High Risk Of Recurrent Thrombosis Research Articles

Recurrent pediatric thrombosis

The objective of this study was to evaluate the underlying diseases, thrombus localization, and other risk factors in pediatric patients with recurrent thrombosis in order to obtain a sense of early awareness of the possible recurrences. We retrospectively evaluated both inherited and acquired thrombophilic risk factors in children with recurrent thrombosis that were diagnosed and treated at Hacettepe University, School of Medicine, Department of Pediatric Hematology, Ankara, Turkey. Both congenital and acquired risk factors associated with recurrent thrombosis, and treatment modalities were analyzed in detail. Among 569 children with thrombosis, 32 (5.6%) presented with recurrent thrombosis. Median age at first presentation in these 32 patients [11 women (34.4%) and 21 men (65.6%)] was 132 months. In all, 29 (90.6%) of the 32 patients had an underlying chronic disorder: the most common of which was congenital heart disease [n = 11 (34.4%)]. At presentation intracardiac localization, including the entrance of the inferior and superior vena cava, was observed in 10 of the patients (31.2%). Thrombosis recurred at the same location in 15 (47%) patients and at a different location in 17 (53%). Median time interval between the first and second episode of thrombosis was 6.5 months (range: 1-180 months). Considering both acquired and congenital thrombophilic factors, three (9.3%) patients, four (12.5%) patients, and 14 (43.8%) patients had five, four, and three risk factors, respectively. More than half of the patients had elevated plasma FVIII (>150 IU/dl) and D-dimer (>0.5 mg/ml) levels. Thrombectomy was performed in three patients with organized, chronic intracardiac thrombus. Tissue plasminogen activator (t-PA) was used more frequently to treat recurrence than the first event (15.6 vs. 28.1%) and consequently the complete resolution rate was higher (40 vs. 77.7%) at the second event. Thrombi partially resolved in 11 of the patients during the initial episode and in 10 patients during recurrence (34 vs. 32%). In all, 29 (87.5%) patients were using prophylaxis at the time of recurrence. [coumadin (n = 16), low molecular weight heparin (n = 12) and aspirin (n = 1)]. In total, four patients (12.5%) died because of their underlying disorders and six (18.7%) developed postthrombotic syndrome during the follow-up. Recurrent thrombosis should be expected, especially in cases with congenital heart disease, incomplete thrombus resolution, and elevated plasma FVIII/D-dimer levels. In the light of this knowledge we suggest aggressive treatment for pediatric patients with a high risk of recurrent thrombosis.

Predictors of recurrent thrombosis and anticoagulant-related bleeding in patients with cancer

9565 Background: Anticoagulant therapy is treatment of choice for cancer-associated thrombosis. However, the risk of symptomatic recurrent thrombosis (RT) is approximately 9% on low molecular weight heparin (LMWH) and 17% on vitamin K antagonist (VKA) therapy, while the risk of anticoagulant-related major bleeding is about 5%. Given such complications are associated with morbidity and increased resource utilization, prognostic factors that identify patients at high risk for RT or bleeding would be useful for individualizing therapy. We performed a post-hoc analysis of the CLOT study (N Eng J Med 2003;349,146–53) for predictors of RT and bleeding in patients with proximal deep vein thrombosis (DVT) or pulmonary embolism (PE) who were randomized to receive either dalteparin LMWH or VKA for 6 months. Methods: Cox proportional hazards modeling analyses were performed using prospectively collected data from the CLOT study database. Potential baseline factors associated with RT and bleeding examined in the models were identified a priori based on published literature. Factors for RT were: dalteparin, age, gender, ECOG status, smoking status, presence of metastases, tumor site, history of DVT or PE, recent surgery, cancer treatment and body mass index. Factors for bleeding were: dalteparin, age, gender, ECOG, tumor type, major surgery, cancer treatment, platelet count, body mass index, creatinine, and concurrent use of antiplatelet agents. Results: Data from 673 cancer patients were available for the analysis. There were 80 patients with RT, 31 with major bleeds and 77 with minor bleeds. Three statistically significant predictors for RT were identified (with their hazard ratio and corresponding 95% CI): dalteparin (0.52; 0.32–0.82), every 10 year increase in age (0.77; 0.66–0.90) and presence of metastases (2.59; 1.20–6.60). Of the tumour sites investigated, lung (3.51; 1.62–7.62) and unknown primaries (3.63; 1.36–1.90) were predictive of RT. None of the factors examined in the models were found to be predictive of bleeding. Conclusions: Baseline factors may identify cancer patients with a higher risk of RT despite anticoagulant therapy. The risk of anticoagulant-related bleeding is not predictable at treatment onset. [Table: see text]

