Cévní prosak

Alergické (Quinckeho) otoky

• Vyvolané působením nejrůznějších alergenů
• Také léků (např. ACE inhibitory) na vnímavé osoby
• Vznikají náhle na libovolném místě těla
• Nejčastěji v obličeji na očních víčkách a na rtech
• Mohou se objevovat také na dolních končetinách kolem kotníků
• Nebezpečný je tento otok, pokud postihne sliznici dýchacích cest
• Může být provázen svěděním kůže, bolestmi hlavy, nevolností a zvracením (břišní koliky)
• Známky jsou projevem postižení vnitřních orgánů
• Charakteristickým rysem je
• Rychlý vznik
• Spontánní ústup během minut nebo několika hodin
• časté recidivy při opakované expozici alergenu
• Dilatace arteriol a prekapilárních svěračů + venokonstrikce + zvýšení kapilární propustnosti působením alergenu (antigenu)

Alkohol

• Deplece vitaminu B1, hořčíku ev. i B6

Angioedem - Quinckeho edém

• Aktivace tkáňových mastocytů s uvolněním vazoaktivních mediátorů
• histamin - časné projevy otoku
• Tryptáza
• Chymáza
• Zesílení reakce:
• Sekundární metabolity
• cytokiny
• Deriváty kyseliny arachidonové
• Aktivace přemostěním 2 vysokoafinních receptorů IgE
• Neimunologicky stimulací látkami:
• Morfin
• Kodein
• Substance P
• Neznámé...

Angioneurotický edém

• Zvýšení permeability kapilár účinkem různých toxinů (bodnutí hmyzem, atp.), při sepsi, šoku, inhalaci dráždivých látek v plicích apod.

3 typy:

• Edém na podkladě IgE zprostředkované reakce u alergií [31]
• Angioedémy [31]
• Defekt inhibitoru C1 proteinu [31]

• The swelling can last for several hours or days
• Swelling finally resolves, the skin will usually appear normal
• no flaking, peeling, scarring, or bruising.
• Swelling of the hands and feet
• Swelling of the throat
• Abdominal pain
• A rash that is not itchy

Angiopoietin 2

Apoptosis of microvascular endothelial cells

Kyselina palmitová

• Palmitate increased ROS generation in microvascular EC
• Palmitate significantly inhibited DNA synthesis and induced apoptotic cell death in EC
• Completely prevented by an antioxidant, N-acetylcysteine
• Palmitate up-regulated pericyte mRNA levels of a receptor for advanced glycation end products
• Potentiated the apoptotic effects of AGE on pericytes.
• Results suggest that palmitate could induce apoptotic cell death in microvascular EC and pericytes through the overgeneration of intracellular ROS,
• Thus be involved in the development of diabetic retinopathy.
• citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.321.7346&rep=rep1&type=pdf

High Glucose

• Induced Downregulation of Connexin 43 Expression
• Promotes Apoptosis in Microvascular Endothelial Cells
• Inhibition of connexin (Cx43) expression and reduced gap junction intercellular communication (GJIC) promote microvascular endothelial cell loss.
• iovs.arvojournals.org/article.aspx?articleid=2125630

Verocytotoxin

• Induced Apoptosis of Human Microvascular Endothelial Cells
• jasn.asnjournals.org/content/12/4/767

Radiation

• Induced apoptosis in microvascular endothelial cells
• www.nature.com/articles/bjc1997119

Arteriolární vazodilatace

Nedostatek bílkovin

• Chybí jejich tzv. onkotický tlak
• Nedostatečný přísun v potravě
• Poruchy vstřebávání živin (a tedy i bílkovin) z trávicího traktu

Bradykinin

C-X-C motif chemokine 10

Chemokine (C-C motif) ligand 2 - CCL2

CD4+T cells

• Help regulate humoral immunity to herpes simplex virus by controlling vascular permeability in an IFN-?-dependent manner that
• Allowed for suf?cient antibody availability within the tissue [51]

CXCL10 (chemokine [C-X-C motif]) ligand 10

Capillary leak syndrome

• Sepsis
• Idiopathic systemic capillary leak syndrome - Clarkson’s disease
• Engraftment syndrome
• Differentiation syndrome
• Ovarian hyperstimulation syndrome
• Hemophagocytic lymphohistiocytosis
• Viral hemorrhagic fevers
• Autoimmune diseases
• Snakebite envenomation
• Ricin poisoning
• Interleukins
• Monoclonal antibodies
• Gemcitabine can also cause capillary leak syndrome [14]
• Acute respiratory distress syndrome (ARDS) [15]
• Severe Dengue fever
• Malaria [15]
• Hematological malignancies
• Blood cancer medications [17]
• Severe trauma
• Cardiopulmonary bypass
• Burns [17]
• Recombinant IL-2 [17]
• Docetaxel [17]

