Hypofibrinolysis, lipoprotein(a), and plasminogen activator inhibitor

Parameters of hypofibrinolysis and thrombophilia were assessed in 20 consecutive patients with bone marrow edema sydrome of the hip who lacked typical risk factors for osteonecrosis. Twenty healthy subjects, matched for age and gender, served as the control subjects. In patients with bone marrow edema syndrome, elevated levels of lipoprotein(a) and plasminogen activator inhibitor were found in nine (45%) and two patients (10%), respectively. Elevation of lipoprotein(a) was present in two patients in the control group; however, plasminogen activator inhibitor levels were normal in this group. Mean levels of lipoprotein(a) were 34.8 mg/dL in the patients with bone marrow edema versus 13.8 mg/dL in the control subjects. Mean concentrations of plasminogen activator inhibitor, apolipoproteins, lipid metabolism parameters, and indicators of thrombophilia did not differ in both groups. Pulsed field gel electrophoresis and Southern blots confirmed the presence of pathologic allelotypes in three patients with elevated levels of lipoprotein(a) who had a familial occurrence of bone marrow edema syndrome. These findings also underline a fundamental role of hypofibrinolysis, mediated by elevated levels of lipoprotein(a) or plasminogen activator inhibitor, or both, in the former idiopathically considered etiology of the bone marrow edema syndrome of the hip.     

The transitory bone marrow edema syndrome of the hip

AIM OF THE STUDY: Since MRI-studies had begun to establish the diagnosis of transitory bone marrow edema syndrome of the hip orthopedic surgeons have tried to integrate this new syndrome into the internationally accepted system of musculoskeletal diseases. Particularly, the relation to non-traumatic osteonecrosis of the femoral head and the possibilities in therapy were investigated in our clinical trial. METHODS: Our clinical trial encompassed 106 patients suffering from the transitory bone marrow edema syndrome diagnosed in our department between the years 1985 and 2000. In order to confirm this diagnosis we used the patients' histories, their clinical courses, MRI studies, scintigraphic bone scans, intraosseal pressure measurements, phlebographies, laboratory data, and histologic specimens. One half of our collective positive for transient bone marrow edema of the hip underwent core-decompression surgery (50 patients), the other half (56 patients) was treated conservatively by analgesic medication combined with restriction of weight-bearing in the affected extremity. RESULTS: Patients positive for transitory bone marrow edema syndrome of the hip are middle-aged individuals with a male to female predominance of 60 : 40. This group has no or only few risk factors usually associated with osteonecrosis of the femoral head. Thus, the missing alcoholic abuse is striking. All patients suffering from transitory bone marrow edema syndrome of the hip recovered completely independent of the therapy we initiated and none of them showed any signs of osteonecrosis. The one half undergoing surgical decompression of the edema by using a 4.5 mm drill experienced an markedly accelerated relief of their clinical symptoms as well as their signal changes on MRI studies. Conventional X-ray pictures and scintigraphic bone scans are not useful for early differentiation between early stages of osteonecrosis and bone marrow edemas. This also accounts for the historical measurements of intraosseal pressure determinations and phlebographies. In contrast to that, MRI studies are effective in early differentiation between osteonecrosis and bone marrow edema syndrome of the hip, especially when contrast medium (gadolinium) is administrated intravenously and fat-suppressed MRI-sequences find use. Beginning osteonecrosis of the femoral head shows a segmental loss of contrast medium, a "double line sign" interface to the intact bone marrow, and only in a few cases they are associated with a huge symptomatic edema. The histologic examination of specimens obtained from 43 patients with transitory bone marrow edema syndrome of the hip revealed no signs of osteonecrosis. CONCLUSION: MRI studies are useful in differentiation between bone marrow edema syndrome of the hip and non-traumatic osteonecrosis of the femoral head in each stage of these two diseases. The thorough differentiation between these two diseases is of extraordinary importance for the clinical work-up of the patients as well as for scientific reasons. The course of primary bone marrow edema is benign as it results in entire recovery. The core decompression surgery offers the chance to shorten the course of the disease.     