Venous Thromboembolism

Patients who have a first episode of venous thromboembolism (VTE) have an elevated risk of a recurrent episode, and this necessitates secondary prophylaxis. Anticoagulant therapy is a double-edged sword, however, as it reduces the risk of recurrent VTE but increases the risk of hemorrhage. This balance must be taken into account when assessing the risk-benefit ratio of long-term anticoagulation. Some clinical characteristics of the index VTE event can help to categorize the individual risk of recurrence. Patients with persistent risk factors such as cancer have a significantly higher risk of recurrent thrombosis. In contrast, VTE provoked by transient risk factors is associated with a lower risk of recurrence. Intrinsic features of patients with VTE (gender, age, hereditary thrombophilia) have also been linked to the risk of recurrent VTE. There is increasing evidence that a normal D-dimer level and the absence of residual venous thrombosis after discontinuation of oral anticoagulation are associated with a lower risk of recurrent VTE events. Future studies are needed to refine the predictive value of known risk factors for VTE recurrence and to discover better markers.

Impact of JAK2V617F Mutational Status on Clinical and Laboratory Phenotype at Diagnosis and during Follow-up in Patients with Essential Thrombocythemia

BACKGROUND: Essential thrombocythemia (ET) is thought to derive from the transformation of a multipotent hematopoietic stem cell, but its molecular pathogenesis remains obscure. An acquired mutation in exon 14 of the Janus tyrosine kinase 2 gene (JAK2) leading to a valine –> phenylalanine change at position 617 (JAK2V617F) in the JH2 pseudokinase domain, has been described in Ph negative chronic myeloproliferative disorders (MPD). It can be found in approximately 95% of polycythemia vera (PV) and in approximately 50–60% of essential thrombocythemia (ET) or primary myelofibrosis. The impact of this mutation on clinical phenotype is still debated. We investigated the frequency of JAK2 mutation and its possible impact and correlation with clinical and laboratory features at diagnosis and during follow-up in ET patients (pts), screened for JAK2 mutational status, referred to our division between 1987 and 2008.METHODS and PATIENTS: JAK2V617F mutation analysis was performed on genomic DNA from bone marrow cells or peripheral blood granulocytes in 115 ET (49 males, 66 females) pts, using allele-specific PCR. Clinical and laboratory features were evaluated at diagnosis and during follow-up, in order to compare ET pts harbouring JAK2 mutation versus (vs) pts harbouring wildtype (WT) gene. For statistical analysis, data were processed using the Graph Pad PRISM 5 DEMO Software. Correlations between clinical variables and JAK2 V617F mutational status were tested for significance (p value < 0,05) by using non-parametric methods, in particular the chi-square test or Fisher's exact test (two by two table) for categorical nominal variables and the Mann-Whitney rank test for ordinal variables. The log-rank (Mantel-Cox) test applied to Kaplan-Meyer method was employed to estimate thrombotic risk and thrombotic event-free-survival (TEFS)RESULTS: 66 ET pts (57,4%) were JAK2V617 positive. JAK2 mutated pts were older (median age 59 vs 48 years, p = 0,0016) and presented at diagnosis significantly higher hemoglobin levels (Hb 14,3 g/dl vs 13,3 g/dl, p= 0,0027), higher hematocrit (Ht 43% vs 39,8%, p < 0,0001) and lower PLT count (PLT 725 vs 841 ×109/L, p = 0,005) respect to WT group. These PV-like features have also maintained during the course of disease, with statistical significance. No difference was observed in term of gender, white blood count, LDH, progression or entity of splenomegaly, and need of cytoreductive therapy between JAK2 mutated and WT ET pts. A highly significant increase of thrombotic complications was registered for JAK2 positive pts. Considering JAK2 WT ET as reference group, the relative risk (RR) of primary thrombotic event was 2,143 (95% CI: 1.053–4.360, p = 0,035) for JAK2 mutated pts (TEFS at 15 years of 60% in JAK2 mutated group vs 75% in WT group, respectively). Arterial events were more frequent than venous events without statistical difference between two ET groups. A trend of higher risk of recurrent thrombosis (p = 0,056) was also showed for JAK2 mutated respect to WT ET pts. There was no difference about the risk of haemorragic complications, time and incidence of evolution in myelofibrosis between JAK2 mutated or WT ET pts.CONCLUSION: In our population, 57,4% ET pts harbor JAK2V617F mutation. This mutation divides ET pts into two distinct subtypes. JAK2 mutated ET pts present older age and laboratory features at diagnosis and during follow-up, compatible with PV-like phenotype. An increased risk of thrombosis, at diagnosis and during the course of disease, has been showed in mutated ET group, in term of recurrent thrombosis too. These observations seem to confirm a phenotype more aggressive since the diagnosis in JAK2 mutated ET group. A possible biological continuum between JAK2 mutated ET and PV, or more in general between JAK2 positive ET and MPD may be supposed.

