Hemostasis and thrombosis in critically ill children

Patients in the pediatric intensive care unit (PICU) often suffer from a variety of pathophysiologic conditions that are associated with abnormal hemostasis. Bleeding is a major complication of any surgery or trauma, thus patients with inherited or acquired coagulopathies or those experiencing massive trauma or undergoing major (especially cardiac) operations present a special challenge to the ICU experts as well as to the hematologist. Awareness of thromboembolic events in the pediatric population has been increasing in the past few years mainly due to improvement in diagnostic tools, advances in new therapy and procedures, together with an increased index of suspicion. Young infants are at greater risk for either bleeding or thromboembolic events, due to lower concentration of vitamin K-dependent procoagulant clotting factors, reduced thrombin potential, and altered fibrinolytic pathway with low levels of the coagulation inhibitors. The combination of infection, hypotension, acidosis, and release of activated substances, such as tumor necrosis factor, is common after severe trauma or in seriously ill ICU patients and often leads to disseminated intravascular coagulation, which may be complicated either by bleeding or thrombosis. The conditions, risk factors, and therapeutic options available for critically ill PICU patients are discussed in this review.     

Venous thromboembolism prophylaxis in medical patients

PURPOSE OF REVIEW: Venous thromboembolism, including deep vein thrombosis and pulmonary embolism, represents a significant source of morbidity and mortality in the United States and worldwide. Most acutely ill medical patients are at risk for venous thromboembolism, and prophylaxis is recommended. However, acutely ill medical patients are heterogeneous, and the degrees of risk, the length of prophylaxis, as well as the most safe and efficacious strategies to prevent venous thromboembolism in specific medical patients continue to evolve. RECENT FINDINGS: Most medically ill patients in the hospital do not receive any form of venous thromboembolism prophylaxis despite evidence that their venous thromboembolism risk is similar to surgical patients. Low-molecular weight heparins demonstrate at least equal efficacy and improved safety over standard unfractionated heparin for the prevention of venous thromboembolism in medical patients. Patients with renal impairment, obesity, or those who are critically ill are special populations for prophylaxis that require individual approaches. Many patients recently discharged from the hospital remain at high risk for thrombosis. SUMMARY: All hospitalized patients should be assessed for venous thromboembolism risk. Most acutely ill medical patients will be in the high- to very high-risk category for thrombosis. Patients who have an estimated thrombosis risk greater than bleeding risk should receive pharmacologic prophylaxis. Low-molecular weight heparin is the preferred drug-based approach over standard unfractionated heparin for the prevention of venous thromboembolism in the acutely ill medical patient. Patients with higher risks for bleeding than thrombosis should receive mechanical methods of prophylaxis. Patients who have not returned to baseline health should be considered for extended venous thromboembolism prophylaxis out of the hospital.     

Venous thromboembolism in intensive care patients

Venous thromboembolism frequently complicates the management of patients with severe medical and surgical illnesses. Because the diagnosis of VTE is especially challenging in critically ill patients, the focus of intensivists should be on characterization of risk factors and the appropriate choice of VTE prophylaxis. LDUH or LMHW is the preferred choice for VTE prophylaxis in ICU patients. Mechanical methods of prophylaxis should be reserved for patients with a high risk for bleeding. The effectiveness of mechanical methods and of combined strategies of prevention and the clinically important outcomes of therapy need to be explored further in critically ill patients. Few diagnostic strategies have been assessed in ICU patients with suspected PE. Ventilation-perfusion lung scans remain a pivotal diagnostic test but retain the same limitations in critically ill patients as seen in other patient populations. Newer noninvasive techniques, such as spiral CT associated with imaging of the extremities, are gaining more wide-spread use, but, thus far, pulmonary angiography remains the most reliable technique to confirm or exclude PE in patients with respiratory failure. A consensus must be reached regarding the most appropriate combination of tests for adequate and cost-effective diagnosis of VTE. Further investigation of diagnostic strategies that include adequate consideration of clinical diagnosis using standardized models and noninvasive imaging are warranted.     

