Deep Venous Thrombosis Resolution Research Articles

Outcomes following interval delayed first rib resection for acute axillosubclavian deep venous thrombosis

BackgroundCurrent management of axillosubclavian deep venous thrombosis (DVT) often uses thrombolysis for the DVT, prompt first rib removal, and occasional venoplasty or stenting. Our institution has increasingly used anticoagulation alone followed by interval first rib resection. We sought to analyze the effectiveness of this simplified technique. MethodsBetween September 2012 and April 2021, 27 patients were identified within the institution's electronic medical record as having undergone first rib resection for upper extremity DVT. Seven of these patients had undergone preoperative thrombolysis before referral and were excluded. Among the remaining 20 patients, preoperative clinic charts were evaluated for age, venous segment involvement, contralateral limb involvement, presence of documented hypercoagulable state, duration of preoperative and postoperative anticoagulation, and postoperative outcomes. ResultsOf the 20 patients (mean age, 26.2 years; 13 males) presenting with acute axillosubclavian DVT, all patients had right (n = 8) or left (n = 12) arm swelling. Five patients had extremity pain and four had extremity discoloration. Ten had axillosubclavian vein involvement, 9 had subclavian vein involvement, and 1 had axillary vein involvement. Two patients were on oral contraceptives and no patients had any other diagnosed hypercoagulable conditions. The mean duration of preoperative and postoperative anticoagulation was 3.2 ± 2.6 months and 2.1 ± 2.1 months, respectively. Nineteen patients underwent supraclavicular first rib resection and 1 patient underwent transaxillary resection. Twelve patients (60%) demonstrated complete DVT resolution by venous duplex examination during the postoperative period and 8 patients (40%) demonstrated partial recanalization/chronic DVT. Complications included one hemothorax and one thoracic duct injury. All 20 patients remain asymptomatic without arm swelling, with a mean follow-up of 55.1 ± 34.7 months. ConclusionsAmong patients presenting with acute axillosubclavian DVT, anticoagulation alone followed by interval first rib resection proved to be successful in providing symptomatic relief in the short to medium term. By eliminating the need for preoperative thrombolysis and postoperative venograms, this potentially cost-saving algorithm simplifies our management for acute venous thoracic outlet syndrome while maintaining good clinical outcomes. Because this study only analyzed our management algorithm's effectiveness in the short to medium term, the long-term effectiveness of this treatment will need to be demonstrated.

Toll-like receptor 4 deficiency in mice impairs venous thrombus resolution.

Objective: Toll-like receptor 4 (TLR4) is crucial to the development of sterile inflammatory responses. The deep venous thrombosis resolution (DVT) is similar to sterile inflammation, so we hypothesize that TLR4 is involved. Methods and Results: We evaluated the effects of TLR4 deficiency on thrombus lysis in vivo, and explored the mechanisms in vitro. DVT mouse model was established by inferior vena cava (IVC) ligation. After the IVC ligation (1, 3, and 7d), the mice were euthanized to collect the venous thrombus. The Tlr4-/- mice had significantly elevated weight/length ratios of thrombi at 3 and 7d and increased collagen content at 3d after IVC ligation, in addition to significantly lesser intrathrombus infiltration of neutrophils and macrophages, lower monocyte chemoattractant protein-1 (MCP-1) and matrix metalloproteinase-9 (MMP-9) expression in thrombus tissue sections and homogenates, and lower pro-MMP-9 activity at 3d after IVC ligation than wild-type mice. After 7days of IVC ligation, VEGF, IFNβ, and MCP-5 protein expression were decreased in venous thrombus from Tlr4-/- mice. 2ml of 3% thioglycolate was injected intraperitoneally and peritoneal exudate was collected 3days later from Tlr4-/- and wild type mice respectively. The intraperitoneal macrophages were isolated from adherent culture after centrifugation. Lipopolysaccharide (LPS) can activate TLR4/NF-κB signalling pathway in a concentration-dependent manner, initiated p65 nuclear translocation, IκBα phosphorylation and degradation, MMP-9 and MCP-1 transcription in WT intraperitoneal macrophages but not in Tlr4-/- intraperitoneal macrophages. Conclusion: TLR4 is involved in venous thrombosis resolution through NF-κB pathway. Loss of TLR4 in mice impairs the process.

