Prothrombotic State In Patients Research Articles

Both Carvedilol and Nebivolol May Improve Platelet Function and Prothrombotic State in Patients With Nonischemic Heart Failure

It is unclear whether carvedilol and nebivolol will produce different effects on platelet function and prothrombotic state in heart failure (HF). Thus, we compared their effects on these functions in patients with nonischemic HF. We included 61 patients with symptomatic nonischemic HF having ejection fraction ≤40%. The patients were randomized to carvedilol (n = 31) or nebivolol (n = 30). Analyses were made at baseline, 3, and 6 months. At 6 months, mean platelet volume (MPV) was significantly lowered by both carvedilol and nebivolol therapy. However, MPV tended to be lower in the carvedilol group (7.7 ± 1.0 vs 8.0 ± 0.7 fL, P = .05). Fibrinogen and d-dimer levels were significantly decreased in but comparable in both the groups. Carvedilol and nebivolol have similar beneficial effects on platelet function and prothrombotic state in patients with nonischemic HF.

A Case of Fatal Pulmonary Embolism in a Patient With Warm Autoimmune Hemolytic Anemia: An Under-appreciated Thrombotic Risk

Autoimmune hemolytic anemia (AIHA) is a rare disorder in which the life span of red blood cells (RBCs) is prematurely decreased by hemolysis by either IgG or IgM auto-antibodies directed against red cell membrane antigens. Many factors are known to trigger this auto-antibody production. Symptoms are non-specific and vary according to the degree of anemia. Although considerable advances have been made in understanding the pathogenesis and securing the diagnosis, progress in management has been slow with no established therapeutic guidelines despite the input of many investigators. Lymphoproliferative disorders (LPDs) and venous thromboembolism (VTE) remain the two most clinically significant associated conditions. VTE is a more serious, acute and often lethal complication of AIHA. There are many mechanisms described for the prothrombotic state in patients with AIHA. Despite the thrombotic implications, risk of VTE is often overlooked and still lacking are standardized risk-stratification criteria and evidence-based thromboprophylactic strategies appropriate for the level of risk. With this case report, our goal is to raise awareness of this frequently unrecognized disorder and its potential for fatal consequences. We also summarize some of the mechanisms involved with the goal of stimulating a clinical discussion aimed at appropriately risk stratifying these patients for robust thromboprophylactic strategies. doi: http://dx.doi.org/10.4021/j h95w

S43 Fractal analysis of whole blood incipient clot confirms an early morning prothrombotic state in patients with untreated Obstructive Sleep Apnoea Syndrome

IntroductionObstructive sleep apnoea syndrome (OSAS) independently increases cardiovascular risk and a pro-thrombotic state has been at least partly implicated. Using fractal analysis we have developed a new biomarker called fractal...

Recurrent deep vein thrombosis and pulmonary embolism in a patient with Klinefelter’s syndrome

Klinefelter's syndrome, which is characterized by small testes, gynecomastia, hypogonadism, and infertility, is the most common cause of primary testicular failure, and commonly has an XXY karyotype. Deep vein thrombosis and thomboembolic events are a rare occurrence in these patients. Although the exact mechanism is not completely understood, it is thought that increased thromboembolic risk in hypogonadic men can be explained by hypofibrinolysis resulting from androgen deficiency. We present the case of a 48-year-old man with Klinefelter's syndrome who experienced recurrent episodes of deep venous thrombosis and pulmonary embolism while undergoing therapeutic anticoagulation. Our report discusses this association and management of the prothrombotic state in patients with Klinefelter's syndrome.

The impact of antiproteinuric therapy on the prothrombotic state in patients with overt proteinuria

