Warfarin-related Hemorrhage Research Articles

A Randomized Clinical Trial of Low-dose Warfarin Therapy for Improving the Longevity of Permanent Arteriovenous Catheters

The patency of a permanent arteriovenous catheter plays a significant role in the functioning of the catheter among patients dependent on the hemodialysis. Thrombosis formation is one of the most critical reasons for the short-term efficacy of the embedded catheters. The present study aimed to evaluate the efficacy and safety of warfarin for hemodialysis catheter failure prevention. This randomized clinical trial has been conducted on patients under hemodialysis using a permanent arteriovenous catheter. The patients were randomly allocated to the control group and the intervention group. The intervention group was treated with warfarin to achieve a target international normalized ratio (INR) of 1.5-2. The control group did not receive any treatment. The patients were followed for 12months to assess the efficacy defined as the incidence of catheter clotting and safety defined as warfarin-related hemorrhage. Eighty-six patients with end-stage renal disease under hemodialysis were included, among which 43 ones were allocated to the intervention group and the latter ones to the control group. The participants of both groups were similar in terms of demographic, clinical, and baseline laboratory characteristics. Four patients (9.3%) presented with warfarin-induced hematoma, among which the warfarin administration stopped for 5.33±1.44days and then restarted again. None of the patients was forced to cease warfarin therapy because of significant hemorrhages. The mean duration of catheter functioning was 8.30±1.75months in the intervention group versus 3.90±1.12months in the controls (P-value<0.001). Based on the findings of the present study, the use of warfarin to achieve an INR level of 1.5-2 could effectively lead to a longer duration of permanent hemodialysis catheter functioning.

Nontraumatic warfarin-related intrapulmonary hemorrhage presenting as a lung mass

BackgroundAlthough bleeding events are the major concern when using oral anticoagulants, intrathoracic hemorrhages due to warfarin are rare. Most cases in the literature have been related to trauma and have manifested as a hemothorax. Here we report a case of a nontraumatic hemorrhage within a pre-existing pulmonary cyst that presented as a lung mass during warfarin therapy.Case presentationA 75-year-old asymptomatic woman presented with a 10-cm-diameter mass on chest radiography that was not evident 6 months prior. She had been taking warfarin for paroxysmal atrial fibrillation and a transient ischemic attack. There was no history of chest trauma, warfarin overdosing, or any suspected interactions with other drugs such as nonsteroidal anti-inflammatory drugs or antibiotics. The prothrombin time/international normalized ratio(PT-INR) was prolonged at 4.73 and her hemoglobin level was 8.7 g/dl. Chest computed tomography(CT)revealed an air-fluid mass adjacent to the right upper and middle lobes with a pleural effusion. A CT scan obtained 15 years prior revealed a cyst at the corresponding site and the mass was diagnosed as a warfarin-related hemorrhage within the pre-existing pulmonary cyst. We performed a surgical resection of the cyst to prevent any worsening hemorrhage and subsequent infection. The postoperative course was uneventful and the patient was discharged on the 3rd postoperative day.ConclusionA warfarin-related thoracic hemorrhage, other than a hemothorax, could manifest as a pulmonary mass on radiography in patients with pre-existing pulmonary cysts. History taking especially of any anticoagulant medications and a precise assessment of the past images are crucial for a correct diagnosis. Once the intrapulmonary cystic hemorrhage becomes evident, prompt withdrawal with a reversal of warfarin and surgical resection are required to prevent a worsening hemorrhage and subsequent infection.

Bleeding risk in warfarinized patients with a therapeutic international normalized ratio: the effect of low factor IX levels

Bleeding is the main complication of warfarin therapy, even patients with an international normalized ratio (INR) in the target range can suffer bleeding, suggesting that INR does not perfectly reflect the therapeutic effect of warfarin. We hypothesized the INR might underestimate the level of anticoagulation in a subject with a lower factor (F) IX level than average. We modeled warfarin anticoagulation in our in vitro thrombin generation (TG) model by adjusting the levels of vitamin K-dependent factors to those of patients with an INR of 2-3. Variation in FIX had a marked effect on TG but had no effect on the prothrombin time (PT)-INR. A prospective observational, cross-sectional clinical study including 341 consecutive patients admitted to the emergency department with an INR between 2 and 3, showed a statistically lower FIX activity in bleeders (P = 0.004) compared with others. No correlation was found between TG capacity and PT-INR results (P = 0.36). However, in patients, presenting with a warfarin-related hemorrhage, TG was significantly lower (P < 0.001) than others. A correlation on the boundary of significance was observed between TG capacity and FIX levels (P = 0.09). These data demonstrates that patients who bleed when their PT-INR is in the target range 2-3 might have defective TG related to a lower level of FIX than expected.