Venous Thromboembolism: A Review of Risk and Prevention in Colorectal Surgery Patients

Hospitalization for surgery has a high risk of developing venous thromboembolism, a condition that encompasses both deep-vein thrombosis and its potentially fatal complication, pulmonary embolism. Colorectal surgery implies a specific high risk for postoperative thromboembolic complications relative to other general surgery. This may be a result of pelvic dissection, the perioperative positioning of these patients, or the presence of additional risk factors common to this patient group, such as cancer, advanced age, or inflammatory bowel disease. The potential impact of venous thromboembolism and the need for effective thromboprophylaxis often are underestimated in these patients. Recommendations for thromboprophylaxis in colorectal surgery patients are based on the American College of Chest Physicians guidelines for thrombosis prevention in general surgery patients, with treatment stratified according to the type of surgery and additional venous thromboembolism risk factors present. Prophylaxis with low-molecular-weight heparin or unfractionated heparin is recommended for colorectal surgery patients classified as moderate to high risk. The small number of studies focusing specifically on colorectal patients, or on cancer or abdominal surgery patients with a colorectal subgroup, has shown that both low-molecular-weight heparin and unfractionated heparin can effectively reduce the incidence of venous thromboembolism. Low-molecular-weight heparin has the practical advantage of once-daily administration and shows a lower risk of heparin-induced thrombocytopenia. This review will assess the risk of venous thromboembolism in colorectal surgery patients and discuss current evidence-based guidelines and recommendations for prevention of venous thromboembolism. Funded by Sanofi-Aventis, NJ. Reprints are not available.     

Treatment of venous thrombosis in the cancer patient

Venous thromboembolism is a common complication in patients with cancer. The management of deep vein thrombosis and pulmonary embolism can be a considerable challenge in patients with cancer. The cancer itself and associated treatments contribute to an ongoing thrombogenic stimulus, while cancer patients are thought to be at increased risk for anticoagulant-induced bleeding. Initial treatment of acute thromboembolism is with intravenous unfractionated heparin or subcutaneous low molecular weight heparin. Treatment at home with low molecular weight heparin is an attractive option in patients with malignant disease. Long-term treatment of acute venous thromboembolism has traditionally been with oral anticoagulants. However, the inconvenience and narrow therapeutic window of oral anticoagulants make such therapy unattractive and problematic in cancer patients. Low molecular weight heparins are being evaluated as an alternative for long-term therapy because their anticoagulant effects are more predictable and laboratory monitoring is unnecessary. Although many clinical issues remain unresolved in the treatment of cancer patients with venous thromboembolism, the future holds much promise as new antithrombotic agents, including factor Xa antagonists and oral thrombin inhibitors, are being tested in clinical trials.     

肺癌合并静脉血栓栓塞症的风险评估

静脉血栓栓塞症(venous thromboembolism,VTE)是癌症常见的并发症和最常见的死亡原因之一,主要包括深静脉血栓栓塞症和肺血栓栓塞症.近年来,随着血栓栓塞性疾病研究的深入,肺癌相关性VTE已引起关注.其中,肺癌患者的预防性抗凝治疗具有很大争议性.初级预防能使肺癌相关性VTE发生风险减少,但相关研究同时提示患者出血风险提高.目前尚不推荐对肺癌患者进行常规抗凝,但对血栓风险高、出血风险低的肺癌患者进行选择性抗凝可使其获益.因此,肺癌相关性VTE的风险评估和分级可提高预防性抗凝的临床获益,减少相关出血事件.     

Heparin-induced thrombocytopenia in pediatrics.