Mechanismus

• Acute kidney injury
• Commonly seen in all of these diseases
• Cytokines
• Likely to be important in the pathophysiology of acute kidney injury in capillary leak syndrome [14]
• Increased capillary permeability by exudating materials of molecular weight less than 20 × 103 Da
• Even molecular weight of 90 × 103 Da in serious condition [17]
• Cells and platelets are generally retained within the vasculature
• Resulting in elevations in white blood cell, red blood cell, and platelet counts [19]

Complement

Connective tissue disease (CTD)

• Anti-SSA antibody might be associated with pathology of SCLS [27]
• Combination therapy with GC and IVIG should be taken into consideration [27]

Scleroderma

Polymyositis (PM)

Juvenile dermatomyositis (JDM)

• IVIG is needed for JDM [27]

Systemic lupus erythematosus (SLE)

• Glukokortikoidy seems effective for SCLS with SLE [27]

Sjögren’s syndrome (SS)

• SCLS with SS
• Efficacy of GC or IVIG seems different in each case [27]

Systemic sclerosis (SSc)

Defekt C1 proteinu

Differentiation syndrome

Retinoic acid syndrome (RAS)

• In people with acute promyelocytic leukemia (APML) and tretinoin treatment or
• arsenic trioxide
• Did not appear in patients treated with tretinoin for other disorders
• RAS depends on the presence of the malignant promyelocytes [20]
• Cytokine release from the differentiating myeloid cells [20]
• Dyspnea, fever, weight gain, hypotension, and pulmonary infiltrates [20]
• Treated by giving dexamethasone [20]

Disruption of endothelial junctions

EPC Increase - Endothelial Progenitor Cells

• Can promote injury repair and regeneration of capillaries

Vascular endothelial growth factor

• Increasing the gene expression of vascular endothelial growth factor
• Can specificly increase the concentration of EPC in peripheral blood
• Promote EPC mobilization and repair of vascular endothelial

Erythropoietin - EPO

• Can promote EPC proliferation and differentiation
• EPO treatment can increase the number of EPC in peripheral blood [17]

Endothelial cell injury

• Manifests as
• Hypertension,
• Proteinuria,
• Thrombotic microangiopathy [18]

After hydrogen peroxide treatment

• Irreversible and develops over a longer period of time [18]

Receiving anti-VEGF therapy

• May develop endothelial injury [18]

Endothelial cadherin internalization

Erythroderma

• Systemic capillary leak syndrome as a complication
• Arises from
• Unstable psoriasis
• Drug eruptions
• Malignancies [31]
• Psoritiac erythroderma increases 30% the daily loss of proteins
• May generate edema
• Muscular weekness
• Hypoalbuminaemia
• Compensatory hypermetabolism
• Increased basal metabolic rate
• Accelerated blood flow
• Hypothermia which is intensified by heat evaporation through the dilated permeable cappilaries
• Inability to respond with vasoconstriction and/or vasodilation [31]
• Can be fatal, especially in the elderly and in people who suffer from heart diseases.
• Skin manifestations are diverse
• Purpuric lesions
• Subcutaneous infiltration
• Livedo
• Rash in sunexposed areas
• Erythematous papules and they occur during the attacks in the idiopathic form [31]

F-actin interakce

• Critical component of the cytoskeleton
• Rearrange into stress fibers that enable retraction of cell boundaries after cellular exposure to diverse permeability mediators
• Episodic serum of SCLS patients
• Induced prominent actin stress fibers [18]

Hereditární angioedém

• Snížená funkce / koncentrace inaktivátorů C1 složky komplementu
• Otok vznikne vaskulárními změnami vlivem aktivovaných složek komplementové kaskády s funkcí podobnou kininu
• často postihuje:
• Obličej, víčka, rty, jazyk, končetiny, genitál
• Projevy:
• Asymetrické, prchavé, často přítomna urtika

Histamin

• histamine levels are elevated only in a few patients with early bacteremia and did not predict outcome
• Increased D-dimer levels on the first day of positive blood culture are predictive of in-hospital mortality.
• histamine levels in sepsis were shown to be significantly higher in non-survivors
• None of our patients had combined liver–kidney impairment, which could potentially lead to insufficient clearance of histamine levels in patients with advanced sepsis, because both organs clear histamine very efficiently
• histamine levels may only become elevated in systemic infection when multiple organ failure occurs, which may be addressed in future studies

Horko

• Sauna i horké koupele [12]

  Ne uplně vždy a ne u každého - záleží na mnoha dalších okolnostech

Hypokalemie

• Nedostatek draslíku v organizmu následkem
• Průjmů
• Nadměrného močení
• Vyšší hladiny kortikoidů
• Vlivem diuretik chron. užívaných
• Po korekci déle trvající acidózy (ev. hypoxie)
• Může vyvolat otok dolních končetin