VTE in Patients with Cancer-Diagnosis, Prevention, and Treatment

Management of venous thromboembolism (VTE) in patients with cancer is challenging. In addition, cancer-associated thrombosis (CAT) is becoming an increasingly prevalent condition because of the aging population, the aggressiveness of anticancer therapies, and the improved survival of patients with cancer. Diagnosis of CAT can be difficult because many cancer patients without acute thrombosis often have with signs and symptoms that mimic those of deep vein thrombosis or pulmonary embolism, while others are found to have clinically silent VTE incidentally on routine staging investigations for their cancer. Prevention of CAT is important for reducing the burden of disease but it has received very little attention from clinicians and researchers. Treatment of CAT is also challenging because oncology patients have a high risk of recurrent thrombosis and major bleeding even while receiving anticoagulant therapy. This review will focus on the current standards of practice for the diagnosis, prevention and treatment of VTE in patients with cancer.

Thrombin generation testing in routine clinical practice: are we there yet?

Thrombin is the central enzyme in the coagulation cascade. Estimation of an individual's potential to generate thrombin may correlate more closely with a hyper- or hypo-coagulable phenotype, compared to traditional coagulation tests. The possible correlation and recent technical advances in thrombin generation measurement has caused a significant interest in the method and the development of commercial assays. Several variations of the assay exist depending on the defect to be investigated. Fluorogenic thrombin generation assays have acceptable intra-laboratory variation but a higher inter-laboratory variation. Variation in preanalytical variables makes comparisons between studies difficult. Thrombin generation is highly variable between individuals and there are suggestions that this may allow individualized treatment based on global haemostatic response in patients with bleeding disorders or on anticoagulant therapy. In patients with thrombotic disorders it may be possible to identify those at higher risk of recurrent thrombosis. For both scenarios, however, data from large prospective studies are lacking or inconclusive and a good relationship between thrombin generation and phenotype remains to be established. Further standardization of the assay is needed before large multicentre studies can be conducted and until then thrombin generation in routine clinical practice is not yet a reality.

Recurrent Thrombosis Is Frequently Associated with Increased Microparticle-Mediated Thrombin Generation.

