Neurological manifestations of the antiphospholipid syndrome: risk assessments and evidence-based medicine

The antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterised by autoantibody production and vascular thrombosis or pregnancy morbidity. Autoantibodies generated against phospholipid and phospholipid-binding proteins often impair phospholipid-dependent clotting assays (lupus anticoagulants). These autoantibodies activate endothelial cells, platelets and biochemical cascades and can exist in autoimmune disorders such as lupus. Consistently positive antibodies may worsen the severity of thrombo-occlusive disease. The most common neurological manifestations of APS include stroke and transient ischaemic attacks due to arterial thromboses. Antiphospholipid antibodies may cause additional neurological impairments through both vascular and immune mechanisms. Antiaggregant or anticoagulant therapies are indicated for APS-related ischaemic strokes. Treatment regimens for asymptomatic antibody-positive patients and those with refractory disease remain controversial. There is scant literature on neurological APS manifestations in paediatric patients. Assessment of traditional cardiovascular and inherited thrombophilia risk factors is essential in patients with APS. Modifiable risk factors and valvular heart disease may worsen thrombotic and cerebrovascular outcomes. Alternative therapies such as statins, anti-malarials, angiotensin-converting enzyme inhibitors and thrombin inhibitors warrant further research.     

Therapeutic plasma exchange for anticoagulant-refractory antiphospholipid syndrome with severe ischemic and necrotic skin lesions: A case series

Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by clinical findings including thrombosis and/or obstetric complication and laboratory findings, e.g. ≥1 positive antiphospholipid antibodies (aPL) (lupus anticoagulant, anticardiolipin IgG/IgM and/or anti-β2-glycoprotein IgG/IgM). A rare APS clinical entity is severe necrosis which is difficult to treat and often does not respond to anticoagulant therapy. Three consecutive patients with primary or secondary APS who presented with necrotic skin lesions secondary to APS were treated with therapeutic plasma exchange (TPE), glucocorticoids and low-molecular-weight heparin. All patients had a rapid-onset, either full or significant recovery of their APS-related necrotic lesions.Upon treatment, one patients showed resolution of lupus anticoagulant. Two patients had a decrease of at least 88 % in aPL titers after the initial treatment, and were kept on TPE maintenance every 5–6 weeks. None of the patients experienced significant side effects of the TPE. This is the first case series showing the clinical benefits of TPE in patients with ischemic and necrotic skin lesions due to severe anticoagulant-refractory vascular APS.     

Argatroban dosing of patients with heparin-induced thrombocytopenia and an elevated aPTT due to antiphospholipid antibody syndrome

OBJECTIVE: To describe the clinical characteristics, management, and outcomes of patients with heparin-induced thrombocytopenia with thrombosis (HITTS) or without thrombosis (HIT) who also had an elevated baseline activated partial thromboplastin time (aPTT) due to antiphospholipid antibody syndrome (APS). CASE SUMMARY: Four patients with HIT/HITTS and an elevated baseline aPTT due to APS were identified. Two patients had venous thrombosis, 1 had limb ischemia, and 1 had isolated HIT. All 4 were managed with a weight-based fixed dose of argatroban without laboratory monitoring. None of the patients had thrombotic or bleeding complications once therapy was initiated. DISCUSSION: Management of patients with HIT/HITTS and an abnormal baseline aPTT due to APS is problematic. We review alternative management strategies, such as monitoring direct thrombin inhibitors with the ecarin clotting time or thrombin inhibition time or using an alternative anticoagulant, such as fondaparinux. As of March 13, 2006, none of these management strategies has been evaluated in a clinical trial for this patient population. We report the successful use of weight-based, fixed-dose argatroban without laboratory monitoring in patients with APS. CONCLUSIONS: Use of a fixed-dose argatroban regimen without laboratory monitoring is a potential management strategy for patients with HIT/HITTS and an elevated baseline aPTT due to APS.     

Plasma exchange for thrombocytopenia in antiphospholipid syndrome: a case report.

