Chapter 62: Heparin-Induced Thrombocytopenia

Heparin-induced thrombocytopenia is a prothrombotic disorder mediated by IgG antibodies that bind to conformational epitopes on PF4 when it is complexed with heparin. Typically, the platelet counts are only moderately reduced. Occasionally patients do not have thrombocytopenia, but their platelet counts decrease by 50% from pretreatment levels

Kelton JG et al. N Engl J Med 2013;368:737–744

Epidemiology

1. Frequency: Determined by heparin type (UFH > LMWH), patient type (surgery > medical), patient gender (F > M); odds ratio 17.4 for postoperative thromboprophylaxis (UFH > LMWH), and duration of heparin therapy (10 –14-day course >1 day: >2% vs. 0.02%)

   1. >1%: Postoperative patients: UFH at prophylactic or therapeutic dose (1–5%); cardiac surgery (1–3%)

   2. 0.1–1%: Postoperative patients: UFH flushes or LMWH in prophylactic or therapeutic dosages (0.1–1%); Medical patients: cancer (1%), UFH at prophylactic or therapeutic dose (0.1–1%), LMWH at prophylactic or therapeutic dose (0.6%), intensive care patients (0.4%)

   3. <0.1%: UFH flushes, obstetrics patients (non-surgical)

2. Thrombotic risk: Isolated HIT (untreated): 30-day cumulative rate ~50% after stopping heparin; initial rate of thrombosis per day over the first 1–2 days after discontinuing heparin: 5–10%

3. Mortality (9 studies, 876 patients): Overall population, ~20%; among patients with thrombosis, ~46%

Lee DH, Warkentin TE. Frequency of heparin-induced thrombocytopenia. In: Warkentin TE, Greinacher A, eds. Heparin-Induced Thrombocytopenia. 4th ed. New York, NY: Informa Healthcare USA; 2007:67–116

Linkins L-A et al. Chest 2012;141(Suppl 2):e495S–e530S

Warkentin TE. Clinical picture of heparin-induced thrombocytopenia. In: Warkentin TE, Greinacher A, eds. Heparin-Induced Thrombocytopenia. 4th ed. New York, NY: Informa Healthcare USA; 2007:21–66

Warkentin TE et al. Chest 2008;133(Suppl 6):340S–380S

Work-up

The diagnosis of HIT is based on both clinical and serologic findings and thus should be considered a clinicopathologic syndrome (Warkentin TE et al. Thromb Haemost 1998;79:1–7)

A. The work-up section for HIT outlines an approach for making or excluding a diagnosis of HIT and when to consider the initiation of alternative anticoagulation therapy for heparin/low-molecular-weight heparin that incorporates the following considerations:

1. Clinical suspicion (determining the magnitude and pattern of platelet count fall correlated with the clinical setting, presence or absence of arterial/venous thromboembolic events and presence of other HIT manifestations). The authors recommend a review of the peripheral blood smear to exclude pseudothrombocytopenia and assess for other abnormalities (eg, TTP) that may influence the differential consideration for HIT (see Table B)

2. Pretest Probability (determining the likelihood of HIT with 4Ts score; see Table C)

3. HIT laboratory testing (see Table D)

4. Posttest Probability (determining the likelihood of HIT that incorporates results of the pretest probability with the strength of the quantitative value from HIT testing; when indicated and where clinically feasible, additional testing for the presence of HIT antibodies with a washed-platelet functional assay) (see Table B)

5. Other considerations that have a bearing on HIT management/treatment:

   1. Weight of the patient in kilograms

   2. Determination of the patient's renal and hepatic status

   3. Presence or absence of any clinical bleeding

   4. Whether or not the patient requires an invasive procedure in the near-term (eg, “next few days”)

   5. Determination of any non-HIT indications for anticoagulation

Alving BM. Blood 2003;101:31–37

Cuker A et al. Blood 2012;120:4160–4167

Greinacher A et al. Thromb Haemost 2005;94:132–135

Linkins L-A et al. Chest 2012;141(2 Suppl):e495S–e530S

Wallis DE et al. Am J Med 1999;106:629–635

Warkentin TE. Br J Haematol 2003;121:535–555

Warkentin TE. Clinical picture of heparin-induced thrombocytopenia. In: Warkentin TE, Greinacher A, eds. Heparin-Induced Thrombocytopenia. 4th ed. New York, NY: Informa Healthcare USA; 2007:21–66

Warkentin TE. Hematology Am Soc Hematol Educ Program 2011;143–149

Warkentin TE. Thromb Haemost 1999;82:439–447

Warkentin TE et al. Ann Intern Med 1997;127:804–812

Warkentin TE et al. Chest 2008;133(6 Suppl):340S–380S

Warkentin TE et al. N Engl J Med 1995;332:1330–1335

Watson H et al. Br J Haematol 2012;159:528–540

1. The 4Ts score is the best studied of currently developed pretest clinical prediction rules to assist physicians in determining the probability of HIT. A recently reported systematic review and metaanalysis estimated the predictive value of the 4Ts in patients with suspected HIT. In this report, 3068 patients^✫ identified with suspected HIT were evaluated both by the 4Ts and a reference standard (functional assay for HIT in all but 1 study) against which the 4Ts could be compared. The results of these analyses showed the following:

