Spontaneous Hemorrhage in COVID 19 Patients

Abstract

Much has been said and known of the possible occurrence of thromboembolism in various organ systems as part of Covid 19. The following Chapter discusses spontaneous hemorrhage in Covid 19 cases. Comparably to potential thromboembolism, it is found in a lesser percentage of patients, yet with serious repercussions on outcomes in the treatment of Covid 19 patients suffering from spontaneous hemorrhage. The Chapter examines and weighs in on the most optimal approaches to diagnosis and treatment of spontaneous hemorrhage in Covid 19 infection.

1. Introduction

COVID-19 is a multisystem disease that can affect any organ – from the lungs, through the brain, skin, kidneys, digestive and nervous systems – since SARS-CoV-2 coronavirus is not merely a respiratory virus, but also pleiotropic.

In some patients with SARS-CoV-2 coronavirus infection no symptoms are registered (asymptomatic form); it can, however, be manifested by mild problems with the upper respiratory tract, such as common cold, but also pneumonia of various degrees of severity (from mild to severe) to life-threatening. Covid 19 is a highly prothrombogenic disease. Much has been said and known of the possible occurrence of thromboembolism in various organ systems. The Chapter focuses on spontaneous hemorrhage found in Covid 19 patients. It is found in lesser percentage of patients, yet with serious repercussions on treatment outcomes.

1.1 Human population and infectious diseases throughout history

Over 8 billion people live on planet Earth. The human population shares its living space with multiple other species. The planet is overpopulated. Clearly, humans live side by side with countless other pathogenic organisms of microscopic size, such as viruses, bacteria, parasites, fungi or other unconventional agents. Common diseases are found both in humans and animals.

The emergence of new diseases with pandemic potential has become one of the global medical challenges. Our knowledge of such diseases, if any, is very limited initially, forcing us to learn to curb such diseases in the most effective way. Viral Covid 19 infection of 2019 is one such disease. At one time, Covid 19 pandemic literally brought to stop numerous processes and flows on planet Earth. It brought scare to human race on across the continents and regardless of the development level of the country where it was recorded. It took time to gather relevant data and optimal algorithms for the treatment of this new viral infection reaching pandemic proportions. It took a while for this “intelligent and insidious” virus to become familiar with the human species and vice versa.

According to the World Health Organization (WHO), around 75% of emerging diseases affecting human population in the last decade are caused by pathogenic organisms originating from animals or animal products. Zoonoses have been known for many centuries, with more than 200 described to date [1].

In its 2020 conclusion, the UN Expert Commission on Biological Diversity warns that “in absence of preventive strategies, pandemics will break out more often, spread faster, kill more people and affect the global economy with more unprecedented devastating effects”.

According to estimates published in the Journal of Science, there are 1.7 million unknown viruses among mammals and birds, of which 540,000 to 850,000 can infect humans. There is evident space for further scientific research, including points of concern, such as the emergence of new unknown diseases, pandemics and the like. In the 20th century, smallpox epidemic alone accounts for 300 to 500 million deaths. Smallpox is believed to be responsible for the death of 10% of the human population over the last thousand years [2]. The Spanish flu pandemic broke out in 1918, killing 21.5 million according to most referenced literature. More recent additional research after looking at the data and registers of developing countries says that between 50 and 100 million died from the Spanish flu [3, 4, 5]. Plague was synonymous with disease, hardships and suffering. People died from the plague in terrible agony. The plague epidemic marked the entire period of the late Middle Ages and part of the early Middle Ages. It is been long since the plague disappeared from Europe, but it is still smoldering in hotspots around the world such as Asia, Africa, North and South America [6]. Dubbed as the queen of diseases, malaria has been known since ancient. Some believe that it is largely responsible for the downfall of the Roman Empire. In the 20th century alone, it accounts for between 150 and 300 million deaths. Malaria still affects 228 million in different parts of the world, with as many as 405,000 deaths, especially in the poorest countries [7]. Epidemic typhus is louse-born by sucking the blood of a patient in the rickettsemia phase. The largest known epidemic of typhus hit Napoleon’s army during the Russian campaign, killing half a million [8].

According to the most recent data from the World Health Organization, one and a half million still die from tuberculosis in the world today, and about ten million fall ill every year [9]. Leprosy is one of the oldest and most terrible diseases affecting people, synonymous with stigma and discrimination due to large bodily deformations. It has been known since ancient times as ‘death before death’. Despite therapy, it is still endemic in some countries. Annually, 200,000 new cases are diagnosed [10].