Predictors of postthrombotic syndrome in pediatric thrombosis: A systematic review and meta‐analysis of the literature

BackgroundPostthrombotic syndrome (PTS) is a significant complication of pediatric deep venous thrombosis (DVT). There is a gap in the understanding of the risk factors associated with the development of pediatric PTS preventing the early identification of those patients at greatest risk, and the development of risk‐stratified interventions. ObjectivesTo conduct a systematic review and meta‐analysis of the literature on prognostic factors for PTS development in pediatric patients. MethodsA systematic search of MEDLINE, EMBASE, and the Cochrane Library from 1960 to December 2018 was performed. Eligible studies reported at least one prognostic factor for PTS development in patients < 21 years of age with a radiographically confirmed DVT. To be included in the meta‐analysis, prognostic factors had to be reported in at least three published studies. Results and conclusionsTwelve studies (n = 1160 patients) met criteria for inclusion. Ninety‐three percent of patients with an extremity DVT (n = 1076) were assessed for PTS. PTS developed in 40% (n = 434) of these patients. Central venous catheter‐associated DVT (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.08‐2.98), complete veno‐occlusion (OR, 1.89; 95% CI, 1.04‐3.46), and incomplete DVT resolution (OR, 2.07; 95% CI, 1.4‐3.07) were identified as candidate prognostic factors for pediatric PTS. These findings should be interpreted in the context of the heterogeneity of the included studies and the limitations of current pediatric PTS assessment tools. Further, the predictive value of these prognostic factors will need to be validated in future collaborative prospective multicenter studies that maximize the homogeneity of pediatric DVT patients.

Noncompressible Filling Defects: Propagation in Isolated Calf Vein Thrombus in the Critical Care Population

The natural history of isolated calf deep venous thrombosis (CDVT) or noncompressible filling defects is controversial. We aimed to characterize our patient population by differentiating those who had just an isolated, asymptomatic deep venous thrombosis (DVT) limited to the calf from those with a symptomatic CDVT. The presence of edema or pain in the calf and findings of thrombus formation within the soleal, gastrocnemius, posterior tibial, or anterior tibial veins describe symptomatic CDVT. Our objective was to study the incidence, evolution, and clinical consequence of asymptomatic CDVT within the critical care population. A retrospective analysis incorporating venous duplex ultrasound scans of neurocritical care patients was performed during a 32-month period from January 2016 to September 2018. Based on a risk assessment profile score >5, a venous duplex ultrasound scan was obtained 3 days after the patient’s admission and weekly thereafter until discharge. Demographics including age, sex, comorbidities, anticoagulation status, principal admission problem, and in-hospital mortality were noted. Symptomatic patients with a diagnosis of a DVT were excluded. The development of a proximal DVT or pulmonary embolus vs resolution of the thrombus during the study period was also recorded. Approximately 5375 lower extremity venous studies were performed. CDVT was identified in 121 (2%) asymptomatic patients. The main admitting diagnosis was traumatic brain injury. The majority (83 patients) underwent follow-up scans consistent with recommendations. During the 32-month period, approximately 50% of them (42/83) had no changes, whereas 36% of patients (30/83) had a complete resolution of the calf vein thrombus. Approximately 13% (11/83) progressed while remaining asymptomatic. Of those 11 patients, 3 patients subsequently developed symptomatic above-knee DVT (3/83 [3.6%]). No pulmonary embolism was recorded. There was no recorded in-hospital mortality. CDVT was identified in only a small percentage of our high-risk patient population who remain without symptoms. Moreover, the rate of progression from asymptomatic CDVT to symptomatic above-knee DVT was only 3.6%. Asymptomatic CDVTs rarely lead to significant clinical consequences and did not correlate with hospital mortality. We recommend against repeated DVT scans after diagnosis of asymptomatic CDVT, more appropriately termed noncompressible venous filling defects, solely based on protocols and without symptoms.

Anti-inflammatory effects of simvastatin during the resolution phase of experimentally formed venous thrombi

Deep venous thrombosis (DVT) is a common vascular disease and is closely linked to inflammation. Over the past decade, the potential antithrombotic effect of statins has been elucidated by clinical...

