Activated partial thromboplastin time after heparin removal (aPTT/HR) in a new scheme of anticoagulant monitoring

Activated partial thromboplastin time after heparin removal (aPTT/HR), a test employing anion exchange chromatography, was devised as an alternative to the prothrombin time after heparin removal (PT/HR) to monitor simultaneous anticoagulation with heparin and coumarins. The potential utility of the aPTT/HR was assessed by performing parallel PTs and aPTTs on 62 consecutive plasmas from coumarin-treated outpatients. All samples had 0.2 units/ml of heparin added and then removed to see if the maneuver influenced therapeutic group assignment. In no instance did reassignment occur. A conditional Irwin-Fisher test (P = 0.000604) and a special multinomial trial analysis (P = 0.002) indicated that the aPTT would be at least comparable to the PT for following coumarin antithrombotic prophylaxis. Since the heparin removal procedure had no influence on therapeutic categorization, the same statistical proof could be applied to the relationship between aPTT/HR and PT/HR. This study indicates that the aPTT can be used to monitor all stages of heparin and/or coumarin anticoagulation.     

Utility of a weight-based heparin nomogram for patients with acute coronary syndromes

Abstract
Background:  Unfractionated heparin has been pivotal in the management of acute coronary syndromes (ACS), and continues to be used widely despite the emerging role of low molecular weight heparins (LMWH). The apparent superiority of LMWH over unfractionated heparin may, at least partially, reside in its more predictable achievement of therapeutic effect, with high rates of non-therapeutic activated partial thromboplastin time (APTT) results being observed in the intravenous heparin treatment groups.
Aim:  To evaluate the impact of introduction of a weight-based heparin nomogram developed for use in patients with ACS on frequency of 'therapeutic' APTT results.
Methods:  The effectiveness of an existing non-weight-based heparin nomogram in achieving a therapeutic APTT was compared sequentially with that of a weight-based heparin nomogram in 89 and 84 consecutive patients admitted with a diagnosis of ACS.
Results:  Patients in whom heparin dosage adjustment was weight based rapidly achieved therapeutic APTT. The median time to achieve an APTT within the target range was 8.75 h in the weight-based group versus >24 h in the non-weight-based group. Utilization of a weight-based nomogram was associated with markedly increased proportions of readings within the therapeutic APTT range at 6 h and at 24 h (51% vs . 26% and 72% vs . 36%, respectively).
Conclusions:  The current study confirms the marked superiority of the weight-based heparin regimen for treatment of patients with ACS. The nomogram dramatically facilitated the attainment of therapeutic APTT, and may represent the optimal method for titration of heparin dosage to individual heparin requirements in patients with ACS. (Intern Med J 2003; 33: 18−25)     

The Determinants of Activated Partial Thromboplastin Time,Relation of Activated Partial Thromboplastin Time to Clinical Outcomes,and Optimal Dosing Regimens for Heparin Treated Patients with Acute Coronary Syndromes: A Review of GUSTO-IIb

Context: Unfractionated heparin remains widely utilized in the treatment of acute coronary syndromes (ACS). However, limited data exist on optimal dosing and range of activated partial thromboplastin time (aPTT) in this setting. A large trial of thrombolysis for acute myocardial infarction has reported an association between longer aPTTs and adverse outcomes. Objectives: Estimate the optimal heparin-dosing regimen in achieving early therapeutic aPTTs (50 to 75 seconds) and determine the association of aPTT and death, reinfarction, and bleeding in population with ACS. Design: Subgroup analysis within a randomized, controlled trial of 5861 patients given unfractionated heparin who had aPTTs at 6, 12, or 24 hours, with outcome analyses by weight categories. Setting: In 373 hospitals in 13 countries from May 1994 to October 1995. Patients: A total of 12,142 patients admitted for ACS, stratified by the presence (n = 4131) or absence (n = 8011) of ST-segment elevation, and randomized to 72 hours of unfractionated heparin. Results: In a simulated weight-adjusted model, based on retrospective grouping by weight, a simulated dose of 60-U/kg bolus and 12-U/kg/h infusion resulted in the highest proportion of therapeutic aPTTs. After adjustment for baseline variables, longer 12-hour aPTT was associated with the composite of 30-day death or reinfarction in patients not treated with thrombolytic therapy (odds ratio, 1.10; 95% CI, 1.00 to 1.22; P = 0.047). Longer aPTT at 6 hours was associated with increased moderate or severe bleeding for the entire cohort. There was also a significant, nonlinear correlation of the 12-hour aPTT with moderate or severe bleeding in thrombolysis-treated patients. Conclusions: For ACS patients who are treated with heparin, aPTT is highly associated with body weight. Longer aPTT within the first 12 hours is associated with adverse outcomes in ACS. Heparin dosing for ACS should be weight based.     

