Evolution of Antibodies Anti-PF4/heparin in a Patient with a History of Heparin-induced Thrombocytopenia Reexposed to Heparin

Abstract Heparin is a widely used anticoagulant. Because of its negative charge, it forms complexes with positively charged platelet factor 4 (PF4). This can induce anti-PF4/heparin IgG Abs. Resulting immune complexes activate platelets, leading to the prothrombotic adverse drug reaction heparin-induced thrombocytopenia (HIT). HIT requires treatment with alternative anticoagulants. Approved for HIT are 2 direct thrombin inhibitors (DTI; lepirudin, argatroban) and danaparoid. They are niche products with limitations. We assessed the effects of the DTI dabigatran, the direct factor Xa-inhibitor rivaroxaban, and of 2-O, 3-O desulfated heparin (ODSH; a partially desulfated heparin with minimal anticoagulant effects) on PF4/heparin complexes and the interaction of anti-PF4/heparin Abs with platelets. Neither dabigatran nor rivaroxaban had any effect on the interaction of PF4 or anti-PF4/heparin Abs with platelets. In contrast, ODSH inhibited PF4 binding to gel-filtered platelets, displaced PF4 from a PF4-transfected cell line, displaced PF4/heparin complexes from platelet surfaces, and inhibited anti-PF4/heparin Ab binding to PF4/heparin complexes and subsequent platelet activation. Dabigatran and rivaroxaban seem to be options for alternative anticoagulation in patients with a history of HIT. ODSH prevents formation of immunogenic PF4/heparin complexes, and, when given together with heparin, may have the potential to reduce the risk for HIT during treatment with heparin.

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Delayed Cutaneous Hypersensitivity Reactions to Hirudin

Archives of Pathology & Laboratory Medicine ◽

10.5858/2001-125-1585-dchrth ◽

2001 ◽

Vol 125 (12) ◽

pp. 1585-1587

Author(s):

Kathleen J. Smith ◽

Juan Rosario-Collazo ◽

Henry Skelton

Keyword(s):

Primary Treatment ◽

Myocardial Infarctions ◽

Hypersensitivity Reactions ◽

Type Ii ◽

Antithrombotic Agent ◽

Heparin Induced Thrombocytopenia ◽

Cutaneous Hypersensitivity ◽

History Of ◽

Delayed Hypersensitivity Reaction ◽

Delayed Cutaneous Hypersensitivity

Abstract Hirudin is one of the new synthetic antithrombin agents, which is most commonly used in patients with type II heparin-induced thrombocytopenia and in patients with hypersensitivity reactions to unfractionated heparin as well as low-molecular-weight heparins. Hirudin is comparable to heparin as an antithrombotic agent and also has been studied as a primary treatment in patients who experienced acute myocardial infarctions. We describe a patient with a history of type II heparin-induced thrombocytopenia who was placed on intravenous hirudin therapy. After extravasation of the intravenous hirudin site, the patient developed a delayed hypersensitivity reaction that histologically showed an epithelioid granulomatous infiltrate. Although rare reports of hypersensitivity reactions to hirudin have been published, these reactions have not been well characterized and the histopathologic changes have not been described.

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Use of Systemic Bivalirudin and an Anticoagulant-Free Purge Solution in a Percutaneous Left Ventricular Assist Device in a Patient With Heparin-Induced Thrombocytopenia

Journal of Pharmacy Practice ◽

10.1177/0897190020930530 ◽

2020 ◽

pp. 089719002093053 ◽

Cited By ~ 1

Author(s):

Hasan Kazmi ◽

Ashley E. Milkovits

Keyword(s):