Abstract 217: How well does the CHADS 2 Stroke Risk Score Predict Major Hemorrhage in Patients with Atrial Fibrillation?

Background: The decision on whether or not to use anticoagulants for atrial fibrillation depends on estimating a patient’s risk of stroke compared to their risk of bleeding. The CHADS 2 risk score is widely used to predict the risk of stroke in patients with atrial fibrillation. Several of the risk factors in CHADS 2 have also been associated with hemorrhage risk, raising the possibility that CHADS 2 could also be used to predict warfarin-associated hemorrhage. Objective: To determine whether the CHADS 2 stroke risk scheme can be used to predict hemorrhage in patients with atrial fibrillation and to compare the predictive ability of CHADS 2 with a risk score specifically designed to predict warfarin-related hemorrhage. Methods: We used data from the ATRIA Study, a cohort of 13,559 adults with atrial fibrillation receiving care in a large integrated healthcare delivery system. The cohort was divided into on-warfarin and off-warfarin periods. Clinical risk factors were obtained from computerized medical databases and used to calculate a CHADS 2 risk score (congestive heart failure, hypertension, age≥75, diabetes, and prior stroke) as well as a previously developed measure of anticoagulation-associated bleeding risk, the ATRIA bleeding risk score (anemia, severe renal disease, age≥75, prior bleed, and hypertension). The primary outcome was hospitalization for major hemorrhage, validated through chart review. The performance of the CHADS 2 and ATRIA scores was compared by c -index and net reclassification improvement. Results: We identified 170 major hemorrhages during 15,300 person-years of follow-up on warfarin, and 162 hemorrhages during 15,530 person-years off warfarin. The CHADS 2 risk score predicted hemorrhage risk better than chance in both warfarin and non-warfarin exposed groups, with a c- index of 0.67 [95% CI = 0.64 - 0.71] and 0.65 [95% CI = 0.62-0.67], respectively. However, the ATRIA bleeding risk score predicted major hemorrhage events better than CHADS 2 , with a c -index of 0.74 [95% CI = 0.72-0.76] for warfarin users and 0.77 [95% CI = 0.75-0.80] for non-warfarin users. The ATRIA bleeding risk score also had better net reclassification improvement than CHADS 2, 35.6% for warfarin users and 26.8% for non-warfarin users. Conclusions: Although some clinical markers of stroke risk such as those included in the CHADS 2 risk score are also associated with increased hemorrhage risk, the CHADS 2 risk score should not be used instead of a validated hemorrhage risk tool to estimate hemorrhage risk.

Recurrent spontaneous pneumomediastinum: a rare but possible event!

A number of risk indices have been formulated in an attempt to predict risk of a major hemorrhage in an individual on warfarin therapy. No single index to date is able to reliably predict this risk in an individual patient. Although most warfarin related hemorrhages are gastrointestinal or intracranial in origin this case represents a particularly rare entity of a major hemorrhage presenting as an encysted empyema. To the best of our knowledge this has never before been described.

The Impact of Factor IX Level on Thrombin Generation and Bleeding During Warfarin Anticoagulation