Is a standard regime for anticoagulation with heparin in unstable angina adequate?*

Abstract Aim: To establish the proportion of patients with unstable angina in whom adequate anticoagulation is achieved using a standard regime of intravenous heparin. Method: A prospective series of 108 Emergency Department attendees over a six-month period with a clinical diagnosis of unstable angina for whom anticoagulation with heparin was prescribed were included in the study. The standard regime was a 5000 unit bolus followed by an intravenous infusion of 1000 units per hour (1200 units if the patient's weight was greater than 80 kg), with subsequent adjustments being made by reference to a nomogram. The activated partial thromboplastin time (APTT) was measured at six and 12 hours after treatment began. Two commonly used criteria for adequate heparinisation were compared: 1. APTT greater than 1.5 times control and 2. APTT in the range 60–85 seconds. Results: There were valid data for 90 patients at six hours and 79 at 12 hours. Compared to the criterion for adequate anticoagulation of APTT greater than 1.5 times the control, 25% of patients were subtherapeutic at six hours and 12% at 12 hours. Compared to the criterion APTT greater than 60 seconds, 53% of patients were subtherapeutic at 6 hours and 47% at 12 hours. At 6 hours, 26% of patients were over-anticoagulated as defined as APTT greater than 85 seconds. This had reduced to 13% by 12 hours. Conclusions: In the context of recent research suggesting that an APTT of greater than 1.5 times the control is sufficient to reduce complications in unstable angina, our results demonstrate that a standard regime of heparinisation will achieve this goal in the majority of patients within 6 hours of starting heparin therapy. However, if an APTT of 60–85 seconds is the goal, this standard regime is inadequate.     

Intracerebral hemorrhage in a patient with SLE and catastrophic antiphospholipid syndrome (CAPS): report of a case

A 31-year-old woman was admitted to the hospital for investigation of left lower limb thrombophlebitis. History, physical examination, and laboratory investigations led to the diagnosis of systemic lupus erythematosus (SLE), complicated by secondary antiphospholipid syndrome (APS). Treatment included steroids, azathioprine, aspirin, and low molecular weight heparin. Sixty-three days later, she was admitted to the hospital again because of high fever, macroscopic hematuria, and dyspnea. Laboratory testing showed anemia and impaired renal function. High-resolution chest computed tomography (CT) revealed bilateral multiple peribronchial infiltrates with hemorrhage. Magnetic resonance imaging (MRI) angiography of the kidneys revealed left renal vein thrombosis combined with ischemia of the left kidney. Cyclophosphamide and methylprednisolone pulse treatment as well as intravenous immunoglobulins were started immediately. Despite intensive immunosuppressive and supportive treatment, she suffered three relapses of alveolar hemorrhage and died on day 40, due to severe intracerebral bleeding. The final diagnosis was catastrophic APS with diffuse alveolar hemorrhage and kidney involvement. The unusual combination of recurrent alveolar hemorrhage and death from intracerebral hemorrhage rather than thrombosis in a CAPS patient is discussed.     

原发性抗磷脂抗体综合征合并肺血栓栓塞症1例并文献复习

目的：了解原发性抗磷脂抗体综合征合并肺血栓栓塞症的临床特征。方法对近期北京医院收治的1例原发性抗磷脂抗体综合征合并肺血栓栓塞症患者进行分析,并复习32例国内外文献发表的原发性抗磷脂抗体综合征合并肺血栓栓塞症病例。结果33例患者中,男18例,女15例,主要症状包括呼吸困难、胸痛、咯血和下肢疼痛等,其中合并呼吸困难、胸痛、咯血三联征的比例为42.4%,双下肢静脉血栓占38.7%,双侧肺动脉栓塞占87.1%,右房和/或右室增大者占56.3%,合并肺动脉高压者占75.0%。部分患者合并血小板减少,活化部分凝血活酶时间明显延长。及时诊断和治疗能取得良好的疗效。结论原发性抗磷脂抗体综合征合并肺血栓栓塞症患者合并三联征(胸痛、咯血、呼吸困难)的比例高,血栓范围广泛,常合并右房和/或右室扩大、血小板和凝血机制异常,及时诊断和治疗可获得良好的疗效。     

