Autoimmune Heparin-Induced Thrombocytopenia
Abstract
:1. Introduction
2. Methods
3. Results
3.1. Five aHIT Disorders
3.2. Delayed-Onset HIT
3.2.1. Terminology
3.2.2. Delayed-Onset HIT as an aHIT Disorder
3.2.3. Definition of Delayed-Onset HIT
3.2.4. Delayed-Onset HIT Reports with aHIT Antibodies
3.2.5. Delayed-Onset HIT Reports without Laboratory Documentation of aHIT Antibodies
3.3. Persisting (Refractory) HIT
3.4. Heparin Flush HIT
3.4.1. Heparin Flushes during Stem Cell Transplantation
3.4.2. Are Heparin Flushes Helpful in Maintaining Catheter Patency?
3.5. Fondaparinux-Associated HIT
3.5.1. Fondaparinux and Anti-PF4 Antibodies
3.5.2. Fondaparinux as a Treatment of HIT
3.5.3. Fondaparinux-Associated aHIT
3.6. Unusually Severe HIT
3.7. Laboratory Diagnosis
3.7.1. Heparin-Independent Platelet-Activating Properties
3.7.2. Immunoassays for aHIT Antibodies
3.7.3. Technical Challenges
3.7.4. False-Positive Detection of Cross-Reactivity
3.8. Pathogenesis of aHIT
3.8.1. aHIT Antibodies
3.8.2. Patient (Platelet) Risk Factors for aHIT
3.9. Treatment of aHIT
3.9.1. General Considerations
3.9.2. Choice of Anticoagulation
3.9.3. High-Dose IVIG
3.9.4. Therapeutic Plasma Exchange (TPE)
3.9.5. Heparin Rechallenge and Monitoring for aHIT
4. Discussion
- Autoimmune HIT (aHIT) presents with an atypical clinical picture (e.g., onset or worsening of thrombocytopenia despite stopping heparin; slow platelet count recovery after stopping heparin; multi-site thromboses; unusual sites of thrombosis [CVST, mesenteric vein, adrenal vein/adrenal necrosis/hemorrhage]; microthrombosis [e.g., venous limb gangrene, symmetrical peripheral gangrene]; overt DIC, and so forth).
- aHIT features highly pathological antibodies with heparin-independent platelet-activating properties (type 3 anti-PF4 antibodies).
- aHIT antibodies appear to recognize the heparin-binding site of PF4 (i.e., aHIT antibodies resemble VITT antibodies in this respect).
- HIT laboratories should be encouraged to perform tests that can demonstrate heparin-independent platelet-activating properties, e.g., performing the SRA (or another platelet activation assay) in the absence of heparin (0 U/mL heparin, or “buffer control”); the addition of PF4 may be required in some instances to optimize detection of the heparin-independent antibodies.
- Laboratories with a clinical and/or research interest in HIT should collaborate to determine whether standardization of the SRA or other platelet activation assays can be achieved, so as to help make the diagnosis of HIT more consistent.
- Anticoagulation: factor Xa inhibitors may have advantages over direct thrombin inhibitors (e.g., avoiding risk of APTT confounding).
- In addition to the frequent measurement of platelet counts, regular d-dimer and fibrinogen levels should also be assessed when managing a patient with aHIT, as a way to gauge whether HIT hypercoagulability is being adequately controlled (fibrinogen levels should be stable or rising, and d-dimer levels should be steadily decreasing, if a patient with aHIT is well-anticoagulated with an alternative non-heparin anticoagulant).
- Adjunct therapies: high-dose IVIG is an important option to de-escalate hypercoagulability in aHIT disorders, with a rapid platelet count increase (if observed) an indirect marker of IVIG efficacy.
- Therapeutic plasma exchange (TPE) is a potential treatment option for IVIG-refractory patients.