Deep vein thrombosis resolution is impaired in diet-induced type 2 diabetic mice

Type 2 diabetes mellitus results in a procoagulant and thrombogenic state that could predispose diabetic individuals to develop venous thrombosis. We sought to determine whether diet-induced type 2 diabetes mellitus affects deep venous thrombosis (DVT) resolution in a murine model. C57Bl/6 mice were fed a low-fat or a high-fat diet (n = 10) for 10 weeks, after which DVT was created in the inferior vena cava (IVC) by a combination of low flow and endothelial damage. The IVC and thrombus were harvested at 1 and 2 weeks. Thrombus resolution and neovascularization were investigated through transfemoral angiography (n = 10), thrombus size (n = 4) and weight (n = 10), and nitric oxide synthase 3 immunoquantification (n = 4). Macrophage content was assessed by CD68 immunoreactivity (n = 4). The fibrinolytic system (urokinase plasminogen activator [uPA] and plasminogen activator inhibitor-1 [PAI-1]) was analyzed by Western immunoblotting (n = 6) and immunohistochemistry (n = 4). Total collagen was stained by Sirius red. Matrix metalloproteinases (MMP)-2 and MMP-9 activities were evaluated by zymography and their expressions by Western immunoblotting (n = 6) and immunohistochemistry (n = 4). Diabetic mice had significantly larger and heavier thrombi at 1 and 2 weeks (P < .05), threefold less neovascularization (P < .05), and 35-fold increase in macrophage content (P < .01), than control mice 2 weeks after surgery. IVC recanalization was documented in 90% of 2-week control mice and in 10% of 2-week diabetic mice (P < .01). Increased vein wall collagen and less uPA and more PAI-1 expressions with a decreased uPA/PAI-1 ratio (31%, P < .01) were documented at 2 weeks in diabetic mice. MMP-2 and MMP-9 activities and expressions were significantly increased in diabetic mice at 1 and 2 weeks (P < .05) compared with control mice. Diet-induced type 2 diabetes may impair DVT resolution through altered inflammatory, fibrinolytic, and MMP responses.

Plasmin and Matrix Metalloproteinase System in Deep Venous Thrombosis Resolution

Deep venous thrombosis (DVT) is a common event in hospitalized medical and surgical patients. Outside of anticoagulation, few good options exist for decreasing the vein wall damage that results after natural thrombolysis. DVT resolution is complex and involves chemokines, leukocytes, and native vein wall cells. Herein some aspects of DVT resolution related to the intersection of inflammation, the plasminogen and matrix metalloproteinase systems, and their respective inhibitors are reviewed. Ultimately, better knowledge of these natural thrombolytic systems may allow local, directed, and specific acceleration of DVT resolution and decreased vein wall damage.

Plasmin Inhibition Increases MMP-9 Activity and Decreases Vein Wall Stiffness During Venous Thrombosis Resolution

Deep venous thrombosis (DVT) resolution involves the plasmin and the matrix metalloproteinase (MMP) system. This study tested the hypothesis that pharmacological inhibition of the plasmin system would impair DVT resolution and worsen vein wall damage. A rat model of stasis DVT by inferior vena cava (IVC) ligation was performed with intravenous control saline or aprotinin (AP; 2.8 mg/kg at operation), and harvest of thrombosed IVC at 7 days. After laser Doppler imaging, DVT were separated and weighed, and vein wall stiffness was assessed by tensiometry. Thrombus and vein wall tissue analysis included total collagen by colorimetric assay, cytokines, chemokines, and d-dimer by ELISA, urokinase-plasminogen activator (uPA), and plasminogen activator inhibitor-1 (PAI-1) by immuno-blotting, MMP-2 and -9 by zymography, and neutrophil (PMN) and monocyte (ED-1) leukocytes by immunohistochemistry. DVT weights were 2-fold greater in the AP-treated rats (P < 0.05), but no significant differences in thrombus perfusion, collagen, or d-dimer levels were found. Vein wall stiffness was reduced 50% (P < 0.05), suggesting less biomechanical injury. The total vein wall MMP-9 was increased (P < 0.05) 5-fold in the AP group compared with controls, while MMP-2 was elevated but did not reach significance. No difference was found in vein wall tumor necrosis factor-alpha, tissue growth factor-beta, vein wall or thrombus monocytes, PMN, or uPA/PAI-1 ratio between groups. AP inhibition of the plasmin system was associated with larger thrombi but less vein wall injury, but no difference in other measures of resolution, possibly because of increased vein wall MMP-9 activity. These data suggest an important redundant mechanism for DVT resolution.