INTRODUCTION. Microparticles (MP) derived from the plasma membranes of platelets (PMP), leukocytes (LMP), red cells (RMP) and endothelial cells (EMP) are known to be associated with a variety of thrombotic and inflammatory disorders. Most studies have measured their numbers in circulation but few have addressed their function and contribution to clinical thrombosis (TBS). We developed an assay to measure microparticle-mediated thrombin generation (MMTG) and evaluated it in patients (pts) with TBS. We report here that MMTG can distinguish pts at high risk of recurrent TBS from those with stable diseases.METHODS. (a) MMTG assay. Platelet-poor plasma (PPP) was obtained from citrated blood by centrifuging platelet-rich plasma (PRP) at 3000xg for 10min, and total MP were sedimented from 1.0 mL of PPP at 20,000xg for 15min. The supernatant was considered particle-free plasma (PFP). The MP were resuspended in normal pooled PFP containing 25 ug/mL corn trypsin inhibitor, then MP sample was tested for MMTG initiated by calcium employing the calibrated automated thrombogram (CAT) method of Hemker et al in a Fluoroskan Ascent plate reader. Measures recorded were the lag times, peaks, and rates (slope) of thrombin generation based on CAT data. In addition, populations and cell origins of the MP were determined by flow cytometry using cell-specific fluorescent antibodies. (b) Clinical study. Sixty-six pts with TBS were studied: 29 with antiphospholipid syndrome, 11 high homocysteine, 17 hypercoagulable state due to defective clotting factors (FVLeiden etc) or natural anticoagulants (ATIII etc), and 9 idiopathic. Of the total, 25 suffered multiple (2–8) thrombotic events within the 5-yr study period (recurrent TBS); the other 41 had only a single episode (stable TBS). All measures were done at least 4 wk after acute events. There were 34 normal controls (NC).RESULTS. (1) MMTG data: Recurrent TBS group showed the highest MP-dependent thrombin generation (lag = 9.1 min, peak = 299.9 nM, and rate = 120.2 nM/min) followed by stable TBS (lag = 12.4, peak = 244.3, and rate = 84.6), and NC (lag = 13.4, peak = 198.6, and rate = 43.1). The difference between groups (recurrent vs. stable; stable vs. NC; recurrent vs. NC) on all three measures were statistically significant, with exception of lag time between stable and NC. (2) MP profiles: Our data showed that recurrent TBS also had highest counts of EMP, PMP, LMP, and RMP, followed by stable TBS, and NC. This trend parallels MMTG data. (3) Sensitivity of MMTG assay: We found that MMTG rate in recurrent TBS was about triple the NC (120.2 vs. 43.1, p<0.0001), with little overlap of standard deviation (SD) indicating good sensitivity to distinguish between these two groups: 76% of recurrent TBS pts had MMTG rate >2 SD above normal mean. (4) We analyzed correlations between MMTG measures and MP counts in all TBS patients: the best correlation was LMP with lag time (p=0.00014), or with rate (p=0.008), suggesting that LMP may carry tissue factor to initiate coagulation. PMP also correlated with rate and peak (p=0.01).CONCLUSIONS. To our knowledge, this is the first laboratory assay to differentiate stable from recurrent thrombotic pts. MMTG assay can be utilized as a global screening test for risk of recurrent TBS. Microparticle mediated thrombin generation (MMTG) may play an important role in the pathogenesis of recurrent TBS.

Recurrent Thrombosis in Patients with Deep Vein Thrombosis and/or Venous Thromboembolism Associated with Anticardiolipin Antibodies

Anticardiolipin antibodies represent one of the main hypercoagulation states associated with venous thromboembolism. The aim of this work was to evaluate symptomatic recurrent thrombosis in patients with anticardiolipin antibodies and deep vein thrombosis of the lower limbs with or without thromboembolism. Sixty patients who suffered from deep vein thrombosis were observed for a 5-year period, whether they had anticardiolipin antibodies or not. The group was made up of 34 females and 26 males with ages ranging from 13 to 73 years. All were diagnosed with deep vein thrombosis by means of phlebography and were tested for anticardiolipin antibodies by use of the ELISA method. The symptomatic signs of recurrent thrombosis were evaluated during this period. In total, 56.6% of the group were considered above normal for anticardiolipin antibodies, 25% positive, another 31.6% borderline, and 43.4% negative. Patients were tested positive when the anticardiolipin antibody count was >15 units/mL, borderline between 10 and 15 units/mL, and normal when <10 units/mL. The method of relative risk was used for statistical analysis of the results. Four positive patients, 1 borderline, and 1 normal patient had recurrent events of thrombosis. In the statistical analysis the relative risk for recurrent thrombosis in the positive patients was 6.0; CI 95%; 1.2 to 29.5. In conclusion patients with deep vein thrombosis who are positive for anticardiolipin antibodies present a higher risk of recurrent thrombosis.

