Lineage 2 Hit and Hit Again

• Journal List
• Postgrad Med J
• v.83(983); 2007 Sep
• PMC2600013

Postgrad Med J. 2007 Sep; 83(983): 575–582.

Heparin induced thrombocytopenia: diagnosis and management update

Received 2007 February 27; Accepted 2007 April 24.

Abstract

Heparin‐induced thrombocytopenia (HIT) is a potentially devastating allowed mediated adverse drug reaction acquired by the emergence of antibodies that actuate platelets in the presence of heparin. Despite thrombocytopenia, haemorrhage is rare; rather, Hitting is strongly associated with thromboembolic complications involving both the arterial and venous systems. A number of laboratory tests are available to ostend the diagnosis; all the same, when HIT is clinically suspected, treatment should not be withheld pending the result. Fortunately, therapeutic strategies have been refined, and new and effective therapeutic agents are available. Handling options are focused on inhibiting thrombin formation or direct thrombin inhibition. Warfarin should non be used until the platelet count has recovered.

Heparin is widely used for thromboprophylaxis or treatment in many clinical situations, including cardiovascular and orthopaedic surgery and invasive procedures, acute coronary syndromes, venous thromboembolism, atrial fibrillation, peripheral occlusive illness, dialysis, and during extracorporeal circulation.^ane One third of hospitalised patients in the Us, or about 12 meg a year, receive heparin.ⁱⁱ Heparin‐induced thrombocytopenia (Hit) is the most of import and nigh frequent drug‐induced type of thrombocytopenia. Information technology is associated with significant morbidity and mortality if unrecognised. Unfortunately, because thrombocytopenia is mutual in hospitalised patients and can exist caused by a variety of factors,ⁱⁱⁱ Striking often remains unrecognised and undiagnosed.

Hit may develop in 2 singled-out forms: type I and type 2. HIT blazon I (likewise known as heparin‐associated thrombocytopenia) is a not‐immunologic response to heparin treatment, mediated by a direct interaction between heparin and circulating platelets causing platelet clumping or sequestration. HIT type I affects upward to 10% of patients, ordinarily occurs within the first 48–72 h after initiation of heparin treatment, and is characterised by a balmy and transient thrombocytopenia (rarely <100 000/mm³), often returning to normal within four days once the heparin is withdrawn.^four No laboratory tests are required to diagnose HIT type I, and it is not associated with an increased risk of thrombosis, whereas HIT type II is immune‐mediated and associated with a risk of thrombosis. It has recently been proposed that the term "Striking type I" exist changed to "non‐immune heparin associated thrombocytopenia" and that the term "HIT type Two" be changed to "HIT" to avert confusion between the 2 syndromes.^v

In this review, nosotros briefly analyse the main characteristics of the clinically relevant, immune‐mediated, Striking type II, focusing particularly on the epidemiology, pathophysiology, clinical manifestations and treatment of this syndrome. For simplicity, in this review the term Hit refers only to HIT blazon II.

Pathophysiology

Low molecular weight heparins (LMWH), molecular weight 2000–x 000 Daltons (Da), are produced by chemical or enzymatic processes from unfractionated heparins (UFH).⁶ UFH are heterogenous mixture of negatively charged, sulfated glycosaminoglycan (3000–30 000 Da) derived from creature sources.⁶ Hit is caused by the germination of antibodies that actuate platelets following heparin administration.⁷ The principal antigen is a complex of heparin and platelet factor 4 (PF4), a small positively charged molecule of uncertain biological function, normally found in α‐granules of platelets.^viii Heparin'due south high affinity for PF4 depends upon molecular weight, concatenation length and its degree of sulfation, which explains the differences in incidence of Hit observed with different heparins.⁸

When heparin binds with PF4, information technology undergoes a conformational modify and becomes immunogenic (fig 1​ ), leading to the generation of heparin–PF4 antibodies (HIT antibodies), most frequently IgG.⁹ The heparin–PF4–IgG multimolecular immune circuitous then activates platelets via their FcγIIa receptors, causing the release of prothrombotic platelet‐derived microparticles, platelet consumption, and thrombocytopenia.⁹ These microparticles in turn promote excessive thrombin generation, frequently resulting in thrombosis. The antigen–antibody complexes too collaborate with monocytes, leading to tissue factor production, and antibiotic‐mediated endothelial injury may occur. Both of these latter processes may contribute further to the activation of the coagulation cascade and thrombin generation.