Idiopathic edema

• Twenty-seven patients
• Easy occurrence of subcutaneous bleeding
• Positive Rumpel-Leede phenomenon were observed in the majority of the patients
• ADH, plasma renin activity and plasma aldosterone concentration
• Did not show abnormalities following water loading in the supine position
• Might contribute to water and sodium retention in the upright position
• Plasma prolactin levels were rather increased
• Urinary excretion of kallikrein and kinin
• Was reduced significantly after water loading in the upright position
• Prolactin and urinary kallikrein-kinin system
• Might also contribute to water and sodium retention in idiopathic edema
• Directly or indirectly through the augmentation of the action of ADH and of aldosterone

Tohoku J. exp. Med., 1980, 130, 71-78, Role of Endocrinological Factors in the Pathogenesis of Idiopathic Edema

-www.jstage.jst.go.jp/article/tjem1920/130/1/130_1_71/_pdf

Jet leg syndrome

• častěji u žen
• Otoky nohou po delším letu v letadle

Kapilární prosak

• Mezi tepenným a žilním systémem
• Stěna je tvořena pouze jednou vrstvou endotelových buněk
• Póry o velikosti 6 až 8 nm - přesně tak, aby se do nich vešel jeden erytrocyt
• Celkově:
• 96 000 km
• Plocha 500 až 1 000 m2 jsou široké
• Tlak se v kapilárách mění podle Starlingova zákona filtrace a resorpce
• V krvi obsažené plazmatické bílkoviny se za normálních okolností přes póry nedostanou
• Slouží tak k udržení stabilního onkotického tlaku
• Na venózním konci kapiláry nasávají odpadní látky metabolismu zpět do žilního systému
• 90 % krevní kapiláry
• 10% lymfatické kapiláry [12]
• Jakákoli dysbalance vede k otoku

Kawasakiho nemoc (KD) - mukokutánní lymfonodulární syndrom

• Děti s horečkou, vyrážkou,
• Konjunktivitidou (zarudnutí očí),
• Enantemem (zarudnutím sliznic úst a hrdla)
• Otoky rukou a nohou
• Zvětšením lymfatických uzlin na krku
• Srdeční komplikace
• Aneuryzmata koronárních tepen (výdutě krevních cév).
• Akutní systemová vaskulitida
• Zánět stěny krevních cév
• Může způsobit rozšíření (aneurysma) kterékoliv středně velké tepny v těle
• Zejména koronární
• Vzácná nemoc
• S Henoch-Schönleinovou pupurou patří k nejčastějším vaskulitidám dětského věku
• 85% pacientů s tímto onemocněním je mladší 5 let
• Horečkou bez zřejmé příčiny
• Dítě je obvykle velmi dráždivé
• Doprovázena nebo následovaná zánětem spojivek (zarudnutí očí), bez hnisavé sekrece
• Může mít vyrážku charakteru spalniček, spály, kopřivky, papulek apod
• Vyrážka nejčastěji postihuje trup, končetiny a často plenkovou oblast
• Vede k zarudnutí a později olupování kůže.
• Postižení dutiny ústní může zahrnovat jasně červené popraskané rty, červený (tzv. malinový) jazyk a zarudnutí hltanu
• Ruce a nohy mohou být oteklé a zarudlé nejčastěji na dlaních a chodidlech
• Prsty na rukou a nohou mohou otékat
• Charakteristické olupování kůže okolo špiček prstů (většinou v průběhu 2.-3.týdne)
• Více než polovina dětí má zvětšené krční mízní uzliny
• často se jedná o jedinou uzlinu vel. přes 1,5cm
• Mohou být přítomny bolesti a/nebo otoky kloubů, bolesti břicha, průjem, dráždivost nebo bolesti hlavy
• U menších dětí očkovaných BCG vakcínou proti tuberkulóze může zduřet a zarudnout jizva po očkování.
• Mohou se objevit srdeční šelesty, poruchy rytmu a odchylky při vyšetření ultrazvukem.
• Všechny srdeční vrstvy mohou být postiženy určitým stupněm zánětu
• Perikarditida (zánět blány obalující srdce)
• Myokarditida (zánět srdečního svalu)
• Postižení chlopní
• Vznik aneuryzmat věnčitých tepen (CAA)
• Jen výjimečně byly popsány případy KD u dospělých.

• Diagnóza KD je stanovena na základě
• Klinického vyšetření lékařem, obvykle během pobytu dítěte v nemocnici.
• Přítomnosti horečky bez zjevné příčiny trvající déle než 5 dní spolu s 4 z 5 následujících projevů:
• Oboustranná konjunktivitida (zánět spojivek)
• Zvětšení mízních uzlin
• Kožní vyrážka
• Postižení dutiny ústní a jazyka
• Změny na končetinách
• Některé děti mají tzv. nekompletní formu onemocnění
• Stanovení diagnózy obtížnější.

