients with liver disease.72 However, in clinical practice, lower doses often are used in dialysis patients with HIT, such as a bolus of 5 mg followed by 0.15 mg/kg/h.73

Argatroban recently has become the treatment of choice for HIT in the United States, and with widespread introduction, it has become apparent that overanticoagulation is a major risk. The relationship between plasma argatroban concentrations and ecarin clotting time is relatively steep (Fig 6), so that what appears to be a relatively small increase in aPPTr represents a much larger increase in argatroban concentration. In addition, monitoring by means of aPTTr may be misleading in patients with abnormal baseline aPPT values, such as those with liver disease, sepsis, lupus anticoagulant/antiphospholipid syndrome, and abnormal natural anticoagulant levels. Therefore, ecarin clotting time may be a more accurate assessment of argatroban anticoagulation (Fig 6). Argatroban also causes prolongation of prothrombin time, particularly in patients with underlying liver disease, and this may make interpretation of the international normalized ratio difficult when patients start oral coumarin therapy.

Catheter Locks 

Because heparins cannot be used as catheter locks, alternative anticoagulants are required. In clinical practice, recombinant tissue plasminogen activator (1 mg/mL),74 hypertonic trisodium citrate (≥4% concentrations, up to citralock 46.7% trisodium citrate [CitraLock, Dirinco AG, Bern, Switzerland]), and recombinant hirudin (lepirudin, 1 to 5 mg/mL)75 have been used successfully. However, it is very important that these catheter locks are fully aspirated before use because a bolus of a strong citrate solution can reduce intracardiac calcium levels and precipitate cardiac arrest, and similarly higher doses of hirudin risk systemic anticoagulation.

Regional Anticoagulation 

The preferred management of patients with HIT or suspected HIT is systemic anticoagulation avoiding heparins.33 However, if systemic anticoagulation is clinically contraindicated, regional anticoagulation typically will be required for effective hemodialysis. Because HIT is a hypercoagulable state, simple saline flushes and predilutional hemodiafiltration have not been successful in maintaining circuit patency.76 For patients without a systemic reaction and a decrease in peripheral platelet count less than 30%, historically aspirin, an inhibitor of platelet activation, has been reported to allow successful dialysis in 4 cases. Doses varied from 40 mg77 to 80.1 mg35 to 1 g daily.78 However, most current clinical guidelines now recommend formal anticoagulation.33, 55

In Europe, prostacyclin and other vasodilatory prostanoids have been used as extracorporeal anticoagulants in patients with HIT.79 Prostacyclin (prostaglandin I2 [PGI2]) and its analogue epoprostenol are potent antiplatelet agents blocking cyclic adenosine monophosphate (cAMP) and have been shown to reduce platelet microthrombi during dialysis therapies.80 Although both agents are potent arterial vasodilators, most patients do not develop symptomatic hypotension because approximately 40% of the dose is removed during passage through the dialyzer. Hypotension can be avoided by ensuring that patients are not hypovolemic and by starting the PGI2 infusion at 0.5 ng/kg/min before the start of dialysis, then increasing the dose over a few minutes up to 5 ng/kg/min (range, 2.5 to 10 ng/kg/min; Table 3).81 Because the half-life is in minutes, a hypotensive episode can be reversed readily by stopping the infusion. Other prostanoids, such as PGE1 (alprostadil), PGE2, and PGD, also can be used as extracorporeal anticoagulants. Because they are not as potent as PGI2 and undergo pulmonary metabolism, higher doses are required, such as alprostadil, 5 to 20 ng/kg/min.

Table 3. Regional and Systemic Anticoagulation Options for Patients With Isolated Heparin-Induced Thrombocytopenia Antibodies When Peripheral Platelet Count Has Returned to Normal
DrugDoseMonitoringComments
WarfarinStart loading dose at 5 mg/d, adjust according to INRINR, 2.0-2.5Risk of thrombosis, skin necrosis if started before platelet count recovered; load over several d with systemic anticoagulant cover
DanaparoidPredialysis bolus: <60 kg, 1,500 IU; 60-80 kg, 2,000 IU; >80 kg, 2,500 IU; adjust according to predialysis anti-Xaanti-Xa activity, 0.4-0.6 IU/mLProlonged t½, need to prevent accumulation; check anti-Xa predialysis
HirudinPredialysis bolus, 0.8-1.5 μg/kgaPTTr, 1.5-2.0; ecarin clotting time, 80-120 s; plasma hirudin, 0.8-1.2 μg/LMonitor predialysis clotting times to detect development of hirudin antibody
Nafamostat maleateBolus, 10-20 mg; maintenance infusion, 0.2-0.8 mg/kg/haPTTr, 1.5-2.5Used in Japan; occasional allergic reactions
ProstacyclinConstant infusion: 2.5-5 ng/kg/minNo reliable laboratory monitoringPotent vasodilator; may cause hypotension
CitrateAdjust dose according to blood flow rate, aiming for citrate, 3-5 mmol/L, entering dialyzer (ionized calcium < 0.4 mmol/L)Monitor systemic and total ionized calciumMay require systemic calcium infusion; possible alkalosis

Note: Anticoagulation has to be assessed on the basis of risk of thrombosis compared with hemorrhage, particularly with the systemic anticoagulants listed in Table 4. Licensing of these drugs varies from country to country; the reader is advised to consult appropriate authorities.

