March 2022: New In Coagulation

by Donna Castellone, MS, MT (ASCP) SH • March 14, 2022



Our Monthly complilation of the latest studies, guidelines and discussions in coagulation.
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The interpretations below are provided by Donna Castellone, MS, MT (ASCP) SH for Aniara Diagnostica.


Dramatic Increase in Response With Combination for Relapsed/Resistant ITP

Immune thrombocytopenia (ITP) is a heterogenous disorder making identification of differences in treatment strategies a trial and error process. One third of patients do not respond to corticosteroids. There is also no gold standard treatment of rituximab with sustained responses in only 30-40% of patients. Patients with relapsed or corticosteroid-resistant ITP had a 33% higher response rate and a 50% increase in sustained responses with all -trans retinoic acid (ATRA) plus low-dose rituximab. Response was defined by platelet count and the absence of bleeding. A sustained response of greater than 18 months increased to 61% with a combination of the agents.

Data included 168 randomized patients. The primary endpoint was a platelet count of ≥30×109/L on two separate occasions at least 7 days apart, at least a doubling of baseline platelet count without additional ITP therapy, and absence of bleeding within 1 year (any time during the year). The secondary endpoint of sustained response was defined as maintenance of a platelet count >30×109/L, absence of bleeding, and no need for additional ITP therapy for 6 consecutive months after achieving an objective response.

 

Ischemic Stroke Rates Higher in Young Women Than Young Men

A systematic review of 19 studies with a total of 69,793 young adults (33,775 women and 36,018 men) has shown that young women (18-35 years) appear to be at higher risk of ischemic stroke when compared to young men. Results showed there were 44% more women with strokes then men, however the gap narrowed in the 35-45 year age group which showed conflicting evidence as to which group had more strokes. This study shows that stroke occurs across the entire age spectrum even if they do not present with traditional risk factors. It is important if a young person presents with focal neurological symptoms to provide medical attention regardless of their profile. Knowing that more young women may present with strokes may be important in implementing strategies to prevent and treat strokes in this age group.

Results in the study showed that there was a significantly higher incidence of ischemic stroke in women younger than age 35 if an incidence rate ratio of 1.44 which became non significant in the 35-45 age group. In the age group of over 45 years, men have a higher risk of stroke than women most likely related to a higher level of atherosclerotic risk factors. MI is more common in younger men than women, so this observation that younger women have a higher risk of stroke suggest that something different may be going on in the mechanism for stroke. These risk factors may include oral contraceptive use, pregnancy, postpartum, preeclampsia and migraine with aura.

 

Prophylactic Meds May Prevent Cesarean Bleeding

An ergot alkaloid agent, methylegonovine, administered before cesarean delivery may decrease the risk of postpartum hemorrhage and decrease the need for blood transfusion. The drug appears to improve uterine tone which is the leading cause of postpartum hemorrhage.

The study was conducted at a single center on 160 randomized controlled women undergoing an intrapartum cesarean birth. Women received either oxytocin plus saline or oxytocin plus methylergonovine. Those who received methylergonovine required significantly less additional uterotonic agents and experienced improved uterine tone with a lower incidence of postpartum hemorrhage.

Additional research would be required to look at benefits across diverse populations since methylergonovine is contraindicated in hypertension, preeclampsia and cardiovascular disorders. Additional variables to be investigated should include prior cesarean deliveries, body mass index, presence of uterine myomas, presence of abnormal placentation (placenta accreta, increta, percreta), and presence of multiple gestation.

 

COVID-19-associated strokes link to higher disability and death risk

Up to one third of COVID-19 patients may develop neurological complications from infection and may present with acute ischemic stroke (AIS). These patients are at a higher risk for severe disability and death when compared with stroke patients pre-COVID. When records from 29 stroke centers of 230 patients were reviewed up to 51% of all patients had poor outcomes with 39.1% dying in the hospital or within 30 days of discharge. In comparison with data from clinical trials pre-pandemic death rates were 27.6% among patients with ischemic strokes.

There is still an unknown interaction between COVID respiratory disease and stroke which is demonstrated in the poor outcome rates. Mortality rates may also have been higher in areas in which patients were from less affluent areas were at greater risk for serious complications such as stroke because of their inability to carry out protective measures such as social distancing of working at home.

 

DAPT De-Escalation Carves Out a Role After Heart Attack PCI

There were 29 randomized trials that compared short dual antiplatelet therapy (DAPT) and DAPT de-escalation against standard 12 month DAPT but not one against the other. De-escalation was indirectly associated with a reduction in net adverse cardiovascular events and increase in major bleeding and no difference in all cause death.

