Venous thromboembolism prophylaxis and treatment in Covid-19

The pulmonary embolism was found to be Pulmonary thrombosis.   

In the summary of the morphological studies, the microscopic thrombi that could be interpreted as real pulmonary embolism were found only in ten percent of patients. Eighty percent of patients had evidence of thrombosis of the small branches in the pulmonary artery and the capillaries, called pulmonary intravascular coagulopathy. Today, it is discussed as the primary mechanism of the death and deterioration in these patients with severe coronavirus infection.   

One of the main reasons for anticoagulation is to improve microcirculation to prevent acute respiratory distress syndrome. To prevent disseminated intravascular coagulation syndrome, which is the end of this septic inflammatory condition.  

On the other hand, we need to prevent thrombosis in the limbs of the adrenal thrombus in the limb to avoid pulmonary embolism that can deteriorate the respiratory status as well. We should take an account that this substantial number of patients suffering from pulmonary artery thrombosis says they need to be followed up. They need to be evaluated after three to six months after these events because we do not know the long-term consequences of these thromboses as this patient develops chronic thromboembolic pulmonary hypertension or not.   

The current guidelines from different professional societies recommend managing the management of this coagulopathy. It identified 11 guidelines, which were revised according to other points & different issues.   

There were different questions about the management of patients with coronavirus, the first question was about the risk stratification for venous thromboembolism, and six of eleven guidelines supported it, and only one guideline did not support it was the anticoagulation forum, and they stated that all patients who were admitted to the hospital should receive low molecular heparins in prophylactic doses independently to their risks, so it was their position and the risk assessment model that what mentioned in these guidelines are Padua score, Caprini score and Improve score. 

The Padua score is well known. According to this score, all hospitalized patients will fulfill the criteria for pharmacological prophylaxis because they will have an acute infection and reduced mobility.   

Professor Caprini represented the Caprini score and modified version of the Caprini score. However, in this situation, let us consider just the classical version of 2005. We can find severe lung disease, the coronavirus infection, with a score of 1. The patient is currently on bed rest is a score of 1, so two scores are always as a patient will receive if they are hospitalized with the coronavirus. Of course, there are some acquired abnormalities that we can find in our patients with the coronavirus and can be interpreted as acquired thrombophilia, so according to this risk assessment model also, most of the patients will fulfill the criteria for pharmacological prophylaxis.   

The improved score in this situation, we cannot find any evidence for pharmacological prophylaxis for admitting to the hospital patients because there are no references for the acute infection to the acute respiratory distress syndrome cases, they are only admitted to the intensive care unit and increased are valued for one point. However, this risk assessment model is not particularly good for assessing patients admitted for treatment of coronavirus.   

One publication was tested to analyze the risk of thromboembolism and the bleeding risk according to the Padua score and the improved score. The results show that many patients fulfilled the criteria; the higher risk for VTE was only 17%, and the increased risk for bleeding was only 7%. However, all DVT events and all the bleeding currents said they were registered only in patients at higher risk of VTE and a higher risk of bleeding. This risk assessment model may not be compassionate, but at least this paper shows that it should work in such kinds of patients.     

The second question is about the prophylactic doses of anticoagulation, especially low molecular heparins; in this issue, all the guidelines suggest that low molecular heparin should be administered to all patients; it could be given to all inpatients, or it could be given according to the VTE risk at least the prophylactic doses of low molecular heparin should be administrated to all patients without increased risk.   

The international society of thrombosis and hemostasis was the first to publish these recommendations. They suggested that low molecular heparins be administered in all patients who do not have contraindications like acute bleeding and low platelets less than 25 000; that is the only contraindication.   

A paper from China reviewed bout 500 patients. About 100 received prophylactic heparins, and there was no difference in the total mortality at the 2018 observation. However, there was a significant decrease in mortality in patients with sepsis-induced coagulopathy and patients with a critically elevated desire. That is why the international society of thrombosis and hemostasis supported the benefits of prophylactic low molecular heparins in patients admitted to the hospital called infection.   