As in adult patients, heparin is used for prophylaxis and treatment of thromboembolism in newborns, children, and adolescents. Patients receiving heparin are potentially at risk to develop heparin-induced thrombocytopenia (HIT). HIT type II has been extensively described in the adult population; only a few reports address HIT type II in pediatric patients (total of 15 neonates, 4 young children, 12 older children and adolescents). The available data are discussed, and the case of a patient with recurrent thrombosis and HIT type II without thrombocytopenia is presented. The review of the literature reveals that HIT type II occurs especially in neonates and adolescents, corresponding to the two age peaks of thrombosis in pediatric patients. Risk factors for thrombosis include hereditary factors, immobilization, and surgery. HIT complications are severe and partly lead to life-threatening thromboembolism. In three patients, an increasing heparin demand was found. In five cases, thrombocytopenia was absent. Heparin was replaced mostly by danaparoid sodium; in three patients hirudin was used as an alternative anticoagulant. HIT type II represents a potentially dangerous complication of heparin therapy in pediatric patients and should be taken into consideration whenever heparin is given for prophylactic or therapeutic use in newborns, children, or adolescents.     

Thromboembolism in children

Acquired and inherited prothrombotic risk factors increase the risk of thrombosis in children. This review is based on "milestone" pediatric reports and new literature data (January 2001-February 2002) on the presence of acquired and inherited prothrombotic risk factors, imaging methods, and treatment modalities in pediatric thromboembolism. After confirming clinically suspected thromboembolism with suitable imaging methods, pediatric patients should be screened for common gene mutations (factor V G1691A, prothrombin G20210A and MTHFR C677T genotypes), rare genetic deficiencies (protein C, protein S, antithrombin, and plasminogen), and new candidates for genetic thrombophilia causing elevated levels of lipoprotein(a), and homocysteine, and probable genetic risk factors (elevations in fibrinogen, factor IX, and factor VIIIC, and decreases in factor XII). Data interpretation is based on age-dependent reference ranges or the identification of causative gene mutations/polymorphisms with respect to individual ethnic backgrounds. Pediatric treatment protocols for acute thromboembolism, including thrombolytic and anticoagulant therapy, are mainly adapted from adult patient protocols.     

Venous thromboembolism in cystic fibrosis

The incidence of venous thromboembolism (VTE) is increasing in the pediatric population. Individuals with cystic fibrosis (CF) have an increased risk of thrombosis due to central venous catheters (CVCs), as well as acquired thrombophilia secondary to inflammation, or deficiencies of anticoagulant proteins due to vitamin K deficiency and/or liver dysfunction. CVC-associated thrombosis commonly results in line occlusion, but may develop into serious life-threatening conditions such as deep venous thrombosis (DVT), superior vena cava syndrome or pulmonary embolism (PE). Post-thrombotic syndrome (PTS) may be a long complication. Local occlusion of the catheter tip may be managed with instillation of thrombolytics (such as tPA) within the lumen of the catheter; however, CVC-associated thrombosis involving the proximal veins is most often is treated with systemic anticoagulation. Initial treatment with heparin is a standard approach, but thrombolytic therapy, which may carry higher bleeding risks, should be considered for life and limb threatening episodes of VTE. Recommended duration of anticoagulation with low molecular weight heparin (LMWH) or warfarin ranges from 3 to 6 months for major removable thrombotic risks; longer anticoagulation is considered for recurrent thrombosis, major persistent thrombophilia, or the continued presence of a major risk factor such as a CVC. While CVCs are the most common risk for development of VTE in children, studies have not demonstrated a clear benefit with routine use of systemic thromboprophylaxis. The incidence and risk factors of VTE in CF patients will be reviewed and principles of diagnosis and management will be summarized.     