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   4Ts Probability Category	Patient Number (%)	PPV (95% CI)	NPV (95% CI)
   Low (score: 1–3)	1712 (55.8)	—	0.998 (0.970–1.000)
   Intermediate (score: 4–5)	1103 (36.0)	0.14 (0.009–0.22)	—
   High (score: 6–8)	253 (8.2)	0.64 (0.400–0.82)	—
   CI, confidence interval; NPV, negative predictive value; PPV, positive predictive value Cuker AA et al. Blood 2012;120:4160–4167 ✫Twelve of 43 screened full-text articles met review inclusion criteria from which the study patients were identified Notes: The pooled estimates of sensitivity and specificity with 95% CI of 4Ts at a cut off of ≥4 were 0.99 (0.86–1.00) and 0.54 (0.43–0.66), respectively The authors make the conclusion that “a low probability 4Ts score appears to be a robust means of excluding HIT” Based on the results of this study, the authors propose an algorithm for the initial evaluation and management of patients with suspected HIT using the 4Ts pretest probability score: (a) score ≥4: discontinue heparin; start alternative anticoagulant; obtain HIT laboratory testing; (b) score ≤3: continue heparin; consider alternative diagnoses While integrating 4Ts in the evaluation and initial management of suspected HIT may reduce overtesting, overdiagnosis, and overtreatment of HIT, the authors emphasize, “that this approach requires investigation in a randomized comparison with institution-based diagnosis”

2. Timing of platelet fall (additional considerations relative to pattern of platelet fall):

   • Typical onset HIT (approximately 67% of presentations): thrombocytopenia occurs 5–10 days after initial exposure to immunizing doses of UFH or LMWH

   • Rapid-onset HIT (approximately 25–30% of presentations): platelet count falls unexpectedly within 24 hours after reexposure to UFH or LMWH. Typically, these patients have had prior UFH or LMWH exposure in the preceding 100 days with circulating HIT antibodies at the time of reexposure

   • Delayed-onset HIT (approximately 3–5% of presentations): thrombocytopenia and/or associated thrombosis that occurs within several days (9–40 days) after stopping UFH or LMWH when given in a perioperative setting or inflammatory states

   • For postoperative cardiac surgery patients, a diagnosis of HIT should be excluded if the platelet count falls ≥50% (and/or a thrombotic events occurs) from the highest postoperative days 4 and 14 (day 0 = day of cardiac surgery) or thrombocytopenia that persists for >4 days after surgery. Following cardiopulmonary bypass (CPB), the platelet count falls by approximately 38% and continues to fall for the first 1–2 days postoperatively before rising in a continuous fashion to a level above the preoperative platelet count

   • No single definition of thrombocytopenia in HIT is appropriate in all clinical situations

3. Evaluation for thrombosis

    In cases of strongly suspected or confirmed HIT, routine venous ultrasonography of the lower limb veins for investigation of DVT is recommended (whether or not there is clinical evidence of lower-limb DVT). In addition, upper-arm venous ultrasonography should be considered in patients who have or recently had indwelling venous catheters (authors' opinion)

4. Clinical manifestations of HIT

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   Common	Uncommon
   DVT (lower > upper extremity) ± PE (~17–55%) Thrombosis preceding thrombocytopenia (~25%) Acute limb ischemia (~5–10%) Acute stroke/MI (~3–5%)	Acute systemic reactions post-IV UFH bolus (~25% of sensitized patients) Erythematous plaques/skin necrosis at UFH/LMWH injection sites (~10–20%) Venous limb gangrene (~5–10% of HIT with DVT acutely treated with a VKA) Decompensated DIC (~5–10%)
   “Rare”
   Adrenal hemorrhagic infarction/necrosis due to adrenal vein thrombosis Warfarin-induced skin necrosis Cerebral dural sinus thrombosis Thrombosis involving arteries of upper limb, renal, mesenteric, spinal, and other sites Cardiac arrest
   Greinacher A et al. Thromb Haemost 2005;94:132–135 Linkins L-A et al. Chest 2012;141(2 Suppl):e495S–e530S Warkentin TE. Clinical picture of heparin-induced thrombocytopenia. In: Warkentin TE, Greinacher A, eds. Heparin-Induced Thrombocytopenia. 4th ed. New York, NY: Informa Healthcare USA; 2007:21–66 Warkentin TE et al. Ann Intern Med 1997;127:804–812 Warkentin TE et al. N Engl J Med 1995;332:1330–1335

Regimen: Argatroban

Bartholomew JR. J Thromb Thrombolysis 2005;19:183–188

Lewis BE et al. Argatroban in heparin-induced thrombocytopenia. In: Warkentin TE, Greinacher A, eds. Heparin-Induced Thrombocytopenia. 4th ed. New York, NY: Informa Healthcare USA; 2007:379–408

Lewis BE et al. Arch Intern Med 2003;163:1849–1856

Lewis BE et al. Circulation 2001;103:1838–1843

Linkins L-A et al. Chest 2012;141(2 Suppl):e495S–e530S

Verme-Gibboney CN, Hursting MJ. Ann Pharmacother 2003;37:970–975

Warkentin T. Thromb Res 2003;110:73–82

ARGATROBAN injection prescribing information. GlaxoSmithKline. April 2012

Mechanism of action: Direct thrombin inhibitor

Half-life: 39–51 minutes

Metabolism: Hepatic clearance (major); 16% unchanged drug eliminated renally

Prior to initiating therapy: Discontinue heparin (if ongoing administration). Do not start if PTT ratio is ≥2.5; baseline CBC, chemistry (eg, LFTs and serum creatinine), and coagulation studies (eg, PT, INR, aPTT)

HIT or HITTS (normal liver function):