The remarkable effect of plasma exchange (PE) was observed on thrombocytopenia in a patient with antiphospholipid syndrome (APS) associated with systemic lupus erythematosus. Three times PE led to recovery from severe thrombocytopenia refractory to treatment with corticosteroid, anticoagulant, and antiplatelet drugs accompanied by a decrease in the serum cardiolipin beta2 glycoprotein I antibody level. This result suggests that PE is a valuable therapeutic tool for refractory thrombocytopenia in APS.     

The antiphospholipid syndrome]

Antiphospholipid antibodies such as anticardiolipin antibodies and lupus anticoagulant are frequently detected in sera from patients with systemic lupus erythmatosus and from those with related autoimmune disorders. Thromboembolic manifestations, fetal losses or thrombocytopenia in association with antiphospholipid antibodies, are hallmarks of the antiphospholipid syndrome (APS). Recent studies indicates that anticardiolipin antibodies bind to beta 2-glycoprotein I and that a part of lupus anticoagulant binds to beta 2-glycoprotein I or to prothrombin. Antiphospholipid antibodies might induce thrombosis by altering the function of vascular endothelial cells or by accelerating the progression of atherosclerosis. Warfarin, heparin or low dose aspirin have been recommended to prevent recurrent episodes of thrombosis in patients with the APS.     

Clinical and laboratory criteria for diagnosis in antiphospholipid syndrome: what is it important for a practitioner to know (a lecture)

The antiphospholipid syndrome (APS) is antibody-induced thrombosis, whose diagnostic basis is the obligatory presence of serological markers along with clinical manifestations. Its laboratory markers are antiphospholipid antibodies (aPAs), the highest informative value has been proven for lupus anticoagulant (LA), cardiolipin antibodies, fl-glycoprotein 1. LA should be determined at a laboratory in accordance with the recommendations of the International Society on Thrombosis and Hemostasis. Obstetric abnormality in APS should be regarded as a thrombotic complication and its management in this case does not differ from that and prevention of thrombosis, aPAs may be detectable in various illnesses, but their blood presence is not an indication for immunosuppressive therapy. The paper describes a case of primary APS in a female patient.     

Deep vein thrombosis in patient with left-sided inferior vena cava draining into the hemiazygos vein: A case report

BACKGROUNDAbnormalities of the inferior vena cava (IVC) are uncommon, and in many cases they are asymptomatic. Even so, it is vital that clinicians be aware of such anomalies prior to surgery in affected individuals. In the present report, we describe a rare anatomical variation of the IVC.CASE SUMMARYA 66-year-old male was admitted to the hospital due to deep vein thrombosis of the right lower extremity. Upon contrast-enhanced computed tomography imaging, we found that this patient presented with a case of left-sided IVC draining into the hemiazygos vein, while his hepatic vein was directly draining into the atrium.CONCLUSIONCases of left-sided IVC can increase patient susceptibility to thromboembolism owing to the resultant changes in blood flow and/or associated vascular compression.     

Radiographic features of intraluminal leiomyosarcoma of the inferior vena cava: an atypical case report

We encountered a 74-year-old woman with a chief complaint of progressive right-sided back pain for more than 1 month. Physical examination and laboratory tests revealed no abnormalities. Multislice computed tomography (MSCT) showed dilatation of the inferior vena cava (IVC). An intraluminal mass of about 8.1 × 5.5 × 3.6 cm in size was found in the IVC, with big central necrosis and irregular peripheral enhancement. The tumor arose from the IVC just beneath the renal vein and reached the iliac bifurcation. Cavography demonstrated a filling defect with complete occlusion of the IVC and extensive collateral circulation. The patient underwent complete resection of tumor and vascular prosthetic graft. Pathological diagnosis was leiomyosarcoma. Because of its low incidences and atypical appearance, we highlight the significance of the imaging feature in its diagnosis in this article.     