Abbreviations: anti-Xa, anti–factor Xa; aPTTr, activated partial thromboplastin time ratio; HIT, heparin-induced thrombocytopenia; INR, international normalized ratio; t½, half-life.

Citrate, by chelating calcium in the extracorporeal circuit, has been used successfully in patients requiring regional anticoagulation only for dialysis because it inhibits not only activation of the clotting cascades, but also platelet activation. The citrate infusion has to be titrated to the blood flow to achieve a predialyzer citrate concentration of 3 to 5 mmol/L, resulting in an ionized calcium level of 0.2 to 0.4 mmol/l (Table 3).82 Citrate anticoagulation typically requires specialist dialysates with reduced calcium and bicarbonate concentrations.83 Because citrate anticoagulation is reversed by calcium infusion, if calcium is infused into the venous return from the dialysis circuit, access clotting may occur because HIT is a procoagulant state.

Nafamostat mesilate, a polyvalent synthetic protease, is widely used in Japan.18 It has a short systemic half-life of around 4 minutes, and approximately 40% is removed by the dialyzer because of its relatively small size. Depending on the size of the patient and initial clotting results, a typical regimen would be a 10- to 20-mg bolus followed by a continuous infusion of 0.2 to 0.8 mg/kg/h, adjusted to maintain an aPTTr of 1.5 to 2.5 (Table 3).84 Greater doses may be required with polyacrylonitrile membranes because of drug adsorption to the dialyzer.76

Regional heparin anticoagulation with protamine reversal cannot be used because unbound heparin inevitably will return to the patient.9

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Longer Term Management of HIT 

HIT typically occurs in hemodialysis patients admitted to the hospital with intercurrent infections and/or other illnesses and patients with acute kidney injury. When patients recover and are discharged to home to attend outpatient dialysis, although intermittent predialysis boluses of lepirudin, danaparoid, and fondaprinux can be continued in the longer term in hemodialysis patients with HIT (Table 3), these treatments are expensive, although other options, such as argatroban and bivalirudin, require continuous infusions (Table 4). Thus, for longer term management, many patients are treated with oral coumarins or direct thrombin inhibitors.

Table 4. Anticoagulation Options for Hemodialysis-Dependent Patients With HIT and Clinical Sequelae
DrugDoseMonitoringComments
Danaparoid⁎ (heparinoid)Bolus, 2,500 IU (decreased to 1,500 IU if < 60 kg), then 400 IU/h for 4 h and 300 IU/h for another 4 h; maintenance, 100 IU/h according to monitoringanti-Xa activity, 0.5-0.8Prolonged t½ in dialysis patients; no specific antidote; consider factor VIIa for severe bleeding and laboratory testing for HIT cross-reactivity
Fondiparinux⁎ (heparinoid)Loading dose, 2.5-5 mg; maintenance, 0.2-0.5 mg/danti-Xa activity, 0.5-0.8Very prolonged t½ in dialysis patients; no specific antidote; consider factor VIIa for severe bleeding; HIT cross-reactivity reported
Lepirudin (direct thrombin inhibitor)Bolus, 0.8-1.5 ug/kg, followed by predialysis maintenance administration (or alternate days) adjusted according to monitoringaPTTr, 1.5-2.0; ecarin clotting time, 80-120 s; plasma hirudin, 0.8-1.2 μg/LProlonged t½ in dialysis patients; no specific antidote; consider factor VIIa for severe bleeding and hemodiafiltration or plasma exchange in cases of antibody
Bivalirudin⁎ (reversible direct thrombin inhibitor)Bolus, 0.5-1.0 mg/kg; maintenance infusion, start 0.1 mg/kg/h, then adjust according to aPTTraPTTr, 1.5-2.5 or ACT 2 × baseline; ecarin clotting time, 80-120 s20% Renal excretion; very limited clinical experience in dialysis patients; avoid in cases of sensitivity reactions to hirudin
Argatroban⁎ (reversible direct thrombin inhibitor)Bolus, 250 μg/kg; maintenance infusion, 0.1-0.2 μg/kg/minaPTTr, 1.5-2.5t½ increased in dialysis patients; increases INR; risk of bleeding (consider factor VII concentrates)

Note: The mainstay of management is to withdraw all heparins, including catheter locks and flushes. Patients with clinical sequelae (HIT and thrombosis) must undergo systemic anticoagulation. The licensing of drugs varies from country to country; the reader is advised to check with relevant authorities.

