A Formula Your Doctor Can Use To Prescribe

Heparin If You Become a Critical Covid-19 Patient

As described more thoroughly in the articles below, Covid-19 generates clot related complications that very frequently and very significantly increase the morbidity and mortality of patients with Heparin administration clinically demonstrating itself as a life saver for many patients. 

Unfortunately, doctors have been in the dark about in which cases should it be administered.

Update: Fairly comprehensive data about anticoagulant use in Covid-19 and their respective contraindications and adverse drug reactions are covered on an individual basis in a study here

That is until now. Early publication data from the Cleveland Clinic Journal of Medicine reveals very reliable data about what marker should indicate immediate administration of Heparin to patients.  

 A critical blood biomarker that indicates that your body is undergoing abnormal clotting events is a measure called D-dimer. Specifically, it means clots, made up critically of fibrin, are forming and breaking down in the body, and D-dimer measures the end product of the breakdown of fibrin. 

The study asserts that "aggressive" anti-coagulation therapy is needed for all Covid-19 patients.

However, in patients with "very high D-dimer levels (6 times the upper limit of normal, greater than 3,000 ng/mL) have the greatest risk of thrombosis and may benefit from active screening and more intensive VTE prophylaxis."

This is absolutely critical because the study noted that other common biological alarm systems for coagulation (like platelet count, fibrinogen, and prothrombins) in the blood were oddly silent even when thrombotic incidents were present in Covid-19 patients. 

In all Covid-19 patients measured by another study the rate of incidence of either deep-vein thrombosis (DVT), pulmonary embolism, or arterial thrombosis was 31%.

Cleveland Clinic corroborated this study with a similar 25-30% detection of DVT alone, in addition "slowed venous flow" was common in patients, which is a similarly lethal symptom in terms of its ability to cause oxygen starvation in organ systems. 

As a result the initial study concluded the following:

"Heparin anticoagulation seems to be the obvious response to such a hypercoagulable process. In addition to its antithrombotic effect, heparin may have anti-inflammatory, anti-complement, and direct antiviral effects that may be beneficial in COVID-19. Heparin inhibits neutrophil activation, binds inflammatory cytokines, and reduces endothelial activation. Experimental models have also shown that heparin directly binds to SARS-CoV spike-protein1, which acts as the viral anchor site for SARS-CoV–ACE2 interaction, and thereby blocks cell entry."

It should be made clear that heparin has mainly had substantial validation in mortality improvement only in severe covid-19 cases and as a result the physicians created a protocol for heparin introduction based on patient symptomology, which is copied below.

"Our current approach is based on POCUS screening for VTE and intensified prophylaxis in high-risk patients (Figure 2Table 1). We divide patients into 3 categories:

  • Category 1: D-dimer greater than 3,000 ng/mL FEU and no evidence of VTE. Patients in category 1 receive standard DVT prophylaxis and are monitored using serial D-dimer testing.

  • Category 2: D-dimer greater than 3,000 ng/mL FEU, POCUS-negative. Patients in category 2 receive intensified DVT prophylaxis.

  • Category 3: Patients with confirmed thrombosis receive full anticoagulation."

Table 1.

In patients with high clinical suspicion of VTE and no contraindication for anticoagulation, full anticoagulation should be initiated empirically, if POCUS or confirmatory tests are not immediately available.

Heparin Substantially Reduces Covid-19 Mortality  

Data from a research letter published in the Journal of the American College of Cardiology revealed critically important insights in the extent to which anti-coagulant therapies reduce mortality of hospitalized covid-19 cases. Importantly, the distinction is also made in how much more important it is to administer anticoagulation therapies for those severe cases of intubated patients.  

Of 395 hospital patients who required mechanical ventilation, 29.1% of those given anti-coagulant therapy died with a median survival of 21 days, compared to a 62.7% death rate and a median survival of 9 days in patients who did not receive AC. 

This is huge. It demonstrates that not only do anti-coagulants help keep people alive, but assist in speeding up the improvement of patient conditions such that they no longer require mechanical ventilation.

 

Mortality rate over time is clearly outlined below, with the left graphic being all Covid-19 patients, and the right being only those who were put on mechanical ventilation. 

Side-effects related to increased bleeding were very minimal, with 1.9% of the total patients not receiving anticoagulants experiencing bleeding events, compared to 3% of those who did receive anticoagulation therapy.