Prophylaxis of venous thromboembolism in medical patients

PURPOSE OF REVIEW: Venous thromboembolism is a multifactorial silent disease and tends not to be suspected by physicians, especially in medical patients. Pulmonary embolism is the most preventable cause of death among hospitalized patients. It is of major importance to assess the risk for venous thromboembolism and to adapt the prophylactic strategy with the aim of improving the risk-benefit ratio of the prophylaxis. RECENT FINDINGS: Prophylaxis of venous thromboembolism can be done by either mechanical means or pharmacologic agents or both. The Medenox trial, the Prime study, the Prince study, the Prevent study, and the Artemis trial demonstrated that acutely ill medical patients are at increased risk of venous thromboembolism and that low molecular weight heparins (enoxaparin 40 mg or dalteparin 5000 IU subcutaneously once daily for 10 days) as well as fondaparinux 2,5 mg subcutaneously once daily for 10 days have a favorable risk-benefit ratio in the prevention of venous thromboembolism in acutely ill medical patients. The publication of the results of the Exclaim study is expected to clarify the optimal duration of prophylaxis in this group of patients. Patients hospitalized in medical intensive care units as well as patients with active cancer or central venous catheters are at increased risk of venous thromboembolism, and the studies published so far demonstrate the favorable risk-benefit ratio of thromboprophylaxis with either low molecular weight heparins or low-dose warfarin. SUMMARY: Acutely ill medical patients are at increased risk of venous thromboembolism. Prophylaxis with low molecular weight heparins and fondaparinux is effective and safe. Initiatives to improve venous thromboembolism prophylaxis should be based on the education of physicians regarding the individualized risk assessment.     

Low-molecular-weight heparin for the treatment of venous thromboembolism in the elderly.

Venous thromboembolism (deep vein thrombosis and/or pulmonary embolism) is a common problem in the elderly population. Indeed, increasing age is a significant risk factor for venous thromboembolism. The treatment of venous thromboembolism in the elderly population presents certain unique problems related to aging, such as decreasing body weight, increasing renal insufficiency and numerous comorbid conditions, which complicate therapy. Treatment of venous thromboembolism in the elderly has been complicated by an increased incidence of bleeding, particularly with the use of warfarin. The risk of bleeding may be substantially reduced by carefully adjusting the warfarin dose to maintain a therapeutic INR and for this purpose anticoagulant management clinics have been shown to be useful. The low-molecular-weight heparins have been shown to be efficacious and safe for the treatment of venous thromboembolism in several clinical trials, including many patients in the older age brackets. Furthermore, these agents can safely be used in the out-of-hospital setting. Long-term use of low-molecular-weight heparin is an alternative to the use of oral anticoagulant therapy, particularly in patients with cancer or recurrent venous thromboembolism.     

Arterial thromboembolism in the pediatric population

The most common cause of arterial thromboembolism in the pediatric population is secondary to arterial catheterization. Non-catheter-related arterial thromboembolism is rare. The frequency of this complication has paralleled the advances in pediatric tertiary care that has lead to increasing numbers of children surviving life-threatening primary illnesses. Previously, these events were very rare and children were managed according to adult protocols. It is now known that the pathophysiology of thrombosis in children differs from that of adults and indeed is different for that of various age groups within the pediatric population, therefore requiring a unique diagnostic and therapeutic approach. This review highlights the available published data to support an evidence-based approach to the complication of arterial thromboembolism in the pediatric population, and underscores the urgent need for further randomized controlled trials.     

Antiphospholipid antibiodies: a critical review of the literature

PURPOSE OF REVIEW: The antiphospholipid antibody syndrome is defined by the presence of antiphospholipid antibodies in patients with recurrent venous or arterial thromboembolism or pregnancy morbidity. Antithrombotic therapies are the mainstay of treatment to reduce the risk of recurrent thromboembolism that characterizes this condition. RECENT FINDINGS: Limitations in the laboratory testing for antiphospholipid antibodies and changes in the diagnostic criteria for antiphospholipid antibody syndrome are important to recognize as they will affect the type of patients enrolled in the clinical trials evaluating antiphospholipid antibody syndrome therapies. In this review, we discuss the laboratory testing and diagnostic criteria for antiphospholipid antibody syndrome, and examine the evidence supporting the optimal antithrombotic management of patients with antiphospholipid antibodies. Studies addressing the management of patients with antiphospholipid antibodies and venous thromboembolism, and antiphospholipid antibodies and ischemic stroke, will be critically reviewed. SUMMARY: Clinical trials and observational studies have evaluated the optimal type, intensity and duration of anticoagulant therapy in patients with antiphospholipid antibodies. Critical evaluation of these studies is required to assess the generalizability of the results and how these results may be applicable to individual patients.     

