肝素诱导的血小板减少性血栓形成1例

患者,女,60岁,因呼吸困难、不能平卧、双下肢水肿4d、晕厥2次于2005年3月5日入院。入院后根据临床表现及心脏超声、心电图、肺灌注扫描诊断为肺动脉血栓栓塞。溶栓后给予肝素5000U负荷量,以800U/h微泵泵入,持续48h后给予低分子肝素5000U,q12h,ip,同时给予华法林2·5mg/d等治疗。患者呼吸困难缓解,可平卧,双下肢水肿消退,周径对称。入院时查血常规WBC6·43×109/L,RBC4·33×1012/L,Hb139g/L,PLT222×109/L;PT12s,APTT30s,INR1·1。患者应用肝素第5天复查血常规:WBC3·67×109/L,RBC3·75×1012/L,Hb118g/L,PLT12×109/L,IN…     

非体外循环冠状动脉旁路移植术中肝素诱导血小板减少并血栓形成一例

1病例资料 患者女性,59岁,因“阵发性心前区闷痛6年,加重1年”,于2012年3月9日入院。既往有高血压、糖尿病病史,一直口服药物治疗,血压、血糖控制可。入院前曾皮下使用肝素抗凝治疗。入院查体：血压140／70mmHg（1mmHg=0．133kPa）,心肺查体未见明显异常。实验室检查,血常规：     

Hirudin in heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia (HIT), a serious side effect of heparin treatment, requires alternative anticoagulation in most affected patients. The recombinant hirudin (r-hirudin) lepirudin has been approved for this purpose after two prospective trials in laboratory-confirmed HIT patients. Other drugs available for this purpose are danaparoid sodium (a heparinoid) and argatroban, a synthetic direct thrombin inhibitor. In this article, recommendations for optimal use of r-hirudin in HIT are given, covering therapy in uncomplicated patients as well as in special situations such as heparin reexposure of HIT patients. Because lepirudin's half-life depends on renal function, it may vary between 1 and 200 hours, which requires individual dose adjustments. Lepirudin compares favorably with danaparoid, based on retrospective data. No direct comparisons of lepirudin with argatroban are available, but argatroban might offer advantages in patients with renal failure, because it is mainly eliminated hepatically. Major hemorrhage, the main risk of lepirudin treatment, occurring in about 15% of patients, makes close monitoring important. New monitoring tools, such as the ecarin clotting time (ECT), might further reduce bleeding risks. Antihirudin antibodies, which can alter the pharmacokinetics as well as the pharmacodynamics of hirudin, can also be countered by close monitoring and appropriate dose adjustments. Whereas hirudins have not yet managed to gain importance in non-HIT indications such as unstable coronary syndromes, they have a major role to play in the treatment of HIT. The choice between the available drugs for HIT, namely lepirudin, danaparoid, and argatroban, has to be made according to the clinical presentation of the patient.     

Delayed-onset heparin-induced thrombocytopenia

Delayed-onset heparin-induced thrombocytopenia is a syndrome in which thrombocytopenia and thrombosis begin several days after heparin discontinuation. Delayed-onset heparin-induced thrombocytopenia is caused by immunoglobulin G antibodies that are reactive against the heparin-platelet factor 4 complex in the absence of circulating heparin. We describe 2 patients with delayed-onset heparin-induced thrombocytopenia who presented to the emergency department. An 88-year-old man and a 62-year-old man experienced thrombocytopenia and thrombosis 9 or more days after heparin cessation and demonstrated a further decrease in platelet count on reexposure to heparin. Delayed-onset heparin-induced thrombocytopenia should be included in the differential diagnosis of a patient with recent heparin exposure who presents with thrombosis or thrombocytopenia.     

