February 6, 2018

Yu-Min Shen, Heather Wolfe, Stephen Barman

JAMA. 2018;319(5):497-498. doi:10.1001/jama.2017.21898

A 45-year-old man was hospitalized with abdominal pain. He was diagnosed with superior mesenteric vein thrombosis with mesenteric ischemia and treated with partial small bowel resection and 2 weeks of enoxaparin while hospitalized. Three weeks later, he presented again with abdominal pain. A computed tomography (CT) scan demonstrated fluid collections adjacent to the ascending colon and bowel wall thickening with intestinal pneumatosis consistent with ischemic bowel. Superior mesenteric vein thrombosis was redemonstrated on CT scan. An intravenous course of piperacillin-tazobactam was started, and an exploratory laparotomy with bowel resection was performed. Postoperatively, intravenous heparin was started. One day following surgery, a CT scan demonstrated a new left femoral vein thrombosis and pulmonary embolism. Laboratory data are shown in Table 1.

一名45岁男性患者因腹痛住院。诊断为肠系膜上静脉血栓形成伴肠系膜缺血，在住院期间接受部分小肠切除及为期2州的伊诺肝素治疗。3周后，患者因腹痛再次就诊。CT扫描显示升结肠附近积液，肠壁增厚伴囊样积气，符合肠缺血表现。CT扫描再次发现肠系膜上静脉血栓形成。开始静脉使用哌拉西林-他唑巴坦，并行剖腹探查肠切除术。术后开始静脉使用肝素。术后1天，CT扫描显示新发左侧股静脉血栓形成及肺栓塞。实验室检查见表1。

问题：How Would You Interpret These Test Results? 你如何解读上述检查结果？

答案：B. Replace heparin with argatroban for heparin-induced thrombocytopenia. 因肝素诱导血小板减少使用阿加曲班替代肝素

Two forms of heparin-induced thrombocytopenia (HIT) have been described. HIT type 1 (occurs ≤20% of patients with HIT) is due to heparin-induced platelet clumping with no increased risk of thrombosis and will not be discussed further in this article. HIT type 2 results from platelet activation by anti-heparin/platelet factor 4 antibody, resulting in a 30-fold increased risk of thrombosis and platelet consumption.¹ Treatment with heparin is more likely than low-molecular-weight heparin to cause HIT (3% vs 1%).²Among patients with HIT, platelet counts typically begin to decrease by at least 50% from baseline level 5 to 14 days after heparin exposure. Rapid-onset HIT occurs in patients previously exposed to heparin. In this condition, the HIT antibody that formed with prior heparin exposure remains active and platelets decrease within 24 hours of heparin reexposure.¹

肝素诱导血小板减少(HIT)有两种类型。1型HIT（在HIT患者中 ≤20%）因肝素诱导血小板聚集发病，血栓形成风险并不增加，在此不赘述。2型HIT因抗肝素/血小板因子4抗体激活血小板发病，导致血栓形成和血小板消耗风险增加30倍。肝素治疗较低分子肝素更容易引起HIT (3% vs 1%)。在HIT患者中，通常在肝素暴露后5-14天，血小板计数从基线水平下降至少50%。既往使用过肝素的患者的HIT可迅速起病。在这种情况下，既往使用肝素时产生的HIT抗体仍具有活性，再次使用肝素24小时内即出现血小板减少。

When HIT is suspected, the 4Ts score is used to determine the pretest probability of HIT (Table 2). Scoring is based on timing and potential magnitude of platelet count decrease, presence of thrombosis, and alternative causes of thrombocytopenia. Patients with 4Ts score of 0 to 3 have less than a 5% risk of HIT and require no further testing. Patients with a 4Ts score of 4 or greater should undergo HIT antibody testing.³

怀疑HIT时，可使用4Ts评分确定HIT的验前概率（表2）。根据血小板计数下降的时间及可能的严重程度，是否合并血栓形成，以及是否存在引起血小板减少的其他原因等进行评分。4Ts评分0-3分者HIT的风险不足5%，无需进一步检查。4Ts评分4分或更高的患者应当进行HIT抗体检测。

Initial testing for the HIT antibody is performed using an enzyme-linked immunosorbent assay (ELISA). ELISA is widely available, performed using a peripheral blood sample, and results are available within 4 hours. Two types of ELISA tests are available: polyspecific ELISA (detects IgG, IgA, and IgM antibodies; [sensitivity, 98.1% and specificity, 74.2%]); and IgG-specific ELISA (detects only IgG antibodies most likely to cause HIT; has better specificity [89%] with minimal decrease in sensitivity [95.8%]).⁴ The positive predictive value ranges from 10% to 93% depending on the patient population, but the negative predictive value exceeds 95%.² As many as 20% of patients develop HIT antibody after heparin exposure, but most will never develop clinically manifest HIT. The Medicare midpoint reimbursement for the IgG-specific ELISA is $20.43.⁵

