Heparin Prophylaxis Research Articles

Endovenous laser ablation: Venous outcomes and thrombotic complications are independent of the presence of deep venous insufficiency

We hypothesize that endovenous laser ablation (EVA) therapy is equally successful in improving venous insufficiency symptoms in patients with or without deep venous insufficiency (DVI). From January 2005 through August 2007, EVA of the great saphenous vein (GSV) was attempted in 364 patients (460 limbs) with symptomatic GSV reflux. The GSV was successfully cannulated and obliterated in all but 17 limbs. EVA was performed alone in 308 limbs (69.5%) and with phlebectomy or perforator ligation (EVAP) in 135 limbs (30.5%). Venous clinical severity scores (VCSS) were recorded preoperatively and at 30, 90, 180, and 360 days postoperatively. Patients were classified as those with or without DVI based on duplex imaging valve closure times at the common femoral vein (CFV) and popliteal vein (PV). In a subset of 181 patients undergoing EVA therapy in the operating room, perioperative thrombosis prophylaxis was administered based on a risk-stratification protocol. Patients were assessed with direct end points (VCSS) and indirect end points (vein occlusion rates). Successful performance of EVA led to complete saphenous vein ablation in 99.8% at 1 month and 95.9% at 1 year. Median VCSS preoperatively was 6 (interquartile range, 5-8), generally decreasing over all time points to 4 (interquartile range, 2-5) beyond 360 days (P < .001). Male gender was independently associated with greater improvement in scores with time (P = .019). Changes in VCSS and duration of vessel occlusion were equivalent regardless of DVI for both isolated EVA and EVAP. For EVAP, the true deep venous thrombosis (DVT) rate was 2.2%, whereas for isolated EVA, the rate was 0% (P = .028); the rate of saphenofemoral thrombus extension was 5.9% for EVAP vs 7.8% for isolated EVA (P = .554). The use of risk-adjusted heparin prophylaxis in patients undergoing EVAP did not have a significant effect on thrombotic complications. There were no differences in true DVT, thrombus extension, or superficial thrombophlebitis between patients with or without DVI. Performance of concomitant phlebectomy, DVI, gender, and age had no effect on the duration of vessel occlusion. EVA produces successful ablation and is associated with sustained improvement in VCSS. These outcomes are independent of the presence of DVI. Finally, the use of a risk-adjusted thrombosis prevention protocol had no effect on the rate of superficial thrombus extension from EVA or EVAP in patients undergoing general anesthesia.

Timing of heparin prophylaxis and bleeding complications in hysterectomy a nationwide prospective cohort study of 9,949 Danish women

To examine bleeding complications and thromboembolic events in relation to timing of heparin prophylaxis after hysterectomy. Nationwide prospective cohort study with 30 days post-operative follow-up within the Danish Hysterectomy Database (DHD). All gynecological departments in Denmark (n=31). 9,949 women who had an elective hysterectomy for benign indication between October 2003 and May 2006 and were reported to DHD (national response rate: 88-99% throughout 2004-2005). Odds ratios (OR) of peri-operative bleeding complications (> or =1,000 ml bleeding during surgery or post-operative wound/vaginal-vault/intraabdominal bleeding or hematoma) and number of events of venous thromboembolism. Logistic regression analysis adjusting for: age, body mass index, alcohol, smoking, meno-/metrorrhagia, uterine weight, department volume, surgeon's experience, route and type of hysterectomy and additional surgery, and stratification on assistant's experience, peri-operative pain prophylaxis with NSAID and daily use of Acetyl Salicylic Acid (ASA)/NSAID. 9,051 women (92%) received thromboprophylaxis with heparin, initiated pre-operatively in 48% and post-operatively in 52%. At least one bleeding complication was noted in 881 women (10%). Post-operative heparin administration was associated with a reduced risk of bleeding complications; OR=0.85 (95% confidence interval 0.73-0.99) compared to pre-operative administration. Excluding cases with potential impaired hemostasis at baseline, the OR was 0.78 (0.64-0.94). There was no fatal embolism. Three of seven pulmonary embolisms and one of three symptomatic deep venous thromboses occurred with the post-operative heparin administration. Post-operative rather than pre-operative administration of heparin prophylaxis may reduce the risk of bleeding complications after hysterectomy without apparent risk of increased thromboembolic events.