Overt proteinuria is a strong risk factor for thromboembolism, owing to changes in the levels of various coagulation proteins and urinary antithrombin loss. The described coagulation disturbances in these patients are based on outdated studies conducted primarily in the 1970s and 1980s. Whether these coagulation disturbances resolve with antiproteinuric therapy has yet to be studied. A total of 32 patients with overt proteinuria (median, 3.7 g day(-1) ; interquartile range, 1.5-5.6) were enrolled in this intervention crossover trial designed to assess optimal antiproteinuric therapy with sodium restriction, losartan, and diuretics. Levels of various procoagulant and anticoagulant proteins, and parameters of two thrombin generation assays (calibrated automated thrombogram [CAT] and prothrombin fragment 1 + 2) were compared between the placebo period and the maximum antiproteinuric treatment period. As a secondary analysis, coagulation measurements of the placebo period in these patients were compared with those of 32 age-matched and sex-matched healthy controls. Median proteinuria was significantly lower during the maximum treatment period (median, 0.9 g day(-1) ; interquartile range, 0.6-1.4; P < 0.001) than during the placebo period. Similarly, levels of various liver-synthesized procoagulant and anticoagulant proteins, activated protein C resistance and prothrombin fragment 1 + 2 levels were significantly lower during the maximum treatment period than during the placebo period. However, von Willebrand factor and factor VIII levels were similar. On the basis of the higher levels of procoagulant proteins (fibrinogen, FV, FVIII, and von Willebrand factor) and both thrombin generation assays, patients were substantially more prothrombotic than healthy controls (P < 0.004). Antiproteinuric therapy ameliorates the prothrombotic state. Proteinuric patients are in a more prothrombotic state than healthy controls.

Pre-analytical and analytical variables affecting the measurement of plasma-derived microparticle tissue factor activity

Introduction Elevated levels of tissue factor positive (TF +) microparticles (MPs) are observed in plasma from a variety of patients with an increased risk of thrombosis. We and others have described the measurement of TF activity in MPs isolated from plasma. The aim of this study was to investigate the effects of pre-analytical and analytical variables on TF activity of MPs isolated from blood of healthy volunteers either untreated or treated ex vivo with bacterial lipopolysaccharide. Materials and methods We evaluated the following parameters: use of different centrifugation speeds to isolate the MPs; comparison of TF activity of MPs isolated from platelet poor plasma versus platelet free plasma; effect of freeze/thaw on MP TF activity; and comparison of the MP TF activity assay with the measurement of TF protein by ELISA or flow cytometry. Results MPs prepared from platelet poor plasma by centrifugation at 20,000 × g or 100,000 × g for 15 minutes had similar levels of TF activity. However, significantly less TF activity was found in MPs isolated from platelet free plasma compared with platelet poor plasma. Interestingly, freeze/thawing of the plasma showed donor to donor variation in MP TF activity, with a moderate increase in some individuals. Conclusion TF + MPs can be quantitatively isolated from platelet poor or platelet free plasma by centrifugation at 20,000 × g for 15 minutes. Measurement of MP TF activity in plasma may be used to detect a prothrombotic state in patients with various diseases.

Plasma gelsolin facilitates interaction between β2 glycoprotein I and α5β1 integrin

Antiphospholipid syndrome (APS) is characterized by thrombosis and the presence of antiphospholipid antibodies (aPL) that directly recognizes plasma β2-glycoprotein I (β2GPI). Tissue factor (TF), the major initiator of the extrinsic coagulation system, is induced on monocytes by aPL in vitro, explaining in part the pathophysiology in APS. We previously reported that the mitogen-activated protein kinase (MAPK) pathway plays an important role in aPL-induced TF expression on monocytes. In this study, we identified plasma gelsolin as a protein associated with β2GPI by using immunoaffinity chromatography and mass spectrometric analysis. An in vivo binding assay showed that endogenous β2GPI interacts with plasma gelsolin, which binds to integrin a5β1 through fibronectin. The tethering of β2GPI to monoclonal anti-β2GPI autoantibody on the cell surface was enhanced in the presence of plasma gelsolin. Immunoblot analysis demonstrated that p38 MAPK protein was phosphorylated by monoclonal anti-β2GPI antibody treatment, and its phosphorylation was attenuated in the presence of anti-integrin a5β1 antibody. Furthermore, focal adhesion kinase, a downstream molecule of the fibronectin-integrin signalling pathway, was phosphorylated by anti-β2GPI antibody treatment. These results indicate that molecules including gelsolin and integrin are involved in the anti-β2GPI antibody-induced MAPK pathway on monocytes and that integrin is a possible therapeutic target to modify a prothrombotic state in patients with APS.

