The patient with cirrhosis: poised to bleed or poised to clot?

It turns out to be a little of both. A number of reviews have addressed this. [1] [2] [3]  Here are some of the key points:

The old maxim that cirrhotic patients are auto-anticoagulated is a myth. Severe liver disease is associated with a delicate balance between bleeding and clotting. In general, cirrhosis tends to be a hypercoagulable state. The relative risk for VTE in such patients has been estimated at around 2.

 

What are the mechanisms for the hypercoagulability of liver disease?

In primary hemostasis, while platelet numbers are often decreased these platelets tend to be hyper-functional. This is due to low levels of ADAM TS 13, correspondingly increased levels of VW factor and multifactorial endothelial dysfunction.

In secondary hemostasis, reasons for hypercoagulability include decreased levels of liver dependent natural anticoagulants such as protein C, protein S, and antithrombin. Factor VIII (not synthesized in the liver) tends to be increased.

There is also impaired fibrinolysis with increased levels of PAI-1 and decreased levels of plasminogen.

What are the clinical implications?

Traditional hemostatic tests are generally used but are of limited reliability. There's been increasing interest in global hemostatic tests such as viscoelastic assays which are conceptually more valid but are not yet ready for translation into clinical practice.

For low risk procedures, prophylactic hemostatic products peri-procedure are generally not indicated.

Antithrombotic treatments should be given in accordance with standard clinical indications recognizing a potentially increased risk of bleeding.

DOACs can be used in many patients but certain published restrictions apply.

Special circumstances where warfarin is favored over DOACs

 When is warfarin favored over DOACs?

 Valvular atrial fibrillation. 

This term is becoming obsolete. For anticoagulation for stroke prevention in atrial fibrillation  DOACs are contraindicated and warfarin favored in severe rheumatic mitral stenosis and mechanical prosthetic valves.

Liver disease. 

If Child Pugh is C DOACs are not recommended. If B, apixaban and rivaroxaban can be used “with caution” (FDA labeling ).   Child Pugh calculator.

 Antiphospholipid syndrome. 

Warfarin is favored (Up to Date). 

Morbid obesity: 

DOAC is okay for BMI up to 40. Above 40 rivaroxaban and apixaban are acceptable but other DOACs should be avoided. 

History of gastrectomy or weight loss surgery: 

Warfarin preferred. This review summarizes the rationale and recommendations regarding morbid obesity and patients who have had weight loss surgery.

In addition, certain drug interactions with DOACs are category X thus prohibiting use.

Antiplatelet therapy reduces mortality in sepsis

From a recent meta-analysis:

Highlights

Antiplatelet drugs can reduce the mortality rate in patients with sepsis.

Aspirin can effectively reduce mortality in patients with sepsis.

Antiplatelet drugs reduce mortality regardless of the timing of administration.

Abstract

Purpose

Abnormal platelet activation plays an important role in the development of sepsis. The effect of antiplatelet drugs on the outcome of patients with sepsis remains unclear. This meta-analysis aimed to determine the effect of antiplatelet drugs on the prognosis of patients with sepsis.

Materials and methods

PubMed, Cochrane Library, CBM, and Embase were searched for all related articles published from inception to April 2018. The primary end point was mortality. Adjusted data were used and statistically analysed.

Results

Ten cohort studies were included. The total number of patients with sepsis was 689,897. Data showed that the use of antiplatelet drugs could effectively reduce the mortality of patients with sepsis (odds ratio (OR) = 0.82, 95% CI: 0.81–0.83, p less than 0.05). Seven studies used aspirin for antiplatelet therapy, and subgroup analysis showed that aspirin effectively reduced ICU or hospital mortality in patients with sepsis (OR = 0.60, 95% CI: 0.53–0.68, p less than 0.05). A subgroup analysis on the timing of anti-platelet drug administration showed that antiplatelet drugs can reduce mortality when administered either before (OR = 0.78, 95% CI: 0.77–0.80) or after sepsis (OR = 0.59, 95% CI: 0.52–0.67).

Conclusions

Antiplatelet drugs, particularly aspirin, could be used to effectively reduce mortality in patients with sepsis.

Antithrombotic therapy for sepsis is not a new concept. The coagulation system is activated and accounts for some of the injury in sepsis. Activated protein C was found beneficial in selected septic patients and was approved as an adjunct in the treatment of sepsis with organ dysfunction in 2001. The company withdrew the product from the market in 2011.