Fatty marrow conversion of the proximal femoral metaphysis in transient bone marrow edema syndrome

Introduction In the proximal femoral metaphysis, hematopoietic marrow is predominant during the adult stage of life. The conversion of hematopoietic marrow to fatty marrow in the proximal femoral metaphysis has been suggested as an etiologic factor of ischemia in the pathogenesis of femoral head osteonecrosis. To determine whether the chronology of fatty marrow conversion of the proximal femoral metaphysis is related to transient bone marrow edema syndrome of the hip, a case control study was conducted on 10 patients with the disease.Materials and methods There were 8 men and 2 women with a mean age of 33 years (range 19–45 years). The 10 patients were matched with 20 controls for gender and age (5-year range). T1-weighted MRI scans of their hips were reviewed. Marrow of the greater trochanter becomes fatty before puberty, and thus, the greater trochanter can be used as a built-in control. The signal intensity of the proximal femoral metaphysis was compared to that of the greater trochanter.Results In all patients, the signal intensity of the proximal femoral metaphysis was isointense (fatty marrow) relative to that of the greater trochanter. In control subjects, the signal intensity was isointense in 8 (40%) and hypointense (hematopoietic marrow) in 12 (60%) (p<0.05).Conclusion The current study shows that the proximal femoral metaphysis is predominantly fatty in transient bone marrow edema syndrome. The conversion of hematopoietic to fatty marrow is known to correlate with decreases in intramedullary blood flow. Thus, the current study suggests that an ischemia of the proximal femur secondary to fatty marrow conversion of the proximal femoral metaphysis might be a cause of transient bone marrow edema syndrome of the hip.     

Increased perfusion of the femoral head in transient bone marrow edema syndrome

The pathophysiology of transient bone marrow edema syndrome is not known. Ischemia has been suggested as the pathophysiologic factor, because the histologic findings are similar to those of early stage osteonecrosis. Angiographic studies of osteonecrotic femoral heads have shown arterial interruption and impaired perfusion. The current report describes the angiographic and scintigraphic findings of transient bone marrow edema syndrome of the hip in a 45-year-old man. The nutrient arteries were dilated, and the femoral head perfusion was increased compared with the unaffected contralateral side. These findings suggest that a vasomotor response plays a role in the pathogenesis of transient bone marrow edema syndrome. The disease might be a reversible process after temporary ischemia of the femoral head.     

股骨上端骨髓水肿综合征的MRI表现特点

目的：分析股骨上端骨髓水肿综合征的MRI表现特点以提高对该病的认识。方法;回顾性分析10例股骨上端骨髓水肿综合征患者的MRI表现,男6例,女4例;年龄36～57岁,平均41．5岁;病史1周～3个月。临床表现为突然发作的髋部疼痛9例,行走能力及髋关节活动受限7例;全部病例无明显外伤史,女性患者未在孕期。随访3～12个月,症状消失3个月复查MRI后结束随访。结果：MRI主要表现为弥漫性骨髓水肿,累及股骨头、颈、粗隆间,10例13髋中骨髓水肿1级6髋,2级5髋,3级2髋。合并髋关节积液9髋,I级积液6髋,Ⅱ级1髋,III级2髋。治疗3-12个月后患者髋部疼痛症状消失,股骨内MRI信号恢复正常。     

Biochemical markers of bone metabolism in bone marrow edema syndrome of the hip

The aim of this study was to evaluate bone metabolism in patients with bone marrow edema syndrome of the hip. In 37 consecutive patients undergoing core decompression of the femoral head, biochemical markers of bone metabolism were measured in aspirates from cancellous bone and in samples obtained simultaneously from peripheral blood. The diagnosis was made by means of radiographs, magnetic resonance imaging (MRI), and core biopsy specimens. Undecalcified microtome section were available for histopathological evaluation. Bone specific alkaline phosphatase (bone ALP), osteocalcin (OC), procollagen Type I N-terminal propeptide (PINP), and C-terminal cross-linking telopeptide (ICTP) were studied. Mean serum levels of analytes were 13.1 ng/mL (OC), 11.2 ng/mL (bone ALP), 4.7 ng/mL (ICTP), and 38.8 ng/mL (PINP). In samples obtained from cancellous bone, mean concentrations of all markers were elevated significantly. The mean bone to serum ratios for bone ALP and OC were 14.1 (P=0.005) and 4.1 (P=0.002), respectively. For collagen Type I metabolites, bone to serum ratios averaged 16.3 (P=0.001) for ICTP and 9.6 (P=0.001) for PINP. Markers of bone formation correlated with each other in serum as well as in aspirates from cancellous bone. Elevation of all markers in aspirates from cancellous bone pointed at increased bone turnover, which correlated with histopathological findings of irregularly woven bone, osteoid seams, and lining cells. Mean serum concentrations of all markers, however, were not different from healthy individuals and thus did not provide any useful clue in the diagnosis of this disease. The lack of osteonecrotic regions in our specimens, the marked increase of bone turnover in samples obtained from edematous lesions, and the fact that none of the patients developed osteonecrosis of the femoral head so far seem to further support the contention that transient bone marrow edema syndrome of the hip is a distinct clinical entity.     