The prevalence of risk factors for venous thromboembolism among hospital patients.

BACKGROUND--This study provides an estimate of the prevalence of risk factors for venous thromboembolism among hospital patients. METHODS--The presence of risk factors for venous thromboembolism was determined from a retrospective review of the medical records of 1,000 randomly selected patients in 16 acute care hospitals in central Massachusetts. RESULTS--The most common risk factors for venous thromboembolism were age 40 years (59%) or more, obesity (28%), and major surgery (23%). The average number of risk factors increased with increasing age. One or more risk factors for venous thromboembolism were present in 78% of hospital patients, two or more in 48%, three or more in 19%, four or more in 6%, and five or more in 1%. CONCLUSION--Risk factors for venous thromboembolism are common among hospital patients, suggesting that prophylaxis should be widely employed. The cost-effectiveness and risk benefit of prophylaxis is well established in patients undergoing major surgery. Further studies are needed to confirm the benefit of prophylaxis in patients with nonsurgical risk factors for venous thromboembolism.     

Dyslipidemia,statins, and venous thromboembolism: a potential risk factor and a potential treatment

The optimal drug for the prevention of venous thromboembolism is one that is efficacious, associated with minimal bleeding risk, and easy to administer. Statins fulfill the latter two criteria, but their efficacy remains unproved. By examining the association between dyslipidemia and venous thromboembolism, as well as the evidence that statins might prevent venous thromboembolism, there may be a new rationale for the use of this class of drugs. There may be a common link between arterial and venous thrombosis. Dyslipidemia may be one of the many systemic factors associated not only with arterial thrombosis, but with venous thromboembolism as well. This may occur through the effects of circulating lipid molecules on the vascular endothelium, platelet function, and coagulation factors. By impeding these mechanisms, statins may be protective against venous thrombosis, but epidemiologic studies are few in number, and no randomized clinical trials have been conducted. Better epidemiologic evidence is required to establish whether dyslipidemia is a risk factor for venous thromboembolism. If future observational studies can demonstrate that statins are associated with a lower risk of venous thromboembolism, then consideration should be given to conducting a randomized clinical trial comparing statins with placebo for the prevention of venous thromboembolism. Until then, the efficacy of statins for the prevention or treatment of venous thromboembolism remains uncertain.     

Miliary tuberculosis leading to acute respiratory distress syndrome: Clinical experience in pediatric intensive care

Acute respiratory distress syndrome (ARDS) represents a rare complication of miliary tuberculosis (TB) in the adult setting, and it is even less common in the pediatric population. The presence of comorbidities and the possibility of a delayed diagnosis may further impair the clinical prognosis of critically ill patients with disseminated TB and acute respiratory failure. In this report, we present a case series of five pediatric patients with miliary TB and ARDS, where rescue and multimodal respiratory support strategies have been applied with a favorable outcome in more than half of them. The burden of miliary TB over time on a general pediatric intensive care unit—including two ARDS patients—is also illustrated.     

Critical illness hyperglycemia in pediatric cardiac surgery

Critical illness hyperglycemia (CIH) is common in pediatric and adult intensive care units (ICUs). Children undergoing surgical repair or palliation of congenital cardiac defects are particularly at risk for CIH and its occurrence has been associated with increased morbidity and mortality in this population. Strict glycemic control through the use of intensive insulin therapy (IIT) has been shown to improve outcomes in some adult and pediatric studies, yet these findings have sparked controversy. The practice of strict glycemic control has been slow in extending to pediatric ICUs because of the documented increase in the incidence of hypoglycemia in patients treated with IIT. Protocol driven approaches with more liberal glycemic targets have been successfully validated in general and cardiac critical care pediatric patients with low rates of hypoglycemia. It is unknown whether a therapeutic benefit is obtained by keeping patients in this more liberal glycemic control target. Definitive randomized controlled trials of IIT utilizing these targets in critically ill children are ongoing.     