Pentosan polysulfate-induced thrombocytopenia: a case diagnosed with an ELISA test used for heparin-induced thrombocytopenia

 We report a patient who developed severe thrombocytopenia and ischemic stroke following pentosan polysulfate treatment. An ELISA test employed in type-II heparin-induced thrombocytopenia was highly positive. To our knowledge, this is the first case in which this test has been performed in a pentosan polysulfate-induced thrombocytopenia (PIT). Our data suggest that the antibody against pentosan polysulfate-platelet complex also cross-reacts with heparin-platelet factor 4 complex. Due to its greater sensitivity and wider availability, this ELISA test should be used in cases where PIT is suspected. Received: 30 January 1996 / Accepted: 22 April 1996     

A case of pulmonary thromboembolism with heparin-induced thrombocytopenia]

In February 2000, a 70-year-old man was admitted to our hospital complaining of back pain and dyspnea on exertion. Pulmonary thromboembolism was diagnosed, and he was treated with intravenous urokinase and heparin. The pulmonary thromboembolism improved, though heparin-induced thrombocytopenia (HIT) was subsequently observed. The thrombocytopenia was then improved by withdrawing the intravenous heparin, but thrombosis appeared extending from both femoral veins to the inferior vena cava. The thrombosis was dispersed by catheter-directed thrombolysis. There have been few reports of HIT in Japan. Heparin is frequently used for the treatment of pulmonary thromboembolism, but special care must be taken, since severe thrombotic complications are associated with HIT.     

Treatment with lepirudin in heparin-induced thrombocytopenia. A case report

We report the case of a 71 old woman presenting a bilateral massive pulmonary embolism with intraventricular right thrombus complicating heparin induced thrombocytopenia (HIT) persistent after one month of conventional anticoagulant processing. We underline the effectiveness of lepirudin (Refludan) in the curative processing of pulmonary embolism allowing here to avoid a complex surgical thromboembolectomy. We evoke the place of this molecule in the curative therapeutic strategy of HIT with thrombotic phenomena.     

Investigation of a platelet factor 4 polymorphism on the immune response in patients with heparin-induced thrombocytopenia

A small fraction of patients who receive heparin develop heparin-induced thrombocytopenia (HIT) and, of these patients, a still smaller proportion develop associated thrombotic complications. Heparin-induced thrombocytopenia is caused by the formation of antibodies that bind to specific complexes of platelet factor 4 (PF4) and heparin. However, it remains uncertain why certain patients form these antibodies and develop HIT or why certain patients have thrombotic events. In this report we describe studies on individuals with and without HIT to determined if a potential PF4 polymorphism could explain differences in susceptibility to HIT. In the 10 control individuals and the 10 patients we studied, we did not find a difference in the PF4 sequences. Genetic difference in the PF4 antigenic target does not explain the occurrence of HIT in susceptible patients.     

Investigation of a platelet factor 4 polymorphism on the immune response in patients with heparin-induced thrombocytopenia

A small fraction of patients who receive heparin develop heparin-induced thrombocytopenia (HIT) and, of these patients, a still smaller proportion develop associated thrombotic complications. Heparin-induced thrombocytopenia is caused by the formation of antibodies that bind to specific complexes of platelet factor 4 (PF4) and heparin. However, it remains uncertain why certain patients form these antibodies and develop HIT or why certain patients have thrombotic events. In this report we describe studies on individuals with and without HIT to determined if a potential PF4 polymorphism could explain differences in susceptibility to HIT. In the 10 control individuals and the 10 patients we studied, we did not find a difference in the PF4 sequences. Genetic difference in the PF4 antigenic target does not explain the occurrence of HIT in susceptible patients.     

Orgaran in heparin-induced thrombocytopenia.

Patients who develop heparin-induced thrombocytopenia (HIT) frequently need further anticoagulation to treat an ongoing thromboembolic problem or to prevent one. Orgaran (Org 10172), a low-molecular-weight (LMW) glycosaminoglycuronan, has shown a low frequency (10%) of cross-reactivity in vitro with sera containing the HIT antibody, in contrast to the much higher frequency of cross-reactivity (approximately 80%) shown by the LMW heparins. This paper summarises the results of intravenous or subcutaneous Orgaran treatment in 57 of 67 Australian patients, in whom the diagnosis of HIT was reasonably confirmed by exclusion of other causes of thrombocytopenia and by objective tests. The presenting indications for Orgaran were: continuous venovenous haemofiltration and haemodialysis (n = 21), thrombo-embolism treatment (n = 23), thrombo-embolism prophylaxis (n = 10), and anticoagulation for coronary artery by-pass graft (n = 4), peripheral by-pass graft surgery and plasmapheresis (n = 1 each). The results showed Orgaran to be a safe, well-tolerated, effective (successful treatment in over 90% of patients) anticoagulant in patients with a high thrombotic and/or bleeding risk even if critically ill and requiring haemofiltration. The complete results of the world-wide study in 161 patients confirmed not only these clinical findings in the subgroup of 57 Australian patients, but also the low cross-reactivity (12%) of Orgaran with the HIT serum factor.     

