Hemorrhagic fever with renal syndrome (HFRS) - symptoms and treatment

Clinical characteristics of hemorrhagic syndrome

Symptoms of hemorrhagic syndrome

The nature and localization of skin rashes during hemorrhagic syndrome determine the symptoms of this pathology.
The main symptom is prolonged bleeding that occurs as a result of injury or exhausting physical activity, severe overexertion, hypothermia or overheating, which can also occur spontaneously.

In every fifth case of the pathology, a rash of a different nature is observed, both small petechiae and large necrotic hematomas may appear, and angiectasias may occur.

Hemorrhagic syndrome can result from taking medications that affect the natural processes of platelets and reduce blood clotting. In addition, patients suffering from Werlhof's disease, hemophilia and prothrombin deficiency may also experience this pathology.

Types of hemorrhagic syndrome

Violation of the internal coagulation pathway of coagulation hemostasis (hematoma type of bleeding)

Congenital and acquired afibrinogenemia

Deficiencies of different types of clotting factors cause different types of diseases called hemophilia, as well as other disorders that are not specific to a specific type.

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Disturbance of the platelet component of hemostasis, the external coagulation pathway of coagulation hemostasis (petechial-spotted type of bleeding)

Disturbance of the platelet component of hemostasis:

Disturbance of the plasma component of hemostasis

Thrombocytopenia

A condition characterized by a decrease in platelet count below 150•109/l, which is accompanied by increased bleeding and problems with stopping bleeding.

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Thrombocytopathy

A disease characterized by increased bleeding due to dysfunction of platelets (blood platelets that provide the initial stage of blood clotting) when their number is normal.

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Deficiency of factors II,V,VII,XI

Diseases associated with impaired coagulation; in these diseases, hemorrhages occur in the joints, muscles and internal organs, both spontaneously and as a result of injury or surgery.

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Combined violation of the platelet and coagulation components of hemostasis (mixed (bruise-hematoma) type of bleeding)

Etiology:

• Von Willebrand's disease (coagulopathy - impaired function of factor VIII, thrombocytopathy - impaired platelet aggregation)
• DIC syndrome (consumptive coagulopathy - decrease in all coagulation factors, hypofibrinogenemia, activation and depletion of fibrinolysis, thrombocytopenia, consumption thrombocytopathy)

Hemorrhagic syndrome:

• Petechial rash, ecchymosis, bleeding from the mucous membranes (nasal, gingival), postoperative, postpartum bleeding.

Disseminated intravascular coagulation

Impaired blood clotting due to massive release of thromboplastic substances from tissues.

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von Willebrand disease

A hereditary blood disease characterized by the occurrence of episodic spontaneous bleeding, which is similar to bleeding in hemophilia.

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Pathology of the microvascular bed (vasculitis-purple type of bleeding)

Petechial bleeding with exudative-inflammatory phenomena, foci of necrosis, hematuria, arthralgia, bleeding of mucous membranes.

Vasculitis:

• infectious, immune;
• systemic;
• hemorrhagic vasculitis (Schonlein-Henoch disease).

Hemorrhagic vasculitis

Systemic aseptic inflammation of the microvasculature with predominant damage to the skin, joints, gastrointestinal tract and renal glomeruli.

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Angiomatous bleeding

Angiomatous bleeding

One of the forms of hereditary vascular disease, characterized by a tendency to bleeding of the mucous membranes.

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About clotting disorders

In this section we will briefly explain the following:

• What are hemorrhagic diseases
• Coagulation process
• How does clotting affect a person?
• Different types of hemorrhagic diseases

What are hemorrhagic diseases?

Hemorrhagic diseases are a general name for a group of diseases in which a person’s ability to clot is impaired. Hemorrhagic diseases are considered to be diseases such as hemophilia A and B, von Willebrand disease, and other rare diseases that can manifest in severe, moderate and mild forms.