真性红细胞增多症并肠梗阻、抗磷脂综合征一例

静脉血栓栓塞性疾病是住院患者常见的并发症之一,具有发生率高、病死率高和住院费用增加等特点。本文报道1例67岁既往有真性红细胞增多症（PV）病史的男性,进食不当后出现腹胀、腹痛。增强CT显示小肠梗阻（SBO）、肠穿孔、阑尾炎和腹膜炎。经禁食、放置肠梗阻减压管、药物抗感染等非手术治疗后,肠梗阻症状改善且病灶局限化。但患者随后出现以左侧锁骨下静脉、颈内静脉和上肢静脉为主的血栓。笔者考虑肠梗阻导致的脓毒症和PV可能是静脉血栓形成的主要因素,给予普通肝素抗凝、羟基脲治疗PV。实验室化验血清抗心磷脂抗体、抗β2糖蛋白1抗体、狼疮抗凝物阳性。经积极的抗凝、糖皮质激素、羟氯喹和抗感染治疗,患者病情改善。出院后随访半年,患者大部分血栓消失。抗磷脂综合征（APS）和骨髓增生性肿瘤（MPN）均与血栓形成风险增加有关,但二者同时存在的报道并不多见。早期针对血栓的病因诊断及治疗对改善病程、预后至关重要。     

Antiphospholipid syndrome and its role in pediatric cerebrovascular diseases: A literature review

Antiphospholipid syndrome (APS) or Hughes syndrome is an acquired thromboinflammatory disorder. Clinical criteria of APS diagnosis are large- and small-vessel thrombosis as well as obstetric problems; laboratory criteria are the presence of antiphospholipid antibodies (lupus anticoagulant, anticardiolipin antibodies and anti-β2-glycoprotein-1). The presence of at least 1 clinical and 1 laboratory criterion allows definitive diagnosis of APS. Primary APS is diagnosed in patients without features of connective tissue disease; secondary APS is diagnosed in patients with clinical signs of autoimmune disease. A high frequency of catastrophic APS as well as a high tendency to evolve from primary APS to secondary syndrome during the course of lupus and lupus-like disease is a feature of pediatric APS. The most characteristic clinical presentation of APS in the pediatric population is venous thrombosis, mainly in the lower limbs, and arterial thrombosis causing ischemic brain stroke. Currently, no diagnostic criteria for pediatric APS exist, which probably results in an underestimation of the problem. Similarly, no therapeutic procedures for APS specific for children have yet been established. In the present literature review, we discussed data concerning APS in children and its role in cerebrovascular diseases, including pediatric arterial ischemic stroke, migraine and cerebral venous thrombosis.     

Fogarty导管取栓治疗血管栓塞的疗效探讨

目的:探讨Fogarty导管取栓术对肢体血管栓塞的治疗效果。方法:用Fogarty导管对54例血管栓塞进行取栓术,配合肢体挤压、溶栓、抗凝等治疗方法。结果:12例动脉栓塞的肢体血运恢复,功能恢复良好;1例动脉栓塞术后效果欠佳,需反复3次取栓;41例静脉栓塞的肢体功能均恢复良好。结论:应用Fogarty导管取栓,配合肢体挤压、溶栓、抗凝等方法治疗肢体血管栓塞,手术安全,疗效满意。     

Contrast-enhanced ultrasonography of intraluminal inferior vena cava leiomyosarcoma: A case report

Primary leiomyosarcoma of the inferior vena cava (IVC) is a rare and fatal disease. Imaging is the main diagnostic method. CT and MRI images of IVC leiomyosarcoma have been published, but ultrasonographic features have been scarcely described, especially with contrast-enhancement. We report the case of a patient in whom ultrasonography incidentally revealed a mass in the IVC. Contrast-enhanced ultrasonography showed heterogeneous enhancement in the arterial phase with some irregular non-enhanced areas, and mild clearance in the venous phase. The location and nature of the lesion as shown by ultrasonography were confirmed by CT and MRI.     