The third question concerns the therapeutic doses of low molecular heparin; it is the most critical question in many countries. Even in Russia, increasing the doses up to the therapeutic ones is a practice. There are some strange approaches, especially in intensive care, you need to increase the doses over the therapeutic ones so according to the monitoring of coagulation by thromboelastography or by the fibrinogen level or something like this, so the patients are receiving a twice therapeutic dose, for example, they increased twice and what about this point of view the four guidelines support therapeutic doses in patients without a confirmed without thromboembolism.   

What is the basis for the increase in doses of low molecular heparin?  

These guidelines are based on this meta-analysis of patients with acute respiratory distress syndrome. It showed improved survival in patients with acute non-specific acute respiratory distress syndrome when they received the low molecular heparins, and this was more common and significant for the increased doses of low molecular heparin compared to the lower doses. There is a remarkable increase in survival, about 17 and 60 %.   

There is another paper now from the journal of thrombosis and hemostasis, which is usually referenced when the authors try to support their decision to increase the doses of the flow of therapeutic anticoagulation, so in this cohort, it was a small cohort of 16 patients who had a very high hypercoagulation according to the viscoelasticity testing of the blood, they had a good result they were able to reduce this coagulopathy however there was no any impact on the survival of this patient as half of the patients died. The main argument in the guidelines does not support the therapeutic doses.   

Another recent study from the Mount Sinai hospital showed the benefits of therapeutic anticoagulation. 3000 patients and about 400 of them received therapeutic anticoagulation, and there was no difference in mortality rates among the total population, but among the patients on the mechanical ventilation, there was a great benefit and reduction of the risk by 53%   

Therapeutic anticoagulation and mortality, in these studies, there is an evident immortal time bias, so the anticoagulation was initiated with a median of two days and inter cartel range from zero to five days so, which means that about 75 % of all patients they received anticoagulation during the five days so they should be alive during these five days and in the control group the patients. The latter did not receive anticoagulation; they died during this period.   

That means that there was no effect of the anticoagulation. That is why today, there is no clear decision that we increase the dose of anticoagulation in patients with a severe and critical form of coronavirus infection.   

Comments on the international society of thrombosis and hemostasis intern guidelines suggest that such coagulopathy that was seen in patients with coronavirus it is some disseminated intravascular coagulation with a thrombotic phenotype, and this kind of disturbance of coagulation should be treated with increased doses of heparins also the high levels of fibrinogen could be observed in such type of patients and high level of fibrinogen can lead to the resistance to heparin center also resistance to the prophylactic doses of the heparin center and can increase the risk of thrombosis.   

There is a paper from Italy who were fighting with a coronavirus for a long time with a very high prevalence and a very high mortality rate and however the doctors suggest again the increasing doses of low molecular heparin because they think that it is a thrombotic microangiopathy and the mechanisms of this disease are not the same as the deep pain thrombosis and the pulmonary embolisms that's why the standard prophylactic doses of the average heparin may be enough to prevent vein thrombosis and of course in combination with the elastic compression stockings but to treat the thrombotic microangiopathy in the pulmonary vessels may be not sufficient, moreover we know there is a very high prevalence of hemorrhagic complication like hemorrhages inside the alveolus and the hemorrhages in the intra alveolar septa so in this situation increasing doses of lower liquid heparins can lead to the deterioration of these hemorrhagic complications in the lungs and it may not increase the survival of such kind of patients that's why the author suggests that not increasing doses of heparins may be a need for these patients but we need to look to another drugs as well the equation to the antiplatelet drugs, to the drugs that affect the vibrant factor or the complement and some other pathological mechanisms that underlie the thrombotic microangiopathy but not just increase the doses of the heparins.   

Inpatients without VTE: mechanical prophylaxis, there is a high inconsistency in it, so there is   

no opinion on to support or not to support the increased doses of liquid heparins and what about the mechanical prophylaxis in this point of view, five deadlines endorse mechanical prophylaxis, and six guidelines do not support mechanical prophylaxis at all, and five guidelines support mechanical prophylaxis if anticoagulation is contraindicated. Two support additional mechanical prophylaxis like intermittent compression in critically ill patients and immobilized patients.   