Abstract 541Bleeding occurs in from 10 – 16% of warfarin-treated patients. Having a PT-INR in the target range is associated with better outcomes. However, even patients with an INR in the target range of 2–3 can suffer bleeding, suggesting that INR does not perfectly reflect the therapeutic effect of warfarin. The goal of our studies was to determine whether the level of specific coagulation factors could predict the risk of bleeding while the INR was in the target range.We modeled warfarin anticoagulation in our previously published in vitro cell based-model by adjusting the levels of vitamin K-dependent factors to those of patients with an INR of 2–3. We then examined the effect of variations in the level of FIX. The cogulation reactions were initiated by monocyte-expressed tissue factor (assayed at 1pM). Variation in FIX had a marked effect on thrombin generation. However, in plasma with the same levels of factors, as expected, variations in FIX had no effect on the PT-INR. Thus, we hypothesized that a subject with a lower FIX level than average may have a lower level of thrombin generation than is indicated by the INR. The INR might, therefore, underestimate the level of anticoagulation in such a subject. If s/he is maintained in the “therapeutic range” as measured by the INR, s/he will actually be over-anticoagulated and prone to hemorrhage.A prospective, single centre clinical study has been carried out to test this hypothesis in warfarinized patients. Between October 2010 and June 2011, 312 consecutive patients admitted to the emergency department of Edouard Herriot Hospital in Lyon, with an INR between 1.8 and 3.2, were included in the study after obtaining informed consent. Twenty six patients were admitted for a bleeding episode, 18 for recurrent thrombosis and 268 for other medical reasons. Patients presenting with bleeding, 17 males and 9 females, were aged 74±14 years old compared to the rest of the patients aged 76±14. Among the 26 bleeders, 7 had a spontaneous intracranial haemorrhage, 2 had a trauma-induced intracranial haemorrhage, 12 presented a gastrointestinal bleeding and 5 exhibited muscle hematomas, severe epistaxis or urinary tract bleeding. PT-INR and vitamin K-dependent factor levels were determined in all patients. Thrombin generation capacity in platelet poor plasma was measured using Calibrated Automated Thrombin generation assay (Thrombinoscope bv, Maastricht, The Netherlands), with tissue factor 1pM and phospholipids PC:PS:PE 4μM.No statistically significant difference was observed in the PT-INR of bleeding patients (INR=2.4±0.4) and those having a thrombosis (INR=2.5±0.5) or patients admitted for other reasons (INR=2.6±0.2). Plasma prothrombin and factor × levels were also similar in all three groups. However, a statistically lower plasma factor IX activity was observed in bleeders (p=0.01, Mann Whitney test) compared to other groups, 47.6±20 IU/dL vs. 63±33 IU/dL.In all the warfarinized subjects with an INR between 1.8 and 3.2, no correlation was found between thrombin generation capacity and PT-INR results (p=0.85, Spearman correlation test). However, a statistically significant correlation was observed between thrombin generation capacity and factor IX levels (p=0.0002). In patients, presenting with warfarin-related haemorrhage, the endogenous thrombin potential (ETP) was significantly lower at 340±335 nM.min (p=0.05) then that of warfarinized subjects who did not suffer bleeding (ETP 406±215 nM.min).These data support our hypothesis based on our in vitro results and show that patients who bleed when their PT-INR is in the target range 2 – 3 might have defective thrombin generation related to a lower level of factor IX than expected. Thus, our results suggest that the appropriate target INR level might not be the same for all patients. Those with factor IX levels that differ significantly from the mean of the population might be managed best by selecting a target INR that is based on the level of thrombin generation. Of course, a “target range” for parameters of thrombin generation during warfarin therapy would need to be developed if the assay were to be used for this purpose. Disclosures:No relevant conflicts of interest to declare.

Complication of warfarin therapy presenting as empyema.

A number of risk indices have been formulated in an attempt to predict risk of a major hemorrhage in an individual on warfarin therapy. No single index to date is able to reliably predict this risk in an individual patient. Although most warfarin related hemorrhages are gastrointestinal or intracranial in origin this case represents a particularly rare entity of a major hemorrhage presenting as an encysted empyema. To the best of our knowledge this has never before been described.

Ethnic Disparities in First Primary Intracerebral Hemorrhage in Northern Israel

Background: Ethnic differences among first primary intracerebral hemorrhage (PICH) patients in an Israeli biethnic population have not yet been studied. Patients and Methods: We included in the study 546 patients (counting warfarin-related hemorrhages) hospitalized during the period from December 1999 through June 2008. Results: The mean age was 71.1 ± 14 years for the Jewish patients and 63.3 ± 13.9 years for the Arab patients (p < 0.0001). Diabetes and smoking were significantly more frequent among the Arab patients. No difference was found between groups by location, extent, or ventricular involvement of PICH. Although the in-hospital mortality rate was significantly higher among the Jewish patients, adjustment of the model combining multiple risk factors for PICH eliminated this difference. Conclusions: There are differences in the demographic and vascular risk factor profiles between Arab and Jewish PICH patients, with the Arabs found to be younger and to suffer more from diabetes. The location and extent of intracerebral hemorrhage as well as functional outcome were similar between the two groups. The apparent higher in-hospital mortality in the group of Jewish patients was eliminated when the influence of multiple covariates other than ethnicity, main vascular risk factors and international normalized ratio level were taken into consideration.

The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage.