Reproducibility and variability of activated clotting time measurements in the cardiac catheterization laboratory.

The objective of this study was to characterize the reproducibility and variability in the measurement to the activated clotting time (ACT) when performed on two different types of instruments, the HemoTec ACT (Medtronic) and the Hemochron 801 (International Technidyne). The ACT has evolved into the most common point-of-care test used in the cardiac catheterization lab to manage patient heparinization. Since the test has not been standardized, different systems frequently produce different results under the same clinical conditions. Duplicate paired ACT tests (n = 885) from 359 patients were performed on both instruments. Prothrombin times (PT) and activated partial thromboplastin times (aPTT) were also determined on subsets of these same samples (PT = 533; aPTT = 487). The performance and relationships between the two tests were determined using a variety of statistical analytical techniques. The average difference between the ACT devices was only 8 sec, yet more than 60% of the measurements varied by more than 10%. Over one-fourth of measurements varied by more than 20%. The reproducibility to the HemoTec instrument was superior to the Hemochron instrument across the entire range of ACTs measured (mean coefficient of variation 2.4% +/- 3.1% vs. 7.2% +/- 6.1% for HemoTec and Hemochron, respectively; P < 0.00001; range = 65-555 sec). The relationship between the two ACTs was nonlinear. In therapeutic ranges used for interventional procedures (200-350 sec), HemoTec and Hemochron ACTs are not comparable to one another. Statistical comparative analysis indicated that the HemoTec ACT has better overall performance.     

特发性血小板减少性紫癜合并抗磷脂抗体综合征患者ACS后成功PCI术1例

1 病例资料患者,女,71岁,因胸闷1d,突发晕厥1次入院.患者本次入院为1d前(上午10时许)活动时出现压迫性胸骨中段胸闷,伴左侧手臂痛,出冷汗,伴头晕恶心,家属急送至我院急诊(约14:00时),患者于急诊门口突发晕厥,心电监护提示心室颤动,立即予心肺复苏、电除颤,10余分钟后好转,急查肌钙蛋白7.52 ng/...     

Multiorgan failure due to rapid occlusive vascular disease in antiphospholipid syndrome: the ‘catastrophic’ antiphospholipid syndrome

The term ‘catastrophic’ antiphospholipid syndrome (CAPS) is defined as an accelerated form of antiphospholipid syndrome (APS) usually resulting in multiorgan failure. These patients have in common: (i) clinical evidence of multiple organ involvement developing in a very short time period; (ii) histopathological evidence of multiple small vessel occlusions (a minority also have large vessel thrombosis); and (iii) laboratory confirmation of the presence of antiphospholipid antibodies (aPL), usually in high titres. Although less than 1% of patients with the APS develop this complication, its potentially lethal outcome emphasizes its importance in clinical medicine.     

Heparin-induced thrombocytopenia associated with interleukin-8-dependent platelet activation in a patient with antiphospholipid syndrome

Platelet factor 4 heparin enzyme immunoassay, platelet aggregation test, and serotonin release assay are commonly used to diagnose and confirm heparin-induced thrombocytopenia. We describe a case of recurrent thrombocytopenia appearing in a few hours after each heparin administration and who tested negative for the three assays. Further analysis revealed anti-interleukin (IL)-8 antibodies and IL-8-dependent platelet activation facilitated by heparin, which may explain this unusual case of heparin-induced thrombocytopenia.     