P143: Pharmacological inhibition of the plasmin system increases matrix metalloproteinase -9 activity and decreases vein wall stiffness during venous thrombosis resolution

Introduction: Deep venous thrombosis (DVT) resolution involves the plasmin and the matrix metalloproteinase (MMP) system. This study tested the hypothesis that pharmacological inhibition of the plasmin system would impair DVT resolution and worsen vein wall damage.Methods: A rat model of stasis DVT by inferior vena cava (IVC) ligation was performed with intravenous control saline or aprotenin (AP; 2.8 mg/Kg at operation), and harvest of thrombosed IVC at 7 days. After laser Doppler (LD) imaging, DVT were separated, weighed, and vein wall stiffness was assessed by tensiometry. Thrombus and vein wall tissue analysis included total collagen and d-dimer by colorimetric assay, cyto- and chemokines by ELISA, uro-plasminogen activator (uPA) and plasminogen activator-1 (PAI-1) by immunoblotting, MMP-2 and -9 by zymography, and neutrophil (PMN) and monocyte (ED-1) leukocytes by immunohistochemistry. Results: DVT were larger in the AP treated rats, but no significant differences in thrombus perfusion, collagen, or fibrin were found (Table). Vein wall stiffness was less, and MMP-9, but not MMP-2 activity was elevated in the AP group. No difference was found in vein wall TNFα, TGFβ, PMN, ED-1 cells, or uPA/PAI-1 ratio between groups. Discussion: AP inhibition of the plasmin system was associated with larger thrombi, but no difference in other measures of resolution, possibly because of increased vein wall MMP-9 activity. Paradoxically, vein wall injury was lessened. These data suggest an important redundant mechanism for DVT resolution.

Differential transcriptional activation of matrix metalloproteinase-2 and membrane type-1 matrix metalloproteinase by experimental deep venous thrombosis and thrombin

Resolution of deep venous thrombosis (DVT) is involved in the pathogenesis of postthrombotic syndrome. Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that are critical in angiogenesis and tissue remodeling. We hypothesized that MMP-2 and its membrane-bound activator membrane type-1 matrix metalloproteinase (MT1-MMP) expression would be expressed and activated during the resolution of DVT. DVT was generated by caval ligation in wild-type and MMP-2 transgenic reporter mice. Ligated and sham-operated (control) cavae were analyzed for MMP-2 transcription (beta-galactosidase activity in MMP-2 reporter mice) and MT1-MMP mRNA by real-time polymerase chain reaction. MMP-2 activity was determined by zymography, and immunohistochemical staining for beta-galactosidase and MT1-MMP protein was used to localize expression. Human umbilical vascular endothelial cells (HUVEC) were treated with 10 U/mL thrombin and MMP-2 and MT1-MMP mRNA levels and MMP-2 activity was determined. MMP-2 activity increased 71% (n = 5, P < .05) at day 8 in ligated vs control cavae by zymography. beta-galactosidase activity showed a 1.2-fold (n = 8, P < .05) and 1.7-fold (n = 8, P < .05) induction in MMP-2 transcription at day 3 and day 8, respectively. No significant MT1-MMP gene induction was seen at day 3 in ligated vs control cavae, but MT1-MMP mRNA was upregulated 2.5-fold (n = 8, P < .05) in ligated cavae at day 8. Immunohistochemical staining localized MMP-2 and MT1-MMP expression to the vein wall and cellular infiltrates of the thrombus. Thrombin-treated HUVEC showed differential responses of MMP-2 and MT1-MMP. Zymography of conditioned media and cell lysates illustrated a 220% (152.6 +/- 8.6 vs 69.445 +/- 5.46 pixels/unit area, n = 5, P < .05) and 150% (74.1 +/- 7.3 vs 49.2 +/- 5.7 pixels/unit area, n = 5, P < .05) increases in MMP-2 activity respectively. MMP-2 mRNA levels were downregulated 30% (0.48 +/- 0.023 vs 0.63 +/- 0.035 copies of MMP-2 mRNA/copy GAPDH, n = 5, P < .05), whereas MT1-MMP message was upregulated 250% (0.147 +/- 0.009 vs 0.059 +/- 0.005 copies of MT1-MMP mRNA/copy GAPDH, n = 5, P < .05). Resolution of DVT is associated with increased MMP-2 transcription and activity as well as MT1-MMP expression. Thrombin may mediate the increase in MT1-MMP noted in DVT. This is the first article studying MMP-2 and MT1-MMP transcription in DVT. These findings add DVT resolution to the class of inflammatory and fibrotic disorders in which transcriptional activation of the MT1-MMP/MMP-2 genes occurs and identify a potential therapeutic target to modulate this clinically relevant process. Postthrombotic syndrome remains a significant clinical problem after deep venous thrombosis (DVT), but the cellular and molecular mechanisms involved in thrombus resolution and vein wall fibrosis remain undefined. Matrix metalloproteinase (MMP) enzymes are critical to cell migration and matrix breakdown. We identify gene transcription and activity of two MMP isoforms, MMP-2 and MMP-14 (membrane type MMP 1, MT1-MMP) in the resolution phase of experimental DVT and in thrombin-treated endothelial cells. These studies define new proteases potentially important to resolution of DVT and development of postthrombotic syndrome.