Left Ventricular Assist Device ◽

Ventricular Assist Device ◽

Severe Aortic Stenosis ◽

Left Ventricular ◽

Assist Device ◽

Ventricular Assist ◽

Heparin Induced Thrombocytopenia ◽

Cardiac Catheterization Laboratory ◽

Left Ventricular Assist ◽

History Of

The use of systemic bivalirudin and an anticoagulant-free purge solution in a percutaneous left ventricular assist device (pVAD) is described in a patient with a history of heparin-induced thrombocytopenia (HIT). An 80-year-old man with a past medical history of severe aortic stenosis and HIT was transferred to our facility for cardiogenic shock. The patient was emergently taken to the cardiac catheterization laboratory for balloon valvuloplasty and Impella pVAD (Abiomed, Inc) implantation. Due to the history of HIT, bivalirudin was chosen as an alternative anticoagulant. The device representative suggested adding bivalirudin 20 mg/500 mL to the Impella purge solution. However, due to the negligible amount of bivalirudin this would provide in comparison to patient’s systemic intravenous bivalirudin dose, we elected not to add bivalirudin to the purge solution. The patient remained on the Impella for 72 hours with intravenous bivalirudin without any evidence of pump thrombosis as evidenced by unchanging flows and stable purge pressures. Unfortunately, despite functional Impella pVAD support, care was withdrawn due to ongoing multi-organ failure. This patient case demonstrated the safe, effective, and practical use of an anticoagulant-free purge solution with systemic bivalirudin in a patient with 72 hours of Impella support.

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Serological investigation of patients with a previous history of heparin-induced thrombocytopenia who are reexposed to heparin

Blood ◽

10.1182/blood-2013-10-533083 ◽

2014 ◽

Vol 123 (16) ◽

pp. 2485-2493 ◽

Cited By ~ 49

Author(s):

Theodore E. Warkentin ◽

Jo-Ann I. Sheppard

Keyword(s):

Previous History ◽

Heparin Induced Thrombocytopenia ◽

Serological Investigation ◽

Key Points ◽

History Of

Key Points Heparin rechallenge despite prior HIT often induces platelet-activating anti-PF4/heparin antibodies but no faster than seen with typical HIT. Risk of HIT recurring after heparin rechallenge is low but possible if IgG with heparin-independent platelet-activating properties are made.

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Adrenal haemorrhage due to heparin-induced thrombocytopenia

Thrombosis and Haemostasis ◽

10.1160/th12-11-0865 ◽

2013 ◽

Vol 109 (04) ◽

pp. 669-675 ◽

Cited By ~ 22

Author(s):

Siva Ketha ◽

Patrick Smithedajkul ◽

Adrian Vella ◽

Rajiv Pruthi ◽

Waldemar Wysokinski ◽

...

Keyword(s):

Natural History ◽

Time Frame ◽

Antiphospholipid Antibody ◽

Thrombotic Complication ◽

Antiphospholipid Antibody Syndrome ◽

Adrenal Haemorrhage ◽

Heparin Induced Thrombocytopenia ◽

Joint Replacement Surgery ◽

History Of ◽

Heparin Exposure

SummaryAdrenal haemorrhage (AH) is a rare but potentially devastating complication of heparin-induced thrombocytopenia (HIT). Neither the prevalence nor the natural history of AH due to HIT are known. The objectives of this study were to identify the spectrum of AH causes, to characterise the frequency of AH due to HIT and determine the natural history of HIT-associated AH. All patients with incident adrenal haemorrhage from January 2002 through June 2012 seen at the Mayo Clinic were identified. Over this time frame, there were a total of 115 patients with AH of which 11 cases (10%; mean age 67 ± 8 years; 73% female) were associated with HIT. Of these, all but one occurred in the postoperative setting and involved both adrenal glands (89%) with acute adrenal insufficiency at the time of diagnosis. Cases were found incidentally during an evaluation for fever, shock, abdominal pain or mental status changes. All HIT patients experienced venous thrombosis at other locations including deep venous thromboses (n=14), pulmonary emboli (n= 4) and arterial thrombosis (n=2). Four patients undergoing total knee arthroplasty had “spontaneous HIT” with AH in the absence of identifiable heparin exposure. Other causes of AH included trauma (29%), sepsis (15%), antiphospholipid antibody syndrome (10%), and metastatic disease (12%). In conclusion, AH is an important but seldom recognised presumed thrombotic complication of HIT, which usually occurs in the postoperative period, especially after orthopaedic procedures. This syndrome can occur in the apparent absence of heparin exposure, especially following major joint replacement surgery.