Loading dose: None

Maintenance dose: Argatroban 2 mcg/kg per minute; administer intravenously. Dilute argatroban in 0.9% sodium chloride injection (0.9% NS), 5% dextrose injection (D5W), or lactated Ringer injection (LRI), to produce a solution with a concentration = 1 mg/mL (eg, 250 mg in 250 mL diluent)

Note: Renal impairment in the absence of hepatic impairment (see below), initial dose: 2 mcg/kg per min

HIT or HITTS (hepatic impairment):

Loading dose: None

Maintenance dose: Argatroban 0.5 mcg/kg per minute; administer intravenously. Dilute argatroban in 0.9% NS, D5W, or LRI to produce a solution with a concentration = 1 mg/mL

• Child-Pugh score >6, total serum bilirubin >1.5 mg/dL (initial dose: 0.5 mcg/kg per minute)

• CHF, multiorgan failure, severe anasarca, postcardiac surgery (initial dose: 0.5–1.2 mcg/kg per minute)

Antidote: None. The drug generally disappears from the circulation within 2–4 hours, or longer in the setting of liver disease. Discontinue the drug if life-threatening bleeding and/or excessive anticoagulation (with or without bleeding) occurs and obtain aPTT and other coagulation tests. rVIIa and FFP have been used to treat patients with severe bleeding

Comment: Above argatroban dosing recommendations per 2012 9th ed ACCP HIT Guidelines

Conversion to Warfarin

1. Initiate warfarin at a modest daily dose (≤5 mg/day) while argatroban is continued

2. If the INR is >4 on co-therapy and assuming a minimum 5-day overlap on an average argatroban dose of ≤2 mcg/kg per minute, discontinue argatroban and repeat the INR after 4–6 hours

   1. If the repeated INR is within the therapeutic range (2–3) for 2 consecutive days, warfarin therapy alone is indicated

   2. If the repeated INR is less than the therapeutic range, resume argatroban and repeat the process daily until the target INR is achieved

3. When the INR is ≥4 in patients receiving warfarin and argatroban >2 mcg/kg per minute, decrease the argatroban dose-rate to 2 mcg/kg per minute for 4–6 hours, then remeasure the INR

   1. If the INR has fallen to <4, argatroban should be resumed to keep the aPTT in the therapeutic range

   2. If the INR is >4 on combination therapy with warfarin and argatroban >2 mcg/kg per minute and assuming a minimum 5-day overlap, discontinue argatroban and repeat the INR after 4–6 hours

      • (1) If the repeated INR is within the therapeutic range (2–3) for 2 consecutive days, continue warfarin therapy alone

      • (2) If the repeated INR is less than the therapeutic range, resume argatroban and repeat the process daily until the target INR is achieved

Adverse Events

Efficacy Results of Study 1

Therapy Monitoring

aPTT 2 hours after starting infusion (and after each dose change), adjust dose (± 0.5 mcg/kg per minute, or less in the setting of hepatic impairment) to give an aPTT 1.5–3 times a patient's baseline aPTT. Monitor aPTT at least daily after the argatroban infusion is at a steady-state level

Regimen: Lepirudin

Greinacher A et al. Blood 2000;96:846–851

Greinacher A et al. Circulation 1999;99:73–80

Greinacher A et al. Circulation 1999;100:587–593

Greinacher A. Lepirudin for the treatment of heparin-induced thrombocytopenia. In: Warkentin TE, Greinacher A, eds. Heparin-Induced Thrombocytopenia. 4th ed. New York, NY: Informa Healthcare USA; 2007:345–378

Linkins L-A et al. Chest 2012;141(2 Suppl):e495S–e530S

Lubenow N et al. J Thromb Haemost 2005;3:2428–2436

Refludan^® (lepirudin [rDNA] for injection); October 2004 product label. BERLEX^®, Montville, NJ

Refludan^® (lepirudin [rDNA] for injection); December 2006 product label. Bayer HealthCare Pharmaceuticals Inc., Wayne, NJ

Willey ML et al. Pharmacotherapy 2002;22:492–499

Mechanism of action: Direct thrombin inhibitor; a recombinant hirudin analog

Half-life: Terminal; mean 1.3 hours (range: 0.8–1.7 hours) in young healthy volunteers

Metabolism: Predominantly renal clearance

Prior to initiating therapy:

Discontinue heparin (if ongoing administration) and allow the patient's aPTT ratio (patient aPTT/median of normal aPTT range) to decline to <2.5 (per PI)

Dose for HIT or HITTS

Loading dose: Either omit or, in the case of perceived life- or limb-threatening thrombosis, give lepirudin 0.2 mg/kg; administer by intravenous injection over 15–20 seconds

Lepirudin preparation for intravenous injection

1. Reconstitute the freeze-dried powder by injecting 1 mL Sterile Water for Injection, USP (SWFI) or 0.9% Sodium Chloride Injection, USP (0.9% NS) into a vial containing lepirudin 50 mg

2. Gently shake the vial to aid dissolution and to obtain a clear, colorless solution with a concentration of 50 mg/mL

3. With a sterile syringe (15–30-mL capacity), aspirate the contents of the vial (reconstituted lepirudin 50 mg in 1 mL)

4. Draw up into the same syringe an additional volume of 0.9% NS or 5% Dextrose Injection, USP (D5W), sufficient to produce a total volume of 10 mL