Etiopathogenesis of pediatric thrombosis

IntroductionThrombosis is a relatively rare event during child-hood, affecting 0.7/100000 children, with the highestfrequency found in newborn infants and adolescents[1,2]. The etiology of thrombosis is influenced by age,neonate versus non-neonate, as well as site, arterialversus venous. Thrombosis during childhood is al-most always multifactorial, with both genetic andenvironmental factors important in the onset andprogression of thrombosis [3,4]. This paper willreview the etiology and pathogenesis of thrombosisin pediatric patients.Infants and children beyond the neonatal periodThe majority of infants and children present withthrombosis while hospitalized for a significant under-lying medical condition. Idiopathic thrombosis is veryrare in childhood; most symptomatic children man-ifest two or more risk factors, as displayed on Table I.Venous thrombi beyond the neonatal periodVenous thrombosis is more common in children thanarterial occlusions. Inflammation related to infection,surgery, trauma, malignancy or connective tissuedisorders is present in most children with venousthrombosis [3,4]. Blood disorders contributing toendothelial damage and stasis including sickle cellanemia, polycythemia and leukemia are rare butimportant risk factors for thrombosis.Indwelling catheters are involved in approximately30 to 60% of cases of venous thrombosis [3,5].Catheter-related thrombi develop in children whorequire long-term support with venous access devicesfor chronic disorders such as cystic fibrosis, hemo-philia, sickle cell anemia or short gut syndrome.However, in the setting of intense inflammation,such as sepsis or trauma, short-term femoral cathetersplaced for resuscitation often result in venous occlu-sion.The term thrombophilia denotes a category ofblood conditions that are associated with an increasedpropensity to develop thrombi. Thrombophilia maybe genetic or acquired and both types are commonlydetermined in children with thrombosis [6,7]. Antith-rombin deficiency is associated with a number ofdisorders including nephrotic syndrome, protein los-ing enteropathy and chemotherapy with L-asparagi-nase. Protein C deficiency is acquired byconsumption during severe bacterial infections suchas meningococcal sepsis and meningitis. Auto-im-mune protein S deficiency has been described follow-ing viral infections such as varicella [8,9].Antiphospholipid antibodies (APA) include thelupus anticoagulant (LA), anticardiolipin antibodyand anti-b2GPI antibodies. In young children APAusually occur following infection and are transient.APA in adolescents more commonly are persistent. Bydefinition, detection of APA six weeks or morefollowing initial determination constitutes the APASyndrome (APAS). However following infections withorganisms such as varicella or streptococcus, APAhave been determined to resolve over several months,without apparent long-term risk of thrombus recur-rence [9]. APAS may be secondary to systemic lupuserythematosus or other collagen vascular disease.However APAS in pediatric patients is usually pri-mary, or idiopathic. Patients with APAS are at highrisk for recurrent thrombosis following discontinua-tion of anticoagulation and most must be treated withwarfarin for an indefinite time [10].

Outpatient Management of the Chronically Anticoagulated Patient for Elective Surgery

With the appropriate use of preadmission clinics, "hospital in the home" programs, and alternatives to intravenous heparin, the majority of chronically anticoagulated patients can be managed as outpatients prior to elective surgery. The preoperative management depends on the original indication for long-term anticoagulation, the interval since the last thromboembolic event, and the extent and type of surgery planned. Only patients who are undergoing major surgery, and who have a high risk of recurrent thrombosis or embolism, require preoperative admission to hospital and conversion to an intravenous heparin regimen. Patients undergoing minor surgery may require no change to their oral anticoagulation. The remainder require cessation of oral anticoagulation and alternative thromboprophylaxis preoperatively, which can be achieved on an outpatient basis using low molecular weight heparin. Outpatient anticoagulation management requires a clear protocol that is understood and agreed to by all parties involved in the care of surgical patients perioperatively.

The risk of recurrent deep venous thrombosis among heterozygous carriers of both factor V Leiden and the G20210A prothrombin mutation.