An international multicentre‐laboratory evaluation of a new assay to detect specifically lupus anticoagulants dependent on the presence of anti‐beta2‐glycoprotein autoantibodies

Summary. Background: Antiphospholipid syndrome (APS) is diagnosed by the simultaneous presence of vascular thrombosis and/or pregnancy morbidity and detection of antiphospholipid antibodies in plasma. Objectives: We have shown that prolongation of clotting time by anti‐beta2‐glycoprotein I (beta2GPI) antibodies correlates better with thrombosis than a positive classic lupus anticoagulant (LAC) assay in a single center study. To confirm or falsify this finding we have conducted a multicenter study. Methods and results: In 325 LAC‐positive samples, we found that the beta2GPI‐dependent LAC correlated 2.0 times better with thrombosis than the classic LAC assay. Although significant, this was a minimal improvement compared with the ‘classic’ LAC. It was published that calcium influences the behavior of anti‐beta2GPI antibodies in coagulation assays. To investigate whether calcium plays a role in the present study, we divided the patient population into two groups: (i) blood was collected in 0.109 m sodium citrate and (ii) blood was drawn in 0.129 m sodium citrate as anticoagulant. We found that a positive result with the beta2GPI‐dependent LAC assay correlated better with thrombosis [odds ratio (OR): 3.3, 95% confidence interval (CI) 1.9–5.8] when 0.109 m sodium citrate was used compared with 0.129 m sodium citrate (OR: 0.4, 95% CI 0.1–1.1). Conclusion: We were able to confirm in an international multicenter study that a positive result in a beta2GPI‐dependent LAC assay correlates better with thrombosis than the classic LAC assay, but that the assay needs further study as it is sensitive to external factors such as the sodium citrate concentration used as anticoagulant in the test sample.     

Clinicomorphological features of nephropathy in primary and secondary antiphospholipid syndrome

AIM: To investigate specific features of extrarenal manifestations of antiphospholipid syndrome (APS) in patients with APS-associated nephropathy (APSN) in primary APS and lupus nephritis (LN) with secondary APS; to compare clinicomorphological signs of APSN in primary and secondary APS. MATERIAL AND METHODS: We examined 44 APSN patients with primary APS and 90 patients with LN: 57 with secondary APS, 33 with antiphospholipid antibodies (APA) without history of thrombosis. In addition to clinical and immunological examination, detection of serological APS markers, morphological examination of renal tissue and ultrasound dopplerography (USDG) of the renal vessels were made (in some patients) for assessment of the condition of intrarenal vascular bed. RESULTS: In patients with primary APS, renal disorder and secondary APS in LN frequency of arterial thrombosis doubles that of venous ones. Renal disorder irrespective of a clinical APS form (primary, secondary) combines with affection of the CNS, heart and skin (livedo). This correlates with frequency of arterial thrombosis. In patients with primary APSN rate of arterial hypertension (AH), especially severe, and renal dysfunction is higher than in LN with APS while this group is characterized by more severe proteinuria, microhematuria and higher incidence of nephrotic syndrome. A direct correlation exists between the incidence of arterial thrombosis and severity of AH, between AH and renal ischemia by USDG. Morphologically, glomerulosclerosis, marked arteriolosclerosis and diffuse interstitial sclerosis occur more often in patients with primary APSN compared to LN patients with APS. CONCLUSION: In primary and secondary (in SLE) APS combination of APSN with impairment of the CNS, heart and skin, correlation of its basic clinical manifestations with arterial thrombosis allow us to single out a special clinical variant of APS manifesting with generalized ischemic lesions of the organs as a result of arterial/arteriolar thrombosis. Irrespective of its nature, APSN has common characteristic features--combination of AH, persistent renal dysfunction and transitory hypercreatininemia--correlating with development of arterial thrombosis; therefore, this pathology can be considered as a variant of thrombotic vascular lesion of the kidneys.     

Cryosupernatant plasma exchange in the treatment of antiphospholipid antibody syndrome with lupus nephritis.