Figure 1 Pathophysiology of HIT. (1) Heparin binds with PF4 and act as immunogens. (2) IgG antibody thus produced forms PF4–heparin–IgG multimolecular complex. (3) The complex and so binds via Fc receptor to platelets and activates them (4a) activated platelet releases additional PF4 and (4b) prothrombotic microparticles. (5) Immune complex interacts with endothelial cells and promotes immune mediated endothelial impairment.

Polymorphism in the platelet FcγIIa receptors plays an important function in determining platelet reactivity and different FcγIIa phenotypes may be responsible for the risk variability to develop Hit¹⁰; however, no correlation betwixt platelet glycoprotein and clotting factor polymorphisms and the gamble of developing Hit has been identified.^eleven

Thrombocytopenia in Hit is largely due to the clearance of activated platelets and antibody‐coated platelets by the reticulo‐endothelial organisation.¹

Incidence

Patients of any age, receiving whatsoever blazon of heparin at any dose past whatever route of administration, are at risk of developing HIT antibodies, but they will all not necessarily develop the clinical syndrome of HIT. It is important to distinguish the frequency of antibiotic detection, antibody germination with thrombocytopenia (HIT), and antibiotic formation with thrombosis.

Upwards to viii% of patients receiving heparin are at risk to develop Hit antibodies,¹² only but one–five% on heparin will progress to develop Hitting with thrombocytopenia^xiii and later on 1 third of them may suffer from arterial and/or venous thrombosis.¹⁴ In general, incidence of HIT is greater with bovine versus porcine heparin (all heparins used in the UK are of porcine origin), with unfractionated heparin versus LMWH (although it must exist highlighted that antibodies developing in patients receiving UFH oftentimes crossreact with LMWH), and in post‐surgical (cardiac > orthopaedic > vascular > general) versus medical (0.8%) or obstetric patients.¹⁵ In orthopaedic patients given subcutaneous rubber heparin, the incidence is approximately v% with UFH and 0.5% with LMWH.^sixteen Hospital‐wide surveillance studies of 32–36 months suggest that Striking occurred in i.2% of all patients who received heparin for >four days.¹⁷

The take chances to develop HIT depends upon various factors (every bit discussed to a higher place) and absence of thrombocytopenia after repeated and prolonged exposure to heparin does not necessarily eliminate the gamble merely indicates that such patients are at depression adventure of developing Striking, although there are limited data to support the argument.

Clinical features

The thrombocytopenia of HIT is typically of moderate severity, with median platelet counts ranging between fifty–eighty×10⁹/fifty.¹⁸ It may be absolute (that is, <150×ten⁹/) or relative (that is, a drop of 50% or more) compared with the pre‐heparin value, although the nadir may remain >150×x⁹/fifty. Astringent thrombocytopenia (platelets <15×10⁹/50) is unusual. This autumn in platelet count typically starts 5–14 days after initiation of heparin,¹⁵ but onset may be rapid or delayed. If a patient has circulating heparin–PF4 antibodies from a recent heparin exposure, the platelet count may drop within minutes or hours, resulting in rapid‐onset Striking.¹⁹ Conversely, in delayed‐onset HIT,²⁰ the thrombocytopenia is delayed for several days, possibly up to 3 weeks, and only becomes evident after heparin treatment has already been stopped.

The platelet count starts to ascension inside 2–3 days and usually returns to normal within 4–10 days after abeyance of heparin treatment, and information technology takes another two–3 months for antibodies to disappear.^thirteen In patients with persistent or worsening thrombocytopenia despite absolute discontinuation of heparin, other possible causes of thrombocytopenia must exist considered and investigated; a decision to recommence heparin should be fabricated subsequently conscientious risk–benefit analysis in individual patients.

Complications

Despite thrombocytopenia, bleeding is rather rare.²¹ HIT is strongly associated with thromboembolic complications which tin exist venous, arterial, or both, and include deep venous thrombosis, pulmonary embolism, myocardial infarction, thrombotic stroke, and occlusion of limb artery requiring amputation.¹⁸ Still, the type and site of thrombosis depends on the patient's clinical profile. Deep vein thrombosis and pulmonary embolism occur more frequently in postoperative patients.¹² Similarly, the presence of a central venous catheter is associated with increased upper‐extremity venous thrombosis.¹ Thrombosis of the cerebral venous sinuses and disseminated intravascular coagulation has also been reported.²² In contrast, arterial thrombosis occurs more frequently than venous thrombosis in HIT patients receiving heparin for cardiovascular diseases.²³

Other complications of HIT include necrotising skin lesions at the injection site in x–20% of patients, and acute systemic reactions, characterised by fever, chills, hypertension, tachycardia, chest hurting and dyspnoea, in upward to 25% of patients with circulating HIT antibodies.²¹ Thrombosis in HIT is associated with a mortality of approximately 20–30%, with an equal percentage of patients becoming permanently disabled past amputation, stroke or other causes.⁴