Hospitalization rates and lengths of stay for VTE in Alberta Canada

Since 2002 they have been sending a fair number of patients home from ER or clinic but once hunkered in patients stay awhile and these numbers haven’t changed much over time:

 

Background

Acute venous thromboembolism leads to significant morbidity and mortality. Advances in pharmacotherapy facilitate outpatient care in low-risk acute venous thromboembolism. The proportion of hospitalized acute venous thromboembolism cases and the average length of stay are not known. We sought to identify predictors of hospitalization, changes in hospitalization rates and length of stay of acute venous thromboembolism over a decade in Alberta, Canada.

Methods

Using linked administrative health databases, we identified adult patients diagnosed primarily with acute venous thromboembolism between April 2002 and March 2012. We measured trends using Poisson regression, adjusted length of stay using analysis of covariance. We identified predictors of hospitalization using multivariate logistic regression.

Results

8198 out of 31,656 acute venous thromboembolism cases were hospitalized. The overall venous thromboembolism admission rates ranged between 23.7% and 27.8% with no evident temporal trend (P = 0.10). The average admission rate was 51.9% for pulmonary embolism and 16.1% for deep vein thrombosis. The mean length of stay for deep vein thrombosis and pulmonary embolism remained unchanged with an adjusted mean for venous thromboembolism of 6.9 ± 1.0 days. Higher Charlson index, older age, male gender, pulmonary embolism at presentation and multiple comorbidities were associated with hospitalization. Hospitalization was associated with 30-day mortality (odds ratio:2.8, 95% CI: 2.2–3.5) whereas the length of stay was not (odds ratio:1.0, 95% CI: 0.99–1.0).

Conclusion

Hospitalization rates and mean length of stay for acute venous thromboembolism did not change significantly between 2002 and 2012. Advances in pharmacotherapy have not yet reduced hospitalization rates or length of stay for venous thromboembolism.

Is thrombophilia testing helpful?

Maybe in very restricted circumstances but not to determine the duration of anticoagulation after VTE.

Growing evidence challenges conservative transfusion dogma

The last few years have seen quite a push toward restrictive transfusion strategies with conservative hemoglobin (less than seven) triggers.  Not only did numerous research publications support such an approach but there are important theoretical concerns. For example banked blood is relatively ineffective in terms of oxygen delivery due to depletion of 2, 3 DPG levels. There's also a concern based on indirect evidence that blood transfusions may be immunosuppressive by poorly understand mechanisms. Guidelines support a conservative (hemoglobin seven) trigger in almost all situations (though allowing room for clinical judgment which might favor a trigger of 8 in some circumstances).
In recent years the discussion around transfusion restriction has morphed into a campaign of sorts with conservative triggers embedded into electronic medical records and institutional policies taking the form of dogma with little regard for clinical judgment or the unique attributes of certain patients.
A paper in Critical Care Medicine challenges this dogma in certain patients:

Patients: Adult cancer patients with septic shock in the first 6 hours of ICU admission.

Interventions: Patients were randomized to the liberal (hemoglobin threshold, less than 9g/dL) or to the restrictive strategy (hemoglobin threshold, less than 7g/dL) of RBC transfusion during ICU stay.

Measurements and Main Results: Patients were randomized to the liberal (n = 149) or to the restrictive transfusion strategy (n = 151) group. Patients in the liberal group received more RBC units than patients in the restrictive group (1 [0-3] vs 0 [0-2] unit; p less than 0.001). At 28 days after randomization, mortality rate in the liberal group (primary endpoint of the study) was 45% (67 patients) versus 56% (84 patients) in the restrictive group (hazard ratio, 0.74; 95% CI, 0.53-1.04; p = 0.08) with no differences in ICU and hospital length of stay. At 90 days after randomization, mortality rate in the liberal group was lower (59% vs 70%) than in the restrictive group (hazard ratio, 0.72; 95% CI, 0.53-0.97; p = 0.03).

Conclusions: We observed a survival trend favoring a liberal transfusion strategy in patients with septic shock when compared with the restrictive strategy. These results went in the opposite direction of the a priori hypothesis and of other trials in the field and need to be confirmed.
Although the survival advantage for more aggressive transfusion did not reach statistical significance 28 days it did at 90 days.