Acute coronary syndrome (ACS) patients may better optimize their ischemic and bleeding risks after angioplasty depending on their individual needs comparing two DAPT modulation strategies. Outcomes favored de-escalation over short DAPT, however statistical significance failed due to the low power of the analysis.

Patients at a greater thrombotic risk may do better with downgrading prasugrel or ticagrelor component of DAPT to either clopidogrel (Plavix) or a lower dose. A short DAPT appears to be better for patients that are at a higher bleeding risk.

Both strategies can be considered viable options to standard DAPT. Incorporating ischemic/bleeding risks into stratification tools into current practice guidelines to elevate both short and de-escalation in patients who present with ACS may be beneficial.

 

DOACs Working Out for CVT Strokes So Far

The observational ACTION-CVT study has shown DOACs having promise in the treatment of cerebral venous thrombosis (CVT). The study included 27 stroke centers across the US, Italy, Switzerland and New Zealand between 2010-2015 with 845 patients meeting inclusion criteria. There was a median age of 44.8 with 64.7% women.

Results were similar between DOAC and warfarin. These outcomes included recurrent VTE, death and partial or complete recanalization. Safety including rates of major hemorrhage favored DOAC treatments after almost one year of follow up. DOACs may be an alternative in patients with CVT, results will still need to be confirmed in large prospective or randomized studies including DOAC-CVT and SECRET. Results from these trials will provide higher levels of evidence to support future management guidelines for CVT.

 

Lytic Post-Thrombectomy Improved Stroke Outcomes

The CHOICE trial randomized 121 patients with large vessel occlusion with complete or near-complete recanalization of a proximal vessel occlusion and successful brain reperfusion on cerebral angiogram after mechanical thrombectomy. Patients were treated within 24 hours of symptoms. The intra-arterial alteplase group got a 15- or 30-minute infusion at 0.225 mg/kg of drug. Interventionalists were allowed to administer alteplase prior to thrombectomy when indicated based on standard care and to stop that 60-minute infusion early at their discretion. Thus, 57% of patients got at least half a dose of pre-thrombectomy lytic and 10% got a lesser dose.

Safety outcomes were at least as good with intra-arterial alteplase use in the trial. No symptomatic intracerebral hemorrhage occurred within 24 hours in the intervention group compared with two cases in the placebo group. Mortality at 90-days also favored intra-arterial alteplase (8% vs 15%. Both were non-significant.

Only 60% of the study enrollment was reached which may have impacted the external validity of the study.

 

Can Tenecteplase Help Late-Presenting Strokes?

CHABLIS-T study looked at 86 adults who presented with anterior large vessel occlusion or severe stenosis ischemic stroke with significant penumbral mismatch on prefusion CT at 4.5-24 hours from the time last seen. The trial used Chinese recombinant human tenecteplase (TNK) tissue type plasminogen activator approved for cardiac but not stroke indications. Patients were randomized into two groups a typical dose of 0.25 mg/kg and a higher dose of 0.32 mg/kg.

Outcomes included symptomatic ICH in 11.6% of patients at the 0.25 mg/kg and 9.3% in those with the 0.32 mg/kg levels. Any intracerebral hemorrhage occurred in 48.8 and 30.2% respectively. Parenchymal hematoma type 2 at 24 to 48 hours occurred 5.8% versus 11.8% at the higher dose, while death or severe disability occurred in 21.2% and 20.6% respectively at 90 days.

Limitations of the study include lack of a control group and a small sample size and only testing Chinese patients which may present with different stroke characteristics.

 

Stroke Clot Composition Linked to Functional Outcomes, Death

The composition of ischemic stroke clots has been linked to mortality and disability prognosis. Clots that are rich in red blood cells (RBCs) had better outcomes when compared to those who had clots containing platelets. A 10% increase in RBC content of a clot increased the odds ratio of functional independence at 90 days to 18% with a decreased odds of death feel to 16%. When the 10% higher platelet count content of the clot the odds of a good neurologic outcome fell by a relative 11% and mortality rose by 16%.

The study used clot samples retrieved as part of the observation EXCELLENT registry that looked at 543 clots from EmboTrap thrombectomy. A RBC- rich clot was defined as those with more than 45% of RBCs, those with 30.7% platelet composition were deemed platelet rich, those with a platelet-to-fibrin ratio at of below the median 1.52 considered low in fibrin. Fibrin content wasn’t a significant factor in mortatlity and functional outcomes.