A new hypothesis for the bone marrow edema pathogenesis during transient osteoporosis

Transient osteoporosis is an infrequent condition of uncertain etiology with pain, limited range of motion and radiographic evidence of osteoporosis affecting one or more joints. It is self-limited, reversible and can involve only the hip (transient osteoporosis of the hip, TOH) or, less frequently, one or more joints contemporaneously or at different times (regional migratory osteoporosis, RMO). We studied four men with transient osteoporosis, including two with TOH and two with RMO. All patients underwent a standard radiographic work-up of the affected joints, arteriovenous Doppler US, computed tomography, magnetic resonance imaging (MRI) and three-phase bone scanning. In all patients, symptoms were related to bone marrow edema demonstrated at MRI and to a transitory regional arterial hyperflow observed at the early scintigraphic analysis. On the basis of our observations, we hypothesize that regional arterial hyperflow may be the cause of the bone marrow edema and therefore of the transient osteoporosis.     

髓芯减压联合高压氧治疗髋关节骨髓水肿综合征

目的探讨髓芯减压联合高压氧治疗髋关节骨髓水肿综合征（BMES）的疗效。方法髓芯减压联合高压氧治疗12例髋关节BMES患者。结果12例均获随访,时间6～24个月。患者疼痛均完全消失,术后4～12周髋关节功能恢复正常。随访期间未发现病情复发及股骨头坏死。结论髓芯减压联合高压氧治疗髋关节BMES,创伤小,并发症少,疗效好。     

股骨头骨髓水肿综合征的诊治及其与股骨头缺血性坏死的鉴别诊断

目的：通过对股骨头骨髓水肿综合征诊治的观察,分析其疾病特点及其与股骨头缺血性坏死的异同。方法：自2004年1月,股骨头骨髓水肿综合征患者19例,男12例,女7例;平均年龄（46．7±10．36）岁。给予药物及物理治疗,治疗前后按照髋关节Harris评分系统进行评分。结果：治疗前平均（43．17±12．62）分,治疗后平均（86．73±14．29）分,治疗前、后评分差异有统计学意义（P〈0．05）。结论：股骨头骨髓水肿综合征疾病特点不同于股骨头缺血性坏死,是一类独立的疾病。     

Magnetic resonance imaging in diagnosis of transient osteoporosis of the hip.

The results of magnetic resonance (MR) imaging in six patients with transient osteoporosis of the hip were reviewed. Short TR/TE (repetition time/echo time) images demonstrated diffusely decreased signal intensity in the femoral head and intracapsular region of the femoral neck. Increased signal intensity was noted with progressive T2 weighting. Bone biopsies were performed in four patients. Histologic findings were nonspecific and included fat necrosis, marrow edema, increased bone resorption, and reactive bone formation. Repeat MR scans in two patients, performed six and eight months after the initial scans, showed an almost complete return to normal marrow signal. All patients became asymptomatic without bony deformity. In the appropriate clinical setting, MR scanning can aid in the diagnosis of transient osteoporosis as the cause of a painful hip.     

Disseminated intravascular coagulation in association with pig-to-primate pulmonary xenotransplantation

BACKGROUND: Profound coagulopathy has been proposed as a barrier to xenotransplantation. Disseminated intravascular coagulation (DIC) has been observed with the rejection of renal and bone marrow xenografts but has not yet been described in pulmonary xenografts. METHODS: This study examined the coagulation parameters in five baboons that received pulmonary xenografts and one baboon that was exposed to porcine lung during an extracorporeal perfusion. Platelet counts, prothrombin times (PT), and levels of fibrinogen, D-dimers, and thrombin-antithrombin III complex (TAT) were analyzed. In addition, serum levels of plasminogen activator inhibitor-1 (PAI-1), thrombomodulin (TM), tissue plasminogen activator (tPA), and tissue factor (TF) were determined. RESULTS: Hyperacute pulmonary xenograft dysfunction, which occurred within 0-9 hr of graft reperfusion, was associated with clinically evident DIC. This coagulopathy was characterized by thrombocytopenia, decreased fibrinogen levels, elevations in PT, and increases in D-dimers and TAT. Furthermore, transient increases in PAI-1, increases in TM, and increases in tPA were observed in the serum of some but not all recipients. None of the baboons demonstrated measurable increases in soluble TF. CONCLUSIONS: Although DIC in renal or bone marrow xenotransplantation develops over a period of days, DIC associated with hyperacute pulmonary xenograft dysfunction develops within hours of graft reperfusion. Thus, the DIC in pulmonary xenotransplantation may represent a unique and/or accelerated version of the coagulopathy observed with renal and bone marrow xenotransplantation.     