Effects of Naoxinduotai capsule on Markers of prothrombotic state in patients with essential hypertension

To investigate the effects of Naoxinduotai capsule on the markers of prothrombotic state as plasminogen activator inhibitor-1 (PAI-1), von Willebrand factor (vWF) and alpha-granular membrane protein (CD62p) in essential hypertension patients of yang hyperactivity and blood stagnation. The 62 essential hypertension patients of yang hyperactivity and blood stagnation were divided into Naoxinduotai capsule + perindopril group (treatment group, 30 subjects) and Perindopril group (control group, 32 subjects). Clinical symptoms, blood pressure and the blood plasma PAI-1, vWF, CD62p of the patients were observed. The blood plasma PAI-1, vWF and CD62p were measured by enzyme-linked immunosorbant assay (ELISA). After 8 weeks treatment, in treatment group the clinical symptoms became better, and there was a significant difference with control group (P < 0.05). Blood pressure was significantly degraded, but there was not a significant difference with control group. The blood plasma PAI-1, vWF, CD62p level was degraded ,and there were significant differences with control group in all the three makers (P < 0.05). Naoxinduotai capsule can treat the essential hypertension patients of Yang hyperactivity and blood stagnation, and it has conspicuous advantages in improving the clinical symptoms and the makers of prothrombotic state.

The impact of acute atrial fibrillation on the prothrombotic state in patients with essential hypertension

Objectives To investigate whether acute atrial fibrillation (AF) creates a prothrombotic state in hypertensive patients, and to assess the evolution in research indices after cardioversion. Design and methods Plasma levels of von Willebrand factor (vWf), soluble P-selectin and fibrin D-dimers were measured in hypertensive patients with acute AF pre-cardioversion and at 1, 7, 14, and 30 days post-cardioversion. The results were compared with hypertensive controls and healthy controls. Results Pre-cardioversion plasma vWf levels in acute AF patients were similar to those of controls; however, post-cardioversion, the vWf levels increased significantly and only returned to baseline levels 14 days later. Compared with controls, acute AF patients had higher levels of fibrin D-dimers, which lasted at least 14 days after cardioversion. Conclusions This study demonstrated that hypertensive patients with acute AF have an abnormal prothrombotic state, which persists for up to 14 days after cardioversion.

Mechanism and Clinical Significance of the Prothrombotic State in Patients With Essential Hypertension

Thrombotic, rather than hemorrhagic, events represent a major complication of hypertension. This study aims to explore the mechanism of the hypercoagulative state in hypertension and to assess its clinical significance. The hypercoagulative state and even the prothrombotic state exists in patients with hypertension. This may be attributed to an impairment of the endothelium. A total of 81 patients suffering from essential hypertension were classified into 3 groups (grade 1: n = 27; grade 2: n = 36; grade 3: n = 18) and an additional 28 nonhypertensive patients were used as the control group. This study determined the changes of platelet activation marker P-selectin (CD62P), plasma fibrinogen, plasminogen activitor inhibitor-1 (PAI-1), and endothelium function. The percentage of CD62P+ platelets and the concentration of plasma fibrinogen and PAI-1 in the hypertension group was significantly higher than those in the control group. These increments coincided with the elevation of blood pressure. A significant difference was found between any of the 2 hypertension subgroups in the percentages of CD62P+ platelets (P < 0.001) and the concentration of PAI-I (P < 0.05). No difference was noted between the hypertension grade 1 and 2 groups in the concentration of plasma fibrinogen (P = 0.079); however, a significant difference was found between any of the other 2 subgroups (P < 0.001). Flow-mediated dilation (FMD) in the hypertension group was significantly lower than that in the control group. The hypercoagulative state exists in patients with hypertension and this state was more obvious with the elevation of blood pressure and coincided with an impairment in the degree of endothelium-dependent vasodilation.

Pro-thrombotic changes in platelet, endothelial and coagulation function following haemodialysis