In a meta-analysis study, elastic compression can decrease the risk of venous thromboembolism, deep vein thrombosis, and pulmonary embolism in hospitalized and surgical patients. Also, massive data support the use of mechanical compression and elastic compressions talking in such patients. Of course, we know the intermediate pneumatic compression, which can reduce the risk of DVT and PE. In this situation, it is more effective than elastic compression alone if the patient has bleeding and has a low platelet level.   

The IPC device may be the only choice to prevent DVT and, of course, the pharmacomechanical approach; combining mechanical prophylaxis with pharmacological prophylaxis gives us additional benefits and reduces DVT and PE.   

Another study combined all these methods with an IPC device, anti-embolic stockings, and low molecular heparin in surgical patients to prevent postoperative DVT and PE. This mechanical approach demonstrated outstanding results and decreased the risk of postoperative complications.   

Inpatients without VTE: extended prophylaxis after discharge, five guidelines support it, one supports all inpatients, and 4 support individual VTE and bleeding risks. Two guidelines mentioned that they do not recommend it routinely. However, it may be suggested in high VTE and low bleeding risk.   

Inpatients: liberal VTE diagnosis, two support it in increased D-dimer patients, four guidelines do not recommend routine D-dimer imaging by d-dimer, and one guideline says no clear position.   

Inpatients: empiric therapeutic anticoagulation if VTE suspected, four guidelines support it, three with delayed imaging and one without delayed imaging, and no guideline mentioned they did not support it.   

Guidelines from the Netherlands suggest the liberal diagnostic of venous thromboembolism according to the d dimer level. You should follow the dimer if it is higher than one thousand or two thousand. If it is rising upward, you may perform some imaging tests or prescribe to the patient the therapeutic anticoagulation.   

Inpatients: switching of oral to parenteral anticoagulants. Nine guidelines support it as three support All OACs to LMWHs, four support VKA to DOACs in eligible patients, and three support OACs to LMWHs in critically ill patients.   

General considerations in most cases, vitamin k antagonists should be switched to direct oral anticoagulants. However, some contraindications include mechanical heart valves, valvular atrial fibrillation, antiphospholipid syndrome with severe impairment, and breastfeeding.   

Outpatients: prophylactic anticoagulation; two guidelines support it in high individual risk for VTE and minimal risk for bleeding; only one does not support it.    

In conclusion 

• The prevalence of VTE in patients with severe and critical forms of COVID-19 is unexpectedly high  
• The prophylactic anticoagulation with LMWH/UFH is recommended for all inpatients  
• The increased (intermediate or therapeutic) doses of LMWH/UFH in patients without VTE are not generally recommended outside the RCT  
• The dose increase may be considered in obesity, elevated D-dimer (> 2-3N), the individual highest risk for VTE (Caprini score >8)  
• The value of mechanical prophylaxis is underestimated without objective reasons  
• Pharmaco-mechanical prophylaxis may be suggested to all ICU patients and individuals at the highest VTE risk (Caprini score >11)  
• Extensive prophylaxis after discharge may be suggested for patients with increased VTE and low bleeding risk. 
• Increased D-dimer (>1,5-2,0 mg/mL) may be an indication for VTE instrumental screening. 
• If VTE is highly suspected according to the clinical signs and D-dimer, but imagining is unavailable due to objective reasons, the therapeutic anticoagulation may be initiated before (without) VTE confirmation  
• If VTE is confirmed, therapeutic anticoagulation with LMWH/UFH is preferred during inpatient treatment  
• After discharge, the DOACs are preferred  
• The duration of anticoagulation in patients with confirmed VTE should be three months, with a focus on CTEPH in those with PE and PA thrombosis  
• Swathing of VKA -> DOC -> LMWH/UFH should be considered in COVID-19 patients  
• Primary VTE prophylaxis for outpatients is not generally recommended