With modern treatment, people with hemorrhagic diseases are able to lead normal and productive lives. At the same time, limited access to treatment can lead to serious consequences in the life of a person with this disease. In fact, bleeding that is not properly treated can be critical and even life-threatening, such as a cerebral hemorrhage.

All hemorrhagic diseases are considered rare (according to the European Union classification), since they occur in less than 5 people out of 10,000 (see table below). Despite the rarity of the diseases, diseases such as hemophilia and von Willebrand (the most common of them) are ahead of many other rare diseases in the sense that there are diagnostics and various types of treatment for them. The difficulty for patients is access to modern treatment, which is often expensive, as well as the availability of specialized medical services, which may be available only in one or two cities in the country.

In addition, patients within the European region face large differences in access to treatment, resulting in markedly different quality of life. The EHC aims to increase others' awareness of the realities of people with bleeding disorders at both European and national level.

This section of the site provides a brief overview of the diseases and also explains what patients with hemorrhagic diseases face. If you are a patient looking for more in-depth medical information, we recommend visiting the following sites:

• Your national association website
• World Federation of Hemophilia website
• Hemophilia Central website
• Orpha.net

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Coagulation process

Clotting factors are proteins in the blood that control bleeding. When a blood vessel is damaged, its walls contract to restrict the flow of blood. Small blood cells, called platelets, then attach to the site of injury and are distributed throughout the blood vessel to stop bleeding.

At the same time, small sacs inside the platelets release chemical signals that attract other cells to the damaged area, allowing them to stick together and form what is called a blood clot.

A large number of different clotting factors work on the surface of activated platelets, performing a complex chemical reaction known as the coagulation cascade to form a fibrin clot, which helps stop bleeding).

Clotting factors circulate in the blood in an inactive form. When a blood vessel is damaged, a clotting cascade is initiated and each clotting factor is activated in a specific order to form a clot. Clotting factors are designated by Roman numerals (for example, factor I or FI), although the clotting cascade does not follow a numerical order.

For a graphical representation of the coagulation cascade, please watch the following video:

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The impact of hemorrhagic diseases on humans

One of the main problems in patients with hemorrhagic disease is damage to the joints, such as the hips, knees, wrists, ankles and shoulders. Joints are part of the body with a large number of blood vessels. Thus, they are more at risk of bleeding. When a joint bleeds, the synovium that is part of the joint absorbs the blood in an attempt to remove it. Blood iron accumulates in the synovium. Doctors believe that iron is the cause of thickening of the synovial lining. The thicker the synovium, the more blood vessels it contains. And this makes subsequent hemorrhage more likely. This situation leads to similar problems experienced by people suffering from arthritis. The more hemorrhages a person has, the more damage to the joint. This can lead to joint disability, causing the joint to become immobile or completely immobile. In addition to the risk of joint disability, such hemorrhages are very painful and, if necessary measures are not taken, treatment can take up to several weeks. This may increase the time spent in hospital and may also result in an inability to participate in school, work, or any other activities. It is for these reasons that it is preferable to prevent hemorrhages rather than treat their consequences.

It is now believed that preventative treatment is the best way to avoid bleeding into the joint. Unfortunately, this type of treatment is often perceived as expensive. However, the EHC is confident that investing in preventing joint bleeding is the best treatment option. Indeed, when bleeding occurs, the patient must be given large amounts of clotting factor to stop the bleeding, and by the end of the year it is likely that the amount of drug spent will be the same as if the patient was on prophylaxis.

For more information about joint damage, we invite you to visit the website of the Canadian Hemophilia Society, which provides an accessible explanation of this phenomenon: https://www.hemophilia.ca/en/bleeding-disorders/hemophilia-a-and-b/the- complications-of-hemophilia/joint-damage/

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Different types of hemorrhagic diseases

The type of bleeding disorder a patient has depends on the type of clotting factor or platelet that is missing or poorly functioning. Below is a table describing the various hemorrhagic diseases:

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Diagnosis of hemorrhagic syndrome

A timely diagnosis will help a specialist prescribe effective treatment, and you will be able to make your blood vessels healthy once and for all. The diagnosis can be confirmed or refuted by passing a series of laboratory tests aimed at obtaining detailed information about the state of the blood. You will also need to conduct coagulation tests; during controversial situations, the diagnostician may perform a sternal puncture for in-depth diagnostics.