Autumn leaves and assorted findings

Autumn leaves and assorted findings

Safety and efficacy of lower-dose unfractionated heparin for prophylaxis of deep vein thrombosis and pulmonary embolism in an Asian population

The objective of this study is to analyze the tolerance and efficacy of the subcutaneous administration of a reduced 2,500-unit low-dose unfractionated heparin given for an efficacious, yet Asian population-sensitive, prophylaxis for deep vein thrombosis and fatal pulmonary embolism. Eighty-seven Japanese patients were operated on either for abdominal or pelvic complications or both, as well as for gynecologic conditions including ovarian, cervical, and corpus cancers. Thirty-two of the patients were administered the experimental low dose of unfractionated calcium heparin for prophylaxis. The 2,500 units of low-dose unfractionated heparin were given subcutaneously 2 h preoperatively and again 12 h postoperatively. Other standard methods of mechanical prophylaxis, including graduated compression stockings and intermittent pneumatic compression, were performed. Fifty-five of the patients were not administered heparin, but did receive the same standard mechanical graduated compression stockings and intermittent pneumatic compression prophylaxis. We compared the surgical and postsurgical complications noted for low-dose unfractionated heparin patients with the results of those who received no heparin prophylaxis and analyzed this data using the Mann-Whitney U-test. There was no significant difference in the mean of the blood loss volumes. There were also no significant differences found in the perioperative bleeding complications between the two groups. However, three (3/55; 6%) of the patients in the no-heparin group suffered a symptomatic pulmonary embolism, although none were fatal. There were no pulmonary embolism onsets in the heparin prophylaxis group. We feel that we have provided evidence that several serious complications, such as perisurgical hemorrhage, deep vein thrombosis, fatal pulmonary embolism, and increased postoperative recovery times, can be prevented by prophylaxis with 2,500-unit low-dose unfractionated heparin.

Heparin-induced osteoporosis and pregnancy

Osteoporosis is the most common serious side effect of long-term unfractionated heparin use. Until recently, it was unknown whether long-term low-molecular-weight heparin was associated with any change in bone mineral density. With increasing long-term low-molecular-weight heparin use, for a variety of indications, this was an important knowledge gap. We recently completed an a-priori planned substudy to assess the effect of low-molecular-weight heparin on bone mineral density in an ongoing multicenter multinational randomized trial designed to compare the effect of low-molecular-weight heparin prophylaxis on pregnancy outcomes in thrombophilic pregnant women. The results revealed that there is no significant difference in mean bone mineral density between a low-molecular-weight heparin prophylaxis group and a no prophylaxis group. The study was not adequately powered to detect differences in absolute fracture risk. Recent results suggest that the use of long-term prophylactic low-molecular-weight heparin in pregnancy is not associated with a significant decrease in bone mineral density. Whether higher doses might be a risk factor for osteoporosis is still an unanswered question. It is also possible that subgroups are more susceptible. Overall, women should be reassured regarding the risk of osteoporosis associated with the use of prophylactic dose of low-molecular-weight heparin during their pregnancy.

Prevention of venous thromboembolism in patients with immobilization of the lower extremities: a meta-analysis of randomized controlled trials.

It is controversial whether the prevention of venous thromboembolism (VTE) in patients with lower-leg immobilization is necessary. To assess the benefits and complications of pharmacological thromboprophylaxis, we performed a meta-analysis of all available randomized controlled trials on this subject. We searched the MEDLINE and EMBASE electronic databases. We included English- and non-English language studies, we hand-searched journals, and we contacted manufacturers. We analyzed data from six randomized trials that investigated pharmacological prophylaxis for the prevention of VTE in 1456 patients with lower-leg immobilization in plaster cast or orthosis. Two reviewers independently assessed the trials for inclusion, extracted data, and assessed trial quality. Differences were resolved by consensus or arbitrage. The pooled estimate from all trials revealed a highly significant and clinically relevant reduction in asymptomatic events with low-molecular-weight heparin (LMWH) prophylaxis, compared to placebo or untreated control [risk ratio (RR) 0.58; 95% confidence interval (CI) 0.39-0.86; P = 0.006). The mean rate of VTE decreased from 17.1% to 9.6% with the use of LMWH. Subgroup analysis of methodologically superior trials (RR 0.68; CI 0.50-0.92; P = 0.01), proximal deep vein thrombosis (RR 0.28; CI 0.11-0.72; P = 0.008), tendon ruptures (RR 0.60; CI 0.38-0.97; P = 0.04), and fractures (RR 0.62; CI 0.45-0.86; P = 0.004) confirmed the robustness of the overall result. Frequency of bleeding did not differ between LMWH prophylaxis and control groups (RR 1.22; CI 0.61-2.46; P = 0.57). Our findings indicate that thromboprophylaxis with LMWH for immobilization of the lower extremities reduces the risk of VTE. This benefit is achieved with no excess bleeding.