Understanding the composition of the clot may enable to tailor treatment accordingly. It may be possible to give intra-arterial antiplatelet for platelet rich clots compared with adjunctive tissue plasminogen activator. It may also be possible to determine not only the source of the clot but if somehow we could correlate the red blood cell, fibrin, and platelet content consistently to the origin of the clot, the type of prophylactic medication used can be changed, whether we use aspirin, warfarin, or one of the newer anticoagulants.

 

Tirofiban: A Questionable Addition to Stroke Thrombectomy

The RESCUE BT trial looked at tirofiban versus placebo to determine if clinical outcomes were improved for stroke patients undergoing endovascular therapy (EVT). This was a phase III randomized double blind trial conducted at 55 hospitals in China. Participants presented with acute ischemic stroke within 24 hours of time last known well all undergoing EVT, median age 67, 41% women. There were 950 individuals randomized to tirofiban (IV bolus 10 μg/kg before EVT followed by continuous infusion for 24 hours) or placebo. Patients got antiplatelets at hour 20 after starting their assigned study drug.

Results showed that tirofiban failed to improve clinical outcomes. This group also had excess symptomatic intracerebral hemorrhage, any cranial hemorrhage and 90 day mortality. Subgroup analysis did show a benefit to stroke patients with large artery atherosclerosis.

 


JOURNAL CLUB


 

Risk of Venous Thromboembolism Associated With Tofacitinib in Patients With Rheumatoid Arthritis

Rishi J. Desai; Ajinkya Pawar; Farzin Khosrow-Khavar; Michael E. Weinblatt; Seoyoung C. Kim Rheumatology. 2022;61(1):121-130.

Abstract

Objective: To evaluate the risk of venous thromboembolism (VTE) with tofacitinib compared with TNFis in patients with RA.

Methods: RA patients initiating tofacitinib or a TNFi without use of any biologic or tofacitinib any time prior were identified from IBM 'MarketScan' (2012–18), Medicare (parts A, B and D, 2012–17) or 'Optum' Clinformatics (2012–19) and followed until treatment discontinuation, treatment switch, insurance disenrollment or administrative censoring. The primary outcome, VTE, was identified using inpatient claims for pulmonary embolism or deep vein thrombosis. A Cox proportional hazards model provided hazard ratio (HR) and 95% CIs after accounting for confounding through propensity score fine-stratification weighting. HRs were pooled across databases with inverse variance meta-analytic method.

Results: A total of 42 201, 25 078 and 20 374 RA patients were identified from MarketScan, Medicare and Optum, respectively, of whom 7.1, 7.1 and 9.7% were tofacitinib initiators. The crude incidence rates per 100 person-years (95% CI) were 0.42 (0.20–0.77) and 0.35 (0.29–0.42) in MarketScan, 1.18 (0.68–1.92) and 0.83 (0.71–0.97) in Medicare, and 0.19 (0.04–0.57) and 0.34 (0.26–0.44) in Optum for tofacitinib and TNFis, respectively. Propensity score-weighted HRs showed no significant differences in the risk of VTE between tofacitinib and TNFis in any database with a pooled HR (95% CI) of 1.13 (0.77–1.65).

Conclusion: Overall, VTE occurred infrequently (<1 per 100) in a total of 87 653 RA patients initiating tofacitinib or a TNFi. We observed no evidence for an increased risk of VTE for tofacitinib vs TNFis in RA patients.

 

A Review of Venous Thromboembolism Risk Assessment and Prophylaxis in Plastic Surgery

Nikhil A. Agrawal, M.D.; Kirsty Hillier, M.D.; Riten Kumar, M.D., M.Sc.; Shayan A. Izaddoost, M.D., Ph.D.; Rod J. Rohrich, M.D.

Plast Reconstr Surg. 2022;149(1):121e-129e.

Abstract

Background: Venous thromboembolism is a significant cause of postoperative death and morbidity. While prophylactic and treatment regimens exist, they usually come with some risk of clinically relevant bleeding and, thus, must be considered carefully for each individual patient.

Methods: This special topic article represents a review of current evidence regarding venous thromboembolism risk, biology, and prevention in plastic surgery patients. The specific types and duration of available prophylaxis are also reviewed. The balance of venous thromboembolism risk must be weighed against the risk of hemorrhage.

Results: Though alternatives exist, the most validated risk assessment tool is the 2005 modification of the Caprini Risk Assessment Model. Controversies remain regarding recommendations for outpatient and low risk cosmetic patients. The authors additionally make recommendations for high-risk patients regarding the use of tranexamic acid, estrogen therapy, anesthesia, and prophylaxis regimens.

Conclusion: Our profession has made great strides in understanding the science behind venous thromboembolism, risk stratification for patients, and prophylactic regimens; yet, continued studies and definitive data are needed.