Linkins LA, Bates SM, Lee AY, et al.
Combination of 4Ts score and PF4/H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia: prospective cohort study
Blood.
2015;126:597-603.
http://www.bloodjournal.org/content/126/5/597.long?sso-checked=true

Thrombocytopenia and heparin exposure are common among hospitalized patients; as a result, clinicians often consider the diagnosis of heparin-induced thrombocytopenia (HIT) when making daily assessments. True HIT is rare, but because its complications can be devastating, providers have a low threshold for performing laboratory testing and discontinuing heparin. ASH has published trial data indicating that clinicians who suspect HIT should calculate a “4Ts” score in order to estimate the patient’s pre-test probability of disease.

Age/sexPatient typeHITT4Ts scorePF4/H-PaGIA resultMean SRA (%)EIA (00)Anticoagulant before SRA resultAnticoagulant after SRA resultClinical outcome (at day 30)
Management failures
         TEBleedDeath
70 M Oncology No POS 96 1.87 Fonda FD Fonda FD 
46 M Oncology DVT POS 90 1.92 Fonda FD Fonda FD 
73 M CVS No POS* 66 2.60 Fonda FD Fonda FD 
81 M CVS HD lines POS 59 2.10 Fonda proph Fonda FD DVT 
77 M CVS No POS 92 2.82 None Dana FD 
53 M Gen surg DVT POS 99 2.81 Fonda proph Argatroban PE 
Age/sexPatient typeHITT4Ts scorePF4/H-PaGIA resultMean SRA (%)EIA (00)Anticoagulant before SRA resultAnticoagulant after SRA resultClinical outcome (at day 30)
Management failures
         TEBleedDeath
70 M Oncology No POS 96 1.87 Fonda FD Fonda FD 
46 M Oncology DVT POS 90 1.92 Fonda FD Fonda FD 
73 M CVS No POS* 66 2.60 Fonda FD Fonda FD 
81 M CVS HD lines POS 59 2.10 Fonda proph Fonda FD DVT 
77 M CVS No POS 92 2.82 None Dana FD 
53 M Gen surg DVT POS 99 2.81 Fonda proph Argatroban PE 

Abbreviations: HITT, HIT positive with thrombosis; SRA, serotonin release assay; EIA, enzyme immunoassay; OD, optical density; TE, thrombotic event; ortho, orthopaedic surgery; ICU, intensive care; CVS, cardiovascular surgery; CCU, cardiac care; gen surg, general surgery; PE, pulmonary embolism; DVT, deep vein thrombosis; CVA, cerebrovascular accident; HD, hemodialysis; POS, positive; NEG, negative; M, male; Fonda FD, fondaparinux full dose; Fonda proph, fondaparinux prophylactic dose; Dana FD, danaparoid fill dose; IND, indeterminate SRA.

*Frozen blood sample

†Fondaparinux was held at time of event

In a prospective management study, Dr. Lori-Ann Linkins and colleagues tested the hypothesis that the use of a rapid particle gel immunoassay (platelet factor 4/heparin [PF4/H]-PaGIA [a gel centrifugation assay in which polymer beads agglutinate if anti-PF4/H antibodies are present]) might be combined with the 4Ts score to improve the initial, rapid assessment of patients with suspected HIT.1  Each of the 526 participants had a 4Ts score calculated, as well as a PF4/H-PaGIA and a serotonin-release assay (SRA) performed. While awaiting SRA results, participants with either a low 4Ts score (irrespective of PF4/H-PaGIA result) or an intermediate 4Ts score plus a negative PF4/H-PaGIA result received prophylactic doses of danaparoid or fondaparinux; all others received therapeutic doses of non-heparin anticoagulants. The authors concluded that HIT could be safely excluded with a low or intermediate 4Ts score plus a negative PaGIA result, but that “any other combination of results justified the use of alternative anticoagulants until HIT could be excluded.” The primary outcome, “management failure,” occurred in six (1.1%; 95% CI, 0.2%-2.1%) of 526 participants. A patient was considered a management failure if he or she was ultimately determined to have HIT after having either a low 4Ts score or the combination of an intermediate 4Ts score plus a negative PF4/H-PaGIA result at the time of the initial evaluation. Serotonin-release assay (SRA) testing, considered to be the gold standard for the diagnosis of HIT in this study, was negative in all 441 patients whose PaGIA results were negative. Of the 321 patients with a low (0-3) 4Ts score, six (1.9 %) were diagnosed with HIT (based on a positive SRA). Of these six patients with both a low 4Ts score and a positive SRA, three patients had a 4Ts score of 3.

In Brief

What are the take-home messages from this study? At first glance, the study creates some uncertainty about whether one can ever use the 4Ts score without laboratory tests to make clinical decisions. For example, is the ASH Pocket Guide (available at http://www.hematology.org/Clinicians/Guidelines-Quality/Quick-Reference.aspx) wrong to suggest that patients with a low 4Ts score need not undergo laboratory testing for HIT? Before reaching such a conclusion, we must remember that clinical prediction rules are only as good as the persons who are calculating them. Thus it is possible that the 4Ts score was miscalculated in some of the six patients in the present study who had a positive SRA despite a low pre-test probability of HIT. Indeed, a meta-analysis of more than 1,700 patients with a low 4Ts score concluded that the negative predictive value of a 4Ts score lower than 4 is 0.998 (95% CI, 0.970-1.000),2  a finding that supports the practice of avoiding laboratory testing (and searching for other explanations for thrombocytopenia) in patients with a 4Ts score of 0 to 3. That notwithstanding, the present study highlights the importance of an accurate 4Ts assessment and suggests that any uncertainty about the clinical data used to calculate the 4Ts score should lead to cessation of heparin, empiric non-heparin anticoagulation, and some form of objective, highly sensitive laboratory testing. Whether the PaGIA replaces the commonly used enzyme-linked immune-fluorescence assays for HIT screening will depend on a variety of factors, including cost, turnaround time, and overall availability.

References

References
1.
Linkins LA, Bates SM, Lee AY, et al.
Combination of 4Ts score and PF4/H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia: prospective cohort study
Blood.
2015;126:597-603.
http://www.bloodjournal.org/content/126/5/597.long?sso-checked=true
2.
Cuker A, Gimotty PA, Crowther MA, et al.
Predictive value of the 4Ts scoring system for heparin-induced thrombocytopenia: a systematic review and meta-analysis
Blood.
2012;120:4160-4167.
http://www.bloodjournal.org/content/120/20/4160.long

Competing Interests

Dr. Garcia indicated no relevant conflicts of interest.