Autoimmune Heparin-Induced Thrombocytopenia

Abstract

Autoimmune thrombocytopenia (aHIT) is a severe subtype of heparin-induced thrombocytopenia (HIT) with atypical clinical features caused by highly pathological IgG antibodies (“aHIT antibodies”) that activate platelets even in the absence of heparin. The clinical features of aHIT include: the onset or worsening of thrombocytopenia despite stopping heparin (“delayed-onset HIT”), thrombocytopenia persistence despite stopping heparin (“persisting” or “refractory HIT”), or triggered by small amounts of heparin (heparin “flush” HIT), most cases of fondaparinux-induced HIT, and patients with unusually severe HIT (e.g., multi-site or microvascular thrombosis, overt disseminated intravascular coagulation [DIC]). Special treatment approaches are required. For example, unlike classic HIT, heparin cessation does not result in de-escalation of antibody-induced hemostasis activation, and thus high-dose intravenous immunoglobulin (IVIG) may be indicated to interrupt aHIT-induced platelet activation; therapeutic plasma exchange may be required if high-dose IVIG is ineffective. Also, aHIT patients are at risk for treatment failure with (activated partial thromboplastin time [APTT]-adjusted) direct thrombin inhibitor (DTI) therapy (argatroban, bivalirudin), either because of APTT confounding (where aHIT-associated DIC and resulting APTT prolongation lead to systematic underdosing/interruption of DTI therapy) or because DTI inhibits thrombin-induced protein C activation. Most HIT laboratories do not test for aHIT antibodies, contributing to aHIT under-recognition.

Recent advances in classic heparin-induced thrombocytopenia (HIT), autoimmune HIT, spontaneous HIT, and vaccine-induced immune thrombotic thrombocytopenia

“…10 DIC is estimated to be present in approximately 50% of patients with VITT and -interestingly -is also relatively frequent in reports of aHIT. 18,19 Markedly elevated Ddimers have been reported in all of the 8 patients who had Ddimers measured in the 9 SpVITT cases series described by Schönborn et al 2…”

“…18 Notably, autoimmune HIT is triggered by heparin or fondaparinux but persists, at least in part, through the action of heparin-independent anti-PF4 antibodies. 19 To date, five distinct aHIT disorders are recognized: delayed-onset HIT, persisting HIT, fondaparinux-induced HIT, heparin "flush" HIT, and unusually severe HIT. Conversely, SpHIT occurs in the absence of previous heparin exposure, with literature documenting only a limited number of cases following orthopedic surgery (n=24) or within the context of an acute medical illness (n=15).…”

“…Platelet count nadir Typically 40-80×10 9 /L 18 Can be below 20×10 9 /L 18 Can be below 20×10 9 /L 18 Typically below 50×10 9 /L 44 Thrombosis frequency 50% 7 Very high (~90%) 19 Very high (>87%) 18,1 Very high (>95%) 18 Venous to arterial thrombosis ratio 4 to 1 arterial thrombosis when compared to patients from other surgical settings (13.2% vs. 2.4%). 46 In a case series of 127 cHIT patients, the most common thrombotic event was pulmonary embolism (PE) (25.2% of patients).…”

“…2 In aHIT, similarly to VITT, thrombosis is highly prevalent, reaching a frequency of 90%. 2,19 This, once again, could reflect the way cases are identified, especially in the context of delayedonset HIT, which occurs or worsens after heparin discontinuation. Likewise, multivessel involvement is frequent in VITT, aHIT, and SpHIT.…”

“…The neurotropism of VITT critically influences its clinical severity and associated mortality rates. In the same systematic review, we showed that the overall mortality of VITT patients is 24% [95% confidence interval (CI) [19][20][21][22][23][24][25][26][27][28][29] and increases to 31% (95% CI [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38] in patients with CVST. The mortality rate reaches 77% (95% CI 58-90) in instances where CVST is complicated by intracranial hemorrhage (ICH).…”