We report a case of a 22-year-old female with antiphospholipid antibody syndrome (APS) associated with systemic lupus erythematosus in whom cryosupernatant plasma exchange was effective and improved both the refractory venous thrombosis in her legs and relapsing thrombocytopenia. A renal biopsy specimen showed not only features of active lupus nephritis but also renal arteriolar thrombosis which is considered to be a type of thrombotic microangiopathy (TMA). Because a pathological role of unusually large von Willebrand factor (vWF) multimers has been reported in patients with TMA including thrombotic thrombocytopenic purpura, plasma exchange using replacement with cryosupernatant, which is free of unusually large vWF multimers, is likely to be an option of treatment modality for patients with refractory and chronic relapsing APS manifesting TMA.     

系统性红斑狼疮合并抗磷脂综合征患者的临床分析

目的 研究系统性红斑狼疮合并抗磷脂综合征(SLE-APS)患者的临床特点.方法 对39例SLE-APS患者的临床和实验室资料进行回顾性分析.结果 39例患者中,有31例共发生了48次血栓栓塞事件,以深静脉血栓及脑梗死为主.26例已婚有生育史女性患者中,有12例发生病态妊娠.28例抗心磷脂抗体阳性;16例狼疮抗凝物阳性.24例患者先确诊SLE,平均9.5年后又出现APS样表现;12例先出现反复病态妊娠或血栓事件,平均4.8年后演变为SLE;3例一发病便同时符合SLE和APS的分类标准.有5例在发生血栓事件或病态妊娠时的狼疮活动指数<5分.结论 SLE-APS患者血栓事件及病态妊娠发生率增多.APS可出现于SLE之前、之后或同时.狼疮患者可以在病情稳定期出现APS的表现.详细询问病史、常规检测抗心磷脂抗体,有助于发现SLE-APS的高危因素,积极预防APS的发生.     

Successful management of infected right iliac pseudoaneurysm caused by penetration of migrated inferior vena cava filter: A case report

BACKGROUNDIndwelling inferior vena cava (IVC) filters might cause various complications, including filter penetration, filter fracture, filter migration, and thrombosis of the IVC. Penetration and migration complications are common, while a caudal migrated double-basket filter with associated infected iliac pseudoaneurysm has seldom been reported.CASE SUMMARYWe report a 64-year-old female admitted for sudden onset of severe right abdominal pain after IVC filter placement for 3 mo. The patient had a history of failed endovascular IVC filter retrieval. Computed tomography showed that the retrieval hook of the filter penetrated the right common iliac artery and vein, leading to right iliac artery pseudoaneurysm accompanied by right ureteral obstruction with ipsilateral hydronephrosis, and bilateral iliac veins were occluded. Emergency open repair was performed to remove the IVC filter, the right iliac pseudoaneurysm, and the compromised segments of the iliac veins and IVC with right common iliac artery reconstruction. Staphylococcus aureus was isolated from the tissue culture. The patient was discharged on postoperative day 12 with anticoagulation therapy and antibiotic therapy after discharge. Six-month follow-up computed tomography revealed that the right common iliac artery was patent, and only mild hydronephrosis was detected.CONCLUSIONAn indwelling IVC filter, even ‘embedded’ within organized thrombus, could still cause life-threatening complications. Open procedures remain the last resort for IVC filters with severe complications.     

The role of hyperhomocysteinemia in systemic lupus erythematosus and antiphospholipid syndrome