Gamble factors

Chance factors suggestive of agin outcomes in Striking include severity of the thrombocytopenia,²⁴ and lower platelet counts which are associated with poor event, malignancy,²⁵ and gender. Females are more than likely to endure thrombotic stroke as an outcome of Hitting.²⁶

Diagnosis

The diagnosis of HIT remains a clinical 1, supported by confirmatory laboratory testing. The criteria for diagnosis of Hitting include:

• normal platelet count before the get-go of heparin

• thrombocytopenia defined as a driblet in platelet count past thirty% to <100×10⁹/50 or a driblet of >50% from the patient'southward baseline platelet count

• onset of thrombocytopenia typically 5–10 days after initiation of heparin handling, which can occur earlier with previous heparin exposure (within 100 days)

• astute thrombotic consequence

• the exclusion of other causes of thrombocytopenia

• the resolution of thrombocytopenia afterward abeyance of heparin

• HIT antibody seroconversion

The "4 T's" of Hit (table 1​ ), as suggested by Warkentin and et al,²⁷ has been recommended by British haemostasis and thrombosis task force for standards in haematology to be used to assess patients with clinical suspicion of HIT.

Tabular array 1 Estimating the pre‐examination probability of heparin induced thrombocytopenia: the "4 T's"

Category	2 points	1 point	0 point
Thrombocytopenia	>l% fall, or nadir of 20–100×109/l	xxx–l% fall, or nadir of 10–19×109/50	30% fall or nadir <10×10nine/l
Timing of platelet count fall	Days five to 10, or ⩽1 day if heparin exposure inside past xxx days	>24-hour interval 10 or unclear (but fits with Hitting), or ⩽1 24-hour interval if heparin exposure within past 30–100 days	⩽ane day (no contempo heparin)
Thrombosis or other sequelae	Proven thrombosis, pare necrosis, or, after heparin bolus, acute systemic reaction	Progressive, recurrent, or silent thrombosis; erythematous pare lesions	None
Other cause for thrombocytopenia	None evident	Possible	Definite

*Points assigned in each of four categories are totalled, and the pre‐test probability of Hitting by total points is as follows: half dozen to 8 = high, 4 to 5 = intermediate; 0 to 3 = depression. Adjusted with permission from Warkentin et al. Hematology/the education program of the American Club of Hematology. Copyright 2003, American Society of Hematology.

HIT is a potentially life‐threatening condition; it should be considered with priority amongst the possible causes of thrombocytopenia with or without thrombosis in a patient receiving heparin, specially in a patient recently discharged from hospital who presents with thromboembolism.²⁸

Laboratory testing

Information technology is recommended that heparin–PF4 antibody testing, in patients with clinical suspicion of HIT, should be considered. However, results of laboratory tests may not exist available for hours to days after being requested. Therefore, it is very important that initiation of proper treatment must never exist delayed awaiting laboratory confirmation of Hitting.

HIT antibodies can be demonstrated in vitro by functional tests and immunoassays.²¹ Functional tests measure platelet activity in the presence of the patient'due south serum and heparin. These include heparin‐induced platelet aggregation (HIPA), the serotonin release assay (SRA) and menstruum cytometric assays that detect platelet microparticle release.

Although the HIPA test (sensitivity 35–85%) is easier to perform and thus more commonly used, the SRA is 95% sensitive and specific, particularly when done platelets are used, only is more complex, technically demanding and might non readily be available in near laboratories.²¹ The immunoassays utilise immuno‐enzymatic tests (ELISA) to detect the Striking antibody that binds to the PF4–heparin complex. Immunoassays have loftier sensitivity of 80–100% but low specificity.²¹ They are technically easier to perform than the functional assays but detect antibodies that do not elicit Striking (faux positives) and has decreased specificity in certain populations such every bit cardiac surgery patients.

No single analysis has 100% sensitivity and specificity, although testing becomes well-nigh constructive when functional and immune assays are done in combination and multiple samples are taken. Even so, comparative and prospective studies have demonstrated that functional tests are more than specific than enzyme immunoassays, are better at detecting the clinically significant Hitting antibodies, and are more helpful in the diagnosis of HIT.

