January 2022: New In Coagulation

by Donna Castellone, MS, MT (ASCP) SH • January 21, 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.

Class I Recall of Percutaneous Thrombolytic Device

The FDA has issued a class 1 recall of Arrow-Trerotola over-the-wire 7FR percutaneous thrombolytic device (PTD) kits because of the risk of the orange inner lumen of the catheter's tip component separating from the basket. If this happens, it may fracture and detach and block the blood vessel resulting in embolization. These devices were distributed between November 2019 and July 2021.


Still Shunning DOACs? Medicare Data Show Who's Not on Board

DOACs are recommended in professional guidelines however many clinicians have continued to favor warfarin. DOAC prescribing volume have risen from 14% in 2013 to 57% in 2018 but warfarin still is their preferred anticoagulant of choice. Even though the data is only until 2018, it appears it still reflects current practices. Many clinical trials have supported the safety of DOACs.

When reviewing the database, with the exception of 1.6% of cardiologists they all prescribed DOACs, but 20% and 12.6% if internal medicine physicians prescribed only warfarin for anticoagulation. Those physicians who began the study in 2013 using warfarin only continuing using it more in 2018. Those who used DOACs in 2013 was independently associated with both the uptake and proportionate use of DOAC. Recent medical school graduates were more likely to prescribe DOACs.

Despite the current costs DOACs are cost-effect when compared to warfarin by reducing thrombotic events, bleeding risks and drug monitoring.


Head Trauma Patients on Blood Thinners Need Surveillance

A retrospective study showed that in 2% of patients on anticoagulants with head trauma may have delayed bleeding into the brain that may not be detected on imaging. Several hospitals have repeat CT scans as part of their routine process. When data was reviewed over a 3 year period for patients with an initial negative CT for ICH with a repeat imaging performed. A total of 1046 patients were included with an average age of 77.5, 547 were women and 499 were men.

There were 576 patients on DOACs, 470 on warfarin or antiplatelet and 345 also additionally taking aspirin. There were 20 patients with a delayed incidence of hemorrhage, three died, 15 were taking an older type of blood thinner, nine were also taking aspirin. Among the five on DOAC, four were also taking aspirin.

Based on these findings, follow up CT was recommended for patients who had no initial intracranial hemorrhage from head trauma who are taking an older blood thinner along with aspirin.


Clinical Challenges: Back to Square One in Anticoagulation for PCI?

Heparin has been the standard of care, and bivalirudin was popular due to a lower risk of bleeding as well as ease of use. This IV direct thrombin inhibitor could help patients achieve continuous therapeutic anticoagulation. It doesn't require using an ACT for heparin during PCI. The EUROMAX trial showed that bivalirudin resulted in reduced bleeds and deaths but with the cost of a greater risk of stent thrombosis. Other trials showed bivalirudin was inferior with ischemic events and bleeding. Additionally it was an expensive drug, but become generic in 2015.

A meta-analysis linked bivalirudin to reductions in cardiac death and bleeding in PCI patients for ST-segment elevation MI (STEMI). Non-STEMI patients saw a reduction only in serious bleeding, rates of mortality, MI and stent thrombosis were unchanged on bivalirudin versus heparin in this analysis.

An unanswered question is whether bivalirudin can hold an advantage over heparin in modern PCI with radial access and no glycoprotein IIb/IIIa inhibitors. Also, if a longer high dose infusion of bivalirudin after PCI might mitigate the risk of stent thrombosis. In the MATRIX trial from 2015, however, there seemed to be no benefit of a post-PCI bivalirudin infusion.

Blood thinners are used in patients undergoing PCI so that equipment doesn’t cause clotting and platelets also need to be deactivated so they do not stick to stents.


Pulmonary Embolism Rule-Out Strategy Safely Reduces Chest Imaging

An age adjusted D-dimer (YEARS) which uses a higher threshold for selected patients who couldn't be ruled out by PE using PERC criteria appeared to be safe in a randomized clinical trial in ED patients other than having a clinical high probability. This intervention cut down on chest imagining when the two criteria sets were combined. IT can also play a role in decreasing the use of CTPA in patients with clinical suspected PE.