Point mutations in the factor V gene (factor V Leiden) and the prothrombin gene (the substitution of A for G at position 20210) are the most common causes of inherited thrombophilia. Whether or not factor V Leiden increases the risk of recurrent deep venous thrombosis is controversial, and there is no information on the risk of recurrence among carriers of both mutations. We studied a retrospective cohort of 624 patients who were referred for a first episode of deep venous thrombosis. After excluding 212 patients with other inherited or acquired causes of thrombophilia, we compared 112 patients who were heterozygous carriers of factor V Leiden with 17 patients who were heterozygous for both factor V Leiden and the prothrombin mutation and 283 patients who had neither mutation. The relative risk of recurrent deep venous thrombosis was calculated with use of a proportional-hazards model. Patients who were heterozygous for factor V Leiden alone had a risk of recurrent deep venous thrombosis that was similar to that among patients who had neither mutation (relative risk, 1.1; 95 percent confidence interval, 0.7 to 1.6; P=0.76). In contrast, patients who were heterozygous for both factor V Leiden and the prothrombin mutation had a higher risk of recurrent thrombosis than did carriers of factor V Leiden alone (relative risk, 2.6; 95 percent confidence interval, 1.3 to 5.1; P=0.002). When the analysis was restricted to patients with spontaneous recurrences (i.e., ones that occurred in the absence of transient risk factors for venous thrombosis), the risk among carriers of both mutations, as compared with carriers of factor V Leiden alone, remained high (relative risk, 3.7; 95 percent confidence interval, 1.7 to 7.7; P<0.001), particularly if the first event had also been spontaneous (relative risk, 5.4; 95 percent confidence interval, 2.0 to 14.1; P<0.001). In contrast, the risk of recurrence in the presence of transient risk factors was similar among carriers of both mutations and carriers of factor V Leiden alone. The risk of recurrent deep venous thrombosis is similar among carriers of factor V Leiden and patients without this mutation. Carriers of both factor V Leiden and the G20210A prothrombin mutation have an increased risk of recurrent deep venous thrombosis after a first episode and are candidates for lifelong anticoagulation.

Recognition and management of patients with antiphospholipid antibody syndrome undergoing cardiac surgery

A NTIPHOSPHOLIPID antibody (APA), a condition that occurs in 2% 1 of the population, may result in a hypercoagulable state. If not recognized, it may increase perioperative morbidity and mortality in patients undergoing cardiac surgery. Antiphospholipid antibodies have been detected in 46% of patients with stroke or transient ischemic attack under age 50 years, 2 and have been reported in 21% of young survivors (younger than 45 years) of myocardial infarction. 3 Their detection and management, therefore, are of considerable clinical significance because a high risk of recurrent thrombosis exists. Two patients who had antiphospholipid antibodies and required cardiac surgery are presented. In case 1, the diagnosis of APA was not made preoperatively. In case 2, the patient was admitted with an established diagnosis of APA.

The anti-phospholipid syndrome.

Preview Antiphospholipid antibodies may be found in a variety of clinical situations, including in the absence of systemic disease. Certainly, for cost-effective healthcare, physicians should not spend resources evaluating otherwise healthy people. However, when features of the antiphospholipid syndrome (APS) are also present, serious venous or arterial thrombosis or recurrent spontaneous abortion may ensue. The authors present a practical overview of the antibodies and how to uncover and manage APS.

Use of the inferior vena cava clip in patients at high risk for pulmonary embolism

Sixteen gynecologic oncology patients at high risk of developing a postoperative pulmonary embolism underwent prophylactic clipping of the inferior vena cava during laparotomy for tumor resection. All patients had a prior history of deep venous thrombosis or pulmonary embolism or had an active deep venous thrombosis at the time of their surgery. Additionally, this group of 16 patients was characterized as being at high risk for recurrent thrombosis in the postoperative period based on traditional risk factors that are representative of most gynecologic oncology patients. The Adams-DeWeese or Moretz clip was used in this series. There were no pulmonary emboli in our 16 patients in the postoperative period or during follow-up. There were no signs of venous stasis attributable to clip placement. The procedure was quick, simple, and complication free and the external clip has the advantage of maintaining effectiveness throughout the patient's lifetime. Prophylactic clipping of the inferior vena cava at the time of laparotomy in patients at an increased risk of thrombosis deserves further study.