Five-year outcome study of deep vein thrombosis in the lower limbs

Venous disease was evaluated in relation to post-thrombotic syndrome 5 years after deep venous thrombosis (DVT) in patients treated with a regimen of low-molecular-weight heparin (LMWH) and warfarin in a Hospital-in-the-Home program. The presence of flow, reflux and compressibility in 51 patients (102 limbs, 54 with DVT and 48 without DVT) was assessed by duplex ultrasound scanning. Blood tests were carried out for prothrombotic screening. Venous disease was related to pathologic severity of post-thrombotic syndrome, characterized by the CEAP (clinical, etiologic, anatomic, pathophysiologic) classification on a scale of 0 to 6. In the 102 limbs studied, 30 patients (59%) had an underlying thrombophilic disorder. The most common cause of DVT was postoperation and prolonged immobilization not related to postoperation. The most common thrombophilic abnormalities were anticardiolipin antibody and a deficiency of protein C or S, or both. Twenty-six limbs (48%) had proximal involvement (proximal and proximal plus distal DVT); resolution (recanalization or normal vein) in these limbs was seen in 85% at 6 months and 96% at 5 years. After 5 years, 25 of these proximal DVT limbs (96%) developed reflux and there were 4 limbs in CEAP class 0, 8 in classes 1 to 3, and 14 in classes 4 to 6. All of the 28 limbs (52%) with distal DVT showed DVT resolution by 6 months. After 5 years, 10 limbs (36%) developed reflux, and 13 limbs were in class 0, 12 in classes 1 to 3, and 3 limbs in classes 4 to 6. No DVT was detected in the 48 contralateral limbs, but reflux was detected in 25 limbs (52%), predominately in the superficial veins (16 limbs, 64%). The resolution of thrombus was more rapid and complete in patients with distal DVT than in those with proximal DVT. Patients with proximal DVT developed a more severe form of post-thrombotic syndrome that was likely related to the development of deep venous reflux. An important finding of this study was an unexpectedly high incidence of venous reflux in the apparently unaffected limb. Although these non-DVT limbs were not investigated at presentation, our data is consistent with the hypothesis that DVT may result in a more systemic disorder of venous function.

Deep vein thrombosis resolution is modulated by monocyte CXCR2-mediated activity in a mouse model.

To determine the role of CXCR2, the receptor for cysteine-X-cysteine (CXC) chemokines, and its primary effector cell, the neutrophil (PMN), on deep venous thrombosis (DVT) resolution. DVT in BALB/c, anti-CXCR2 antibody-treated, and BALB/c CXCR2(-/-) mice were created by infrarenal inferior vena cava (IVC) ligation and the thrombus harvested at various time points over 21 days. The CXCR2(-/-) mice had significantly larger thrombi at early time points (days 2 to 8), and significantly decreased intrathrombus PMNs, monocytes, and neovascularization as compared with controls. Thrombus KC/CXCL1 was significantly higher at 2 days in CXCR2-/- thrombi as measured by enzyme-linked immunosorbent assay. Fibrin content was significantly higher, with less uPA gene expression at 4 days in CXCR2-/- thrombi. Late fibrotic maturation of the thrombus was delayed in the CXCR2-/- mice, with significantly decreased 8 day MMP-2 activity, whereas MMP-9 activity was elevated as compared with controls. Similar impairment in DVT resolution was found at 8 days with anti-CXCR2 inhibition. However, systemic neutropenia, unlike CXCR2 deletion, did not increase the thrombus size as compared with controls. Normal DVT resolution involves CXCR2-mediated neovascularization, collagen turnover, and fibrinolysis, and it is probably primarily monocyte-dependent.