Purpose: Patients on hemodialysis (HD) have an increased risk of thrombotic events, including myocardial infarction and vascular access thrombosis. The study hypothesis is that a single session of dialysis leads to platelet, endothelial & coagulation activation. Our aim is to determine the effect of a single HD session on prothrombotic vascular biomarkers before and after a single session of hemodialysis. Methods: Blood samples were taken from the vascular access of 55 patients immediately before and after a hemodialysis session. Platelet function was assessed by (1) flow cytometric measurement of P-selectin expression and fibrinogen binding ± ADP stimulation, (2) Ultegra rapid platelet function assay (RPFA) using the agonists thrombin receptor activating peptide (TRAP) and arachidonic acid (AA), (3) soluble P-selectin, and (4) soluble CD40L. Coagulation (thrombin-antithrombin III [TAT] and D-dimer), endothelial von Willebrand factor (vWF) and high sensitivity C-Reactive protein (hsCRP) were assessed by ELISA. Results: Unfractionated heparin was given to all patients during dialysis and 30 patients (55%) were on antiplatelet agents. Post-hemodialysis there were significant increases in unstimulated platelet P-selectin (p=.037), stimulated P-selectin (p<.001), soluble P-selectin (p<.001) and soluble CD40L (p=.036). Stimulated platelet fibrinogen binding was increased post-hemodialysis (p<.001) but unstimulated fibrinogen binding was unchanged. TRAP- (p<.001) and AA-(p=.009) stimulated aggregation were reduced post-hemodialysis. There were increases post-hemodialysis in TAT (p<.001), D-dimer (p<.001), vWF (p<.001) and hsCRP (p=.011). Conclusion: This study has shown that despite heparin therapy, a single session of HD induced increases in platelet, endothelial, and coagulation activation. More effective medical strategies to reduce the prothrombotic state of patients on hemodialysis should be investigated.

Whole blood coagulation assessment using rotation thrombelastogram thromboelastometry in patients with acute deep vein thrombosis

Common tests for the assessment of blood coagulation in the acute phase of deep vein thrombosis are of limited value for the evaluation of the associated hypercoagulability. The new rotation thromboelastometry by rotation thrombelastogram has the potential to provide information on whole blood clot formation and prothrombotic state in patients with acute deep vein thrombosis. Rotation thrombelastogram parameters were evaluated in whole blood of 30 patients with a first episode of acute deep vein thrombosis and 40 healthy controls. The effect of factor VIII and fibrinogen levels on rotation thrombelastogram assays was also assessed in the study population and in a model of blood supplemented by increasing amounts of fibrinogen. All assays performed were consistent with a remarkable hypercoagulable profile in deep vein thrombosis patients as compared with controls. In particular, maximum clot firmness and the area under curve values, which are expected to better correlate with the hypercoagulable state in the acute phase of deep vein thrombosis, were significantly higher in patients than in controls. As expected, fibrinogen was shown to be one of the main determinants of the hypercoagulability in rotation thrombelastogram assays. In a small subset of acute deep vein thrombosis patients, inherited thrombophilia had no influence on rotation thrombelastogram parameters. The new rotation thrombelastogram thromboelastometry is a useful tool to detect acute deep vein thrombosis-related hypercoagulability. Prospective studies are needed to define the potential applications of rotation thrombelastogram in the management of deep vein thrombosis patients.

Plasma D-dimer concentration in patients with systemic sclerosis

It has been reported that increased plasma D-dimer is a reliable marker of systemic prothrombotic state in patients with cardiovascular diseases. To evaluate plasma D-dimer concentration in patients with systemic sclerosis (SSc) and healthy controls. We also investigated a possible relationship between the presence of a high plasma D-dimer concentration and clinical and biological parameters in patients with SSc. Measurements of plasma D-dimer concentration were performed in 69 consecutive patients with SSc and 69 age- and sex-matched controls. Clinical and biological findings were compared between patients with and without a high concentration of plasma D-dimer (i.e. >or=500 ng mL(-1)). Median plasma D-dimer concentrations appeared significantly increased in patients with SSc compared with control subjects (506 vs. 211 ng mL(-1); P<0.001). Furthermore, a high concentration of plasma D-dimer (>or=500 ng mL(-1)) was detected more frequently in patients with SSc than in healthy controls (47.8% vs. 4.5%; P<0.0001). Among vascular manifestations related to SSc, macrovascular impairment responsible for peripheral ischaemia was more frequent in patients with SSc with high levels of D-dimer (>or=500 ng mL(-1)), compared with those without (21% vs. 6%; P=0.05). The association between high levels of plasma D-dimer (>or=500 ng mL(-1)) and macrovascular involvement in patients with SSc is likely to be an innovative issue. We suggest that D-dimer levels may be a helpful additional test to identify patients with SSc at risk to develop thrombotic arterial complications (peripheral arterial disease, stroke and coronary event); such patients with high levels of plasma D-dimer (>or=500 ng mL(-1)) may require close monitoring of vascular parameters, including especially macrovascular impairment.