Bone marrow edema syndrome associated with uterine myoma: a case report

A patient with bone marrow edema syndrome of the hip associated with a uterine myoma is presented. A 51-year-old woman could not walk because of severe pain in both hips and had been referred to the authors' institute. Magnetic resonance imaging scans showed abnormal intensity on T1- and T2-weighted images in both femoral heads and a large mass arising from the uterus which was diagnosed as a uterine myoma. A 99mTc-methylene diphosphonate scintigraph showed diffuse uptake in both femoral heads. The pain in both hips decreased shortly after a hysterectomy and the patient could walk without crutches within 2 weeks after the gynecologic surgery. Magnetic resonance imaging scans taken 8 months after surgery showed high signal intensity on T1- and T2-weighted images, indicating normal bone marrow in the femoral heads. To the authors' knowledge, this is the first case report showing a bone marrow edema syndrome of the hip associated with uterine myoma. The pathophysiologic mechanisms for bone marrow edema syndrome of the hip in the current patient and in pregnancy may be identical. More specifically, a large intrapelvic mass may cause an increase of intrapelvic pressure and subsequent blood stasis in both conditions. The current case suggests the possible factors of bone marrow edema syndrome of the hip which need to be investigated.     

Nephrotic syndrome with renal vein thrombosis: pathogenetic importance of a plasmin inhibitor (alpha 2-antiplasmin)

Tests of fibrinolysis were measured by fibrin plate methods in 44 patients with nephrotic syndrome, in 14 of whom renal vein thrombosis was demonstrated. In both groups the level of total fibrinolytic activity was normal, that of vascular plasminogen activator was decreased, and that of an inhibitor of plasminogen activation was elevated. The level of a plasmin inhibitor, measured by the fibrin plate method, was elevated in 13 of 14 patients with, but only in 12 of 30 without, renal vein thrombosis (p less than 0.005). The plasmin inhibitor was identical with alpha 2-antiplasmin. The data suggest that an increased level of alpha 2-antiplasmin may be a factor in determining susceptibility to the development and persistence of renal vein thrombosis in patients with nephrotic syndrome.     

The plasminogen activator inhibitor-1 gene, hypofibrinolysis, and osteonecrosis

In 59 patients with osteonecrosis of the hip, four genes associated with thrombophilia or hypofibrinolysis along with coagulation tests were studied to determine the pathoetiologic associations of heritable coagulation disorders with osteonecrosis. Patients did not differ from healthy control subjects for the thrombophilic Factor V Leiden, prothrombin, or methylenetetrahydrofolate reductase mutations. The plasminogen activator inhibitor-1 gene was shifted toward homozygosity for the 4G polymorphism; 41% of patients with osteonecrosis were homozygous for the 4G/4G polymorphism versus 20% of 40 healthy control subjects. The gene product of the 4G polymorphism, hypofibrinolytic plasminogen activator inhibitor activity, was higher in patients than in control subjects (median 19.2 versus 6.3 U/mL); 61% of patients had high plasminogen activator inhibitor activity (> or = 16.4 U/mL) versus 5% of control subjects. Stimulated tissue plasminogen activator activity (inhibited by plasminogen activator inhibitor activity) was lower in patients than in control subjects (3.10 versus 5.98 IU/mL); 31% of patients had low stimulated tissue plasminogen activator activity (< 2.28 IU/mL) versus 3% of control subjects. Heritable hypofibrinolysis conferred by the 4G/4G mutation of the plasminogen activator inhibitor-1 gene seems to be a major pathoetiology of primary osteonecrosis.     