Common risk factors for both arterial and venous thrombosis

Arterial and venous thromboses have traditionally been viewed as distinct conditions, with differences in risk factors, pathology and treatment. However, recent epidemiological studies have suggested associations between venous thromboembolism, arterial thromboembolism (myocardial infarction and stroke) and atherosclerosis. While several biological mechanisms might contribute to these associations, common risk factors for both arterial and venous thrombosis probably play the major role. This article summarizes the evidence for shared risk factors (clinical, biochemical and haematological) that supports this conclusion. At a practical level, it is suggested that following routine treatment of venous thromboembolism with a course of anticoagulant drugs, patients should be routinely assessed not only for risk of recurrent venous thromboembolism but also for risk of arterial thromboembolism. Appropriate lifestyle advice and medication (including aspirin) should then be considered.     

The effects of race/ethnicity and sex on the risk of venous thromboembolism

PURPOSE OF THE REVIEW: Recently, studies on large diverse populations have described important ethnic/racial differences in venous thromboembolism incidence, and sex has been reported as an important predictor of recurrence. We review the influence of race/ethnicity and sex on venous thromboembolism, concentrating on articles from 2005 to 2007. RECENT FINDINGS: Most studies found that women have a 40-400% lower risk of recurrent venous thromboembolism than men. Studies of ethnicity/race on risk provide strong evidence that African-American patients are the highest risk group for first-time venous thromboembolism, while Hispanic patients' risk is about half that of Caucasians. African-Americans and Hispanics have a higher risk of recurrence than Caucasians, but sex and the type of index venous thromboembolism event seem to play a role in this risk. Asian/Pacific Islanders have a markedly lower risk of first-time and cancer-associated venous thromboembolism. There is little difference in incidence in African-Americans, Hispanics, and Caucasians diagnosed with cancer. Sex does not seem to be associated with risk in cancer patients. SUMMARY: Sex and race/ethnicity are important factors in the risk of first-time and recurrent venous thromboembolism and need to be included as risk assessment and diagnostic prediction tools are developed or updated.     

Risk factors for in-hospital venous thromboembolism in children: a case-control study employing diagnostic validation

Background

Studies evaluating risk factors for in-hospital venous thromboembolism in children are limited by quality assurance of case definition and/or lack of controlled comparison. The objective of this study is to determine risk factors for the development of in-hospital venous thromboembolism in children.

Design and Methods

In a case-control study at The Children’s Hospital, Colorado, from 1^st January 2003 to 31^st December 2009 we employed diagnostic validation methods to determine pediatric in-hospital venous thromboembolism risk factors. Clinical data on putative risk factors were retrospectively collected from medical records of children with International Classification of Diseases, 9th edition codes of venous thromboembolism at discharge, in whom radiological reports confirmed venous thromboembolism and no signs/symptoms of venous thromboembolism were noted on admission.

Results

We verified 78 cases of in-hospital venous thromboembolism, yielding an average incidence of 5 per 10,000 hospitalized children per year. Logistical regression analyses revealed that mechanical ventilation, systemic infection, and hospitalization duration of five days or over were statistically significant, independent risk factors for in-hospital venous thromboembolism (OR=3.29, 95%CI=1.53–7.06, P=0.002; OR=3.05, 95%CI=1.57–5.94, P=0.001; and OR=1.03, 95%CI=1.01–1.04, P=0.001, respectively). Using these factors in a risk model, post-test probability of venous thromboembolism was 3.6%.

Conclusions

These data indicate that risk of in-hospital venous thromboembolism in children with this risk factor combination may exceed that of hospitalized adults in whom prophylactic anticoagulation is indicated. Substantiation of these findings via multicenter studies could provide the basis for future risk-stratified randomized control trials of pediatric venous thromboembolism prevention.