Increased Prothrombotic State in Patients with Advancing HIV Disease.

HIV-infected patients are at high risk for venous and arterial thrombosis. We hypothesized that advancing stages of HIV are associated with thrombophilic abnormalities that could predispose to thrombosis. A total of 109 consecutive HIV infected patients were included in the study and twice screened for currently known thrombophilic defects with a time interval of at least 3 months. Ten percent of HIV infected patients had confirmed decreased protein C levels (< 65 IU/dL), 41% had confirmed elevated factor VIII levels (> 150 IU/dL), 22% had confirmed high fibrinogen levels (> 3.5 g/L) and 60% had a confirmed free protein S deficiency (< 65 IU/dL). Median factor VIII levels were higher in patients with AIDS defining illness compared to non AIDS defining illness (226 IU/dL versus 149 IU/dL; P< 0.001), while median free protein S levels were lower in these subgroups (45 IU/dL, versus 58 IU/dL; P< 0.001). Advancing HIV, stratified by CD4 levels of > 500 cells/μL, 200–500 cells/μL or < 500 cells/μL, respectively, was associated with increasing factor VIII levels, fibrinogen levels and decreasing free protein S levels (Figure 1). When factor VIII levels were < 100 IU/dL, median fibrinogen levels were 2.4 g/L, which was 0.3 g/L lower than when factor VIII levels were 100–150 IU/dL (P=0.033) and 0.9 g/L lower than when factor VIII levels were > 150 IU/dL (P< 0.001). Free protein S levels were 70 IU/dL when factor VIII levels were < 100 IU/dL, which decreased to 60 IU/dL when factor VIII levels were 100–150 IU/dL (P=0.010) and to 52 IU/dL when factor VIII levels were > 150 IU/dL (P< 0.001). We conclude that HIV infected patients have multiple prolonged thrombophilic abnormalities compared to the normal population, which increase with advancing HIV disease, thus providing a biologic mechanism for the increased prevalence of venous and arterial thrombosis in HIV. [Display omitted]

Medication-Induced Weight Gain and Dyslipidemia in Patients With Schizophrenia

Our friend and colleague Wayne Fenton asked to write this article for the Journal because of his desire to educate other psychiatrists about the treatment of schizophrenia, including what he recognized to be a growing problem with the metabolic syndrome. This lifelong passion, which he pursued from his psychiatry residency at Yale, through his directorship of Chestnut Lodge, to his position at NIMH as Director of the Division of Adult Translational Research and Associate Director for Clinical Affairs, ended tragically with his killing during an evaluation of a psychotic young man. Wayne had worked tirelessly to secure support for new drug discovery in the NIMH programs that he directed. The Journal will be initiating in 2007 a series of articles on the discovery of new mental illness treatments. We will dedicate this series to Wayne's memory and include with it a memorial of his life and contributions to the treatment of mental illness.

Effects of Rosiglitazone and Pioglitazone Combined with Metformin on the Prothrombotic State of Patients with Type 2 Diabetes Mellitus and Metabolic Syndrome

In this multicentre, randomized, double-blind, controlled, parallel-group trial, 103 patients with type 2 diabetes mellitus and metabolic syndrome were randomized to receive one of two thiazolidinediones--pioglitazone or rosiglitazone--in combination with 1500 mg/day of metformin, increasing up to 3000 mg/day, for 12 months. Anthropometric, metabolic, coagulation and fibrinolysis parameters were assessed at baseline and after 3, 6, 9 and 12 months. Significant decreases in glycosylated haemoglobin, fasting plasma glucose and post-prandial plasma glucose levels were seen after 9 and 12 months in both groups, and significant decreases in fasting plasma insulin and post-prandial plasma insulin levels were seen after 12 months in both groups. In both groups, improvement in the homeostasis model assessment index compared with baseline was obtained only after 12 months. Plasminogen activator inhibitor-1 levels were significantly lower in both groups after 12 months compared with baseline values. In patients with type 2 diabetes mellitus and metabolic syndrome, the combination of metformin plus thiazolidinediones improved glycaemic control and produced a slight but significant reduction in plasminogen activator inhibitor-1 levels.