Monitoring

Because the driblet in platelet count is a master way of recognising Striking, routine monitoring of the platelet count is recommended for nigh patients receiving heparin treatment. The American Higher of Chest Physicians, in collaboration with the College of American Pathologists, have published a guideline^fifteen in relation to monitoring of platelet count in patients at high hazard for Hitting. These recommendations are summarised in tabular array 2​ . British guidelines²⁹ recommend a baseline platelet count before initiating heparin treatment in all patients to allow estimation of relative changes. In higher gamble patients, such equally individuals receiving unfractionated heparin at therapeutic doses, the platelet count should exist checked at least every other day from 24-hour interval 4 to 14 of treatment (or until heparin is stopped, whichever is sooner). In lower run a risk surgical, medical and obstetric patients, monitoring should be at least on every second to fourth solar day between days iv and 14 while on heparin handling. Obstetric patients receiving prophylactic doses of LMWH do not need routine platelet monitoring.

Tabular array 2 Consensus guideline for platelet count monitoring for heparin induced thrombocytopenia^xv

Population	Example	Monitoring guideline*
Recent heparin exposure	Patients starting UFH or LMWH and who received UFH within the previous 100 days; patients whose heparin exposure history is unknown	Obtain baseline platelet count and repeat platelet count inside 24 h of starting heparin
Astute, systemic reactions subsequently intravenous UFH bolus	Patients with acute inflammatory, cardiorespiratory, neurological, or other unusual symptoms and signs inside 30 min after an intravenous UFH bolus	Obtain platelet count immediately to compare with recent prior platelet counts
Risk of HIT >1%†	Patients receiving UFH at therapeutic doses	Monitor at least every ii days until 24-hour interval 14 of handling or until UFH is stopped, whichever comes outset
	Postoperative patients receiving UFH antithrombotic prophylaxis	Monitor at to the lowest degree every two days between postoperative days 4 and 14† or until UFH is stopped, whichever comes start
Risk of HIT 0.1–one%†	Medical/obstetric patients receiving prophylactic‐dose UFH, or LMWH after first receiving UFH; postoperative patients receiving prophylactic dose LMWH, or intravascular catheter UFH flushes	Monitor every 2 or three days from days iv to fourteen† or until UFH is stopped, whichever comes first, when practical
Hazard of HIT <0.1%†	Medical/obstetric patients receiving only LMWH; medical patients receiving catheter UFH flushes	Equally clinically indicated (no routine monitoring)

Handling

The "four T'southward" scoring system tin can be used as a guide to identify patients who are at high, intermediate or low risk of developing Striking. In our opinion, heparin should immediately exist discontinued both in loftier risk and intermediate risk patients—although an alternative anticoagulant should also be initiated in the former but should only be considered in the latter later on laboratory confirmation. Low run a risk patients only need connected platelet monitoring.

General principles

When Hit is suspected clinically, the following measures should exist taken:

• Immediate cessation of all formulations of heparin is mandatory including heparin flushes, heparin coated catheters, heparinised dialysate and any other sources

• Ship claret samples for laboratory confirmation

• Initiate alternative anticoagulation. The duration of treatment is not well divers; nevertheless, it should be continued for at to the lowest degree 2–3 months to prevent recurrence of thrombosis

• Monitor advisedly for thrombotic upshot

• Monitor platelet count till recovery

• Warfarin should not be used until the platelet count has recovered

• Avert safe platelet transfusion because they may exacerbate the hypercoagulable land, leading to additional thrombosis; nevertheless, if the patient develops bleeding or is undergoing major surgical intervention, therapeutic platelet transfusion can be considered.

Conventional strategies

Discontinuation of heparin alone will neither stop continuing thrombin generation nor avoid subsequent thrombotic events. The run a risk ranges from v–10% per mean solar day in the first few days,³⁰ increasing to 40–l% over the next several days or weeks.³¹ LMWH cannot be used in patients with HIT because of the strong crossreactivity of the HIT antibody with the LMWH–PF4 circuitous.³² Warfarin is no longer recommended in the early phase of Hitting because information technology can paradoxically worsen the thrombosis and crusade venous limb gangrene and skin necrosis.^fifteen The probable mechanism is an imbalance betwixt the natural anticoagulant and procoagulant proteins associated with Hit‐related consumption, which are exacerbated during warfarin induction. If a patient is receiving coumarin treatment when diagnosed with Hit, vitamin K administration is recommended to reverse the coumarin effects.^xv Prostacyclin analogues act equally natural vasodilators and inhibit platelet aggregation, simply there is no protection from thrombosis.

Alternative anticoagulants

Currently, three non‐heparin anticoagulants that exercise not crossreact with HIT antibodies are available for alternative anticoagulation in Hitting. These include danaparoid³³ and lepirudin³⁴ which available for use in the Britain, whereas argatroban is used in Due north America.³⁵ These drugs are immediately active and are direct inhibitors of thrombin, but they too inhibit thrombin generation and are routinely monitored with the activated partial thromboplastin fourth dimension (aPTT) or, at college levels of anticoagulation, the activated clotting time (ACT) for argatroban, ecarin clotting time (ECT) for lepirudin, or anti‐Xa assays for danaparoid.