Read the published research letter here: https://www.sciencedirect.com/science/article/pii/S0735109720352189

Counteracting the Expected Clotting of Severe

Covid-19 with the Anti-coagulant Heparin

In reviewing Cleveland Clinic's helpful web series (https://www.ccjm.org/cc/covid-19-curbside-consults), the institution has provided an excellent coagulopathy algorithm that can be very helpful in management considerations of COVID-19 patients.

Coagulopathy is rapidly being recognized as a major problem with severe COVID-19, whereby small and large clots develop inside blood vessels causing a myriad of tissue and organ damage. These clots are appear in the lungs and interfere with breathing (outlined in the next article), and in arteries where they cause strokes, heart attacks and kidney impairments

Here is what the Cleveland Clinic initiailly disseminated on May 14 2020:

Heparin anti-coagulation seems to be the obvious response to such a hyper-coagulable process.

In addition to its anti-thrombotic effect, heparin may have anti-inflammatory, anti-complement, and direct antiviral effects that may be beneficial in COVID-19.

Heparin inhibits neutrophil activation, binds inflammatory cytokines, and reduces endothelial activation. 

Experimental models have also shown that heparin directly binds to SARS-CoV spike-protein1, which acts as the viral anchor site for SARS-CoV–ACE2 interaction, and thereby blocks cell entry.


While promising, these effects have yet to be demonstrated in clinical practice, and specific data on the management of CAC are extremely limited.

One study of 449 patients with severe COVID-19 showed no overall mortality difference (29.7% vs 30.3%, P = .910) between patients who did not and those who did receive heparin (94 patients on low-molecular-weight heparin, 5 patients on unfractionated heparin; prophylactic doses).

There was, however, a significant difference in mortality rates (32.8% vs 52.4%, P = .017) in the subgroup of patients with a D-dimer more than 6 times the upper limit of normal (> 3 μg/mL). The authors concluded that heparin improves mortality rates in patients with severe COVID-19 and cited a Chinese consensus statement as recommending anti-coagulation in severe COVID-19. It must be emphasized that this study retrospectively compared heparin prophylaxis vs no prophylaxis. It remains unclear if therapeutic anti-coagulation would provide additional benefit.

Thrombolysis in patients that deteriorate despite anti-coagulation has also been suggested. A small case series of patients with persistent severe hypoxia and markedly elevated D-dimer showed improvement in oxygenation after low-dose tissue plasminogen activator. Despite initial improvement and no reported adverse effects, the ultimate outcome in this series was poor.

Given this lack of evidence, the ASH (American Society of Hematology) and ISTH (International Society on Thrombosis and Haemostasis) currently do not recommend treatment above and beyond standard prophylaxis unless there is an established indication.

Both societies strongly recommend DVT prophylaxis in all patients on admission using low-molecular-weight heparin (unfractionated heparin in renal failure, fondaparinux in heparin-induced thrombocytopenia) and stress that prophylaxis should be continued even in the setting of thrombocytopenia (platelet count > 25 × 109/L). 

Reference link: https://www.ccjm.org/content/early/2020/05/12/ccjm.87a.ccc024

NEJM Identifies Unusual Pattern of Lung

Damage and Injury Caused by COVID-19

A new study in the NEJM identifies an unusual pattern of lung damage and injury from COVID-19.

 

It has been found common that Covid-19 causes capillary walls in the lungs become so weak that they bleed, leak protein, and slow the flow of blood, with thrombosis and micro-thrombosis occurring as a result. Prevention of thromboses through the use of anti-coagulants has improved survival rates substantially and demonstrates that the choking off of blood flow in micro-capillaries is far more lethal a risk then that posed by the prospect of increased bleeding risk.

 

Postmortem analysis of COVID-19 patient's lungs show severe injury to arterial/vasculature lining and predominance of intracellular virus in this tissue. 

 

The detection of relatively higher presence of virus in endothelial cells in the lungs means the effects of the virus in the lungs will be far more predictable to clinicians and an area of focus for researchers.

Key Findings:

 

Pulmonary vessels in the COVID-19 autopsies showed widespread thrombosis with microangiopathy.

 

Capillaries in lung alveoli from COVID-19 patients had 9-times more microthrombi as in patients with influenza.

 

COVID-19 lungs showed 2.7-fold more new vessel growth as seen in the influenza cases. 

All specimens from the Covid-19 group had diffuse alveolar damage with necrosis of alveolar lining cells.

Link to NEJM Study: https://www.nejm.org/doi/full/10.1056/NEJMoa2015432 

A micro-capillary sample from a deceased Covid-19 patient's lung shows a close-up look at clotting occurring at points indicated by the black arrows. 

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