Is There an Interaction Between Active Inflammatory Process and Prothrombotic State in Patients with Chronic Atrial Fibrillation?

Is There an Interaction Between Active Inflammatory Process and Prothrombotic State in Patients with Chronic Atrial Fibrillation?

Association of the R92Q TNFRSF1A mutation and extracranial deep vein thrombosis in patients with Behçet's disease

Behçet's disease is a chronic, relapsing, multisystemic inflammatory disorder characterized by recurrent oral and genital ulcers and by ocular, articular, vascular, and central nervous system involvement. The tumor necrosis factor alpha (TNFalpha) pathway is likely involved in the pathophysiology of Behçet's disease. One of the 2 TNFalpha receptors is TNF receptor superfamily 1A (TNFRSF1A). We searched for R92Q TNFRSF1A mutations in patients with Behçet's disease. A search for TNFRSF1A mutations was performed by polymerase chain reaction amplification of the TNFRSF1A gene, followed by denaturing high-performance liquid chromatography scanning. Among the 74 unrelated European patients with Behçet's disease, 5 (6.8%) carried the R92Q TNFRSF1A mutation. The frequency of the R92Q mutation in patients with Behçet's disease was significantly higher than that in controls (P = 0.006 by Fisher's exact test). Deep vein thrombosis was significantly associated with the R92Q mutation (P = 0.001 [with Bonferroni adjustment for multiple comparisons]). Among the 30 patients with thrombosis, 10 had cerebral thrombophlebitis. None of these patients had the R92Q mutation. Among the 20 patients with Behçet's disease who had extracranial deep vein thrombosis, 6 had the R92Q mutation, whereas 14 did not (P < 0.0001) The R92Q mutation in patients with Behçet's disease is associated with an increased risk of extracranial venous thrombosis. This new finding may help in understanding the complex prothrombotic state in patients with Behçet's disease.

Human Atherosclerotic Plaque Contains Viable Invasive Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis

To the Editor: Because epidemiological evidence supports an association between cardiovascular and periodontal disease, we assessed whether periodontal pathogens were present in atherosclerotic lesions. To detect invasive bacteria, the natural tropism of the bacteria toward human tissues was exploited. Further, bacterial presence was demonstrated using quantitative polymerase chain reaction (Q-PCR). This confirms the presence of periodontal pathogens in atherosclerotic lesions, whereby the bacteria could contribute to the vascular pathology either directly through their cytotoxicity or indirectly by inducing or exacerbating inflammation. Cardiovascular disease (CVD) is the leading cause of death in the in the United States.1 According to the American Heart Association’s statistics from 2003, there were no previous symptoms in 50% of men and 63% of women who died suddenly from CHD. In a 10-year follow-up study, ≈25% of coronary deaths in males and 15% in females occurred in persons in the lowest two quintiles of the multivariate Framingham Heart Study risk scores.2 This and other data have led to an emerging paradigm shift from coronary heart disease having a purely hereditary/nutritional causation to possibly having an infectious component.3 Many epidemiological studies strongly suggest that periodontitis may be a risk factor for coronary heart disease (CHD).4 Serologically, edentulousness and serum IgG-antibodies to Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis in 1163 men were recently shown to be associated with CHD.5 In a larger prospective study of 6950 subjects, the same authors provide serological evidence that an infection caused by major periodontal pathogens is associated with future stroke.6 Previous studies have identified 16S rRNA of oral microbial pathogens, including P gingivalis and A actinomycetemcomitans , …

The changes and meaning of the markers of prothrombotic state in patients with pregnancy induced hypertension

目的 探讨血栓前状态与妊娠高血压综合征(PIH)的关系及作用.方法使用流式细胞术(FC)及酶联免疫法(ELISA)测定PIH患者50例(PIH组)和正常妊娠晚期患者15例(对照组)的静脉假血友病因子(vwFAg)、血小板膜蛋白P选择素(P-seIeetin)、D-二聚体(D-dimer)和纤维蛋白原(Fg)的水平变化.并对轻、中、重妊娠高血压综合征组的上述指标进行比较.结果与对照组相比,重度妊娠高血压综合征组血浆vwFAg、P-selectin、D-dimer、Fg水平均显著升高(P＜0.05).结论重度妊娠高血压综合征患者存在血栓前状态,血桂前状态与PIH有关。