Syphilis has been a constant and unwanted companion of mankind for more than 400 years. Since its first emergence, syphilis has been a stigmatized, shameful disease. It affected the lives of millions in all walks of life. Epidemics of various diseases occurred during the 19th century were quite common. Here, cholera stands out, causing an exceptionally high mortality rate.

1.2 Human population and infectious diseases in the 21st century

In early 21st century, bird flu caused by the A/H5N1 virus subtype was recorded in Asia in 2003. During 2009, the so-called swine flu caused by the H1N1 influenza virus emerged. The disease began to spread human to human, rising to the level of pandemic. SARS-CoV appeared in China 21 years ago (2002), as a severe viral respiratory disease that can cause death of up to 15% of the infected. In 2012, a new global threat emerged in Saudi Arabia, a disease called MERS-CoV, causing severe respiratory illness. Although most patients are geographically associated with the Arabian Peninsula, MERS-CoV has also been detected in other parts of the world. In 2013, global concern grew over the emergence of the Ebola virus disease in West Africa. Millions were at risk, and thousands fell ill.

The above overview portrays a series of very serious and severe diseases leaving significant and profound consequences on the evolution and development of the human population. In philosophical terms, a war is being waged on planet Earth as to who the real ruler of our living space is. Logically, man as a ‘rational being’ should be the one running the processes on the planet Earth. But looking at the adaptability of animals and other species, bacteria, viruses and many other microscopic organisms show that humans are in no position to claim the title of ‘genuine managers’ or the main stakeholders of the planet Earth in full capacity. Old and new diseases with old and new causative agents have led to the emergence of more resistant and more adaptable disease causative agents. Finding the most adequate patterns in the treatment of old and emerging diseases has become a genuine medical challenge.

2. Covid 19 and hemorrhage

2.1 Coronaviruses

Coronaviruses (lat. corona: wreath, crown < Greek. ϰορώνη: curved or rounded eend of something, ring + virus), are a group of viruses from the Coronaviridae family. The viral particle is spherical in shape with a diameter of 120 to 160 nm, and the spiky transmembrane glycoprotein outgrowths on the envelope with a length of 12 to 24 nm resemble a crown. The genome consists of single-stranded positive RNA composed of 26 to 32 thousand nucleotides, which ranks coronaviruses among the RNA viruses with the largest genomes. The viral particle consists of four to six structural polypeptides, with four viral proteins: the so-called spike protein (S-protein), nucleocapsid protein (N), membrane protein (M) and envelope protein (E). The virus enters the cytoplasm of the host cell by fusion of the viral envelope and the cytoplasmic membrane, mediated by the S-protein. Coronaviruses are not newly discovered viruses, but come with their own history. These viruses were first described in the sixties of the last century, as the isolates of the HCoV-229E and HCoV-OC43 viruses, highly widespread and common around the world. They appear sporadically, seasonally and possibly in smaller epidemics in the winter, and lead to an acute febrile illness of the upper respiratory system much like a common cold.

2.2 Who are Covid 19 patients susceptible to develop thromboembolic complications

Most frequent patients include bed-ridden, elderly, adipose, male, patients previously suffering from thrombosis and cancer patients. They are also patients with other significant comorbidities and those who are hospitalized in the intensive care unit and have medium-severe and severe forms of Covid 19. In patients with thrombosis, blood coagulation is increased, there is damage to the endothelium of blood vessels by the SARS-CoV-2 virus itself and multiple inflammatory processes. In Covid 19, the activities of several blood clotting factors (factor VIII, von Willebrand factor, fibrinogen and D-dimer) are also elevated (Figure 1).

Figure 1.

Covid 19 pneumonia.

Axial HRCT images of a 38-year-old man with COVID-19 ARDS admitted to ICU at the same level, performed at different times: baseline scan (A) and 7-month follow-up (B). The baseline scan (A) shows typical imaging features indicative of severe COVID-19 pneumonia, including extensive bilateral parenchymal consolidations, mainly affecting the posterior regions of lower lobes, bilateral focal ground-glass opacities in the anterior regions and patchy consolidation, peripherally distributed, resembling pulmonary fibrosis. The 7-month scan (B) shows a complete resolution of the parenchymal consolidations and the apparent fibrotic abnormalities.