Perioperative plasma antithrombin activity with "low-dose" heparin prophylaxis. Perioperatively acquired antithrombin III deficiency as a cause for the failure of heparin prophylaxis?

Antithrombin III activity was estimated using a chromogenic substrate perioperatively in the plasma of 200 patients undergoing major elective abdominal surgery during low-dose heparin prophylaxis. With an initial value of 10.9 +/- 2 IU/ml there was a mean postoperative lowering of plasma antithrombin activity in all patients with a minimum on the second postoperative day. In patients with empirically established increased risk of thromboembolism the postoperative depression of antithrombin was significantly more pronounced (P less than 0.01) than in the control groups. An increased risk prevailed particularly in patients with malignant diseases and in major surgery, i.e. of prolonged duration. In such cases with increased risk of thromboembolism routine assessment of antithrombin III is recommended.

Antithrombin III in hip surgery

Antithrombin III is an important element of the endogenous thrombosis protection system. Congenital Anti-thrombin III deficiencies are associated with increased incidence of thrombo-embolisms. If Antithrombin III is determined at the time of operation, postoperative deficiencies resulting from an increased turnover rate can be identified. Determination of Antithrombin III is not suitable for prognosticating the occurrence of thrombo-embolic complications in isolated cases. Antithrombin III can be administered in the form of fresh frozen plasma (FFP), though it is also available as Antithrombin III concentrate. So far no investigations have been carried out to establish whether it is possible to improve thrombosis protection with or without heparin prophylaxis by concentrated Antithrombin III substitution.

Heparin prophylaxis did not increase mortality and was beneficial in adults with sepsis receiving drotrecogin alfa

Source Citation Levi M, Levy M, Williams MD, et al. Prophylactic heparin in patients with severe sepsis treated with drotrecogin alfa (activated). Am J Respir Crit Care Med. 2007;176:483-90. 17556722

Vein wall re-endothelialization after deep vein thrombosis is improved with low-molecular-weight heparin

Vein wall endothelial turnover after stasis deep vein thrombosis (DVT) has not been well characterized. The purpose of this study was to quantify re-endothelialization after DVT and determine if low-molecular-weight heparin (LMWH) therapy affects this process. Stasis DVT was generated in the rat by inferior vena cava ligation, with harvest at 1, 4, and 14 days. Immunohistologic quantification of vascular smooth muscle cells and luminal endothelialization was estimated by positive staining for alpha-smooth muscle actin and von Willebrand factor, respectively. In separate experiments, rats were treated either before or after DVT with subcutaneous LMWH (3 mg/kg daily) until harvesting at 4 and 14 days. The inferior vena cava was processed for histologic analysis or was processed for organ culture after the thrombus was gently removed. The vein wall was stimulated in vitro with interleukin-1beta (1 ng/mL), and the supernatant was processed at 48 hours for nitric oxide. Cells were processed by real-time polymerase chain reaction for endothelial nitric oxide synthase, inducible nitric oxide synthase, cyclooxygenase-1 and -2, and thrombomodulin at 4 and 14 days, and collagen I and III at 14 days. Comparisons were done with analysis of variance or t test. A P < .05 was significant. Thrombus size peaked at 4 days, whereas luminal re-endothelialization increased over time (1 day, 11% +/- 2%; 4 days, 23% +/- 4%; 14 days, 64% +/- 7% (+) von Willebrand factor staining; P < .01, n = 3 to 4, compared with non-DVT control). Similarly, vascular smooth muscle cell staining was lowest at day 1 and gradually returned to baseline by 14 days. Both before and after DVT, LMWH significantly increased luminal re-endothelialization, without a difference in thrombus size at 4 days, but no significant difference was noted at 14 days despite smaller thrombi with LMWH treatment. Pretreatment with LMWH was associated with increased vascular smooth muscle cell area and recovery of certain inducible endothelial specific genes. No significant difference in nitric oxide levels in the supernatant was found at 4 days. At 14 days, type III collagen was significantly elevated with LMWH treatment. Venous re-endothelialization occurs progressively as the DVT resolves and can be accelerated with LMWH treatment, although this effect appears limited to the early time frame. These findings may have clinical relevance for LMWH timing and treatment compared with mechanical forms of therapy. How the vein wall endothelium responds after deep vein thrombosis (DVT) has not been well documented owing to limited human specimens. This report shows that low-molecular-weight heparin accelerates or protects the endothelium and preserves medial smooth muscle cell integrity after DVT, but that this effect is limited to a relatively early time period. Although most DVT prophylaxis is pharmacologic (a heparin agent), use of nonpharmacologic measures is also common. The use of heparin prophylaxis, compared with after DVT treatment, and the acceleration of post-DVT re-endothelialization require clinical correlation.

