Heparin‐induced thrombocytopenia‐associated thrombosis: from arterial to venous to venous limb gangrene

Abstract

Heparin-induced thrombocytopenia (HIT) is an acquired immune-mediated hypercoagulability state that is strongly associated with thrombosis. During the 1970s and 1980s, the prevailing concept was that HIT was associated only with arterial thrombosis, through its unique pathogenesis via heparin-dependent, platelet-activating IgG antibodies. However, in 1990, when I began to encounter HIT in my clinical practice, I found that most such patients developed symptomatic venous thrombosis. This historical sketch summarizes some of the research that challenged the dogma of HIT being a mainly arterial prothrombotic disorder. Two studies - one a substudy of a randomized trial of post-orthopedic surgery thromboprophylaxis, and the second a retrospective five-hospital analysis of consecutive patients with positive test results for HIT antibodies - showed a marked predominance of venous over arterial thrombosis complicating HIT (~ 4 : 1). By the end of the 1990s, an even more dramatic manifestation of HIT-associated venous thrombosis was recognized: venous limb gangrene. Here, ischemic limb necrosis occurs despite palpable arterial pulses, as a result of both macrovascular and microvascular venous thrombosis. The surprising explanation was natural anticoagulant impairment (severe depletion of protein C, a vitamin K-dependent anticoagulant) resulting from treatment of HIT-associated deep vein thrombosis with warfarin (vitamin K antagonist). These insights from HIT research helped to elucidate the pathogenesis of ischemic limb losses in other intense non-HIT hypercoagulability states, including warfarin-associated venous limb gangrene complicating cancer-associated hypercoagulability, and symmetrical peripheral gangrene complicating disseminated intravascular coagulation of critical illness, in which proximate 'shock liver' helps to explain the profound failure of natural anticoagulant systems (protein C; antithrombin) in predisposing to peripheral limb microthrombosis in circulatory shock.

Daumenmikrothrombose/Daumennekrose eines Patienten mit heparininduzierter Thrombozytopenie

“…Dieser Fallbericht zeigt, dass die HIT, neben lebensbedrohlichen thromboembolischen Ereignissen wie z. B. der Lungenembolie, auch zunächst mit klinisch nicht sofort wahrnehmbaren Mikrothrombosen einhergehen kann [4]. Die beginnende Nekrose des Daumens war der ausschlaggebende Faktor, um differenzialdiagnostisch eine HIT miteinzubeziehen.…”

Cleavage of anti-PF4/heparin IgG by a bacterial protease and potential benefit in heparin-induced thrombocytopenia

“…1,2 Despite having thrombocytopenia, affected patients usually develop thrombosis, and this particular clinical presentation is explained by the central role of Fcg receptors in the pathophysiology of HIT. 3,4 Indeed, the HIT Ab immunoglobulin G (IgG) directly activates platelets and monocytes in the presence of heparin after Fc gamma type 2 receptor A (FcgRIIA) engagement. [5][6][7] The cross-linking of FcgRIIA by immune complexes on the cell surface leads to ordered receptor clustering favoring the phosphorylation of tyrosine residues by Src kinases within the immunoreceptor tyrosine-based activation motif of FcgRIIA, which results in platelet activation with granule content secretion and platelet aggregation.…”

Spontaneous heparin-induced thrombocytopenia syndrome presenting as bilateral adrenal infarction after knee arthroplasty

“…HIT is caused by platelet-activating IgG that recognises complexes comprised of platelet factor 4 (PF4) bound to heparin or certain other polyanions 3. HIT is highly prothrombotic (relative risk of thrombosis, 12-fold to 15-fold), with at least 50% of patients developing symptomatic thrombosis 4 5…”