Equally in all scenarios where antithrombotic drugs are used, the do good is partially offset by haemorrhagic complications. Estimated incidence, as reported in retrospective studies, of major bleeding is higher with lepirudin (13–nineteen%) than argatroban (6–vii%).²¹ When choosing an alternative anticoagulant, consideration should be given to its demonstrated efficacy and safety in the intended use, likely risks and benefits of treatment strategies, availability of the drug and methods for monitoring, and the patient's clinical status, including renal and hepatic role.

Lepirudin

Recombinant hirudin (lepirudin), originally produced from the medicinal leech, is a 65 amino acid peptide with a molecular weight of approximately 7000 Da. Information technology is a direct, irreversible thrombin inhibitor, binding both gratis and jell‐bound thrombin. It has a half‐life of 60–xc min with renal excretion. The incidence of the combined end bespeak of expiry, new thromboembolic complications and limb amputation is lower in HIT patients treated with lepirudin with³⁴ or without³⁶ thrombosis. Currently, the recommended¹⁵ initial dose for patients with thrombosis is 0.iv mg/kg followed past a 0.15 mg/kg/h infusion (table iii​ ), adjusted to aPTT ratios of one.5–ii.5, corresponding to a lepirudin concentration of approximately 0.vi–1.4 mg/l. A lower dose (0.1 mg/kg/h) without a bolus is recommended in Hitting patients without thrombosis.³⁶ The gamble of major haemorrhage is directly related to the aPTT ratio, lepirudin concentrations and serum creatinine concentrations.

Table 3 Therapeutic dosing regimen for danaparoid and lepirudin²⁹

Drug	Weight	Iv bolus	IV infusion	Monitoring
Danaparoid	<60 kg	1500 U	400 U/h for first iv h, 300 U/h for next 4 h, and then 150–200 U/h	Anti‐Xa factor
	60–74 kg	2250 U		Range: 0.5–0.8 U/ml
	75–90 kg	3000 U
	>90 kg	3750 U
Lepirudin	Maximum 100 kg	0.4 mg/kg	Beginning at 0.15 mg/kg/h and titrate for target aPTT	aPTT i.five–ii.5
				Plasma concentration: 0.6–1.4 mg/l

aPTT, activated partial thromboplastin time, Iv, intravenous.

Lepirudin should be used with caution and in a reduced dosage in patients with serum creatinine values >i.vi mg/dl (141.iv μmol/fifty); it is contraindicated in patients on haemodialysis or with acute renal failure.³⁷ Approximately 50% of patients may develop anti‐hirudin antibodies that bind the drug to form lepirudin–antibody complexes, too large for renal excretion, resulting in prolongation of the one-half‐life, increased plasma lepirudin concentrations and the need to reduce dose.³⁸ Anaphylaxis, including anaphylactic decease, occurs in an estimated 0.fifteen% of patients on start exposure and in 0.2% of patients upon re‐exposure.³⁹ Omitting the bolus dose may reduce the severity of anaphylaxis and not‐hirudin anticoagulants should be considered for use in patients with previous lepirudin exposure.³⁹

Danaparoid

Danaparoid is a mixture of heparin, dermatan, and chondroitin sulfates and exerts its anticoagulant effects predominantly by inhibiting factor Xa and to a much lesser degree by inhibiting thrombin. It exhibits in vitro crossreactivity to Striking sera in about ten–50% of cases,^forty but in vivo crossreactivity is rare although well described⁴¹ and has been associated with unfortunate treatment failures.⁴² Danaparoid has a long half‐life, nigh 100% bioavailability, and is cleared renally.

Danaparoid is canonical by the U.s.a. Food and Drug Administration (FDA) for venous thrombosis prophylaxis afterwards orthopaedic surgery but non for the treatment of HIT, even though it has the longest track record of currently bachelor agents. In the Eu²⁹ it is approved for employ in 2 distinct regimens: a depression dose ("prophylactic") and a high dose ("therapeutic") regimens. The recommended dose for thromboprophylaxis in Striking patients without thrombosis is 750 U, administered subcutaneously twice or iii times daily. The recommended treatment of HIT patients with thrombosis is 1500–3750 U bolus (depending on body weight) followed by a 400 U/h infusion for 4 h, and then a 300 U/h infusion for 4 h, then a 150–200 U/h infusion for at least 5 days (table 3​ ), with a target of 0.5–0.8 anti‐factor Xa U/ml in plasma.