205: Low Molecular Weight Heparin (LMWH) Prophylaxis (PPX) in Pediatric Recipients following Pediatric Myeloablative Stem Cell Transplant (SCT) at High Risk for Sinusoidal Obstructive Syndrome (SOS): Is it Safe and Does it Make a Difference?

SOS is a clinical syndrome following SCT of jaundice, painful hepatomegaly and weight gain with an incidence of 20% (2–54%) and a mortality rate of 30–50%. The Children's Group reported a 10% incidence of SOS in pediatric recipients (n = 2725; mild:3.1%, moderate:5.2%, severe:2%) with a 1.8% mortality rate (Neider, ASBMT, 2007). Risk factors include hepatitis, transaminitis, hepatic irradiation, second SCT, and myeloablative conditioning regimens (busulfan >8 mg/kg, cyclophosphamide ≥120 mg/kg, TBI, and/or melphalan ≥135 mg/m2).

Antithrombin alfa in hereditary antithrombin deficient patients: A phase 3 study of prophylactic intravenous administration in high risk situations

During surgery and childbirth, patients with hereditary antithrombin (AT) deficiency are at high risk for thrombosis, and heparin prophylaxis may not be sufficiently efficacious. In these patients, exogenous AT may be used in association with heparin. A recombinant human AT (generic name: antithrombin alfa) has been developed. This multi-center study assessed the efficacy and safety of prophylactic intravenous administration of antithrombin alfa to hereditary AT deficient patients in high risk situations, including elective surgery, childbirth, or cesarean section. Antithrombin alfa was administered prior to and during the high risk period for restoration and maintenance of AT activity at 100% of normal. Heparin, low-molecular-weight heparin, and/or vitamin K antagonists were used according to standard of care. The primary efficacy endpoint was the incidence of acute deep vein thrombosis (DVT) from baseline up to day 30 post dosing as assessed by independent central review of duplex ultrasonograms and/or venograms. Safety was assessed based on adverse events (AEs) and laboratory evaluations. Five surgical and nine obstetrical hereditary AT deficiency patients received antithrombin alfa for a mean period of seven days. No clinically overt DVT occurred. Central review of ultrasonograms identified signs of acute DVT in two out of 13 evaluable patients. No antithrombin alfa-related AEs were reported. No patient developed anti-antithrombin alfa antibodies. In conclusion, this study suggests that antithrombin alfa is a safe and effective alternative to human plasma-derived AT for treating hereditary AT deficiency patients at high risk for thromboembolic events.

Comparison of the two-year outcomes and costs of prophylaxis in medical patients at risk of venous thromboembolism