The trial included a cluster randomized crossover design in two ED in Spain and 16 in France. Patients were enrolled upon clinical suspicion of a PE due to acute onset of chest pain, worsening acute dyspnea, syncope or a combination. PERC criteria were:

  • Age ≥50 years
  • Pulse rate ≥100/min
  • Arterial oxygen saturation ≤94%
  • Unilateral leg swelling
  • Hemoptysis
  • Recent trauma or surgery
  • Prior PE or deep venous thrombosis
  • Exogenous estrogen use

An assessment of the YEARS algorithm and its three clinical criteria which include clinical signs of DVT, hemoptysis and PE together with D-dimer. If there were no YEARS criteria they were ruled out if the D-dimer was below 1000 ng/mL, if there was YEARS criteria there were rules out if the D-dimer was below the threshold for their age. (age x 10 ng/mL for age 50+).

There were 80% of the participants in the intervention group that had zero YEARS criteria. No missed PE occurred in these patients. As a result the study was underpowered for patients with non-zero years score and a D-dimer level above the age adjusted threshold but below 1000ng/mL.


Hemostatic Powder on Par for Stopping Acute Upper GI Bleeds

The study randomized 224 patients with nonvariceal acute bleeding to either TC-325 (n=111) or standard hemostatic treatment (n=113). TC-325 (Hemospray) a hemostatic powder which was given to treat endoscopic control of acute bleeds from nonvariceal upper GI bleeds. TC-325 contains aluminum phyllosilicate clay and has been shown to stop cases of active bleeding by forming an adhesive barrier at the site. Of the patients who received TC-325 90.1% had their bleeding controlled within 30 days versus 80% of those in the standard treatment group. There were fewer treatment failures during an initial attempt at endoscopic control.

Fewer treatment failures during an initial attempt at endoscopic control were seen in the TC-325 group compared to the standard treatment arm. No difference in recurrent bleeding within 30 days was observed between study arms nor were there significant differences in treatment for further bleeding between the TC-325 and standard treatment groups.


Fitusiran Prophylaxis Cuts Bleeding in Hemophilia A/B

Fitusiran is an investigation prophylatctic drug based on the small interfering RNA molecule which targets AT to restore thrombin generation to rebalance hemostasis.

The ATLAS-INH looked at fitusiran in hemophilia A (n=29) and B (n=9) patient 12 years and older with inhibitors, randomized on a 2:1 basis to receive 80 mg sub q fitusiran or continue with bypassing agents (BPAs). The observed median ABR for all, spontaneous, and joint bleeding events was 16.8, 13.4, and 11.7, respectively, for BPA patients, and 0.0 for each of those bleeding events in the fitusiran arm.

ATLAS-A/B looked at fitusiran in patients without inhibitors. There were patients on fitusiran (n=79) and 40 patients in the BPA arm. 93 had hemophilia A (62 in the fitusiran arm and 31 in the BPA arm) and 27 had hemophilia B (18 in the fitusiran arm and nine in the BPA arm), The number of bleeding events were reduced by 90% when compared with patients treated with on demand BPAs.

Adverse events due to treatment in the ATLAS-INH included 11 events of elevated ALT in the fitusiran arm and discontinued the drug. Thromboembolic events occurred in two patients. In ATLAS AB, adverse events included cholelithiasis in two patients.


Clinical Challenges: Gene Therapy for Hemophilia on the Horizon

There have been huge strides in gene therapy for hemophilia B, with hemophilia A not far behind. There have been almost two decades of clinical trials, commercial availability may become a reality in the next 12 to 18 months. Gene therapy uses a protein shell from an adeno-associated virus (AAV) to deliver the transgene for factor VIII or IX to hepatocytes. From there it is delivered into the nucleus and uses the natural machinery there to synthesize these factors.

Many hemophilia patients are ineligible for gene therapies in development because they have too many antibodies with cross reactivity to the one used byt the gene therapy platforms. A healthy liver is also required. The patient must undergo a period of immunosuppression to reduce the risk of cytotoxic T-cell attack against treated hepatocytes. This can result in destroying the gene therapy treated cells.

A follow up of a phase I/II trial of hemophilia A 16/18 treated patients had a 91% reduction in annualized bleeding events and maintained their levels of FVIII. The remaining two had immune responses that couldn't be overcome with steroids. In the phase III HOPE B trial 52/54 patients with moderate to severe hemophilia B experience a functional cure etranacogene dezaparvovec vector, with a 91% reduction in bleeding rate over 6 months. The data at 18 months showed superiority in bleeding response compared with factor IX treatment and higher factor IX activity than at 6 months.