After obtaining a complete picture of the disease, determining its stage, causes and severity of hemorrhagic syndrome, treatment will be prescribed.

Treatment of hemorrhagic syndrome

The basis for choosing a treatment method for hemorrhagic syndrome is determining the cause of the disease, but there are the following key principles:

• Regardless of the cause, the patient is provided with emergency medical care to stop the bleeding. For this, vikasol, calcium chloride, vitamin C, and thromboplastin solution are used.
• If pathology occurs while taking potent medications, their discontinuation is mandatory.
• Local therapy for hemorrhages is carried out using dry thrombin, homeostatic sponges, aminomethylbenzoic acid (Amben).
• In case of heavy blood loss, transfusion of blood or its fractions may be necessary, preferably directly from the donor.
• Also, for hemorrhagic syndrome of various etiologies, serotonin preparations, for example, Dynaton, are used.

Prevention of hemorrhagic syndrome

The most important and fundamental part of the prevention of hemorrhagic syndrome is a complete medical examination for the timely identification and elimination of its possible causes.

Newborn premature babies need subcutaneous vitamin K and breastfeeding as soon as possible after birth.

The dietary nutrition of patients prone to this pathology should be based on increased consumption of vitamin K, as well as proteins, vegetables and fruits. In addition, such people need to avoid physical activity that leads to injury and injury.

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Norilsk Interdistrict Children's Hospital

A.I. Lobanov, O.G. Lobanova

The article discusses the problems of hemorrhagic disease of newborns with late onset. Currently, in maternity hospitals, the prevention of hemorrhagic disease is not carried out for all newborns. A clinical analysis of 9 cases of the disease was carried out. A dangerous feature of the late manifestation of hemorrhagic disease (after a month of life) is the development of massive intracranial hemorrhages against the background of increased bleeding. The late onset of hemorrhage due to vitamin K deficiency is characterized by a combination of three factors: lack of prevention of hemorrhagic disease, breastfeeding and transient cholestasis.

In the practice of a pediatric resuscitator, non-traumatic intracranial hemorrhages in children in the first months of life are quite rare. It is not always possible to determine the true cause of hemorrhage. At the same time, it is known that one of the reasons for the development of intracranial hemorrhages in children in the first months of life is late hemorrhagic disease of the newborn (LDH). It is impossible to predict the development of late onset of the disease, so prevention of tension-type headache at the maternity hospital stage is extremely important.

The development of HDN in newborns, especially those who are breastfed, is preceded by vitamin K deficiency: gamma-carboxylation of vitamin K-dependent blood coagulation factors is impaired in the hepatocyte. As a result, factors that have not undergone carboxylation lose their ability to participate in the blood clotting process. Immunologically, they are found in the blood in normal quantities, in the form of non-carboxylated and non-functioning molecules, denoted in the literature by the abbreviation PIVKA (Protein-Induced by Vitamin K Absence) [1].

These defective coagulation factors are not able to qualitatively influence blood coagulation processes, which leads to the development of tension-type headache. The most dangerous manifestation of this pathology is intracranial hemorrhage, which occurs against the background of general bleeding (skin hemorrhages, gastrointestinal bleeding).

For the period from 2004 to 2008. 9 children with non-traumatic intracranial hemorrhages were hospitalized in the intensive care unit of City Clinical Hospital No. 4 in Izhevsk. The age of the patients ranged from 1 to 2.5 months of life. Six children were hospitalized from home and three from city hospitals.