A decision-analytic model incorporating a Markov process to assess the incremental cost and effectiveness of venous thromboembolism (VTE) prevention strategies was used. Modeling was carried out using a hypothetical cohort of medical patients at risk of VTE. The model compared clinical effectiveness (primary and recurrent VTE, death), safety (adverse events), and direct medical costs between patients receiving enoxaparin prophylaxis, unfractionated heparin (UFH) prophylaxis, and no prophylaxis (n = 10,000 for each arm). Monte Carlo simulation was performed to identify changes in inputs that would affect the results. The estimated incidence ofVTE at two years (including recurrent VTE) was 6.8% with enoxaparin prophylaxis, 7.9% with UFH prophylaxis, and 17.9% with no prophylaxis. Two-year mortality occurred in 15.7% of enoxaparin patients and 16.0% of UFH patients, with the incidences of major bleeding in these groups being 0.7% and 1.2%, respectively. However, both enoxaparin and UFH prophylaxis were associated with higher rates of major bleeds than no prophylaxis (0.6%). Total average costs per patient were (US dollars) $1,264 (for enoxaparin prophylaxis, $1,585 for UFH prophylaxis, and $2,245 for no prophylaxis). No realistic parameter changes resulted in enoxaparin prophylaxis being more costly than UFH prophylaxis. For the healthcare payer, considering all direct medical costs associated with VTE up to two years after an admission for acute illness, prophylaxis with enoxaparin was more effective and less costly than UFH. This identifies enoxaparin as a potentially favorable VTE prophylaxis regimen compared with UFH and no prophylaxis in at-risk medical patients.

Pleural mesothelioma and venous thrombosis: the eosinophilia link

Peripheral blood eosinophilia and vascular occlusions are rare occurrences in patients with pleural mesothelioma whereas eosinophilia may associate with thrombosis. We describe a patient with mesothelioma who developed peripheral blood eosinophilia followed by deep vein thrombosis despite being on low molecular weight heparin prophylaxis. We discuss the genesis of peripheral blood eosinophilia and thrombosis in pleural mesothelioma.

Efficacy and safety of anticoagulant prophylaxis to prevent venous thromboembolism in acutely ill medical inpatients: a meta‐analysis

Venous thromboembolism (VTE) is a potentially serious complication of hospitalization and immobilization. The use of anticoagulant prophylaxis in acutely ill medical inpatients is still under debate. New data including a recent meta-analysis have recently been published. We aim at studying the efficacy and safety of anticoagulant prophylaxis in acutely ill medical inpatients, and demonstrate differences between meta-analyses due to different data extraction from the heterogeneous studies included. The Cochrane Library, MEDLINE and EMBASE were searched from 1980 to present. Manual searches were performed regarding abstracts from major meetings. Seven blinded randomized controlled clinical trials assessing the prophylactic effect of heparin in acutely ill medical patients were identified and included in the meta-analysis. Low-molecular weight heparin (LMWH) prophylaxis prevented 48% of symptomatic pulmonary embolism (PE), 48% of symptomatic deep vein thrombosis (DVT) (not significant) and 51% of asymptomatic DVT. A nonsignificant trend towards higher bleeding risk during LMWH prophylaxis was found. Death was not significantly affected. We compared our data with a recent meta-analysis with different study selection and data extraction and found similar results. As DVT and PE are manifestations of the same illness, VTE, one can argue that anticoagulant prophylaxis prevents approximately half of the expected events. Most medical inpatients have short hospital stays, and a low risk of VTE. The important task for the clinician is to identify patients with a sufficiently high risk of symptomatic VTE to warrant LMWH prophylaxis. Despite differences in study selection and data extraction, our study shows results similar to a recent meta-analysis.

MP-18.11: Venous thromboembolism in radical prostatectomy: Is postoperative heparinoid prophylaxis recommended?

The need and timing of perioperative heparinoid prophylaxis is matter of debate. Basically, the administration of heparinoid prophylaxis is performed preoperatively in European practice to improve effectiveness, while postoperative prophylaxis or no treatment at all is performed in North American practice to improve safety. The aim of our work is to review the incidence of venous thromboembolism (VTE) after radical retropubic prostatectomy (RRP) in patients submitted to preoperative blood donation and to postoperative low molecular weight heparin prophylaxis.

Thrombophilias in pregnancy and their role in preeclampsia

Thrombophilias are inherited or acquired conditions that predispose the affected individual to thromboembolism. Several studies have demonstrated that the presence of thrombophilic defects is a risk factor for adverse pregnancy outcome. Preeclampsia (PE) is associated with vascular and endothelial damage and thrombophilias may play an important role in this pathology. Most studies have found an association between early-onset PE and thrombophilia. Early recognition of PE is essential for optimal treatment but, at present, specific markers of the disease are lacking. Therapy must address the prevention of maternal complications and improvement of neonatal outcome. There is no clear evidence to support the use of heparin prophylaxis for PE. A high dose of antithrombin concentrate may represent a possible therapy in early-onset PE. Preventive and conservative treatment of PE with early diagnosis and a new therapeutic approach will allow the prolongation of pregnancy with fewer maternal and fetal complications.