Case studies in heparin-induced thrombocytopenia

Type II heparin-induced thrombocytopenia (HIT) is an immunological disorder characterized by antibodies to heparin-platelet factor 4 complexes and a high risk of thrombotic complications. Here, we present illustrative case histories to educate the reader on evaluation and management of this complex syndrome. Cases include typical and unusual presentations of the syndrome, and commonly encountered problems and pitfalls of therapy. Major points illustrated are, (1) occurrence of HIT with any dose or form of heparin; (2) misperceptions on the diagnostic criteria; (3) correct (thrombin inhibitors) and incorrect (platelet transfusions and warfarin) management; (4) influence of management strategy on clinical outcomes; (5) severity of the syndrome; and (6) potential for both anamnestic response to heparin and disappearance of HIT antibodies over time. Effective therapy of HIT involves both the prompt recognition of the syndrome and its proper management.     

Venous thromboembolism in heparin-induced thrombocytopenia

Deep-vein thrombosis (DVT) and pulmonary embolism are among the most common complications of heparin-induced thrombocytopenia (HIT), an antibody-mediated adverse effect of heparin that leads paradoxically to in vivo activation of platelets and the coagulation system. Inappropriate treatment of HIT-associated DVT with warfarin can cause the DVT to progress to limb gangrene: this results from impaired ability of the protein C natural anticoagulant pathway to down-regulate thrombin generation, thus leading to microvascular thrombosis and tissue necrosis. Appreciation of the importance of coagulation system activation in HIT provides a rationale for treatments that reduce thrombin generation, either via inhibiting factor Xa (danaparoid) or via inhibiting thrombin directly (lepirudin). Clinicians should know how to distinguish HIT from other thrombocytopenic disorders: for example, thrombocytopenia associated with pulmonary embolism can mimic HIT (pseudo-HIT), and acute dyspnea that can mimic acute pulmonary embolism can result from acute in vivo platelet activation in a patient with HIT antibodies who receives heparin bolus therapy (pseudo-pulmonary embolism).     

The role of platelet factor 4 in platelet aggregation induced by the antibodies implicated in heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is a severe side effect of heparin treatment. Recent studies using immunological methods demonstrated that antibodies contained in plasma, or in purified total immunoglobulin (Ig)G from patients suffering HIT, recognize as target antigen the complex heparin/platelet factor (PF4). In the present study, the role of PF4 in in-vitro platelet aggregation induced by purified total IgG or platelet-poor plasma from patients suffering HIT was investigated. In order to demonstrate the functional role of PF4, an anti-PF4 antibody that specifically blocked PF4 was used. In an experimental system composed of washed platelet suspension, incubation of F(ab')2 fragments (0.125 microg/ml) of the polyclonal anti-PF4 antibody resulted in complete inhibition of platelet aggregation triggered by purified total IgG from patients suffering HIT and heparin. In platelet-rich plasma, a significantly higher concentration (4.25 microg/ml) of the anti-PF4 F(ab')2 was required to inhibit platelet aggregation induced by HIT-PPP and heparin. Intermediate concentrations of the anti-PF4 antibody partially inhibited platelet aggregation. In plasma milieu, the concentration of PF4 was about five-fold higher in comparison with that measured in the purified system. The intensity of platelet aggregation depended on the concentration of HIT-IgG. Platelet aggregation was abolished in the presence of high concentrations of heparin (superior or equal to 10 IU/ml). The present study shows that PF4 is essential for platelet aggregation triggered by the antibodies related to HIT in the presence of heparin. The concentration of PF4 that is available to bind with heparin or with the HIT-related antibodies is critical for platelet aggregation induced by HIT antibodies.