Contact factor deficiencies and cardiopulmonary bypass surgery: detection of the defect and monitoring of heparin

Contact factor pathway deficiencies do not cause surgical bleeding but make heparin monitoring by the activated partial thromboplastin time (APTT) and activated clotting time (ACT) unreliable. Heparin monitoring during cardiopulmonary bypass (CPB) surgery in these patients is particularly challenging. Here we describe heparin monitoring during CPB using the chromogenic anti Xa assay in two patients with severe factor XII deficiency (FXII < 0.01 U/mL) and one patient with severe prekallikrein (PK) deficiency (PK < 0.01 U/mL). Anti Xa levels of the three patients during CPB varied between 3.8 and 4.8 U/mL in keeping with a control group (mean anti Xa 4.5 U/mL and ACT > 480 s). There were no bleeding or thrombotic complications. We also found that detection of severe PK deficiency by the APTT in the PK deficient patient was dependent on the reagent used and discuss the sensitivity of different APTT reagents for contact factor deficiencies. We conclude that the sensitivity of APTT methods for contact pathway deficiencies is highly variable and although insensitivity is not a clinical problem in terms of bleeding, it can be a cause of discrepancy between different APTT reagents and the ACT. This can lead to confusion about a possible haemorrhagic tendency and delays in surgery. If these patients need to undergo cardiac surgery requiring high dose heparin treatment, monitoring by chromogenic anti Xa assay is a good alternative.     

Transitory bone marrow oedema of the hip in pregnant patient with antiphospholipid syndrome: A case report

BackgroundTransient bone marrow oedema (BMO) of the hip presents with pain, is diagnosed by magnetic resonance imaging (MRI), and usually resolves within 6 months. Risk factors include pregnancy. Avascular necrosis of bone and an association with BMO are among the less common presentations of antiphospholipid syndrome (APS).Aim of the workTo present a young Croatian female APS patient who developed transient BMO during pregnancy which spontaneously resolved postpartum.Case reportAfter developing left leg deep vein thrombosis and positive lupus anticoagulant at 22 years old, the patient was diagnosed with primary APS. Antinuclear antibody was borderline, but classification criteria for SLE were not fulfilled. She had an early missed abortion during her first pregnancy while receiving low-weight molecular heparin (LWMH) (enoxaparin 40 mg), and her second pregnancy was to term with LWMH, aspirin, and hydroxychloroquine 200 mg daily. During the third trimester of this pregnancy, she developed excruciating bilateral hip pain to the point she could barely walk. Based on an MRI scan, the patient was diagnosed with bilateral BMO of the femoral head. The condition improved and resolved within four months with conservative treatment postpartum, as confirmed by followup MRI.ConclusionConsidering that pregnancy and APS are risk factors for BMO, both played a role in the development of BMO and the severity of presentation. This case report presents a differential diagnosis of hip pain in pregnant patients, especially with APS. Although APS is commonly associated with AVN, it may also be associated with transient BMO.     

Differential diagnosis and clinical management of isolated prolonged activated partial thromboplastin time in a patient with Hashimoto thyroiditis-associated thyroid cancer: A case report

Rationale:Patients preparing for surgery may have isolated, prolonged activated partial thromboplastin time (APTT). Cause analysis is warranted in patients who had neither bleeding symptom nor thromboembolic events because isolated prolongation of APTT may lead to unnecessary delayed surgical intervention or invasive procedure, even ineffective plasma infusion treatments. Here, we report a case of Hashimoto thyroiditis-associated thyroid cancer whose APTT was isolated prolonged and discuss the challenges of diagnosis and clinical management of this patient.Patient concerns:A 57-year-old woman was admitted to the hospital due to thyroid cancer. Anticoagulant assay was performed for this patient before surgery, she had normal values for prothrombin time, thrombin time, and fibrinogen, but had isolated prolonged APTT value (20 seconds longer than normal). However, the routine laboratory of the local hospital showed normal APTT and she did not have any abnormal bleeding or thrombotic episodes. Lupus anticoagulant (LA) was strongly positive according to mixing studies and modified dilute Russell viper venom time method, it was responsible for prolonged APTT.Diagnoses:Hashimoto thyroiditis-associated thyroid cancer whose APTT was isolated prolonged.Interventions:The isolated prolongation of APTT in this patient was due to LA. She had no history of anticoagulant medications and no spontaneous bleeding episodes. There should be no specific intervention before thyroidectomy.Outcomes:This thyroid cancer patient had an uneventful surgery and was discharged after a week.Lessons:Prolonged APTT is not considered an absolute indication for plasma infusion therapy in patients with LA. The correct identification of the cause of APTT prolongation is essential for proper treatment of the individuals.     