Spontaneous bilateral carotid and vertebral artery dissections associated with multiple disparate intracranial aneurysms, subarachnoid hemorrhage and spontaneous resolution: Case report and literature review

Spontaneous bilateral carotid and vertebral artery dissections (CADs and VADs) are rare. A 29-year-old female presented with a collapse, 4 weeks after a sudden onset of severe neck and shoulder pain. CT scan revealed diffuse subarachnoid hemorrhage (SAH) and early hydrocephalus. Angiography revealed bilateral CADs and VADs, along with multiple fusiform and saccular aneurysms. Systemic vessels – including the renal arteries – were normal, and no risk factors or underlying vasculopathy were apparent. The presumed source of SAH (a posterior cerebral artery aneurysm) was successfully clipped. Each dissection, by contrast, was managed conservatively with heparin prophylaxis; and spontaneous CAD and VAD resolution occurred within 6 months. We present a unique case of four-vessel dissection associated with multiple disparate saccular and fusiform aneurysms. We suspect that underlying vasculopathy – perhaps novel – may become apparent with time.

Low molecular weight heparins in cancer patients: to treat thromboembolic events, the tumor, or both?

The interrelationship between cancer and thrombosis is well known. Recent data help physicians to optimize the management of thrombotic complications occurring in cancer patients. However, many issues are still uncertain. First, although the development of venous thromboembolism (VTE) in a patient with known cancer is the most common presentation, concerns remain about the optimal duration and dosages of anticoagulants. Questions also arise concerning the need to implement heparin prophylaxis in the course of chemotherapy. Secondly, in some patients, thrombosis precedes the diagnosis of malignancy. In this case, the question is whether or not to screen patients for an occult cancer. Thirdly, very recent studies have shown the hemostatic system plays a key role at different stages of tumor growth. Anticoagulants, especially low molecular weight heparin (LMWH), appear therefore to be an attractive strategy not only for managing the risk for thrombosis but, possibly, to improve patient outcome and survival. However, the use of these compounds in settings other than VTE is questionable. Finally, most of the data come from studies evaluating patients with different types of cancer at different stages, thus making results difficult to evaluate. Additional research is required to clarify the biological mechanisms involved and to answer still unresolved clinical questions. In this review, the evidence for the use of LMWHs in cancer patients will be presented and remaining doubts discussed.

Management of Superficial Vein Thrombosis and Thrombophlebitis: Status and Expert Opinion Document

Superficial vein thrombosis is characterized by clotting of superficial veins (ie, following direct trauma) with minimal inflammatory components. Superficial thrombophlebitis is a minimally thrombotic process of superficial veins associated with inflammatory changes and/or infection. Treatments generally include analgesics, elastic compression, anti-inflammatory agents, exercise and ambulation, and, in some cases, local or systemic anticoagulants. It is better to avoid bed rest and reduced mobility. Topical analgesia with nonsteroidal, anti-inflammatory creams applied locally to the superficial vein thrombosis/superficial thrombophlebitis area controls symptoms. Hirudoid cream (heparinoid) shortens the duration of signs/symptoms. Locally acting anticoagulants/antithrombotics (Viatromb, Lipohep, spray Na-heparin) have positive effects on pain and on the reduction in thrombus size. Intravenous catheters should be changed every 24 to 48 hours (depending on venous flow and clinical parameters) to prevent superficial vein thrombosis/superficial thrombophlebitis and removed in case of events. Low molecular weight heparin prophylaxis and nitroglycerin patches distal to peripheral lines may reduce the incidence of superficial vein thrombosis/superficial thrombophlebitis in patients with vein catheters. In case of superficial vein thrombosis/superficial thrombophlebitis, vein lines should be removed. In neoplastic diseases and hematological disorders, anticoagulants may be necessary. Exercise reduces pain and the possibility of deep vein thrombosis. Only in cases in which pain is very severe is bed rest necessary. Deep vein thrombosis prophylaxis should be established in patients with reduced mobility. Antibiotics usually do not have a place in superficial vein thrombosis/superficial thrombophlebitis unless there are documented infections. Prevention of superficial vein thrombosis should be considered on the basis of patient's history and clinical evaluation.