Abbreviations: ACT, activated clotting time; anti-Xa, anti–factor Xa; aPTTr, activated partial thromboplastin time ratio; HIT, heparin-induced thrombocytopenia; INR, international normalized ratio; t½, half-life.

⁎Danaparoid and fondiparinux are not licensed in the United States; argatroban, bivalirudin, and fondaparinux are not licensed in all European Union countries.

When using danaparoid for dialysis alone, monitoring and adjusting the loading dose is based not only on anti-Xa activity during the dialysis session, but also on anti-Xa activity before the start of the subsequent dialysis session. In adult practice, an initial loading dose of 3,750 U is recommended (decreased to 2,500 U in patients weighing < 55 kg) provided there is no additional hemorrhagic risk and then 2,500 U before the subsequent dialysis (2,000 U if < 55 kg). Thereafter, the dose is adjusted on the basis of the predialysis anti-Xa activity, aiming for a value less than 0.2 IU/mL, and/or the presence of fibrin threads in the dialysis chamber, aiming for intradialytic anti-Xa activity of 0.4 to 0.6 IU/mL (Table 3).76, 85

In patients with systemic thrombosis, warfarin therapy should be started only when the peripheral platelet count has recovered to greater than 150 × 109/L33 because premature warfarin therapy may lead to skin necrosis,86 particularly in cases of protein C deficiency. To prevent rebound hypercoagulability, warfarin therapy should be started at 5 mg/d rather than a larger loading dose, and under the cover of a systemic anticoagulant which should continue until a therapeutic international normalized ratio has been achieved, preferably with a 5-day overlap of systemic anticoagulation.33 This is particularly important in patients treated with argatroban, which can increase the international normalized ratio, and it therefore is important to slowly implement warfarin therapy patients while on argatroban therapy.

Oral direct thrombin inhibitors, such as ximelagatran, dabigatran, and rivoroxaban, are being introduced into clinical practice and could become an alternative longer term oral anticoagulant option.

For patients who are unable to tolerate warfarin or other coumarins, anticoagulation with danaparoid or hirudin is required because these agents can be administered as boluses with hemodialysis. When the period of increased prothrombotic risk has passed, lower doses can be used to reduce the risk of overanticoagulation and hemorrhage (Table 3).

Can Hemodialysis Patients With HIT Be Successfully Rechallenged With Heparins? 

A central question in long-term management is when it is safe to rechallenge patients with heparins. Typically, HIT antibodies are transitory, with a median time to disappearance of 50 to 80 days,21, 55, 73 and most guidelines recommend a minimum of 6 months of warfarin therapy for patients who developed thrombotic complications with HIT.33 However, in some patients, antibodies may persist for several years,21, 87 and as such, rechallenge potentially could be life threatening. Thus, there are no official guidelines for hemodialysis patients. In our own clinical practice, hemodialysis patients with HIT are retested every 3 months by using an ELISA, and if results are negative, they are retested 2 weeks later. If the second test result is negative, patients are restarted on low-molecular-weight heparin for dialysis anticoagulation,88 and peripheral platelet count is monitored during the next 10 dialysis sessions. Anecdotally, other centers have also successfully rechallenged patients only after results of both the HIT ELISA and a functional platelet aggregation assay were normal.21 Following this protocol, all patients have been re-treated successfully with low-molecular-weight heparin without complication. One patient subsequently developed heparin-PF4 complex antibodies on ELISA screening, but without complications, and after further treatment with danaparoid is now reestablished on heparin therapy.

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Summary 

Heparin is the most common drug causing thrombocytopenia. There is an iceberg effect, with many more asymptomatic hemodialysis patients who develop antibodies to the heparin-PF4 complex compared with those who develop thrombocytopenia and then those who experience thrombotic complications, acute systemic reactions, and multiple thromboses. The diagnosis of HIT depends on clinical suspicion in combination with confirmatory laboratory tests; however, because none of the currently available tests have 100% sensitivity and/or specificity, the diagnosis is based on the clinical course and response to heparin therapy withdrawal.

When HIT is suspected, heparin withdrawal is the key to management while awaiting laboratory test results, in combination with an alternative systemic anticoagulant. Although danaparoid has the greatest effect in terms of reducing platelet activation by antibodies to the heparin-PF4 complex, it has been superseded in North America by the direct thrombin inhibitors, in particular, argatroban.

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Acknowledgements 

Support: None.

Financial Disclosure: None.

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 Originally published online as doi:10.1053/j.ajkd.2009.03.012 on June 1, 2009.

PII: S0272-6386(09)00608-8

doi:10.1053/j.ajkd.2009.03.012

American Journal of Kidney Diseases
Volume 54, Issue 2 , Pages 361-374, August 2009

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