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学位を持っても、センスのない、感染制御専門薬剤師のブログ.  I have Ph.D. but less sense ID pharmacist.

Heparin-induced thrombocytopenia (HIT)

Heparin-induced thrombocytopenia (HIT) を疑う重症な症例に出会いました。



Heparin-induced thrombocytopenia (HIT) is a life-threatening, immune-mediated complication of exposure to heparin (unfractionated or low molecular weight [LMW] heparin) that occurs in up to 5 percent of patients exposed. HIT is caused by autoantibodies to platelet factor 4 (PF4) complexed with heparin. These antibodies cause thrombocytopenia and thrombosis by peripheral platelet consumption and platelet activation, respectively.
Risk factors for HIT include unfractionated rather than LMW heparin in surgical patients, higher heparin doses, female sex, surgery, and possibly age, but HIT can occur in any patient following any heparin exposure. 
The most common and often the first manifestation of HIT is thrombocytopenia, occurring in up to 90 percent of those affected. Thrombosis occurs in up to 50 percent, with venous being more common than arterial thrombi; thrombosis is the presenting finding in up to 25 percent of patients. Thrombosis can lead to skin necrosis, limb gangrene, and organ infarction. Acute systemic anaphylactic reactions have also been described.
We always consider clinical and laboratory evidence in evaluating patients for HIT. However, definitive laboratory data may not be available for several days, and it may be necessary to make a presumptive diagnosis of HIT while awaiting these data. Not diagnosing HIT when it is present or mistakenly diagnosing HIT when it is absent both carry significant risks (eg, life-threatening thrombosis or life-threatening bleeding, respectively).
The 4 T's score  is used to estimate the likelihood of HIT based on readily available clinical data, including the degree of Thrombocytopenia, Timing of platelet count drop, presence of Thrombosis, and absence of oTher causes of thrombocytopenia.
We make a presumptive diagnosis of HIT if the 4 T's score is intermediate or high probability. 
If the 4 T's score is low probability, we generally do not pursue HIT antibody testing, because the risk of HIT is exceedingly low. However, the score does not substitute for a hematologist's clinical judgment; in rare or complex cases, a clinician may suspect HIT despite a low probability 4 T's score (eg, platelet count just outside a cutoff value, uncertainty regarding alternative causes of thrombocytopenia), and a presumptive clinical diagnosis of HIT may be made
Patients with a presumptive diagnosis of HIT should have immediate discontinuation of all sources of heparin, and administration of a non-heparin anticoagulant unless there is bleeding or a high risk of bleeding, to reduce the risk of life-threatening thrombosis if the patient has HIT. 
We confirm or refute the diagnosis of HIT using HIT antibody testing (eg, immunoassay and sometimes functional assay). We generally limit HIT antibody testing to those with an intermediate or high probability 4 T's score. 
We generally start with an immunoassay (eg, ELISA), and interpret the results based on the optical density (OD) result as follows :
ELISA OD <0.40 – HIT excluded. We do not perform functional HIT antibody testing unless the clinical picture changes or the clinical picture is discordant (eg, high probability 4 T's score). 
ELISA OD >2.00 – HIT confirmed. We do not perform functional HIT antibody testing. 
ELISA OD 0.40 to 2.00 – Indeterminant. We continue administration of the non-heparin anticoagulant and heparin avoidance; and we perform a functional assay.
We perform a functional assay if the ELISA OD is 0.40 to 2.00 or the clinical and laboratory findings are discordant. A positive functional assay confirms a diagnosis of HIT, and a negative functional assay excludes a HIT diagnosis.
If the diagnosis of HIT is confirmed by definitive HIT antibody testing, we continue the non-heparin anticoagulant; the patient should avoid heparin for life.
Patients with renal failure and after cardiopulmonary bypass have a high incidence of heparin-induced antibodies with unclear clinical significance. We only test for HIT antibodies in these patients if there is a high suspicion of HIT based on clinical findings. 
If the diagnosis of HIT is excluded, we discontinue the non-heparin anticoagulant; restart heparin if indicated; and evaluate the patient for alternate causes of thrombocytopenia. The differential diagnosis of HIT includes disseminated intravascular coagulation/sepsis, immune thrombocytopenia, post-transfusion purpura, thrombotic microangiopathy, drug-induced thrombocytopenia, venous thrombosis unrelated to heparin, cardiopulmonary bypass, lupus or antiphospholipid antibody syndrome, and delayed-type hypersensitivity reactions to heparin. 