Thrombocytopenia developing in hospitalized patients

Here’s a nice review.

What the hospitalist needs to know about the TTP-HUS spectrum

This is the best review I’ve ever seen on this. Free full text.

Be careful using a restrictive transfusion strategy in patients with cardiovascular disease

From a recent review:

There is biological plausibility that patients with CVD may benefit from higher transfusion thresholds than patients without CVD. Evidence from a systematic review and meta‐analysis in this population suggest that there is no difference in 30‐day mortality, but there is an increased risk of ACS in patients with CVD who were randomized to a restrictive transfusion threshold compared with a more liberal threshold. We suggest that a more liberal transfusion threshold (greater than 80 g/l) in this population should be used until a high‐quality trial including endpoints for longer term mortality, ACS, quality of life and cost effectiveness has been performed.

Unraveling the mystery of thrombotic storm

This free full text article is worth reading in its entirety.

Diagnosis of upper extremity DVT

From a recent review:

Highlights

•The evidence on the diagnostic management of upper extremity deep vein thrombosis is scarce.

•Only one study evaluated the use of a diagnostic algorithm, similar to the one used for deep vein thrombosis of the lower extremities.

•Further studies are needed to validate the algorithm, especially in high-risk subgroups.

Abstract

Upper extremity deep vein thrombosis (UEDVT) accounts for 4% to 10% of all cases of deep vein thrombosis. UEDVT may present with localized pain, erythema, and swelling of the arm, but may also be detected incidentally by diagnostic imaging tests performed for other reasons. Prompt and accurate diagnosis is crucial to prevent pulmonary embolism and long-term complications as the post-thrombotic syndrome of the arm. Unlike the diagnostic management of deep vein thrombosis (DVT) of the lower extremities, which is well established, the work-up of patients with clinically suspected UEDVT remains uncertain with limited evidence from studies of small size and poor methodological quality. Currently, only one prospective study evaluated the use of an algorithm, similar to the one used for DVT of the lower extremities, for the diagnostic workup of clinically suspected UEDVT. The algorithm combined clinical probability assessment, D-dimer testing and ultrasonography and appeared to safely and effectively exclude UEDVT. However, before recommending its use in routine clinical practice, external validation of this strategy and improvements of the efficiency are needed, especially in high-risk subgroups in whom the performance of the algorithm appeared to be suboptimal, such as hospitalized or cancer patients.

In this review, we critically assess the accuracy and efficacy of current diagnostic tools and provide clinical guidance for the diagnostic management of clinically suspected UEDVT.

Treating portal vein thrombosis in patients with cirrhosis

From a recently published study:

Highlights

•LMWH is effective in about 60% of LC with PVT patients.

•The resolution of thrombus associated with LMWH use is accompanied by improvement in liver function.

•It is more effective for PVT treatment to start LMWH early and to maintain it for a long time.

•LMWH treatment of usual dose and schedule is tolerable for LC patients.

Abstract

Introduction

Portal vein thrombosis (PVT) is a well-known complication in patients with liver cirrhosis (LC). The aim of this study is to investigate the outcomes of cirrhotic patients with PVT treated with low-molecular-weight heparin (LMWH).

Method

Ninety-one LC patients with PVT were treated with dalteparin or enoxaparin for six months. Patients with major bleeding during the last three months, severe thrombocytopenia, or impaired renal function were excluded.

Results

The median age was 62.9 years, and 59 patients had hepatocellular carcinoma. The overall recanalization rate was 61.5%. Patients with a favorable Child-Pugh class and those recently diagnosed as having a thrombus showed significantly better responses. In those who responded to the anticoagulation therapy, the post-treatment bilirubin and platelet levels were improved compared to those in the pre-treatment state. The relapse rate for PVT was 56.6%, and the median time to relapse was 4.0 months. Bleeding was reported in 13 patients (14.4%), and two patients died due to fatal bleeding. A history of variceal bleeding and low serum albumin were risk factors for bleeding.

Conclusion

LMWH therapy for PVT in LC is effective. Advanced LC and a delayed start of anticoagulation treatment decrease the effect of LMWH. Despite its effectiveness, there is a risk of hemorrhage, hence anticoagulation should be carefully considered, especially in patients with advanced LC and a history of variceal bleeding.