2.3 Covid 19 patients with spontaneous hemorrhage

According to data, hemorrhage-related complications in elderly patients on anticoagulant therapy are estimated at around 5%, with an incidence of spontaneous hematomas of around 0.6% [11]. In cases of formation of large hematomas with hemodynamic instability, the prognosis is poor with multiple failure and organ failure [12], reaching a mortality of 30 to 50% [13, 14]. It has been proven that the COVID-19 infection causes a disorder of hemostasis [15], with a procoagulant state. This has led to the inclusion of thromboprophylactic (anticoagulant) therapy in most treatment protocols. There are also studies related to heparin-induced thrombocytopenia [16, 17]. The rationale behind is that a certain number of patients develop kidney failure due to coronavirus infection. This results in a prolonged half-life of heparin, which then circulates longer in the plasma. All this leads to ‘pseudo overdose’, increasing the risk of hemorrhage [18]. The incidence of hematoma in patients with COVID-19 due to coagulation disorders caused by the infection, together with thrombocytopenia due to heparin and overdose in patients with renal failure will be the subject of further research (Figure 2).

Figure 2.

Spontaneous hepatic hematoma as part of Covid 19.

In patients with spontaneous hematoma or hemorrhage, (CT), computed tomography and (CT) angiography are absolutely needed and highly sensitive procedures to adequately diagnose the resulting hematomas, allowing for the size, location and artery responsible for the hemorrhage to be determined in full. It also identifies the location or vascular origin of hemorrhage in 95.2% of cases [19].

According to the available relevant papers, hemorrhages occurred in 2.22% of patients in the total number of those hospitalized with Covid 19 infection, that is, in 7.88% of the total number of patients hospitalized in ICU. Hemorrhage occurred in most cases in patients on anticoagulation, more so in men with multiple comorbidities, aged between 60 and 79 years. It mostly occurred in one anatomical region (especially retroperitoneal), with the most extensive hemorrhage in the chest wall [20]. This complication was diagnosed on average 16.7 days after admission and hospitalization. It occurred most often in severe forms of Covid 19 in patients who underwent invasive mechanical respiratory support, that is, cyclic pronation-supination measures. Hematomas were active in slightly less than half of the cases. The vast majority of patients were treated conservatively and survived [20].

COVID-19 is a highly prothrombogenic disease and therefore thromboprophylaxis is mandatory in hospitalized COVID-19 patients in order to improve treatment outcomes.

2.4 Thrombocytopenia

Zimmerman was the first to discover platelets in 1860, and their role in blood clotting was further elaborated in 1878 by Zimmerman and Hayran [21]. In short, platelets are essential for maintaining the integrity of the vascular endothelium and controlling bleeding from injury to small blood vessels through the formation of platelet plugs [22]. It is known thrombocytopenia is found in 2.5 percent of the normal population (Table 1) [23].

Mild: 100,000–150,000/μL

Moderate: 50,000–100,000/μL.

Severe: <50000/μL.

Table 1.

Classification of thrombocytopenia.

Thrombocytopenia is not a disease, but a diagnosis. Effective interpretation of thrombocytopenia requires gathering detailed information from the patient or the patient’s family, followed by thorough examination and lab tests. Thrombocytopenia can occur with recently introduced new drugs or drugs taken only occasionally. Recent infections and previously diagnosed hematological diseases are mentioned as a possible reason for its occurrence. There are also non-hematological diseases that are known to reduce the number of platelets (eclampsia, sepsis, DIC, anaphylactic shock, hypothermia, massive transfusions). It is also found in cases of prior family history of hemorrhage, recent vaccination with live virus, in patients with poor nutritional status, pregnancy, recent organ transplantation from a donor sensitized to platelet alloantigens, and recent transfusion containing platelets in an allosensitized recipient. Possible alcohol consumption and risk factors for HIV should also be looked into. For asymptomatic patients with low platelet count, the physician should initially try to rule out artifactual or pseudothrombocytopenia as the etiology. Thrombocytopenia also requires that family history in terms of congenital thrombocytopenia is also looked at [24].