Danaparoid in a high dose regimen is equivalent to lepirudin in the handling of Hitting with or without thrombosis; reduction in the incidence of the combined end point of decease, new thromboembolic complications and limb amputation is comparable with lepirudin.⁴³ In United kingdom of great britain and northern ireland, the safety dose is not recommended in the handling of HIT.

Argatroban

Argatroban, a direct inhibitor of thrombin, is an arginine‐based synthetic anticoagulant that reversibly binds with the catalytic site of thrombin. Although the British guideline²⁹ does non recommend argatroban, it is approved past the Usa FDA for prophylaxis or treatment of thrombosis³⁵ and during coronary angioplasty⁴⁴ in patients with Hitting. The recommended initial dose is 2 µg/kg/min adjusted to achieve aPTTs one.v–3 times the baseline value which provides adequate anticoagulation for 90% of patients.²¹

A major advantage of argatroban is that it is cleared by the liver and, therefore, can exist used safely in patients with renal insufficiency. Argatroban also has the shortest half‐life among all alternative anticoagulants and tin be discontinued speedily if invasive procedures are necessary or if bleeding is encountered. There is no evidence of antibody generation to argatroban on prolonged or repeated administration, and no anaphylactic deaths take been reported.

Risk of bleeding with direct thrombin inhibitors

Unlike whatsoever other anticoagulant treatment, bleeding is a major safety concern with direct thrombin inhibitors considering no specific antidotes are available and protamine sulfate only negligibly neutralises danaparoid. Unintentional excessive anticoagulation associated with or without haemorrhage should be managed past stopping or reducing the dose of direct thrombin inhibitors. With direct thrombin inhibitors, anticoagulant effects decrease to baseline, typically inside hours, in accordance with the drug's emptying half‐life and the patient's organ function. Still, the half‐life of argatroban (39–51 min) and lepirudin (1.seven h) are increased in hepatic impairment⁴⁵ and renal impairment,⁴⁶ respectively. Considering danaparoid has a long half‐life (up to 25 h), rapid reversal after drug discontinuation is not an pick. Haemodialysis or haemofiltration tin can sometimes reduce concentrations of lepirudin,⁴⁷ but dialytic clearance of argatroban by high‐flux membranes is clinically insignificant.⁴⁸

Boosted treatment considerations

Fondaparinux, a synthetic pentasaccharide (smaller than LMWH) that is structurally related to the anti‐thrombin bounden site of heparin, is expected to be less likely to induce Hit. Nevertheless, it is not however recommended for the utilise in patients with HIT, although preliminary data advise that assistants of fondaparinux ii.5 mg for at to the lowest degree 5 days to patients with HIT is not associated with continued or recurrent thrombocytopenia and no thrombotic complications occurred.⁴⁹

Melagatran, and its oral prodrug ximelagatran, are small molecules that bind only at the thrombin active sites; they had been under intensive investigation before being withdrawn by the manufacturer (AstraZeneca) due to multiple reports of severe liver injury attributed to the drug. Bonny features included predictable pharmacokinetics and bioavailability, allowing for fixed dosing and predictable anticoagulant response, no need for routine coagulation monitoring, and rapid onset and offset of action.⁶

Bivalirudin is a hirudin analogue that has been constructive in trials of angioplasty in patients with Hitting, just is non approved for treatment of HIT. It is cleared by a combination of renal mechanisms and proteolytic cleavage, which may offer a pharmacological do good for anticoagulation of patients with comorbid hepatic and renal affliction.

Aspirin is beneficial in vitro and may have some clinical benefit. Platelet glycoprotein IIb/IIIa inhibitors reduce thrombin generation indirectly and inhibit platelet aggregation. Prostacyclin analogues act as natural vasodilators and inhibit platelet aggregation. All the same, these agents lack direct anticoagulant effects and practice not inhibit Fc receptor‐mediated activation of platelets past Hit antibody.^fifty Hence, these agents should not be used as frontline treatment in HIT.

Surgical thromboembolectomy or systemic or local thrombolysis, every bit adjunctive handling to alternative parenteral anticoagulation, may be advisable for selected patients with large vessel arterial thromboembolism or severe pulmonary embolism. Plasmapheresis and utilise of intravenous immunoglobulin has been helpful in anecdotal reports, but whether information technology is of boosted benefit to current treatments is unclear. Inferior vena cava filters have led to worsening of thrombotic problems in a number of cases. Their use in HIT has not been studied, and near physicians avoid their use.