Post-thrombotic syndrome: prevention and treatment

From a recent review:

Highlights

•PTS can be more easily prevented by preventing first or recurrent DVT, than treated.

•Optimal anticoagulation is essential to reduce the risk and severity of PTS.

•Patients with iliofemoral DVT may require a more aggressive treatment approach over anticoagulation alone.

•Treatment of PTS is primarily based on compression therapy.

•Selected patients with severe PTS can be referred for consideration of interventional procedures in expert centers.

Abstract

Post-thrombotic syndrome (PTS) is a complication that develops in up to 50% of patients with deep vein thrombosis (DVT) and manifests as symptoms and signs of chronic venous insufficiency of varying severity. PTS negatively affects patient's quality of life and causes significant burden to the healthcare system. The risk for PTS development can be markedly reduced by preventing DVT and providing appropriate anticoagulation once it develops. Patients with extensive proximal (iliofemoral) DVT may benefit from invasive interventions, such as catheter-directed thrombolysis. The effectiveness of elastic compression stockings (ECS) for PTS prevention has not been conclusively demonstrated in randomized trials.

Treatment of PTS is primarily based on ECS, exercise and lifestyle modifications. The effectiveness of various pharmacologic agents for PTS treatment remains controversial. Surgical or radiological interventions for vein reconstruction or revascularization may be considered in refractory cases.

This review summarizes current evidence regarding prevention and treatment of PTS of the lower limbs in adults.

Note that regarding regional thrombolysis, the ACCP guidelines do not generally recommend it. They do acknowledge that the therapeutic decision may be driven by patient preferences and values.

Reinitiation of systemic anticoagulation after a head bleed

From a recent study:

Methods—We searched published medical literature to identify cohort studies involving adults with anticoagulation-associated ICH. Our predictor variable was resumption of anticoagulation. Outcome measures were thromboembolic events (stroke and myocardial infarction) and recurrence of ICH. After assessing study heterogeneity and publication bias, we performed a meta-analysis using random-effects models to assess the strength of association between anticoagulation resumption and our outcomes.

Results—Eight studies were eligible for inclusion in the meta-analysis, with 5306 ICH patients. Almost all studies evaluated anticoagulation with vitamin K antagonists. Reinitiation of anticoagulation was associated with a significantly lower risk of thromboembolic complications (pooled relative risk, 0.34; 95% confidence interval, 0.25–0.45; Q=5.12, P for heterogeneity=0.28). There was no evidence of increased risk of recurrent ICH after reinstatement of anticoagulation therapy, although there was significant heterogeneity among included studies (pooled relative risk, 1.01; 95% confidence interval, 0.58–1.77; Q=24.68, P for heterogeneity less than 0.001). No significant publication bias was detected in our analyses.

Conclusions—In observational studies, reinstitution of anticoagulation after ICH was associated with a lower risk of thromboembolic complications and a similar risk of ICH recurrence. Randomized clinical trials are needed to determine the true risk–benefit profile of anticoagulation resumption after ICH.

But the big question: how soon can you restart?

Reinitiation of anticoagulation occurred at a median of 10 to 39 days (Table 2). Four studies did not report the exact timing of resumption of anticoagulation, 12,15,16,19 but the majority of patients were prescribed anticoagulation within the first 3 months after ICH.

Epidemiology of post-thrombotic syndrome

Here is a recent review. From the paper:

Highlights

•Post-thrombotic syndrome is the most frequent complication of DVT.

•After a proximal DVT, 20–50% of patients will develop PTS.

•Most important PTS predictors are extensive proximal DVT and ipsilateral recurrence.

Abstract

The post thrombotic syndrome (PTS) refers to clinical manifestations of chronic venous insufficiency (CVI) following a deep-vein thrombosis (DVT). PTS is the most frequent complication of DVT, which develops in 20 to 50% of cases after proximal DVT and is severe in 5–10% of cases. The reported prevalence of PTS differs widely among studies because of differences in study populations, tools used to assess PTS, and time interval between acute DVT and PTS assessment. The two most important predictors of PTS are extensive proximal character of DVT and previous ipsilateral DVT. Other reported risk factors include pre-existing CVI, obesity, quality of anticoagulant treatment, older age and residual venous obstruction. Standardization of PTS assessment tools combined with the development of patient self-reported PTS scales are likely to constitute a breakthrough in research of the epidemiology of PTS, by allowing comparison between studies, meta-analyses and increasing the feasibility of longer follow-up of DVT patients. This should enable identification of patient populations at high risk of severe PTS, new predictors of PTS and targets for potential new treatments. In this perspective, identification of biomarkers that are predictive of PTS such as markers of inflammation is crucial in ongoing research.