Anamnesis

When collecting anamnesis, it was found that all children were from an almost normal pregnancy, term birth, and were breastfed. In the maternity hospital, all newborns were vaccinated against hepatitis B and BCG. Prophylactic administration of sodium menadione (Vikasol) to newborns has not been carried out. On days 5-7, all children were discharged home. Subsequently, 2 children were vaccinated against hepatitis B twice.

Debut Clinic

The onset of the disease was almost the same in all children. 1-2 days before the occurrence of intracranial hemorrhage, hemorrhagic elements appeared on the skin or oral mucosa (Table 1).

Single deep ecchymoses with a diameter of 5 to 20 mm were found by parents more often on the extremities, less often on the torso. Small multiple hemorrhages on the oral mucosa were detected already during examination in the intensive care unit. One sick child had blood in the stool and prolonged bleeding from the injection site during repeated vaccination against hepatitis B. Upon consultation with a surgeon, no pathology was identified.

In all patients, intracranial hemorrhage manifested itself with sudden, painful, but short-lived crying. 8 children immediately developed constant and persistent vomiting, in two cases with blood. Vomiting was not observed in only one child. At first, the children showed periodic restlessness, began to moan, refused to feed, then became apathetic and indifferent to their surroundings. 7 children had tonic convulsions. The skin became increasingly pale. Short-term low-grade fever gave way to hypothermia.

Almost all children were hospitalized very late: the time spent at home from the moment of hemorrhage to hospitalization ranged from one day or more. Upon admission to the intensive care unit, 8 children were in extremely serious condition. All of them had decompensation of pulmonary ventilation, systemic circulatory disorders, focal and cerebral neurological symptoms, and disorders of coagulation hemostasis. In 6 cases, those admitted had rare, arrhythmic breathing or its complete absence. In 2 cases, respiratory disturbances were only in the form of severe tachypnea (respiratory rate - within 100/min).

All patients had severe pallor of the skin and mucous membranes with a cyanotic tint, as well as bleeding from the injection sites. In 2 children there were signs of mild pulmonary and gastric bleeding, in the form of hemorrhagic discharge from the endotracheal tube and gastric tube. Eight children had a slight jaundiced skin tone upon admission. The deficit in circulating blood volume ranged from 30 to 39% of the norm (the norm of bcc in children in the first months of life is 85 ml/kg; bccfact = body weight/weight part of bcc according to hematocrit in the table). Blood pressure ranged from 80/40 to 110/72 mmHg. Art. In 7 cases, children had tachycardia with dull heart sounds. In the neurological status of 6 children, disturbances in the central regulation of breathing were observed. Pathological forms of breathing in the form of severe bradypnea or apnea in these children developed even before hospitalization and continued to progress until the complete loss of automatic breathing. Brainstem reflexes from mucous membranes (cornea, pharynx, trachea) were not evoked. There was severe dryness and swelling of the oral mucosa and sclera. The oculocephalic reflex was absent. Fixed, bilateral, paralytic mydriasis and diffuse muscle atony were detected.

In all children, the large fontanel was bulging, dense to the touch, with no pulsation. Severe hypothermia of the scalp was noted. 5 children experienced attacks of hormetonia (periodic tonic tension of the muscles of the limbs and trunk, occurring against the background of muscle atonia spontaneously or under the influence of irritants, lasting no more than 10 s). In this case, the appearance of hormetonia is associated with damage to the trunk at the level of the midbrain and pons due to transtentorial herniation, when functional separation of the trunk and cerebral hemispheres occurs. As the coma deepened, the attacks of hormetonia stopped. Thus, all 6 patients were diagnosed with a 3rd degree coma (extraordinary). All patients admitted to the intensive care unit in a state of extreme coma died.

Two children were diagnosed with grade 1-2 coma upon admission to the intensive care unit. Tonic convulsions, transient symptoms of damage to the III, VI, VII pairs of cranial nerves, and tachypnea were noted. The large fontanelle was dense, bulging, but retained its pulsation. The reaction of the pupils to light, brainstem reflexes from the mucous membranes (cornea, pharynx, trachea), and oculocephalic reflex remained intact. One patient had signs of moderate intracranial hypertension in his neurological status.