Warfarin and Striking

If warfarin treatment is indicated for an underlying medical condition or Hitting‐associated deep vein thrombosis (DVT), it must exist delayed until acceptable alternative parenteral anticoagulation has been provided and platelet counts have recovered substantially^xv (to at to the lowest degree 100×10^nine/l or preferably 150×x⁹/l). Warfarin should exist started at the expected maintenance dose (maximum 5 mg) and not at a loading dose. Parenteral anticoagulation should exist overlapped with warfarin for minimum of five days until a target international normalised ratio (INR) range has been achieved for at least 2 days.¹⁵

Direct thrombin inhibitors as a class prolong the prothrombin fourth dimension and INR,⁵¹ the extent of which depends on the drug and its concentration; this effect is specially pronounced with argatroban,⁴⁶ making the transition to warfarin more hard. If warfarin has already been started when Striking is recognised, reversal of warfarin with vitamin K is recommended¹⁵ for two reasons: to minimise the risk of microvascular thrombosis and consequent skin necrosis, and to foreclose under dosing of direct thrombin inhibitors.

Key points

• Heparin induced thrombocytopenia (HIT) is an allowed‐mediated effect that can take severe life‐ and limb‐threatening complications.

• Despite thrombocytopenia, bleeding is rare; rather, HIT is strongly associated with thromboembolic complications.

• When a diagnosis of Hit is suspected immediate cessation of all forms of heparin, including unfractionated heparin (UFH), low molecular weight heparin (LMWH) and heparin flushes, is imperative.

• Handling of Hit should exist initiated based on clinical suspicion and must never be delayed pending laboratory confirmation of Hitting.

• A direct thrombin inhibitor, such every bit lepirudin, danaparoid or argatroban, is considered the agent of choice for treatment of Hit.

• Warfarin should not be used until the platelet count has recovered.

Anticoagulation in patients with a history of HIT

Following the evolution of hypersensitivity to a drug, it is mostly accepted that further exposure should be avoided if possible. Anticoagulation in patients with a history of Striking depends upon the type of surgery, whether it tin can be delayed or not, whether anticoagulation is desired for therapeutic or safe reasons, and whether patient is HIT antibodies positive or negative. HIT antibodies are transient with a median fourth dimension to disappearance of 50–fourscore days.²⁹ Because the consequences of recurrent HIT may exist devastating, in the vast majority of cases (excluding cardiac and vascular) where a patient with previous Hitting requires a catamenia of anticoagulation or anticoagulant prophylaxis, it is acceptable to apply an anticoagulant alternative to UFH or LMWH.^xv

Cardiovascular surgery

The haemostasis and thrombosis job strength of the British Haematology Society recommends²⁹ that in all patients with a history of HIT, who lack detectable HIT antibodies and crave cardiac or vascular surgery, care must be taken to minimise heparin exposure, using it merely during surgery and administering alternative anticoagulation, when needed, before and later on surgery.

In patients with acute or active Hit or with a history of Hitting and lingering HIT antibodies, cardiovascular surgery should be delayed until HIT is fully resolved and antibodies are undetectable past a sensitive assay. If delay is impossible or the urgency of the situation precludes assessment of Striking antibody condition in a patient with a history of HIT, alternative anticoagulation should preferably be used intraoperatively.^{fifteen ,29}

Limited experience exists with lepirudin, argatroban, bivalirudin, and danaparoid, sometimes together with antiplatelet agents, in this setting. Information technology is emphasised that prophylactic, effective doses of alternative anticoagulants during cardiovascular surgery have not been validated in clinical trials.

Percutaneous coronary intervention

The American College of Chest Physicians advise the employ of an culling anticoagulant in patients with or at risk for Hit who is undergoing percutaneous coronary intervention (PCI). Argatroban is the only alternative anticoagulant approved in the Us for the purpose, and its rubber and efficacy in this setting is validated.⁴⁴ Bivalirudin is FDA approved as an anticoagulant in patients undergoing percutaneous transluminal coronary angioplasty,⁵² but feel with lepirudin in patients with HIT undergoing PCI is express.⁵⁰ The British Club of Haematology does not provide whatsoever guidance in this setting.

Haemodialysis

Only anecdotal reports are available on anticoagulation for dialysis‐dependant patients with HIT. Suggested alternatives include saline solution flushing, citrate, danaparoid, lepirudin and argatroban. Table 4​ shows the regimens for danaparoid and lepirudin for alternating mean solar day haemodialysis in patients who have previously had Striking.²⁹

Table 4 Regimens for danaparoid and lepirudin for alternate day haemodialysis in patients who accept previously had HIT²⁹

Drugs	Iv bolus		Monitoring
Danaparoid	3750 (2500) U* earlier first and 2nd dialyses; 3000 U before tertiary dialysis; and so according to pre‐dialysis anti‐Xa level		Anti‐Xa 0.5–0.8 U/ml
	<0.iii	3000 (2000) U
	0.three–0.35	2500 (1500) U
	0.35–0.4	2000 (1500) U
	>0.iv	0 U
Lepirudin	Lepirudin fourscore–150 μg/kg before dialysis		aPTT 2.0–two.5

Paediatrics

Reports on the treatment of paediatric HIT patients are generally anecdotal.⁵³ A study is ongoing in the USA to evaluate argatroban anticoagulation, including its pharmacokinetics, in paediatric patients in whom heparin use is problematic.