   1. The resulting solution has a concentration of 5 mg/mL and is administered by intravenous injection

   2. The diluted product (5 mg/mL) should be used immediately, but remains stable at room temperature for up to 24 hours

   3. The diluted product should be warmed to room temperature before use

       Lepirudin is administered by direct intravenous injection at a dosage based on a patient's body weight

Lepirudin infusion rate is determined by the patient's serum creatinine level and body weight with slower infusion rates for patients with higher serum creatinine levels (See table below)

Lepirudin preparation for intravenous injection

1. Reconstitute two vials of lepirudin by injecting into each vial 1 mL SWFI or 0.9% NS

2. Gently shake the vials to aid dissolution and to obtain a clear, colorless solution with a concentration of 50 mg/mL

3. With a syringe, transfer the contents of both vials to a parenteral product container containing 500 mL (final concentration = 0.2 mg/mL) or 250 mL (final concentration = 0.4 mg/mL) of 0.9% NS or D5W

    Lepirudin is administered by intravenous infusion at a dosage based on body weight at a rate adjusted for a patient's serum creatinine

Therapy Monitoring

1. Check aPTT ratio (using the patient's baseline or mean of laboratory normal range) 4 hours after starting lepirudin infusion and 4 hours after the rate of infusion has been changed until it is apparent that a steady state aPTT is achieved within the therapeutic range

Conversion to Warfarin

1. Once the patient is scheduled to begin a vitamin K antagonist for oral anticoagulation, the dose of lepirudin should be gradually reduced to result in an aPTT ratio just above 1.5 before initiating oral anticoagulation

2. After the platelet count has substantially recovered (eg, usually to >150,000/mm³) initiate warfarin at a modest daily dose (≤5 mg/day) while lepirudin is continued maintaining an aPTT ratio of 1.5–2.0

3. After not less than 5 days on combined therapy and with INR in the target range (2–3) for 2 consecutive days on the combined anticoagulants, discontinue lepirudin and repeat INR ~4 hours later to confirm that it is still within the target range. If the INR falls below the target range, resume lepirudin (maintaining an aPTT ratio to just above 1.5, but between 1.5–2.0) for another 24 hours and repeat the process

Efficacy

Adverse Events

Notes

The rationale for the revised lepirudin dose and monitoring recommendations is based on further analyses of prospective and retrospective studies, and increasing clinical experience. These analyses provide evidence that the lepirudin dosages used in the approval studies was too high

Regimen: Bivalirudin

Angiomax (bivalirudin) for injection, product label: May 2013. The Medicines Company; Parsippany, NJ

Bartholomew JR. Bivalirudin for the treatment of heparin-induced thrombocytopenia. In: Warkentin TE, Greinacher A, eds. Heparin-Induced Thrombocytopenia. 4th ed. New York, NY: Informa Healthcare USA; 2007:409–439

Francis JL et al. Blood 2003;102:571 (abstract)

Kiser TH et al. Pharmacotherapy 2008;28:1115–1124

Koster A et al. Anesth Analg 2003;96:1316–1319

Reed MD et al. Pharmacotherapy 2002;22:105S–111S

Robson R. J Invasive Cardiol 2000;12(Suppl F): 33F–36F

Robson R et al. Clin Pharmacol Ther 2002;71:433–439

Mechanism of action: Direct thrombin inhibitor

Half-life: 25–36 minutes

Metabolism: 80% proteolytic cleavage by plasma proteases; 20% renal mechanisms

Prior to initiating therapy:

Discontinue heparin (if administration is ongoing) and allow the patient's aPTT ratio to decline to <2.5 (patient aPTT/median of normal aPTT range)

Dose for HIT or HITTS: (off-label experience)

Loading dose: None

Maintenance dose: Bivalirudin 0.15–0.20 mg/kg per hour; administer as a continuous intravenous infusion using a solution containing 250 mg bivalirudin in 500 mL 0.9% sodium chloride or 5% dextrose injection.

Antidote: None. Large amounts of bivalirudin can be removed by hemofiltration (65,000-kDa large-pore filter) or plasmapheresis

Initial Dose-Rates are Based on Renal Function

Efficacy

Conversion to Warfarin

1. Initiate warfarin at a modest daily dose (≤5 mg/day) while bivalirudin is continued maintaining an aPTT ratio of 1.5–2.0

2. After not less than 5 days on combined therapy and with INR in the target range (2–3) for 2 consecutive days on combined therapy, stop bivalirudin and repeat INR ~4 hours later to confirm that it is still within the target range. If the INR falls below the target range, resume bivalirudin (maintaining an aPTT ratio of 1.5–2.0) for another 24 hours and repeat the process daily until the INR is within therapeutic range (2–3), then discontinue bivalirudin

Notes

1. Drugs incompatible with bivalirudin when administered through the same IV tubing: alteplase, amiodarone hydrochloride, amphotericin B, chlorpromazine hydrochloride, diazepam, prochlorperazine edisylate, reteplase, streptokinase, vancomycin hydrochloride

2. Bivalirudin was conditionally compatible with dobutamine concentrations ≤4 mg/mL, but incompatible with dobutamine 12.5 mg/mL

3. Labeled indications for bivalirudin include (doses for the labeled indication are not shown):

   1. Use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty

   2. For patients with or at high-risk of HIT/HITTS undergoing percutaneous coronary intervention

Adverse Events

Bleeding is the major adverse effect and occurs more frequently in patients with renal impairment

Allergic reactions: 1/3639 patients (0.03%) reported in clinical trials from 1993–1995