单次低剂量脂多糖联合甲基强的松龙诱导股骨头坏死的实验研究

目的 探讨单一低剂量脂多糖(lipopolysaccharide,LPS)及后续3次高剂量甲基强的松龙(methylprednisolone,MPS)注射引起激素性股骨头坏死(osteonecrosis of femoral head,ONFH)的发生情况及其发生机制. 方法 健康成年雄性26～30周龄新西兰大白兔25只,体重(3.0 ±0.3)kg.随机取19只为处理组,经耳缘静脉注射10 μg/kg LPS,24 h后于右侧臀肌注射20 mg/kg MPS琥珀酸钠,共3次,每次间隔24 h;余6只为对照组,于相同时间点注射等量生理盐水.于注射LPS前、3次注射MPS前及最后1次注射MPS后24 h行血液学检查.于最后1次注射MPS后6周行双髋部MRI扫描,于股骨头区抽吸骨髓检测局部干细胞活性,并取双侧股骨头行组织病理学检查. 结果 LPS注射后48 h,1只动物死亡,余动物均存活至实验完成.经组织病理学观察,处理组中16只动物为ONFH (病理),ONFH发生率为88.9%(16/18),坏死区域主要位于干骺端,微血管内有纤维血栓形成,髓内脂肪细胞体积明显增大并堆积;对照组股骨头均正常.MRJ诊断准确率为93.8%(15/16).处理组中16只ONFH (病理)动物,与正常值(注射LPS前)比较组织纤溶酶原激活剂/纤溶酶原激活剂抑制因子1(tisssue plasminogen aetivator/plasminogen activator inhibitor 1,t-PA/PAI-1)和活化部分凝血激酶时间(activated partial thromboplastin time,APTT)明显下降(P＜0.05),低密度脂蛋白/高密度脂蛋白明显增高(P＜0.05);对照组以上指标与正常值比较差异均无统计学意义(P＞0.05).各时间点处理组ONFH (病理)动物t-PA/PAI-1和APTT与对照组比较,差异有统计学意义(P＜0.05).处理组ONFH (病理)兔股骨头区骨髓产生的成纤维细胞集落形成单位总数为8.50 4±9.63,与对照组的70.17±7.78比较,差异有统计学意义(P＜0.05). 结论 单次低剂量LPS联合MPS是制备激素性ONFH模型的成功方法,血液的高凝和/或高纤溶状态、脂质代谢的紊乱、多能干细胞数量活性的降低等多因素作用可能是诱导激素性ONFH的关键.     

Transient osteoporosis of the hip: A case report

We report a case of transient osteoporosis of the hip (TOH) in a 59-year-old man including the clinical presentation, diagnostic studies, management and clinical progress. TOH is a rare self-limiting condition that typically affects middle-aged men or, less frequently, women in the third trimester of pregnancy. Affected individuals present clinically with acute hip pain, limping gait, and limited ranges of hip motion. TOH may begin spontaneously or after a minor trauma. Radiographs are typically unremarkable but MR imaging studies yield findings consistent with bone marrow edema. TOH is referred to as regional migratory osteoporosis if it travels to other joints or the contralateral hip. TOH often resembles osteonecrosis but the two conditions must be differentiated due to different prognoses and management approaches. The term TOH is often used interchangeably and synonymously with transient bone marrow edema.     

Risk factors for pulmonary emboli after total hip or knee arthroplasty

Because it is difficult to predict which patients may sustain a pulmonary embolism after total hip or knee arthroplasty, we assessed multiple thrombophilic and hypofibrinolytic parameters to identify risk factors. Twenty-nine patients who survived a known pulmonary embolism after total knee or total hip arthroplasty were matched by age, gender, race, arthritic diagnosis, procedure, and surgery date with 29 patient-controls who had a total hip or knee arthroplasty but who did not have a symptomatic known pulmonary embolism or deep vein thrombosis. Twenty-one serologic measures and five genes associated with thrombophilia, hypofibrinolysis, or both were assessed without knowledge of group assignment. All patients with pulmonary embolism had at least one abnormality of plasminogen activator inhibitor activity, dilute Russell's viper venom time, prothrombin time, or total cholesterol versus 13 of 27 (48%) control patients. Forty-seven percent of patients who experienced pulmonary embolism had at least two abnormalities of plasminogen activator inhibitor activity, dilute Russell's viper venom time, prothrombin time, or total cholesterol, versus 7% of control patients. Preoperatively, to identify patients at high risk of pulmonary embolism, plasminogen activator inhibitor activity, dilute Russell's viper venom time, prothrombin time, and cholesterol levels were most predictive. Using at least one abnormality of these four measures as a screening test to detect risk of pulmonary embolism, the test is sensitive (100%), and the predictive value of a negative test is high (100%). After additional prospective study, this may allow identification of patients at low risk (the majority of patients) in whom anticoagulation may not be required and a small group of patients at high risk for pulmonary embolism in whom prophylactic anticoagulation should be provided.     