2.5 Thrombocytopenia and Covid 19

According to referenced literature, mild thrombocytopenia is present in 45 to 55% of patients positive for COVID-19 [25], but also, thrombocytopenia is found in 95% of patients with a severe form of Covid 19 infection [26]. Viral infection caused by Sars CoV-2 can vary from asymptomatic clinical forms to severe respiratory forms with acute respiratory distress. The hematopoietic system can also react to COVID-19 in several ways, from mild forms to life-threatening forms [27]. Moderate and severe forms of the disease can lead to the formation of thrombus and pulmonary embolism [25]. Usually, thrombocytopenia occurs 10 to 14 days after the onset of disease symptoms [28]. It becomes a potential biomarker of negative prognosis in COVID-19 patients [29]. The most frequently mentioned pathophysiological mechanism is that the SARS-CoV-2 virus causes hyperinflammation and hypercoagulability.

Risk factors for thrombocytopenia are older age, male, high APACHE II score, neutropenia, lymphopenia, elevated CRP and low PaO 2 /FiO 2 ratio. Thrombocytopenia can also be caused by a decrease in thrombopoietin (a regulator of megakaryopoiesis and platelet production) following hepatocyte damage in SARS-CoV-2 infection. In the bone marrow, viral infection of megakaryocytes can induce apoptosis and reduce platelet maturation. However, several cases have been presented in the medical literature showing that COVID-19 infection is associated with the onset or recurrence of immune thrombocytopenia (ITP), characterized by isolated thrombocytopenia, without any tendency to thrombosis [30]. Another possible interpretation is that the formed antibodies and immune complexes can enhance the removal of platelets in the circulation and that excessive activation of platelets can cause their increased removal in spleen and liver. Some patients may develop consumptive thrombocytopenia [30, 31, 32].

2.6 Coagulopathy in COVID-19

Development of consumptive coagulopathy (a blood clotting disorder in which coagulation factors and then platelets are consumed) is one of the most significant indicators of a poor outcome in COVID-19. An analysis of patients with COVID-19 pneumonia showed that abnormal coagulation tests at hospital admission were associated with a higher risk of death.

Here we have raised a real issue that requires additional efforts by doctors to understand these processes, since in consumptive coagulopathy or disseminated intravascular coagulation, there is simultaneously an increased risk of both hemorrhage and thrombosis, which is all associated with a high risk of fatal outcome in patients [33].

2.7 Guidelines for thromboprophylaxis in COVID-19

Numerous international medical associations have published recommendations on thromboprophylaxis for patients with COVID-19. Thus, the International Society on Thrombosis and Hemostasis (ISTH) notes that all hospitalized COVID-19 patients should receive medicinal thromboprophylaxis, the so-called low molecular weight heparin, unless suffering contraindications (for example, active hemorrhage or low platelet values - less than 25x109/L). Similar are the recommendations and guidelines of the American Society of Hematology (ASH), CHEST and ACC (American College of Cardiology) [34].

To highlight, if the patient is already on anticoagulant therapy for other reasons, the patient can continue with the existing chronic therapy unless contraindicated due to a change in the patient’s clinical status (for example, the inability to administer drugs orally, developed an increased risk of hemorrhage, etc.). In such cases, the preference is to change the method of administration to low-molecular-weight heparin, administered as a subcutaneous injection.

2.8 Mechanism of spontaneous hemorrhage in Covid 19 patients

Covid 19 patients can develop spontaneous hemorrhage, but the mechanism of its occurrence has not yet been fully understood in all aspects. The most plausible explanation is that it is most likely due to a cascade of possible reasons that individually or combined cause the hemorrhage to occur. Coagulopathy, Cytokine storm, systematic inflammation, low platelet count, endothelitis with endothelial dysfunction, almost always accompanying cough associated with pneumonia with frequent changes in intratocacal and intra-abdominal pressure are some of the most frequently mentioned reasons for the occurrence of spontaneous hemorrhage in Covid 19 patients. Pronation maneuvers, treatment with anticoagulants, obesity, increased vascular sensitivity determined by a pro-inflammatory state, barotrauma from C-PAP ventilation, and cough with consequent increase in intra-abdominal pressure are among the risk factors for hemorrhage in patients with COVID- 19.

2.9 Who are the patients at risk for spontaneous hemorrhage?

It is important to detect patients who are at absolute risk of hemorrhage and for whom prescribed anticoagulant therapy may cause more harm than good. These are patients with DIC, thrombocytopenia, or previous hemorrhage tendencies. Patients who are already being treated for intracranial and genitourinary hemorrhages, epistaxis, and patients with tracheostomy should also be kept in mind.

2.10 Can we be more efficient in the detection and treatment of patients susceptible to spontaneous hemorrhage

Due care is needed in the projections of possible benefit and harm in patients with mild to moderate form of Covid 19 infection. Patients should be examined in the broader context of the patient’s health.