Laboratory examination

In peripheral blood tests, most patients showed a significant decrease in hemoglobin levels (Table 2).

In all patients, blood clotting time (Morawitz) was sharply prolonged. The prothrombin index was determined in only one patient and was reduced. The platelet count was normal or elevated and tended to increase further as the day progressed. Normal fibrinogen levels were observed in 4 patients; in the rest, fibrinogen was not determined. Direct bilirubin remained elevated in 8 children, liver enzymes were slightly elevated in 1. Diagnosis

All children had subarachnoid hemorrhages. In 8 cases the hemorrhages were massive. Diagnosis of intracranial hemorrhages was carried out on the basis of anamnesis, clinical data and ultrasound examinations. Carrying out neuroimaging research methods (CT, MRI of the brain) in the vast majority of patients was impossible due to the extremely serious condition of the patients. In 3 patients, after the bleeding subsided, when intracranial hypertension (irreversible cerebral edema) was not extremely pronounced, the hemorrhage was confirmed by lumbar puncture (one day later). Liquor often flowed out under low or normal pressure and was red-brown in color. When centrifuged, sharp xanthochromia was revealed; microscopy revealed large numbers of altered (hemolyzed) red blood cells. A biochemical study of the cerebrospinal fluid determined low levels of glucose and high levels of protein and lactic acid (lactate). Therapy

8 children were on artificial ventilation. All patients underwent correction of blood volume, hemostatic and metabolic disorders, as well as anticonvulsant and neuroprotective therapy. Relief of bleeding began with the introduction of 10 mg of Vikasol through a tube, a single transfusion of fresh frozen plasma in a volume of 15 ml/kg. With the cessation of bleeding (usually after 10-12 hours), further administration of sodium menadione (intramuscular) was continued to create a depot of 5 mg/day for 2-3 days. Eight patients received red blood cell transfusion due to the development of posthemorrhagic anemia. Subsequently, none of the patients had any bleeding. Autopsy results

At autopsy, massive subarachnoid hemorrhages were discovered in the dead children; in 2 cases with the presence of blood also in the subdural space and in 1 case - in the ventricular system of the brain. In 2 cases the brain was in a state of necrosis. In addition, all the dead children had changes in the liver, most often in the form of nonspecific reactive hepatitis with extracellular cholestasis and initial fibrosis of the portal tracts.

Discussion

During clinical observation, it was noted that all children admitted to the intensive care unit with generalized bleeding were united by a number of common factors and clinical features characteristic of the late onset of HDN. The main factor is the lack of prevention of tension-type headache. The incidence of late onset tension-type headache without vitamin K prophylaxis, according to some data, is 5-20 cases per 100 thousand newborns [2]. None of the 9 children admitted to the intensive care unit with generalized bleeding were treated in the maternity hospital with the administration of sodium menadione.

The second factor is breastfeeding. All observed children were full-term and were exclusively breastfed. Under physiological conditions, vitamin K (K± or phylloquinone) enters the child’s body with food (breast milk) and is additionally synthesized in the intestine in the form of vitamin K2 or menaquinone. But the synthesis of vitamin K2 in the intestines occurs mainly by Bacteroides fragilis and some Escherichia coli - flora that is colonized during artificial feeding.

During natural feeding, the intestines are populated by Bifidobacterium, Lactobacillus and Clostridium - flora that are practically incapable of synthesizing vitamin K2 [3]. The third factor is the phenomenon of transient cholestasis. They were noted in 8 cases. Natural vitamin K is absorbed in the small intestine in the presence of bile and fat. A decrease in bile flow leads to malabsorption of fats and fat-soluble vitamins, increasing even greater vitamin K deficiency. Newborns, due to the immaturity of the excretory function of the liver, are especially prone to cholestasis [4].