Migrating bone marrow edema syndrome: a cause of recurring knee pain

Bone marrow edema syndrome is a condition of unknown etiology, presenting with painful limping. It is characterized by normal radiographs, but magnetic resonance imaging findings change with bone marrow edema. When there is osteopenia in the radiographs, the condition is called transient osteoporosis. The term migratory bone marrow edema syndrome is used when there is involvement of another joint, or another compartment in the same joint, which typically occurs within 6 months of onset of primary symptoms. Here, a case of migratory bone marrow edema syndrome in a 47-year-old male patient, which was conservatively managed, is reported.     

Hypofibrinolysis, thrombophilia, osteonecrosis

In the context of additional characterization of the pathoetiologic associations of heritable hypofibrinolysis and thrombophilia with osteonecrosis of the hip, the authors assessed 15 women and 21 men at entry to a 12-week treatment study of the amelioration of Ficat Stages I or II osteonecrosis by low molecular weight heparin (Enoxaparin). All 36 patients had osteonecrosis of the hip; four patients had unifocal osteonecrosis, 25 patients had two joints affected, five had three affected joints, and two had four affected joints. In 11 of 15 women (73%), hyperestrogenemia of pregnancy (20%) or exogenous estrogen supplementation (53%) were associated with the development of osteonecrosis. Five gene mutations affecting coagulation and nine serologic coagulation tests were studied. Compared with control subjects, patients were more likely to have heterozygosity and homozygosity for the hypofibrinolytic 4G polymorphism of the plasminogen activator inhibitor-1 gene. Moreover, the plasminogen activator inhibitor-1 gene product, plasminogen activator inhibitor activity, the major determinant of hypofibrinolysis, was 10 times more likely to be high (> 21.1 U/mL) in patients than in control subjects (31% versus 3%), with a median of 15.7 versus 6.3 U/mL. Compared with controls, patients were more likely to have the thrombophilic methylenetetrahydrofolate reductase gene mutation. In addition, the thrombophilic methylenetetrahydrofolate reductase gene product, homocysteine, was four times more likely to be high (> 13.5 umol/L) in patients than in control subjects (20% versus 5%), with a median of 9.1 versus 7 umol/L. Twenty-three percent of patients had low levels (< 65%) of the thrombophilic free protein S versus 3% of control subjects. Patients were more likely than control subjects to have hypofibrinolytic high lipoprotein (a) (> or = 35 mg/dL), 33% versus 13%. Median lipoprotein (a) was higher in patients than in control subjects, 15 versus 5 mg/dL. Heritable hypofibrinolysis and thrombophilia, often augmented in women by hyperestrogenemia, seem to be major pathoetiologies of osteonecrosis. If the association between coagulation disorders and osteonecrosis reflects cause and effect, as postulated, then anticoagulation with Enoxaparin should be a promising therapy for patients with osteonecrosis.     

Modulation of the fibrinolytic system by major peripheral ischemia

Purpose: A rat model was developed to investigate the effects of acute peripheral ischemia on the components of the fibrinolytic system.Methods: Laparotomy was performed and ischemia was introduced by total aortic clamping at a subrenal position. Control animals underwent sham laparotomy alone. Plasma and tissue samples were collected for analysis at 30, 60, 90, and 120 minutes after operation.Results: Functional assays of rat plasma revealed a dramatic and transient increase in tissue-type plasminogen activator (tPA) activity within 30 minutes of the onset of ischemia. A simultaneous decline in plasminogen activator inhibitor activity was observed. Immunohistochemical analysis suggested this initial increase in tPA activity resulted primarily from the release of stored tPA from ischemic vascular tissues. Northern blot analysis revealed that both tPA and plasminogen activator inhibitor – 1 messenger RNA levels were elevated at 60 to 120 minutes in well-perfused tissues distant from the ischemic insult.Conclusions: Collectively, these data demonstrate that acute peripheral ischemia results in a rapid and transient increase in plasma fibrinolytic activity, concomitant with the early release of stored tPA from ischemic vascular tissues. In addition, peripheral ischemia appears to stimulate both tPA and plasminogen activator inhibitor – 1 gene expression in well-perfused tissues at later time points, consistent with the existence of humoral mediators. (J VASC SURG 1994;19:516-24.)