Data looked pretty stable, two of the hemophilia A trials showed an unexpected decreased by about 40% in factor VIII expression from year 1 to 2, with one showing decline continuing out to 5 years. The majority of patients haven't needed to return to factor VIII replacement.

Gene therapy isn't for everyone, and patients only get one shot at therapy, the second generation might be better and more durable. Results look great, but it isn't perfect, it is important to have a discussion with patients and establish risk tolerance.


Psoriasis Tied to Small Increase in Risk of Venous Thromboembolism, Peripheral Vascular Disease

The risks associated with psoriasis include venous thromboembolism (VTE) and peripheral vascular disease (PVD) based on findings of a systematic review with meta-analysis. These findings support the current psoriasis guidelines on the awareness of these cardiovascular comorbidities. Risk factors such as obesity, physical inactivity, smoking, and varicose veins should be carefully followed or treated in patients with psoriasis and medications like hormone related therapies should be given with caution.

Of the 13 cohort studies, including a total of more than 12 million participants, eight were conducted in Europe, four in North America, and one in Asia. An analysis of the nine studies (12,052,781 participants) that explored a possible association between psoriasis and VTE revealed that psoriasis patients were at a 26% higher risk of VTE than patients without the skin condition. Based on the four studies (383,201 participants) that looked at PVD, psoriasis patients were at a 27% higher risk of the vascular disorder than patients who did not have the skin condition.

VTE is rare and was found to be at less than 1/10 of a percent (0.096%) is similar to that in the general population of 0.07%. Controlling additional risk factors as well as psoriasis itself may minimize risks.


Apixaban Outmatches Rivaroxaban for VTE in Study

A retrospective analysis of 40000 patients with recurrent VTE was evaluated with safety being evaluated based on intracranial and GI bleeding. The results show that apixaban appears to be safer and more effective than rivaroxaban for reducing risk of VTE and bleeding.

Apixaban was associated with a 23% lower rate of recurrent VTE with a 15% lower rate of DVT and a 41% lower rate of PE and 40% fewer bleeding rates including GI and 46% lower ICH.

These findings were maintained in various sensitivity and subgroup analysis. Some patients had transient risk factors and were compared with VTE patients with chronic risk factors. This study looked at severe outcomes that resulted in inpatient hospitalization, so the generalization to outpatient and less severe outcomes may or may not be inferred. A randomized trail is needed to alter clinical decision making.


No Serious CV Risks for Elderly After Pfizer COVID-19 Vaccine

The Pfizer-BioNTech mRNA vaccine was the first SARS-CoV-2 vaccine authorized in France and has been widely used in older people. The phase 3 trials of the vaccine showed no increase in cardiovascular events, but older people were underrepresented in the trials. As of April 30, 2021, nearly 3.9 million French adults aged 75 or older had received at least one dose of the Pfizer COVID-19 vaccine and 3.2 million had received two doses.

During the 4.5-month study period, 11,113 elderly were hospitalized for acute MI, 17,014 for ischemic stroke, 4804 for hemorrhagic stroke, and 7221 for PE. Of these, 58.6%, 54.0%, 42.7%, and 55.3%, respectively, had received at least one dose of vaccine. In the 14 days following receipt of either dose, no significant increased risk was found for any outcome including MI, ischemic stroke, PE, cardiovascular events.


Clots Kept at Bay for COVID Patients on OAC After Discharge

An open label trial MICHELLE was conducted at 14 centers in Brazil on COVID patients in which 997patients were screened and 320 randomized to receive either rivaroxaban(10mg/day) or no anticoagulation for 35 days. Average age 57.1 year, 40% women, excluded those at excess risk of bleeding. A VTE risk score of 4 or greater was calculated for 38% of participants, with the remainder at 2-3. Those at high VTE score but low bleeding risk did better taking prophylactic dose rivaroxaban for 35 days versus those taking no anticoagulation.

The composite efficacy outcome - comprising symptomatic or fatal VTE, asymptomatic VTE on imaging, symptomatic arterial thromboembolism, and cardiovascular death at day 35 - reached 3.14% with rivaroxaban and 9.43% with no anticoagulation with the difference driven by excess pulmonary embolisms in the control group. These results are in contrast with the ACTION trial which found no benefit to the use of rivaroxaban.

Pending trials on extended thromboprophylaxis after COVID-19 recovery include a study at one Mexican center; the XACT trial being conducted in Austin, Texas; the larger ACTIV-4c trial across the U.S.; and HEAL-COVID from the U.K.