Therapy Monitoring

1. Titrate bivalirudin to maintain a therapeutic aPTT (1.5 to 2.5-times a patient's baseline aPTT or mean of laboratory range)

2. Repeat aPTT at 6-hour intervals and adjust bivalirudin in increments of 0.05 mg/kg per hour until a therapeutic aPTT is achieved

3. Once a therapeutic aPTT is achieved and confirmed on a subsequent aPTT obtained at 6 hours, then monitor aPTT daily

4. In the event there is a significant reduction or improvement in renal function while on bivalirudin therapy, more frequent aPTT monitoring is suggested (eg, every 6 hours) to determine that a therapeutic range aPTT is being maintained with subsequent dose adjustments (decrements or increments) as indicated

5. Once a steady state therapeutic aPTT is achieved, monitor aPTT daily

Regimen: Danaparoid Sodium: (Danaparoid Sodium is not Currently Available in the United States)

Chong BH et al. Blood 1989;73:1592–1596

Chong BH et al. Thromb Haemost 2001;86:1170–1175

Chong BH, Magnani HN. Danaparoid for the treatment of heparin-induced thrombocytopenia. In: Warkentin TE, Greinacher A, eds. Heparin-Induced Thrombocytopenia, 4th ed. New York, NY: Informa Healthcare USA;2007:319–343

Chong BH, Magnani HN. Haemostasis 1992;22:85–91

de Valk HW et al. Ann Intern Med 1995;123:1–9

Farner B et al. Thromb Haemost 2001;85:950–957

Greinacher A et al. Thromb Haemost 1992;67:545–549

Magnani HN, Gallus A. Thromb Haemost 2006;95:967–981

ORGARAN^®, Danaparoid Sodium Injection, 750 anti-Xa units/ampoule (1250 anti-Xa units/mL); April 14, 2011 product label. Merck Canada Inc., Kirkland, Quebec

Mechanism of action: Factor Xa inhibitor; weak inhibitor of Factor IIa

Anti-Xa terminal half-life: ≈25 hours

Metabolism: Predominantly renal clearance

Prior to initiating therapy:

Discontinue heparin (if ongoing administration) and allow the patient's aPTT ratio (patient aPTT/median of normal aPTT range) to decline to <2.5

plasma anti-Xa level ~0.8 Units/mL (see Therapy Monitoring below)

HIT and HITTS with normal renal function

Subcutaneous regimen

Loading dose: None

Maintenance dose:

≥60 kg: Danaparoid sodium 2250 anti-Xa units (approx. 165 mg); administer by subcutaneous injection every 12 hours

<60 kg: Danaparoid sodium 1500 anti-Xa units (approx. 110 mg); administer by subcutaneous injection every 12 hours

HIT and HITTS with normal renal function

IV regimen

Loading dose: According to weight as follows:

Adverse Effects

Population: 1478 patients from compassionate use program, ADRs, and published literature:

• Composite of new/extended thrombosis, new/persistent platelet count reduction, unplanned amputation (follow-up duration: up to 3 months): 16.4%

• Frequency of thrombotic events: 11%

• Major bleeding: 8.1%

Therapy Monitoring

Monitoring is not required in most situations. However, anti-Xa levels, using a standard calibration curve for danaparoid, should be followed in patients with:

• Low or high body weights

• Substantial renal impairment

• Life- or limb-threatening thrombosis

• High bleeding risk

• A critical illness or clinical instability

In these patients, obtain anti-Xa levels at approximately 6 hours after a change in dose until a plasma anti-Xa level of 0.5–0.8 units/mL is achieved, then daily

A higher target anti-Xa level (approximately 1 unit/mL) should be sought for a patient with life- or limb-threatening venous or arterial thrombosis or clotting during renal replacement therapy

A lower target anti-Xa level (eg, approximately 0.3 units/mL) may be appropriate for a patient judged to have a high risk of bleeding

Efficacy

Maintenance dose: Administer danaparoid sodium by continuous intravenous infusion. Dilute danaparoid in 0.9% sodium chloride injection and administer as follows:

  400 anti-Xa units/hour for 4 hours, then

  300 anti-Xa units/hour for 4 hours, then

  150 – 200 anti-Xa units/hour for ≥5 days

In selected patients, such as those with any evidence of renal dysfunction the administration rate should be titrated to achieve a plasma anti-Xa level of 0.5–0.8 Units/mL (see Therapy Monitoring)

Venous thromboembolism prophylaxis (prior HIT): Danaparoid sodium 750 units; administer by subcutaneous injection every 8 or 12 hours

Antidote: None

Protamine sulfate is not a neutralizing agent for danaparoid sodium overdose. In cases of major bleeding, danaparoid sodium should be discontinued or temporarily interrupted (with subsequent continuation at a lower dose). Routine hematological counts and other coagulation parameters should be measured. Transfusion with fresh frozen plasma, or, if bleeding is uncontrolled, plasmapheresis or surgery should be considered

Note:

For patients with strongly suspected or confirmed HIT, use a therapeutic regimen

In selected patients, such as those with any evidence of renal dysfunction, the administration rate should be titrated to achieve a plasma anti-Xa level of 0.5–0.8 Units/mL (see Therapy Monitoring)

In elderly patients, danaparoid sodium dosage-rate reduction is not necessary unless kidney or liver function is impaired

Conversion to Warfarin

1. Initiate warfarin in low doses (maximum daily doses: warfarin 5 mg or phenprocoumon 6 mg) while danaparoid sodium is continued at therapeutic dosages