Meta-analysis on aspirin combined with low-molecular-weight heparin for improving the live birth rate in patients with antiphospholipid syndrome and its correlation with d-dimer levels

Background:Antiphospholipid antibody syndrome (APS) is a systemic, autoimmune, prothrombotic disease characterized by persistent antiphospholipid antibodies, thrombosis, recurrent abortion, complications during pregnancy, and occasionally thrombocytopenia. At present, there is no consensus on the treatment of this disease. Long-term anticoagulation is recommended in most cases in patients with thrombotic APS. This study aimed to evaluate whether aspirin combined with low-molecular-weight heparin (LMWH) can improve the live birth rate in antiphospholipid syndrome and its correlation with D-dimer.Methods:The data were retrieved from the WanFang Data, CBM, VIP, CNKI, the Cochrane Library, PubMed, EMBASE, OVID, and Web of Science databases. We collected data on randomized controlled trials of aspirin combined with LMWH in the treatment of pregnant women with APS. The “Risk of Bias Assessment” tool and the “Jadad Scale” provided by the Cochrane Collaboration were used to evaluate the risk of bias and quality of the collected literature. The risk ratio (RR) and its 95% confidence interval (CI) were determined using Statase-64 software.Results:In this study, a total of 11 studies were included, comprising a total of 2101 patients. The live birth rate in pregnant women with APS was higher on administration of aspirin combined with LMWH than with aspirin alone (RR = 1.29, 95% CI = 1.22–1.35, P < .001). d-dimer concentration in plasma predicted the live birth rate, which was higher below the baseline than above it (RR = 1.16, 95% CI = 1.09–1.23, P < .001). The subgroup analysis of the live birth rate was carried out based on the course of treatment, and the results were consistent with the overall results. Begg funnel plot test revealed no publication bias. Sensitivity analysis showed that deleting any study did not affect the results.Conclusion:Aspirin combined with LMWH for APS may improve live birth rate, and detection of d-dimer levels in APS pregnant women may predict pregnancy complications and guide the use of anticoagulants.     

Structural characterization and functional effects of a circulating heparan sulfate in a patient with hepatocellular carcinoma

A circulating anticoagulant was isolated from the plasma of a 42-year-old man with cirrhosis and hepatocellular carcinoma who had an unusual coagulation test profile. The patient developed a fatal coagulopathy, unresponsive to protamine therapy or plasma exchange following liver biopsy. However, at presentation, routine hemostasis assays were normal. The patient had mucocutaneous bleeding but the sole laboratory abnormality was a prolonged thrombin time (TT = 99 s, normal 25–35 s). Protamine titration indicated activity equivalent to a heparin concentration of 6–7 U/ml. Antithrombin III (AT III) antigen and activity were markedly elevated. The anticoagulant activity, purified from plasma by DEAE chromatography, was identified as a glycosaminoglycan (GAG). GAG anti-thrombin activity was completely abolished by heparin lyase III. Based on the degree of sulfation and HPLC pattern, the GAG was classified as heparan sulfate. Low levels (4 μM) of purified GAG markedly prolonged the TT (>120 s) but not the activated partial thromboplastin time (PTT) (31.4 s). In a Factor Xa assay, the GAG exhibited a potency equivalent to 0.06 U of low molecular weight heparin per nmol of uronic acid. Patients with endogenous circulating glycosaminoglycans can present with unusual laboratory coagulation test profiles. These reflect complex dysfunction of hemostasis, leading to difficulty in providing diagnosis and effective care. Am. J. Hematol. 58:285–292, 1998. © 1998 Wiley-Liss, Inc.     

Case report: Hepatic involvement in antiphospholipid syndrome

Three cases of hepatic involvement in antiphospholipid syndrome are described. One patient had catastrophic antiphospholipid syndrome with haemorrhages and necrosis in the liver parenchyma. The second patient had blood clots in the small hepatic vessels. The third patient had autoimmune hepatitis type I associated with antiphospholipid syndrome. Other possible hepatic manifestations of antiphospholipid syndrome are also discussed.