Clinical Information

There are established and emerging disorders that are collectively termed thrombocytopenia and thrombosis syndromes; the most commonly recognized is heparin-induced thrombocytopenia (HIT). Newer associations have also been recognized including adenovirus vector-based SARS-CoV-2 vaccine-induced thrombocytopenia and HIT-like syndromes that occur in the absence of exposure to heparin (currently termed spontaneous or autoimmune HIT). In this situation, the heparin platelet-factor 4 (PF4) IgG antibody typically develops after surgery or infection.

HIT is a serious immune-mediated syndrome (ie, type II HIT or immune HIT) that occurs in 1% to 5% of patients treated with unfractionated heparin and at a lower frequency in patients treated with low-molecular weight heparin.

The 4Ts score is a validated scoring system to estimate the pretest clinical probability of HIT. Scores are assigned to the degree and timing of onset of thrombocytopenia, and the presence or absence of thrombosis (arterial or venous) in the absence of other potential explanations for the thrombocytopenia. In HIT, typical onset of thrombocytopenia is between days 5 and 10 of heparin therapy, but thrombocytopenia can arise earlier (<5 days after heparin exposure, ie, rapid onset of HIT) or later (>4 weeks after heparin exposure, ie, delayed onset of HIT). The platelet count typically decreases by 40% to 50% from baseline or the postoperative peak (in surgical patients), even though the absolute count may remain normal and the thrombocytopenia resolves within 7 to 14 days of cessation of heparin therapy (unless there is another coexisting cause of thrombocytopenia). Development or progression of (venous or arterial) thrombosis is termed heparin-induced thrombocytopenia with thrombosis syndrome and can occur in 30% to 50% of patients, rarely even following discontinuation of heparin therapy.

Other Syndromes of Thrombocytopenia and Thrombosis:

There are an increasing number of reports of patients who develop thrombocytopenia and thrombosis after surgery, particularly after orthopedic surgery and after selected infections. The clinical course and laboratory characteristics of this group of patients are similar to the classical HIT occurring with heparin exposure except perhaps development of high titer antibodies against heparin/PF4 complexes. An emerging recognition is the development of thrombocytopenia and thrombosis occurring 3 to 4 weeks after adenovirus vector SARS-CoV-2 exposure. The clinical course is also similar to immune HIT.

Laboratory Characteristics of HIT:

HIT is caused, in at least 90% of cases, by antibodies to antigen complexes of heparinoid (heparin or similar glycosaminoglycans) and PF4. PF4 is a platelet-specific heparin-binding protein that is abundant in platelet alpha granules from which it is secreted following platelet stimulation. A reservoir of PF4 normally accumulates on vascular endothelium. Following heparin administration, immunogenic complexes of PF4 and heparin can provide an antigenic stimulus for antibody development in some patients. Antibodies bound to platelets that display complexes of PF4/heparin antigen can activate platelets via interaction of the Fc immunoglobulin tail of the IgG antibody with platelet Fc gamma IIa receptors, leading to perpetuation of the pathologic process that can cause platelet-rich thrombi in some cases.

Functional assays for HIT antibody detection rely on antibody-mediated heparin-dependent platelet activation. The endpoint of platelet activation may be platelet aggregation or platelet secretion of serotonin or adenosine triphosphate (ATP) using patient serum or plasma supplemented with heparin and platelets from carefully normal selected donors. The sensitivity of functional assays for HIT ranges from 50% to 60% for heparin-dependent platelet aggregation assays to 70% to 80% for serotonin release assays. The specificity of positive functional tests for HIT diagnosis is believed to be high (≥90%). However, because of their complexity, functional tests for detecting HIT antibodies are not widely available.

Enzyme-linked immunosorbent assays (ELISA) are available to detect HIT type 2 (HIT-II) antibodies and are based on the detection of human IgG antibodies that react with solid phase antigen complexes of heparinoid and human PF4 (H/PF4) complexes. The ELISA for H/PF4 antibodies is very sensitive for antibody detection but relatively nonspecific for clinical HIT diagnosis.

Routine screening of all patients prior to, during, or following heparin use is currently not recommended. A positive H/PF4 ELISA result has relatively low and uncertain predictive value for the development of clinical HIT-II.

Clinical Picture of Immune HIT or HIT-like Syndromes:

HIT in patients not previously exposed to heparin:

1. Decrease in platelet count (thrombocytopenia) of 50% from baseline or postoperative peak.

2. Onset of thrombocytopenia beginning approximately 5 to 10 days after initiation of heparin. This may or may not be associated with new or progressive thrombosis in patients treated with heparin.

Patients previously exposed to heparin (especially within the preceding 100 days): in addition to the above findings, the onset of thrombocytopenia could occur within 24 to 48 hours after reexposure to heparin.

Spontaneous or Autoimmune HIT:

Patients typically present a week to 10 days after surgery or viral infections with symptoms of thrombosis (venous thromboembolism) or abdominal pain (suggesting adrenal infarction) and thrombocytopenia.

Vaccine Induced Thrombocytopenia and Thrombosis:

Patients typically present 4 days to 4 weeks after receiving the vaccine. Symptoms may include new onset of severe headache (suggesting cerebral venous sinus thrombosis), abdominal pain (suggesting mesenteric/portal vein thrombosis), or venous/arterial thromboembolism.