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Name of aHIT Disorder | Concept (Definition) |
---|---|
Delayed-onset HIT | Platelet count fall that begins or worsens despite stopping heparin |
Persisting (refractory) HIT | Delayed platelet count recovery despite stopping heparin (>1 week) |
Heparin “flush” HIT | HIT that occurs with exposure only to small amounts of heparin |
Fondaparinux-induced HIT | HIT associated with proximate exposure to fondaparinux |
Unusually severe HIT | Marked thrombocytopenia, multiple-site thromboses, overt DIC, etc. |
Study | Key Observations, Including Heparin-Independent Serotonin-Release (HISR) | HISR (%) |
---|---|---|
Case-series with controls | ||
[41] | Greater HISR in 12 aHIT patients vs. 24 HIT controls (p < 0.05) | 50% (mean) |
[54] | Delayed platelet count recovery: aHIT vs. cHIT (5/5 vs. 1/6; p = 0.015) | >50% |
[55] | Higher frequency of HISR in aHIT pts vs. controls (4/4 vs. 34/100; p = 0.016) | >80% |
[56] | 3 cases with SRA-positive refractory HIT (IVIG-responsive) | >40% PEA [low PF4] a |
[57] | 3/3 pts with post-discharge HIT had HISR (80%, 83%, 99%) | >80% |
[58] | aHIT: higher thrombosis rate, lower platelet nadirs, slower platelet count recovery | ≥30% |
Relationship between platelet counts and HISR (serial blood samples) | ||
[59] | Inverse relationship between HISR and platelet count (n = 1 pt) | >80% (peak) |
[55] | Inverse relationship between HISR and platelet count (n = 2 pts) | >90% (peak) |
[60] | Inverse relationship between HISR and platelet count (n = 1 pt) | >90% (peak) |
[61] | Abrupt plt count rise and parallel decrease in HISR post-IVIG (n = 1 pt) | 90% (peak) |
aHIT pts (case reports) with laboratory evidence of HISR | ||
[52] | Delayed/persisting with DIC, microvascular ischemia, nadir = 2 | >80% b |
[62] | Delayed; warfarin-induced microthrombosis (see Figure 3A), nadir = 71 | >40% |
[63] | Delayed; postoperative platelet count fall, DVT (see Figure 3B), nadir = 28 | >40% |
[64] | Delayed/persisting; stroke, adrenal hemorrhages, DVT, DIC, nadir = 68 | >90% |
[65] | Delayed, DVT, while on Fx; serial rise and fall of HISR, nadir = 13 (post-UFH) | >70% |
[66] | Delayed/persisting, recurrent (i.e., repeat UFH; previous HIT), DVT, nadir = 20 | >90% |
[67] | Delayed, adrenal hemorrhages, DVT, nadir = 117 | >90% |
[68] | Delayed/severe, DIC, multilimb microvascular gangrene, death; nadir = 10 | >90% |
[69] | Delayed, persisting, DVTs, Fx cross-reactivity, nadir = 3 | HIPA + 5 min c |
[70] | Delayed/persisting; no thrombosis (ascribed to rivaroxaban), nadir = 56 | >70% |
[71] | Severe, DIC with coagulation factor depletion, death, nadir = 65 | >60% |
[72] | Delayed/persisting, DIC, microvascular limb ischemia, death, nadir = 16 | >80% |
[73] | Delayed/persisting, DVTs (argatroban failure), nadir = 16 | 100% |
[74] | Delayed, multiple arterial/venous (incl. adrenal) thrombi, IVIG, nadir = 10 | 100% |
[75] | Delayed, CVST, DIC, argatroban failure, death, nadir = 7 | HIPA + c |
[76] | Delayed/persisting, venous limb gangrene (bivalirudin failure), IVIG, nadir = 9 | 100% |
[77] | Delayed/persisting, DVT, IVIG, nadir = 12 | HIPA + 5 min c |
[78] | Persisting, multiple venous/arterial thrombi (argatroban failure), IVIG, nadir = 25 | ATP release c |