Platelet transfusion is associated with hospital acquired infection in the critically ill

Recent study.

Thrombophilia history: not a good predictor in the peri procedure management of anticoagulation

From a 2016 paper:

Background

Appropriate periprocedural management of the chronically anticoagulated patient with an inherited or acquired thrombophilia is uncertain. The objective of this study was to test “thrombophilia” as a potential predictor of the 3-month cumulative incidence of thromboembolism and major bleeding among chronically anticoagulated patients undergoing an invasive procedure.

Methods

In a prospective cohort study, consecutive chronically anticoagulated patients referred to the Mayo Thrombophilia Center for standardized periprocedural anticoagulation management who had venous thromboembolism and complete thrombophilia testing were categorized as “severe,” “non-severe,” or “no identifiable” thrombophilia. The 3-month cumulative incidence rates of thromboembolism, bleeding, and death were estimated using the Kaplan-Meier product limit method.

Results

Among 362 patients with complete thrombophilia testing, 165 (46%) had a defined thrombophilia; 76 patients had severe thrombophilia, mainly due to antiphospholipid syndrome (66%). Half of the patients in each of the 3 groups received pre- and postprocedure heparin. During follow-up, there were no thromboembolic events, rare major bleeding events (1% for each group), and 4 deaths. Due to the very low event rates for each of these outcomes, Cox proportional hazard modeling could not be performed.

Conclusions

Periprocedural event rates were low irrespective of thrombophilia status. Inherited or acquired thrombophilia was not a predictor of thromboembolism, major bleeding, or mortality after temporary interruption of chronic anticoagulation for an invasive procedure.

TAVR reverses the acquired Von Willebrand syndrome in severe aortic stenosis

At least as evidenced in the test tube:

Abstract

Background

In this study, we sought to analyze the incidence and relevance of von Willebrand factor (VWF) abnormalities in patients undergoing transcatheter aortic valve implantation (TAVI), especially on perioperative bleeding. Furthermore, we hypothesized that, similar to aortic valve surgery, TAVI results in a restoration of VWF abnormalities.

Methods and results

We performed a prospective analysis of periinterventional VWF parameters in 74 patients (80 ± 7 years, female in 37.5%) undergoing transfemoral TAVI for severe symptomatic aortic valve stenosis. At baseline, VWF:Ag was 210 ± 90 IU/dl with a mean VWF activity of 166 ± 106 IU/dl; activity-to-antigen ratio was 0.85 ± 0.45. Heyde's syndrome (severe aortic stenosis plus GI bleeding from angiodyplasia) was observed in 2/74 (2.7%). Whereas preprocedural loss of high-molecular-weight (HMW) VWF multimers was found in thirty-six patients (48.6%), none of the patients fulfilled criteria for possible acquired VW syndrome. After TAVI, an increase of both VWF:Ag and activity compared to baseline was observed (p less than 0.01). In patients with HMW multimer loss, post-interventional recovery of multimers occurred in all cases. In the two patients with Heyde's syndrome, a trend towards reduced VWF:Ag was seen, with loss of HMW multimers in one patient. Of interest, all patients suffering from periprocedural major bleeding (5/74; 6.8%) exhibited activity-to-antigen ratios less than 0.7, indicating subclinical VWF dysfunction.

Conclusion

Whereas clinically relevant VWF dysfunction is rare, loss of HMW VWF multimers is common in TAVI patients. Similar to surgery, TAVI leads to a restoration of this loss. Furthermore, VWF parameters may be useful parameter to evaluate risk of periprocedural bleeding.

We could be treating more PE patients at home

Via the green journal.

Careful clinical assessment to determine which patients are at low risk is important but maybe that’s too much trouble for some.

Enoxaparin dose for VTE prophylaxis in obese patients

Consider 60 mg as opposed to 40 mg in patients with BMI of 30 and above.

The higher dose in obese patients was associated with better anti-Xa levels and no increase in bleeding. This was a small study.