It is imperative to detect patients at risk for hemorrhage by taking a very detailed history with detailed insight into the previous medical records of the patient with Covid 19.

Covid 19 can develop and manifest itself in several forms of illness (mild, medium and severe) but also in several variants with predominant symptoms (respiratory, gastrointestinal, neurological and other).

In a patient with Covid 19 with a moderate and severe form of infection, it is essential to consider a personalized modulated therapy with low molecular weight heparins, which will be optimized depending on the possible improvement or deterioration of the patient’s general condition and health.

• Multidimensional assessment of the patient’s condition will include the analysis of laboratory findings, blood count, renal parameters, inflammation parameters and assessment of the patient’s general condition, especially in the period 10 to 14 days after hospitalization, as this is the time when the largest number of spontaneous hemorrhage occurs.

Several points to bear in mind in case of Covid 19 infection.

• It may not be possible to establish adequate contact with the patient.

• Concerned family and other accompanying members may not give all but only partial information about previous illnesses or if the patient is prone to hemorrhage.

• The patient but also the patient’s family can be an important factor in obtaining relevant data essential for treatment. In the case of mass and other forms of illness, we need to simulate the most difficult scenarios and situations should be run.

Clinical situation in case.

The patient is in a very serious general condition on controlled mechanical ventilation with a severe Covid 19 form. The patient has family living in another city or country with no possibility of contact. It may be useful to reiterate:

If we already have a CT angio examination of a patient diagnosed with hemorrhage, clear information should be obtained on the following:

• Whether or not the patient is actively bleeding,

• Exact localisation, blood vessel, size of the bleed area, approximately calculated possible amount of blood in the hematoma,

• Run a clinical and biochemical assessment of the patient’s condition,

Whether active treatment is required in a patient who is hemodynamically unstable. Assessment of methods to stop hemorrhage.

• Interventional radiology – Surgery

  Preference is given to interventional radiology due to better results, faster and more effective targeted treatment of bleeding and faster overall recovery.

• In order to stratify and improve results and outcomes in treatment in a personalized approach to patients, medical professionals should have all fully functional and easily accessible IT tools at their disposal.

• Emerging diseases, unknown or partially known in their forms of manifestation, will require genuine commitment but also great knowledge of doctors and other medical workers in order to treat them successfully.

• The oft-repeated phrase of ‘Personalized Medicine’ will be in future tested in reality to see to what extent can we independently manage these new diseases that we have yet to become familiar with.

Speaking of spontaneous hemorrhage in narrow terms, the actual number of small or hidden hemorrhages can only be speculated. This area will need to be further defined. It is also important to say that there are several adopted revised protocols for the medical treatment of Covid 19 patients. What is common to all these protocols is the use of anticoagulants, which reduce the mortality rate.

3. Conclusion

Historical overview and analysis stand as a reminded that human population had been exposed to numerous mass diseases, pandemics and temptations accounting for hundreds of millions of lives. Some of these diseases have been largely eradicated, yet some are still smoldering with the emergence of bran new, utterly unexplored and fully undefined diseases.

More and more diseases noticeably originate from the same causative agents, affecting the health of both humans and animals, as well as other species with which we share the planet Earth.

Speaking of the Covid 19 pandemic, “we are still getting to know Covid 19 and the virus is getting to know the human population”. We have gained loads of useful scientific knowledge about this disease, but the process is not fully finalized. In consideration of spontaneous hemorrhage as part of the Covid 19 infection, our activities should go along the lines how to improve the final outcomes in the treatment of this complication. It is very important to answer the following questions:

• How to prevent the possible hemorrhage.

• How to detect it timely and precisely.

• How to treat most adequately.

Spontaneous hemorrhage can be prevented by a well-trained doctor after conducting a solid interview, obtaining relevant anamnestic data and objectively interpreting the obtained laboratory findings. Mindful of all these elements gathered, a polymorphic disease such as Covid 19 will require dedicated medical professionals, personalized modulated therapy and optimized diagnostic and therapeutic treatment especially in patients at risk of hemorrhage.

Early or timely detection of a patient suffering from hemorrhage as part of the Covid 19 disease will be all the more complicated as it is most common in patients with severe forms of this disease. Repeated clinical examinations, the search for hidden areas of bleeding, more detailed monitoring of laboratory findings and the hemodynamic state of the patient will be a guarantee of better results.