AIM: To assess the role of hyperhomocysteinemia (HHC) in development of vascular complications in systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). MATERIAL AND METHODS: A total of 125 participants (24 males and 101 females aged 38 +/- 13 years) were divided into three groups: group 1--SLE patients (n=51); group 2--SLE+APS patients (n=49); group 3--primary APS patients (n=25). The patients had the disease for 14 +/- 11 years. Lupus anticoagulant (LA) and anticardiolipin antibodies (aCL) marked APS serologically. Homocystein (HC) was assayed by high performance liquid chromatography. HHC (HC > 15 mcg/l) was diagnosed in 82 of 125 (66%) patients: in 59% patients of group 1, 67%--of group 2 and 76%--of group 3. There was a relationship between HHC and digital necrosis (DN): 80% of DN patients had HHC while HHC was diagnosed in 57% patients free of DN (chi-square = 4.76, p = 0.03). Development of occlusions in APS was associated with HHC. Elevated levels of HC in blood was registered in 43 of 55 (78%) APS patients with thromboses vs. 9 of 19 (47%) patients with APS free of thromboses (p = 0.03). HHC occurred significantly more frequently in patients with arterial thromboses (in all 14 patients) than in patients with venous thromboses (in 16 of 23--69.6%, p = 0.03) and in the absence of thromboses (in 9 of 19, 47.4%, p = 0.04). HHC was associated with thromboses of cerebral, peripheral arteries (90 vs. 47% in patients without thrombosis, p = 0.005; 84 vs. 47%, p = 0.04, respectively), coronary vessels (79 vs. 47%, p = 0.04). In APS patients having arterial thromboses with duration of postthrombocytic period (PTP), estimated as time from thrombosis to entering the trial, less than 2 months, HC concentration was significantly higher (22.9 +/- 7.0 mcg/l) compared to patients with PTP more than 2 years (16.6 +/- 3.7 mcg/l (p = 0.04). CONCLUSION: More than 50% patients with SLE and APS, irrespective of APS variants, had an elevated HC level in the blood. Correlation between HHC and development of thromboses, primarily arterial, in APS gives grounds for the role of HHC in development of vascular complications in SLE and APS.     

Catastrophic antiphospholipid syndrome: diagnosis and treatment

AIM: To analyse data on patients who developed catastrophic antiphospholipid syndrome (CAPS) in primary and secondary APS, to assess outcomes of CAPS. MATERIAL AND METHODS: We analysed retrospectively the data on 164 patients with systemic lupus erythematosus (SLE) and APS, on 76 patients with primary APS (PAPS) treated in the Institute of Rheumatology from 1989. Verification of vascular complications was made using ultrasonic dopplerography (UDG) of peripheral vessels, echocardiography of the heart, CT of the brain, abdominal organs. Anticardiolipin antibodies (ACLab) and lupus anticoagulant (LA) served as serological markers of APS. RESULTS: In the observation period of 9.4 +/- 4.2 years, 33 patients (23 females and 10 males) out of 164 patients with SLE+APS developed CAPS, 8 of them survived while 25 died. CAPS patients had no differences by age, duration of the disease, its activity and symptoms from patients who had no CAPS. Ten out of 76 patients with PAPS developed CAPS, 7 of them died. The analysis of the concomitant factors which may initiate PAPS showed that in SLE and APS these factors consisted of initial menopause (n = 2), infection (n = 12), including pneumonia (n = 7), acute respiratory disease (n = 3), food poisoning (n = 1), abscess (n = 1). Cancer was in one patient, trauma after road accident in one patient. Trigger factor was not determined in 13 patients. In PAPS provoking factors were pneumonia (n = 2) and abscess (n = 1), in 7 patients these factors were not detected. CONCLUSION: Any infection in SLE patients should be adequately treated with antibiotics; APS patients treated surgically should receive parenteral anticoagulants instead of oral ones; puerperas with APS must receive adequate parenteral anticoagulant therapy for at least 6 weeks; in exacerbation of SLE, APS patients should receive parenteral anticoagulants with following hypocoagulation with oral anticoagulants.     

脑静脉窦血栓和抗磷脂综合征

目的 脑静脉窭血栓(CVT)是抗磷脂综合征(APS)罕见的神经系统表现,为研究APS合并CVT的临床及神经影像特点,对有关患者的资料进行总结并和既往文献报道进行比较.方法 收集APS合并CVT患者的资料,并系统回顾相关Medline文献.结果 8例患者,男女比1:1,年龄20～48岁,平均(32.3±10.0)岁;狼疮抗凝物(LA)阳性和抗心磷脂抗体(ACL)阳性分别为6例和2例;迄今为止,文献共报道51例APS合并CVT的病例,年龄3周至74岁,平均(31.8±12.6)岁;LA阳性: ACL阳性为11:14.结论 对于无明确原发高凝状态的CVT患者,常规进行LA和ACL的筛查很必要;复发性CVT在LA阳性的APS患者中常见.