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Heparin-induced thrombocytopenia and cardiovascular surgery

Hematology ◽

10.1182/hematology.2021000289 ◽

2021 ◽

Vol 2021 (1) ◽

pp. 536-544

Author(s):

Allyson M. Pishko ◽

Adam Cuker

Keyword(s):

Cardiac Surgery ◽

Antiplatelet Agent ◽

Serotonin Release ◽

Functional Assay ◽

Platelet Factor ◽

Heparin Induced Thrombocytopenia ◽

Heparin Complexes ◽

Institutional Experience ◽

History Of ◽

Postoperative Setting

Abstract Clinicians generally counsel patients with a history of heparin-induced thrombocytopenia (HIT) to avoid heparin products lifelong. Although there are now many alternative (nonheparin) anticoagulants available, heparin avoidance remains challenging for cardiac surgery. Heparin is often preferred in the cardiac surgery setting based on the vast experience with the agent, ease of monitoring, and reversibility. To “clear” a patient with a history of HIT for cardiac surgery, hematologists must first confirm the diagnosis of HIT, which can be challenging due to the ubiquity of heparin exposure and frequency of thrombocytopenia in patients in the cardiac intensive care unit. Next, the “phase of HIT” (acute HIT, subacute HIT A/B, or remote HIT) should be established based on platelet count, immunoassay for antibodies to platelet factor 4/heparin complexes, and a functional assay (eg, serotonin release assay). As long as the HIT functional assay remains positive (acute HIT or subacute HIT A), cardiac surgery should be delayed if possible. If surgery cannot be delayed, an alternative anticoagulant (preferably bivalirudin) may be used. Alternatively, heparin may be used with either preoperative/intraoperative plasma exchange or together with a potent antiplatelet agent. The optimal strategy among these options is not known, and the choice depends on institutional experience and availability of alternative anticoagulants. In the later phases of HIT (subacute HIT B or remote HIT), brief intraoperative exposure to heparin followed by an alternative anticoagulant as needed in the postoperative setting is recommended.

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Fondaparinux in an Obese Child with Heparin-Induced Thrombocytopenia and a History of Renal Failure

The Journal of Pediatric Pharmacology and Therapeutics ◽

10.5863/1551-6776-18.4.303 ◽

2013 ◽

Vol 18 (4) ◽

pp. 303-310 ◽

Cited By ~ 2

Author(s):

Peter N. Johnson ◽

Emily C. Benefield ◽

Phi-Yen N. Bui ◽

Richard A. Marlar ◽

Morris R. Gessouroun

Keyword(s):

Renal Failure ◽

Oral Anticoagulation ◽

Obese Child ◽

Total Colectomy ◽

Factor Xa ◽

Optimal Dose ◽

Heparin Induced Thrombocytopenia ◽

Future Studies ◽

Vein Thrombosis ◽

History Of

A 9-year-old obese child with a history of ulcerative colitis was admitted to the intensive care unit for significant blood loss, hemorrhagic shock, and acute renal failure. Following complications from total colectomy secondary to multiple perforations, the patient developed heparin-induced thrombocytopenia (HIT) and subsequent portal vein thrombosis. Subcutaneous (SQ) fondaparinux therapy was initiated because the patient was unable to transition to oral anticoagulation. An anti-factor Xa assay was developed and used to adjust his fondaparinux therapy. Based on hemorrhagic complications and fondaparinux-based anti-factor Xa assay results, the fondaparinux was adjusted to a final dosage of 4.5 mg (0.066 mg/kg) SQ daily. In children unable to transition to oral anticoagulation, fondaparinux may be an alternative for the treatment of thrombosis associated with HIT. We noted that our patient required a lower dose per kilogram of fondaparinux than described in previous published reports. Despite this lower dosage per kilogram, our patient developed bleeding despite dosage reductions; subsequently, a few doses were held. It is unclear if this was related to his obesity, history of renal failure, or a combination of factors. Future studies should determine the optimal dose for special populations of children (e.g., those with obesity and renal failure). Until then, clinicians should routinely monitor and titrate fondaparinux therapy, ideally using a fondaparinux-specific anti-factor Xa assay.

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