Prevention

The incidence of Hitting can exist reduced by:

• Limiting courses of heparin to <five days, if possible.

• Using LMWH in place of heparin for thromboprophylaxis in high‐risk postoperative patients.

• Porcine UFH is associated with lower incidence of HIT then bovine UFH.

• In general, monitoring the platelet count at least every other day between days iv and 14 of heparin exposure or until heparin is discontinued.

• Taking intendance not to automatically initiate heparin if a patient is re‐admitted for a thrombotic event; the medical tape must be thoroughly reviewed for use of heparin on a previous admission (within the by 100 days). Unfortunately, in some cases, the previous heparin exposure may non be recorded in the medical tape (for example, heparin flushes).

• Orders for employ of heparin flushes and heparinised normal saline must be written and signed past a medico and apply of heparin flushes and heparinised normal saline must exist documented in the patient's medical record.

Patient data and record keeping

The diagnosis of HIT should exist clearly recorded in the patient's notes and marked as a serious allergy. The condition should be clearly explained to the patient and an data leaflet may exist helpful in this respect. The patient should be issued with an antibiotic card.

Multiple choice questions (truthful (T)/imitation (F); answers after the references)

ane. Regarding incidence of Striking:

1. Incidence is highest in cardiac surgery patients

2. Occurs more than ofttimes with porcine than bovine heparin

3. Incidence is not influenced by the dose, blazon and road of heparin administration

4. Severe thrombocytopenia (platelet count <xv×10⁹/50) in HIT is very common.

5. Obstetric patients are at low gamble for Hitting

2. Clinical features of Hitting include:

1. Fall in platelet count typically starting within hours after initiation of heparin

2. Thrombocytopenia is severe and frequently results in bleeding

3. Thrombosis in HIT is associated with a mortality of approximately xx–xxx%

4. Obstetric patients are peculiarly at risk of developing thrombotic complications

5. Females are more probable to suffer thrombotic stroke as an consequence of their Striking

3. Pathology of HIT:

1. The chief antigen is a complex of heparin and platelet cistron four (PF4)

2. The principle antibody generated is an IgA antibody

3. UFH antibody does not crossreact with LMWH antibody

4. All patients who develop HIT antibodies will subsequently develop clinical syndrome of HIT

5. Hit antibodies brainstorm to disappear in four–ten days after cessation of heparin handling

iv. Treatment strategies for HIT:

1. UFH should exist immediately substituted with LMWH

2. Argatroban is the nigh normally used culling anticoagulant in the UK

3. Warfarin is contraindicated in Hitting

4. Danaparoid exerts its anticoagulant effects predominantly by inhibiting factor Xa

5. Anaphylaxis is a recognised complication associated with argatroban

5. Regarding HIT:

1. Routine monitoring of the platelet count is recommended for most patients receiving heparin treatment

2. Thrombocytopenia should exist treated with transfusion of washed platelets

3. Excessive anticoagulation associated with danaparoid can completely be reversed with protamine sulfate

4. In patients with a history of HIT, heparin tin can safely exist used intraoperatively during cardiac surgery

5. Prostacyclin analogues are rubber anticoagulants for haemodialysis in patients with Hitting

Abbreviations

Deed - activated clotting time (Deed)

aPTT - activated fractional thromboplastin fourth dimension

DVT - deep vein thrombosis

ECT - ecarin clotting time

FDA - Food and Drug Administration

HIPA - heparin‐induced platelet aggregation, Hitting, heparin‐induced thrombocytopenia

INR - international normalised ratio

LMWH - low molecular weight heparins

PCI - percutaneous coronary intervention

PF4 - platelet factor 4

SRA - serotonin release analysis

UFH - unfractionated heparins

ANSWERS

1. (A) T (B) F (C) F (D) F (Due east) T

2. (A) T (B) F (C) T (D) F (E) T

3. (A) T (B) F (C) F (D) F (Due east) F

4. (A) F (B) F (C) T (D) T (Eastward) F

5. (A) T (B) F (C) F (D) T (Eastward) F

Footnotes

Competing interests: None declared.

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