In 8 out of 9 children admitted to intensive care after the age of 1 month of life, the level of direct bilirubin still remained elevated (from 12 to 27 mmol/l), which indicates transient, functional and excretory liver failure. Of the clinical features characteristic of the late onset of HDN, it should be noted: firstly, the development of massive intracranial hemorrhages in combination with skin hemorrhages and bleeding from the gastrointestinal tract. Secondly, the observed children did not have severe pathology at the onset of the disease with a high risk of developing DIC syndrome.

Almost on the eve of the development of late TTH, all children were examined by local pediatricians. Thirdly, late hospitalization of these children in the intensive care unit. The reason for the late hospitalization of the observed children was the fact that the increase in intracranial pressure in children in the first months of life occurs more slowly due to the fact that the child’s skull (before the fusion of the cranial sutures and the closure of the fontanelles) remains temporarily pliable and adapts to the emerging conditions. When blood enters the intrathecal space of the brain, the threatened symptoms are delayed for some time, so the parents sought medical help too late.

Fourthly, changes in peripheral blood and cerebrospinal fluid. These changes are adaptive reactions of a sanogenetic nature. They are caused by blood poured into the intrathecal space and its breakdown products. Therefore, the observed children experienced a reactive increase in body temperature, changes in peripheral blood were noted in the form of leukocytosis and a shift in the leukocyte formula to the left. The entry of the blood itself and its breakdown products into the cerebrospinal fluid space caused reactively expressed pleocytosis and hyperproteinrachia. These changes are also protective (sanogenetic) in nature and disappear as the cerebrospinal fluid is cleared of blood by the end of 2-3 weeks.

Blood breakdown products have pronounced toxicity (oxyhemoglobin, serotonin, bilirubin, etc.) and additionally cause severe cerebral ischemia, leading to cerebral infarction. And finally, another feature of late HDN is the hypocoagulation direction of the results of available tests for assessing hemostasis and their stabilization during the administration of vitamin K (Vikasol).

The basis of laboratory diagnosis of tension-type headache is the determination of prothrombin time and index, which reflect the total level of (three out of four) vitamin K-dependent coagulation factors (II, VII, X) (Table 3).

In TTH, the platelet count and thrombin time should be normal [5]. In 8 observed children, the prothrombin index was not determined, and in 1 it was reduced. None of the observations revealed a decrease in the number of platelets; on the contrary, in response to prolonged bleeding, compensatory thrombocytosis developed in 7 cases. This circumstance excludes the involvement of platelets in pathological consumption reactions associated with DIC syndrome.

In the absence of clinical signs of DIC, fibrinogen was not detected upon admission in more than half of the patients. This is due to a number of reasons, such as a decrease in the protein-synthetic function of the liver during the development of a critical condition, the influence of hypovolemia, hypoxia, and acidosis. In the classic form of HDN, which occurs in newborns in the maternity hospital, in contrast to its later form, intracranial hemorrhages, such severity and decompensation of vital functions do not occur.

Conclusion

Based on the clinical observation, it can be concluded that full-term newborns are susceptible to the occurrence of late tension-type headache, in whom a combination of factors such as the lack of prophylactic administration of sodium menadione, breastfeeding and transient cholestasis became possible. In newborns who are expected to breastfeed, prevention of tension-type headache is especially important.

REFERENCES 1. Barkagan 3. S. Introduction to clinical hemostasiology. - M.: Newdiamed-AO, 1998. - P. 21-23. 2. Dolgov V.V., Svirin P.V. Laboratory diagnosis of hemostasis disorders. - M.: Triada, 2005. - 213 p. 3. Gusel V. A., Markova I. V. Pediatrician’s Handbook of Clinical Pharmacology. - Leningrad, 1989. - pp. 161-163. 4. Shabalov N. P. Neonatology. Volume 2. - St. Petersburg, 1996. - P. 95. 5. Barkagan 3. S. Hemorrhagic diseases and syndromes. - M.: Medicine, 1988. - 498 p.

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