Clinical picture of heparin-induced thrombocytopenia (HIT) and its differentiation from non-HIT thrombocytopenia

Abstract

SummaryHIT is an acquired antibody-mediated disorder strongly associated with thrombosis, including microthrombosis secondary to disseminated intravascular dissemination (DIC). The clinical features of HIT are reviewed from the perspective of the 4Ts scoring system for HIT, which emphasises its characteristic timing of onset of thrombocytopenia. HIT antibodies recognize multimolecular complexes of platelet factor 4 (PF4)/heparin. However, a subset of HIT sera recognise PF4 bound to platelet chondroitin sulfate; these antibodies activate platelets in vitro and in vivo even in the absence of heparin, thus explaining: delayed-onset HIT (where HIT begins or worsens after stopping heparin); persisting HIT (where HIT takes several weeks to recover); spontaneous HIT syndrome (a disorder clinically and serologically resembling HIT but without proximate heparin exposure); and fondaparinux-associated HIT (four distinct syndromes featuring thrombocytopenia that begins or worsens during treatment with fondaparinux), with a new patient case presented with ongoing thrombocytopenia (and fatal haemorrhage) during treatment of HIT with fondaparinux, with fondaparinux-dependent platelet activation induced by patient serum ("fondaparinux cross-reactivity"). Ironically, despite existence of fondaparinux-associated HIT, this pentasaccharide anticoagulant is a frequent treatment for HIT (including one used by the author). HIT can be confused with other disorders, including those with a) timing similar to HIT (e. g. abciximab-associated thrombocytopenia of delayedonset); b) combined thrombocytopenia/thrombosis (e. g. symmetrical peripheral gangrene secondary to acute DIC and shock liver); and c) both timing of onset and thrombosis (e. g. warfarin-associated venous limb gangrene complicating cancer-associated DIC). By understanding clinical and pathophysiological similarities and differences between HIT and non-HIT mimicking disorders, the clinician is better able to make the correct diagnosis.

Autoimmune heparin‐induced thrombocytopenia

“…Although fondaparinux is now widely used as an (off‐label) treatment for HIT , a few reports have implicated fondaparinux failure, including persisting or worsening thrombocytopenia with uncontrolled DIC. In these report, in vitro cross‐reactivity for fondaparinux was demonstrated .…”

Laboratory diagnosis of heparin‐induced thrombocytopenia

“…These highly pathogenic antibodies are able to bind and cross‐link PF4 molecules with (nonheparin) platelet‐associated polyanions (chondroitin sulfate, polyphosphates) or even in the absence of polyanion altogether. Table lists various presentations of HIT in which most (or all) patients have aHIT antibodies …”

“…Persisting HIT refers to patients with prolonged time to platelet count recovery. For example, well‐documented cases of HIT have been reported where the platelet count takes more than one month to recover . Interestingly, there is an inverse relationship between the severity of thrombocytopenia and the degree of heparin‐independent platelet activation induced by patient serum .…”

“…In these cases, aHIT antibodies have been observed where platelet activation was further enhanced in vitro in the presence of fondaparinux. Rarely, persisting thrombocytopenia and laboratory features of overt DIC have occurred in aHIT patients treated with fondaparinux, in whom in vitro “cross‐reactivity” with fondaparinux was demonstrated …”

Plasma exchange for heparin‐induced thrombocytopenia in patients on extracorporeal circuits: A challenging case and a survey of the field

“…Heparin‐induced thrombocytopenia (HIT) is a serious immune‐mediated complication of heparin administration that occurs due to the formation of IgG antibodies against platelet factor 4‐(PF4‐) heparin complexes . The recognition of IgG‐bound PF4‐heparin complexes by platelet Fc gamma receptors can subsequently trigger platelet activation, consumptive thrombocytopenia, and thrombosis.…”