2. After not less than 5 days on combined therapy and the INR is in the target range (2–3) for 2 consecutive days on co-therapy discontinue danaparoid therapy

3. In addition, if an acute thrombosis is present, overlapping danaparoid-warfarin should be continued until the thrombosis is controlled on clinical grounds

Regimen: Fondaparinux

ARIXTRA™ (fondaparinux sodium injection) Solution for subcutaneous injection; September 2003 product label. GlaxoSmithKline, Research Triangle Park, NC

Bradner JE, Eikelboom JW. Emerging anticoagulants and heparin-induced thrombocytopenia: Indirect and direct Factor Xa inhibitors and oral thrombin inhibitors. In: Warkentin TE, Greinacher A, eds. Heparin-Induced Thrombocytopenia. 4th ed. New York, NY: Informa Healthcare USA; 2007:441–461

Efird LE, Kockler DR. Ann Pharmacother 2006;40:1383–1387

Lobo B et al. Thromb Haemost 2008;99:208–214

Papadopoulos S et al. Pharmacotherapy 2007;27:921–926

Savi P et al. Blood 2005;105:139–144

Warkentin TE. Thromb Haemost 2008;99:2–3

Mechanism of action: Synthetic pentassaccharide that is a selective factor Xa inhibitor

Anti-Xa terminal half-life: 17–21 hours

Metabolism: Renally eliminated

Prior to initiating therapy:

Discontinue heparin (if administration is ongoing) and allow the patient's aPTT ratio (patient aPTT/median of normal aPTT range) to decline to <2.5

Dose for HIT and HITTS with normal renal function (off-label experience)

Subcutaneous regimen

(Do not use if creatinine clearance <30 mL/min)

Loading dose: None

Maintenance doses:

Venous thromboembolism prophylaxis (prior HIT): Fondaparinux 2.5 mg every 24 hours

Antidote: None available. If an overdose with bleeding has occurred, discontinue fondaparinux, search for the primary cause of bleeding and initiate appropriate therapy (eg, surgical hemostasis, blood replacement, fresh plasma transfusion, or plasmapheresis). Recombinant factor VIIa with tranexamic acid has been used to manage hemorrhagic shock in an orthopedic patient complicating fondaparinux use (Huvers F et al. Neth J Med 2005;63:184–186)

Comments:

1. Antiplatelet factor 4 heparin antibodies are as likely to form with fondaparinux as with enoxaparin. Fondaparinux is less likely to cause HIT, however, in part because it forms poorly with the PF4 antigens recognized by HIT antibodies and is less likely to induce platelet activation (Warkentin TE et al. Blood 2005;106:3791–3796)

2. Potential strategy for fondaparinux to avoid problems during the transition from direct thrombin inhibitors (DTI) to warfarin therapy: After platelet counts normalize on a DTI, replace the DTI with fondaparinux and begin transition to warfarin (avoids fondaparinux use in acute HIT for which efficacy and safety not yet established). 8th ACCP Guidelines on HIT (Warkentin TE et al. Chest 2008;133(6 Suppl):340S–380S)

3. One case of HIT associated with fondaparinux has been reported

Warkentin TE. N Engl J Med 2007;356:2653–2654

Adverse Effects

Major bleeding reported as between 1.2% for treatment of venous thromboembolism and 2.7% for prophylaxis of patients undergoing orthopedic surgery; non-HIT thrombocytopenia; elevations in ALT and AST

Buller HR et al. Ann Intern Med 2004;140:867–873

Turpie AGG et al. Arch Intern Med 2002;162: 1833–1840

Therapy Monitoring

Monitoring is not required in most situations. However, anti-Xa levels, using a standard calibration curve for fondaparinux, should be considered in patients with low body weights (<50 kg) or renal impairment

• In these patients, obtain anti-Xa levels to fondaparinux. These should be expressed in milligrams and cannot be compared to anti-Xa levels of UFH or LMWH. The mean peak steady-state plasma concentration is in the range of 1.2–1.26 mg/L per the package insert

Efficacy

Conversion to Warfarin

1. Initiate warfarin co-therapy with fondaparinux as outlined in the section on Oral Therapy: Warfarin

2. Overlap both anticoagulants for at least 5 days ensuring that the INR is in the target range (2–3) for at least 2 consecutive days before discontinuing fondaparinux therapy

3. Fondaparinux may cause only subtle prolongation of the prothrombin time (1 second); thereby, simplifying bridging to warfarin (Bijsterveld NR et al. Circulation 2002;106:2550–2554)

Comment: FDA-approved indications for fondaparinux include venous thromboembolism prevention in hip fracture, elective hip or knee replacement, abdominal surgery, and acute treatment of DVT or PE in conjunction with warfarin, management of unstable angina or non-ST segment elevation myocardial infarction (MI) for the prevention of death and subsequent MI, and management of ST segment elevation MI for the prevention of death and MI in patients who are managed with thrombolytics or who initially are to receive no form of reperfusion therapy

Special Therapeutic Approaches

HIT in dialysis patients

Heparin must not be added to any flushing solution and no heparin-coated devices should be used in this population. LMWH is also to be avoided. Argatroban is theoretically an ideal agent for use in this patient population because of its predominant hepatic elimination with no initial dose adjustments required based on renal dysfunction alone. Regimens using lepirudin and danaparoid have also been published (Fischer K-G. Hemodial Int 2007;11:178–189)