HIT抗体的初始检测可采用ELISA法。ELISA检测已得到广泛使用，检测可采用外周血标本，4小时内即可得到结果。目前有2种ELISA检测方法：多特异性ELISA（检测IgG, IgA, 和 IgM 抗体；[敏感性 98.1%，特异性 74.2%]）；特异性IgG ELISA（仅检测最容易引起HIT的IgG 抗体；特异性更好 [89%] ，敏感性轻度降低 [95.8%]）。根据患者人群不同，阳性预期值为10%至93%，但阴性预期值超过95%。多达20%的患者在肝素暴露后产生HIT抗体，但多数从未发生临床HIT。Medicare 对特异性 IgG ELISA的报销中位数为20.43美元。

The patient was exposed previously to enoxaparin, with a time course consistent with rapid-onset HIT. Given the high clinical suspicion for HIT (4Ts score, 6), heparin was discontinued. The HIT antibody IgG ELISA was positive with 2.163 optical density units, consistent with HIT.

此例患者既往使用过伊诺肝素，其疗程符合迅速起病HIT的特点。由于临床高度怀疑HIT（4Ts评分6分），遂停用肝素。ELISA检测 HIT IgG抗体结果为2.163 OPU（光密度单位），符合HIT。

Due to the low specificity of the HIT ELISA assays, positive results should be confirmed by the serotonin release assay (SRA), a functional assay that detects platelet activation in the presence of patient serum and heparin. The SRA has an estimated sensitivity of 88% and specificity near 100%.⁶ A higher ELISA antibody titer is associated with higher rates of positive SRA. An IgG ELISA titer of 2.0 or greater is associated with SRA positivity of 91.6%.⁷ SRA is seldom performed due to limited availability. Alternatively, a second ELISA can be performed with a reagent containing high-dose heparin. If an initially positive HIT antibody titer is inhibited by more than 50% with high-dose heparin, the presence of HIT antibody is confirmed.⁸

由于HIT ELISA检测方法的特异性很低，一旦得到阳性结果，应当通过5-羟色胺释放检测(SRA)方法确诊。SRA是一种功能性检测方法，可使用含有肝素的患者血清检测血小板激活。SRA的敏感性为88%，特异性接近100%。较高的ELISA抗体滴度伴随较高的SRA阳性率。ELISA IgG 滴度2.0或更高，伴随SRA阳性率91.6%。由于缺乏设备，很少进行SRA检测。此外，可使用含有大剂量肝素的试剂进行另一种ELISA检测。如果大剂量肝素能够将初始检测阳性的HIT抗体滴度抑制超过50%，则可确诊存在HIT抗体。

Treatment of HIT requires discontinuation of heparin products and initiation of a nonheparin anticoagulant to treat the immediate hypercoagulable state. Direct thrombin inhibitors, fondaparinux, and direct oral anticoagulants are effective. Patients should continue taking nonheparin anticoagulants until the platelet count is normal. For those without thrombosis, the optimal duration of anticoagulation is unknown; experts recommend 1 month of anticoagulation due to the high risk of thrombosis. Those with known thrombosis secondary to HIT should receive anticoagulants for 3 months.⁹

HIT的治疗要求停用肝素制品，并开始使用非肝素类抗凝药物治疗高凝状态。直接凝血酶抑制剂、磺达肝癸钠和口服抗凝剂都有效。患者应当继续使用非肝素类抗凝药物，直至血小板计数正常。对于那些没有血栓形成的患者，抗凝治疗的适当疗程尚属未知；因血栓形成风险较高，专家建议抗凝一个月。已经因HIT发生血栓形成的患者应当接受抗凝治疗3个月。

The patient was treated initially with argatroban followed by fondaparinux once the platelet count was 150 × 10³/μL. Warfarin was not prescribed because of concern for poor absorption following the bowel resection. After a 1-year hospitalization, the patient died of fungemia unrelated to HIT.

患者首先使用阿加曲班治疗，当血小板计数达到150× 10³/μL时改用磺达肝癸钠。由于顾虑到肠切除手术后胃肠吸收功能不佳，因此没有使用华法令。一年后，患者因真菌血症（与HIT无关）死亡。

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