4 T's score
Calculating the score — The 4 T's score is used for estimating the likelihood of HIT based on readily available clinical features. It is used to make a presumptive diagnosis of HIT until laboratory data are available, and then integrated with laboratory data to make a final diagnosis.
The score assesses the degree of Thrombocytopenia, the Timing relative to heparin exposure, the presence of Thrombosis, and oTher causes for thrombocytopenia. Points are assigned as follows:
  • Platelet count fall >50 percent and nadir ≥20,000/microL – 2 points
  • Platelet count fall 30 to 50 percent or nadir 10 to 19,000/microL – 1 points
  • Platelet count fall <30 percent or nadir <10,000/microL – 0 points
●Timing of platelet count fall
  • Clear onset between days 5 and 10 or platelet count fall at ≤1 day if prior heparin exposure within the last 30 days – 2 points
  • Consistent with fall at 5 to 10 days but unclear (eg, missing platelet counts), onset after day 10, or fall ≤1 day with prior heparin exposure within 30 to 100 days – 1 point
  • Platelet count fall at <4 days without recent exposure – 0 points
●Thrombosis or other sequelae
  • Confirmed new thrombosis, skin necrosis, or acute systemic reaction after intravenous unfractionated heparin bolus – 2 points
  • Progressive or recurrent thrombosis, non-necrotizing (erythematous) skin lesions, or suspected thrombosis that has not been proven – 1 point
  • None – 0 points
●Other causes for thrombocytopenia
  • None apparent – 2 points
  • Possible – 1 point
  • Definite – 0 points
Interpretation — A point value for each of the four categories is determined, and the sum of these values gives a total from 0 to 8. Pretest probabilities for HIT are as follows:
  • 0 to 3 points – Low probability
  • 4 to 5 points – Intermediate probability
  • 6 to 8 points – High probability
Importantly, the 4 T's score captures the major clinical features of HIT (eg, thrombocytopenia, thrombosis, skin necrosis, and acute systemic reactions) and the likelihood that these findings are due to heparin rather than another cause (based on the temporal relationship to heparin and the absence of other causes). Although patients receiving heparin are at a higher-than-average baseline risk of thrombosis (eg, venous thromboembolism [VTE] or myocardial infarction [MI]), the development of VTE or MI alone will not generate an intermediate or high probability score.
The 4 T's score has been prospectively validated for patients exposed to unfractionated heparin in two centers. In 111 patients with a low probability of HIT, only one had clinically significant HIT antibodies (0.9 percent). In contrast, clinically significant HIT antibodies were present in 11.4 and 34 percent of those with intermediate and high probability scores, respectively.
Further validation of the utility of the 4 T's score comes from a meta-analysis of 3068 patients with clinically suspected HIT who were followed prospectively (eight trials) or evaluated retrospectively (five trials). In this meta-analysis, the proportion of those with a low probability 4 T's score who had a negative functional assay for HIT antibodies (ie, the negative predictive value [NPV]) was 0.998 (95% CI 0.97-1.0). This NPV of a low probability score remained high regardless of the party performing the scoring (clinician or study coordinator), the patient population being studied (medical or surgical), or the prevalence of HIT in the population. The proportions of those with an intermediate or high probability score who had a positive functional assay for HIT antibodies (ie, positive predictive values [PPVs]) were 0.14 and 0.64, respectively. These findings support our practice of limiting laboratory testing for HIT to patients with an intermediate or high probability 4 T's score (ie, 4 to 8 points) or in complex clinical settings in which HIT is suspected clinically but the 4 T's score is less reliable because of missing or incomplete information. 
In a study of 526 patients with possible HIT, 6 of 321 with a low probability 4T’s score (1.9 percent) had a positive functional assay (SRA), resulting in the NPV for a low probability 4T’s score of 98.1 percent. Addition of a rapid gel immunoassay (PF4/H-PaGIA) improved the NPV to 100 percent. However, such a gel immunoassay with rapid turnaround is not widely available, and in this study, all patients were treated with a non-heparin anticoagulant (prophylactic or therapeutic dose, depending on the clinical setting) while awaiting the SRA results.