HIT in cancer patients

1. Establishing a diagnosis of HIT among patients with cancer is complex due to the multiple potential causes of thrombocytopenia (eg, cancer treatment-, non-cancer treatment- and disease-related mechanisms), timing of treatment-related myelosuppressive effects that have the potential to mimic HIT platelet-pattern declinations and a population enriched for thromboembolic risk

2. While the current NCCN Guidelines Version 2.2013 for Venous Thromboembolic Disease (section on HIT) utilizes the 4T's Score to calculate the pre-test probability for the cancer patient with suspected HIT, applying the 4T's Score in this population has potential inherent biases. For example, the 4T's may lead to both under-scoring (score of “0” for “probable other causes present” giving a potential maximum score of 6 of 8 OR a score of “1” for progressive or recurrent thrombosis that may be attributable to HIT) or over-scoring (scores of “2” in each of the domains for “>50% platelet decline” or “timing of platelet decline” or “presence of thrombosis” that may be related to the malignancy and/or its treatment temporarily occurring with, but unrelated to the use of UFH or LMWH; authors' comment). With these considerations in mind and in lieu of a HIT pre-test probability scoring system validated in the cancer patient population, the 4T's score provides a framework from which to guide clinical reasoning and management considerations for the cancer patient in whom HIT is suspected (See: NCCN Clinical Practice Guidelines in Oncology [NCCN Guidelines^®]. Venous Thromboembolic Disease: Heparin Induced Thrombocytopenia [HIT]. Version 2.2013; www.NCCN.org Miriovsky BJ, Ortel TL. J Natl Compr Canc Netw 2011;9:781–787)

HIT in pregnancy

1. The incidence of HIT is reported to be lower during pregnancy than in the nonpregnant population, particularly when LMWH is used for thromboprophylaxis or at therapeutic doses (1 in 1167 pregnancies [3 studies]; zero in 2777 pregnancies [systematic review])

2. With HIT development, heparin (LMWH) should be discontinued and treatment initiated with a nonheparin anticoagulant for HIT (see Table E. Summary Guidelines on the Treatment/Management and Prevention of HIT)

3. There is limited data describing the treatment of HIT developing during pregnancy. The quality of evidence on the safety and efficacy of nonheparin anticoagulants in this patient population is low (Linkins LA et al. Chest 2012;141(2 suppl):e495S–e530S)

4. Danaparoid

   1. The largest experience for danaparoid use in pregnancy with HIT comes from a retrospective review of 18 case reports including 30 women who presented up to 120 days of HIT diagnosis (“current HIT” group). The report also includes the experience of danaparoid use during pregnancy in “past HIT” (n = 17 pregnancies; 9 case reports) and “non-HIT” (n = 44 pregnancies; 15 case reports) groups. These 3 groups will be collectively referred to as the all-group cohort. All patients had previously failed heparin or LMWH. The following information presented pertains exclusively to the “current HIT” group except where otherwise specified

      1. HIT diagnosis confirmation. HIT diagnosis evaluation among the “current HIT” and “past HIT” groups was reported as group-nondesignated compiled data and included (+) serology (n = 38; functional test: n = 29; ELISA: n = 9), “rechallenge” thrombocytopenia (n = 2), and “highly likely” HIT with (−) serology/no information (remaining patients)

      2. Thrombotic history. Seventy percent had at least 1 acquired (n = 10) or inherited (n = 11) clotting disorder among other important comorbidities. Ninety-three percent had a thromboembolic event presenting ≤5 days (n = 15), >5 days earlier (n = 13), or in a previous or “outside” pregnancy (n = 7) in relation to initiating danaparoid treatment

      3. Danaparoid use and pregnancy outcome. Danaparoid was started during the first, second, and third trimesters in 50%, 28.6%, and 21.4% of pregnancies, respectively. Danaparoid was administered intravenously or subcutaneously at various daily doses, including: <1500 units (n = 1), 1500–2500 units (n = 11), and >2500 units (n = 16) (doses not identified, n = 2). The median durations of danaparoid administration during the intrapartum and postpartum periods were 14 weeks (range: <1–33 weeks) and 7 days (range: 2–56 days), respectively. Danaparoid was administered until delivery in 96.3% (vaginal deliveries: n = 17; C-section deliveries: n = 9). From the all-groups cohort experience in this report, danaparoid was usually stopped a median of <12 hours before vaginal delivery and a median of 24 hours before C-section (only known for 19 patients). In the same all-group cohort, danaparoid was restarted (postpartum) in 37 (49.3%) of 75 patients who received it until live delivery. Among them, 14 and 10 patients, respectively, restarted it a median of <12 hours (but within 24 hours) and >24 hours to 3 days after vaginal delivery, respectively, and a median approximately 9 hours after C-section (n = 13; range: 2–72 hours) when hemostasis was achieved. The live birth rate was 96.3% (26/27) among individuals for whom the outcome of pregnancy was known. One fetal death occurred as a result of prematurity

      4. Intrapartum maternal adverse events (AEs) included:

         • (a) New venous thromboembolic events (n = 5; at least 2 responded to increased danaparoid dosing);

         • (b) Nonfatal bleeding event (n = 2; 1 patient with a small placental hematoma during C-section use of dextran after danaparoid discontinuation; 1 patient with injection site bleeding that stopped after danaparoid dose reduction);

         • (c) Maternal death (n = 2; 1 patient on day 2 danaparoid resulting from severe bleeding during emergency C-section for full placenta previa; 1 patient 5 days after danaparoid cessation for elective C-section who developed placental abruption, severe bleeding, heart failure and refused blood transfusion); and