Neutropenia impairs venous thrombosis resolution in the rat

Neutrophil influx is one of the first events in a formed deep venous thrombosis (DVT), but whether these cells are active participants in the resolution process is not clear. This study tests the hypothesis that neutrophils (PMN) are active participants in DVT resolution. Thrombosis was induced by inferior vena caval (IVC) ligation in male Sprague-Dawley rats, and rats were sacrificed at 2, 4, or 7 days for evaluation of the thrombus. Neutropenia was induced by rabbit anti-rat PMN serum, and controls received rabbit serum. Venography was performed at the 7-day time point. Immunohistochemical staining was performed to quantify intrathrombus PMNs and monocytes, and the myeloperoxidase (MPO) assay was performed to assess intrathrombus neutrophil activity. Intrathrombus concentrations of kerotinocyte cytokine (KC), macrophage inflammatory protein-2 (MIP-2), gamma interferon inducible protein-10 (IP-10), macrophage inflammatory protein-1 alpha (MIP-1 alpha), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor (TNF)-alpha were quantified by enzyme immunoassay at each time point and normalized to total protein. Total collagen was determined at day 7. Peripheral blood smears showed a 94% PMN reduction at 2 days (P <.05), recovering to 44% of control at 7 days. Intrathrombus PMNs were significantly lower in neutropenic rats at 2 and 4 days, but there were no differences in intrathrombus monocytes. The MPO assay confirmed reduced neutrophil activity at 4 days. Thrombi from neutropenic rats were larger at 2 and 7 days compared with controls. In vivo thrombus area at 7 days as assessed by venography was also greater in neutropenic rats as compared with controls. The intrathrombus KC concentration was increased more than 20-fold in the neutropenic rats at 2 days, but there were no significant differences in other intrathrombus chemokines. Finally, intrathrombus collagen was increased over threefold in neutropenic rats as compared with controls. Neutropenia impairs DVT resolution by several measures, most likely by altering normal fibrinolytic activity and thrombus collagen turnover.

Dalteparin for deep venous thrombosis: a hospital-in-the-home program.

To assess the efficacy, safety and cost savings of home treatment of lower-limb deep venous thrombosis (DVT). A hospital-in-the-home treatment program. One hundred patients with acute lower limb DVT (53 proximal, 47 distal), and no contraindication to home treatment, were entered into the program from March 1995 to February 1997. All patients received dalteparin, 200 units/kg subcutaneously, once daily for a minimum of five days, with commencement of oral anticoagulation (warfarin) on Day 2. Patients with proximal DVT had lung ventilation-perfusion scans performed and were admitted to hospital for at least 24 hours. Patients with distal DVT were discharged directly to home treatment. Clinical responses and the results of sequential duplex ultrasonography at one week, one month, three months and six months. There were no major, but six minor, bleeding complications, two of which led to dalteparin being withdrawn. Sixteen patients had lung ventilation-perfusion scans showing a high probability of pulmonary embolism. All were asymptomatic, and follow-up for at least three months showed no symptomatic thromboembolic events. Duplex ultrasonography showed progression of thrombosis in the first week of therapy in 13.2% of distal and 2.7% of proximal thromboses. Thereafter, distal DVT improved at a much greater rate than proximal DVT; after six months complete resolution was seen in 60.7% of distal and 18.5% of proximal thromboses, respectively. Cost saving was $197 per bed-day equivalent compared with inpatient care. At 15 months' follow-up, swelling and/or pain was reported by 49% of patients with distal DVT and 66% of those with proximal DVT. Once-daily dalteparin therapy for DVT in a hospital-in-the-home setting was safe, efficacious and cost effective. However, DVT resolution is a slow process, with significant long term morbidity.