Warfarin sodium is highly effective for prevention of embolic stroke, particularly in nonvalvular atrial fibrillation, but its expected benefit can be offset by risk of intracerebral hemorrhage (ICH). We studied the determinants of ICH outcome to quantify the independent effect of warfarin. Consecutive patients with supratentorial ICH treated in a tertiary care hospital with a neurointensive care unit were prospectively identified during a 7-year period, and data on hemorrhage location, clinical characteristics, and warfarin use were collected. Independent predictors of 3-month mortality were determined using multiple logistic regression analysis. Of 435 consecutive patients aged 55 years or older, 102 (23.4%) were taking warfarin at the time of ICH. Three-month mortality was 25.8% for those not taking warfarin and 52.0% for those taking warfarin. Independent predictors of death were warfarin use (odds ratio [OR], 2.2; 95% confidence interval [CI], 1.3-3.8), age 70 years or older (OR, 2.4; 95% CI, 1.4-4.0), and presence of diabetes mellitus (OR, 1.8; 95% CI, 1.0-3.3). Although 68.0% of all warfarin-related hemorrhages occurred at an international normalized ratio (INR) of 3.0 or less, increasing degrees of anticoagulation were strongly associated with increasing risk of death compared with no warfarin use. Patients taking warfarin had a doubling in the rate of intracerebral hemorrhage mortality in a dose-dependent manner. The data suggest that careful control of the INR, already known to limit the risk of warfarin-related ICH, may also limit its severity.

Leukoaraiosis is associated with warfarin-related hemorrhage following ischemic stroke.

Prior ischemic stroke is a risk factor for intracerebral hemorrhage (ICH) in patients taking warfarin, but the mechanism is not known. This study investigates radiographic and clinical characteristics of patients with warfarin-related ICH following ischemic stroke. In this case-control study, the authors selected all patients with warfarin-related ICH and previous symptomatic ischemic stroke from a prospective cohort of consecutive patients with ICH. Control subjects were similarly aged patients with history of symptomatic stroke randomly chosen from an anticoagulant therapy unit. The 26 eligible ICH cases and 56 controls were compared for vascular risk factors, stroke characteristics, and extent of leukoaraiosis (graded in anterior and posterior brain regions on a validated scale of 0 to 4). The presence and severity of leukoaraiosis on CT scan correlated strongly with the occurrence of ICH. Leukoaraiosis was seen in 24 of 26 cases (92%) compared with 27 of 56 controls (48%), yielding an odds ratio of 12.9 (95% CI 2.8 to 59.8). Other clinical factors associated with ICH included an international normalized ratio >3.0, history of multiple previous strokes, and the presence of carotid artery stenosis. The relationship between leukoaraiosis and ICH persisted in multivariable analyses controlling for these risk factors as well as hypertension and diabetes mellitus. Leukoaraiosis is an independent risk factor for warfarin-related ICH in survivors of ischemic stroke, including those in the commonly employed range of anticoagulation.

The St. Jude valve: Analysis of thromboembolism, warfarin-related hemorrhage, and survival

From March 1978–1986, 590 St. Jude prostheses (232 aortic, 232 mitral, and 63 double aortic-mitral) were implanted in 527 patients (mean age 63 years) and followed for up to 8 years (mean 33 months; three lost; 99% complete). The early (30-day) mortality rate was 8.9% and was strongly associated with preoperatively depressed left ventricular function (ejection fraction <0.55), ischemic mitral regurgitation, and advanced functional class (IV) ( p < 0.05). Actuarial survival rates at 5 years were 72% ± 4%, 72% ± 8%, and 63 ± 4% after aortic, double, and mitral valve replacement ( p < 0.01). There have been no structural failures. Embolism (28 events, 2.1%/patient-year) was less common with warfarin treatment (1.5%/patient-year; n = 492) than with antiplatelet (3.2%/patient-year; n = 19) or no drug therapy (18.9%/patient-year; n = 16) ( p < 0.01). One embolic event was fatal (3.6%). Warfarin-treated patients remained 91% ± 1% free of emboli after 8 years. Valve thrombosis (six events; 0.4%/patient-year) occurred exclusively in patients not treated with effective warfarin therapy; one (17%) died. The most common complication was hemorrhage (39 events; 2.9%/patient-year); nine (23%) were fatal, and these constituted 82% of 11 valve-related late deaths. In warfarin-treated patients (target prothrombin time ratio 1.5 to 2.5), hemorrhage was twice as frequent (2.9%/patient-year) as embolism (1.5%/patient-year). In conclusion, warfarin anticoagulation is recommended in all patients. Although the operative and late survival rates reported in this study reflect in part the inclusion of high-risk patients with advanced functional class, left ventricular dysfunction, and ischemic mitral regurgitation, a major cause of valve-related morbidity and late death was warfarin-related hemorrhage. A downward revision in the target prothrombin time ratio to 1.5 to 2.0 may result in fewer bleeding complications. The optimal antithrombotic regimen in children remains to be defined.