         • (d) Emergency below-knee amputation resulting from pre–danaparoid-treatment gangrene as a result of phlegmasia cerulea dolens that did not improve with thrombolytic or danaparoid treatment (pregnancy terminated during the same operation; n = 1)

      5. Postpartum AEs (1 each) included major bleeding and skin necrosis at previous danaparoid injection sites (3 days after completing transition to VKA with normal protein C antigen levels)

      6. Cord blood and breast milk. Anti-Xa activity was absent from 3 infants' cord blood tested after delivery and none or <0.07 units/mL in breast milk samples from 3 mothers given danaparoid postpartum (which would be deactivated in a neonate's or infant's stomach)

      7. The reviewer concluded the successful birth rate and adverse event profile indicates that danaparoid “can be a safe alternative antithrombotic in pregnancies complicated by HIT” (Magnani HN. Thromb Res 2010;125:297–302)

5. Fondaparinux

   1. Indirect evidence for the safety of subcutaneously administered fondaparinux during pregnancy (without HIT) is derived from 1 small prospective cohort study of 12 pregnancies (1 with twins) among 10 patients. All patients were treated initially with a LMWH for a history of DVT attributed to oral contraceptives use (n = 6), idiopathic venous thromboembolism (n = 3), or recurrent fetal loss (n = 1). Fondaparinux 2.5 mg subcutaneously, twice daily, was administered as a result of hypersensitivity skin reactions to LMWH in all patients (n = 8 during second trimester; n = 2 during third trimester). Fondaparinux was discontinued at the start of spontaneous labor, restarted 4–8 hours after delivery (when blood loss was normal), and discontinued 6 weeks postpartum. The results of this study showed: (a) no hypersensitivity skin reactions during fondaparinux; (b) no early or late fetal loss; (c) a mean gestational age of 39 weeks at delivery; (d) mean blood loss during delivery of 450 mL (3 patients experienced blood loss >1000 mL); (e) no bleeding or thrombosis during pregnancy or upon restarting fondaparinux in the postpartum period; and (f) none among 13 infants with congenital anomalies or neonatal bleeding (Knol HM et al. J Thromb Haemost 2010;8:1876–1879)

   2. Fondaparinux has been shown to cross the human placenta. In 1 study of 5 pregnant women with allergy to heparin who were subsequently treated with fondaparinux, low measureable anti-Xa levels in the umbilical cord blood (n = 4) were observed (at approximately 1/10 the concentration in maternal plasma). Neonatal bleeding did not occur in the infants of these women (Dempfle CE. N Engl J Med 2004;350:1914–1915)

   3. One case report describes the successful use of fondaparinux in the treatment of HIT in a 24-year-old pregnant woman. At 34 weeks' gestation the patient developed dyspnea and was found to have bilateral pulmonary emboli by spiral CT and a saddle embolus on transthoracic echocardiogram. Following initial therapeutic heparinization and transition to LMWH, platelet counts fell by >50% from baseline over 7 days, a H-PF4 ELISA was (+), and a diagnosis of HIT was made (other diagnoses excluded). Fondaparinux 7.5 mg once daily was administered subcutaneously with subsequent platelet count normalization by 37 weeks gestation followed by treatment cessation 24 hours prior to C-section. After a complication-free delivery (with normal neonate platelet counts) fondaparinux was reintroduced on POD-1, warfarin overlap began on POD-2, and discharge on POD-8 with therapeutic warfarin alone (with her neonate) (Ciurzyński M et al. Med Sci Monit 2011;17:CS56–CS59)

HIT in cardiac patients undergoing percutaneous coronary interventions

In patients with acute or subacute HIT the 2012 ACCP Evidence-based guidelines for HIT recommends the use of bivalirudin (Grade 2B) or argatroban (Grade 2C) over other non-heparin anticoagulants. The 2012 British Committee for Standards in Haematology guidelines on the diagnosis and management of HIT (second edition) recommends the use of bivalirudin (2B) in patients with previous or present HIT who require coronary intervention including angiography and PCI

Linkins L-A et al. Chest 2012;141(2 Suppl):e495S–e530S

Watson H et al. Br J Haematol 2012;159:528–540

Catheter flushes in patients with HIT

• There are no published trials specifically evaluating the use of bivalirudin as a flush solution. In the EVOLUTION-ON and CHOOSE-ON/OFF trials, bivalirudin 0.1-mg/mL flushes were used before and after cardiopulmonary bypass per protocol. The frequency of flushing arterial lines and the quantity of solution used each time was at the discretion of the physician (Veale JJ et al. J Extra Corpor Technol 2005;37:296–302)

• Among non-HIT patients, Horne et al randomly assigned 49 patients undergoing or who had received bone marrow transplantation to receive either lepirudin 3 mL (300 mcg; n = 25) or heparin 3 mL (300 units; n = 24) to prevent withdrawl occlusion of double- or triple-lumen central line catheters. Withdrawl occlusion and alteplase instillation occurred in 20% of patients who received lepirudin and 12.5% of patients treated with heparin (Horne MK et al. Pharmacotherapy 2006;26:1262–1267)

• Lepirudin use for dialysis port flush was reported in a trauma patient who developed HIT. From a 50-mg vial reconstituted to 0.5 mg/mL, 0.5 mg was administered intravenously and 1.3 mL into each dialysis port. The strategy was repeated for 10 dialysis sessions without catheter occlusion (Patel VB et al. Thromb Haemost 1999;82:1205–1206)