Study | Trigger | Nadir | HIT Thrombosi(e)s | Treatment | Other | Refractory |
---|---|---|---|---|---|---|
[45] | U-cpb | 51 a | LAT | Warf, aspirin | Post-D/C; amp | |
[45] | U-cpb | 29 | DVT | DS | Post-D/C | |
[45] | U-cpb | 25 | LAT | DS, Lep | Post-D/C; amp | Yes |
[45] | U-cpb | 40 | DVT, PE | Lep; IVC filter | Post-D/C | |
[82] | U-rx | 15 a | DVTs × 3 | Lep; IVC filter | Post-D/C | |
[82] | U-cpb | 54 a | SVG-thrombosis × 1 | Lep | Post-D/C | |
[83] | U-cpb | 7 | VLG × 2 limbs | Arg | VLG (Warf) | Yes |
[83] | U-cpb | 18 | VLG × 2 limbs | Lep | VLG (Warf) | Yes |
[84] | U-vasc | 5 | DVT; graft thrombus | Arg, CS, IVIG | Arg-fail (DVT) | Yes |
[84] | U-vasc | 16 | DVTs × 2 | Arg, CS, IVIG, Fx | DIC | Yes |
[85] | U-rx | 19 | DVT | Arg, Fx, CS, IVIG | In Vitro IVIG studies | Yes |
[85] | U-pr | 18 | DVT | Arg, IVIG | In Vitro IVIG studies | Yes |
[86] | U-rx | 7 | DVT, PE, ecchymoses | IVC filter, Warf, IVIG | DIC | Yes |
[87] | U-rx | 24 | DVT, purpura | Warf | DIC | Yes |
[88] | U-pr | 7 | CVST, DVT, PE | Nil | Post-D/C, DIC | Yes |
[89] | U-cpb | 39 | DVT × 2, VLG × 2 | Lep | Post-D/C; amps | |
[90] | U-cpb | 69 | MI, SVG-thrombosis × 4 | Lep | Post-D/C | |
[91] | U-cpb | 8 | DVT, SPG × 3 limbs | Arg | Amps × 3 limbs | Yes |
[92] | U-cpb | 40 | PE; SPG × 4 limbs | Lep | DIC, Lep-fail; amps | Yes |
[93] | L-pr | 58 a | PE | Arg | Post-D/C; death | Yes |
[94] | U-cpb | 3 | Ecchymoses | Arg | No sequelae | Yes |
[95] | U-rx | 8 | DVT progr, IVC filter | Arg, Lep, CS, TPE, Ritux | Lep/Arg-fail, amps × 2 | Yes |
[96] | L-pr | 23 | DVT, PE | Fx, DS, Riv | Fx/DS-fail (↑dD) | Yes |
[97] | U-cpb | 12 | Testicular, b PE | DS, Biv, TPE | X-R assays conducted | Yes |
[98] | U-cpb | 8 | LAT, DVT/PE, Lt atrial | Arg, Biv, CS, IVIG | Post-D/C | Yes |
[99] | U-rx | 26 | Nil HIT thrombosis | IVC filter, Fx, Arg, IVIG | No sequelae | Yes |
[100] | U-hd | 15 | DVT | Arg, IVIG, apix | Post-D/C | Yes |
[101] | L-pr | 25 | CVST | Arg, CS, IVIG, Warf | Post-D/C | Yes |
[102] | L-pr | <10 | CVST, DVT | Arg, Biv, CS, IVIG | Arg-fail (worse DVT) | Yes |
[103] | U-hd | 16 | DVT | Arg, IVIG, Apix | Arg-fail (DVT) | Yes |
[104] | U-pr | 4 | DVTs × 4 limbs | Arg, Biv, CS, IVIG | Arg-fail (DVT ischemia) | Yes |
[105] | L-pr | 32 a | CVST | Biv | Post-D/C | |
[106] | U-pr | 36 | LAT, PE, PFO c | Arg, IVIG | Post-D/C | |
[107] | U-MI | ~100 | DVT, LAT | Heparin continued | Amp × 1 | |
[108] | U-pr | 28 | DVT | Arg, tPA, IVIG | Post-D/C | Yes |
[109] | U-pr | <12 | DVT × 3, PE | Riv | Post-D/C | |
[110] | L-pr | 8 | Bilateral LAT | Arg, IVIG | Post-D/C | |
[111] | U-cpb | 24 | Strokes (arterial) | Arg, IVIG | DIC; Arg fail (↑dD) | Yes |
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Warkentin, T.E. Autoimmune Heparin-Induced Thrombocytopenia. J. Clin. Med. 2023, 12, 6921. https://doi.org/10.3390/jcm12216921
Warkentin TE. Autoimmune Heparin-Induced Thrombocytopenia. Journal of Clinical Medicine. 2023; 12(21):6921. https://doi.org/10.3390/jcm12216921
Chicago/Turabian StyleWarkentin, Theodore E. 2023. "Autoimmune Heparin-Induced Thrombocytopenia" Journal of Clinical Medicine 12, no. 21: 6921. https://doi.org/10.3390/jcm12216921