• KD probíhá ve 3 fázích:
• Akutní
• První 2 týdny
• Teplota a další symptomy
• Subakutní
• 2-4 týdne
• Stoupá počet trombocytů (krevních destiček) a mohou vznikat aneuryzmata
• Fáze rekonvalescence
• 1-3 měsíce
• Upraví se laboratorní nálezy a některé cévní abnormality vymizí nebo se zmenší.
• Neléčená KD zpravidla ustoupí samovolně zhruba za 2 týdny, jejím následkem však může být trvalé poškození věnčitých tepen.
• Terapie
• Jedna dávka vysokodávkovaných, nitrožilně podaných imunoglobulinů (IVIG)
• U velké části pacientů zabraňují postižení věnčitých tepen
• Aspirin -Do normalizace hodnot destiček
• Pacientům, u kterých obtíže neustoupí po 1-2 dávkách IVIG, se podávají kortikosteroidy ve vysokých dávkách nebo tzv. biologická léčba.

Kipple Trenaury syndrom

• I tromboflebitidy
• Někdy i zn. hypopl. typu prim. lymfedemu
• Hypetrofie kostí
• Hemangiomy
• A/V aneurysma - Parkesův Weberův syndrom

Kompartment syndrom

Nikotin - kouření cigaret

Lipopolysaccharide exposure

Lymphokine-activated killer (LAK) cells engagement

Leukotriene B4

• Might be related to increased vascular permeability
• Plasma extravasaton and others [17]
• Leukotriene B4 plays a central role in capillary permeability and, in vitro, its increase was detected [31]

Systemic Capillary Leak Syndrome - Clarkson's Syndrome - SCLS

• Rare acquired disorder, not hereditary, cause of SCLS is not yet known
• Acute and severe recurrent attacks associated with a rapid fall in blood pressure
• Often last several days and require emergency care, sometimes fatal
• Most often in adults and the disease is very rare in children [13]
• Idiopathic SCLS has been reported preceding hematologic malignancy [25]
• často s: IgG kappa or gamma monoclonal gammopathy [25]

Symptoms of acute form and treatment

Prodromal phase

• Until the 48th hour with weight gain, fatigue, faintness, low-grade fever, and head and neck or gastrointestinal symptoms related to mucosal edema.
• Brief warning, which can include nasal congestion and cough
• Can be mistaken for a viral upper respiratory infection
• Develop malaise, nausea, lightheadedness, a faint feeling, abdominal pain, headache and swelling of the extremities
• Mucocutaneous and visceral edema [16]
• Characteristic absence of fever, chills, rash, or signs of infection
• Overt prostration and fainting may occur.
• Disappearance of the syndrome is rare.
• Remissions may be spontaneous or they may follow treatment.
• May be more common in children than adults [13]

First phase Attack

• Often lasts several days is called the resuscitation phase
• Controlling the capillary leak and maintaining blood pressure
• Albumin and fluid leak from the capillaries into the tissue spaces causes swelling
• Similar effects on the circulation as dehydration, slowing the flow of oxygen carrying blood to tissues
• Blood pressure falls and the red cells concentrate [13]
• Intravenous fluid replacement is usually required immediately and in high-volume in order to prevent excessive drops in blood pressure
• Intravenous albumin and colloid may be used
• May have temporary benefit to increase blood flow to vital organs like the kidneys
• Colloid hydroxyethyl starch as the generation of plasma is still the effective and available drug in clinical for CLS treatment
• Hydroxyethyl starch of 130 × 103 Da and 200 × 103 Da molecular weight, polygeline of (27.5 - 39.5) × 103 Da molecular weight and so on
• In theory, they may have better expansion effect
• Macromolecular plasma substitutes seems to be better
• Don’t advocate adding FFP and/or human serum albumin for emergency treatment of CLS [17]
• Goal is NOT to attempt to maintain absolutely normal blood pressure or urine flow
• But to maintain the blood pressure at just sufficiently high enough levels to avoid permanent damage to vital organs
• Acute renal ischemia and failure [17]
• Spare the patient from the risks of excess fluid administration [13]
• Vasoactive amines are recommended in case of early signs of hypoperfusion
• If possible with norepinephrine
• Is less arrhythmogenic and if necessary extrarenal purging in case of acute renal failure [16]
• Large amount of liquid leaks from the capillary wall - cause
• Ascites under abdominal wall, gastrointestinal wall and peritoneal edema, then anorexia, nausea, vomiting, abdominal distension, and luminal expansion.
• Pancreatic tissue edema and trypsin penetrates into the abdominal cavity
• Will make damage increased [17]
• Liver cell congestion, edema, degeneration
• Other pathological changes will impaire liver function and acute liver injury appears [17]
• Increased pulmonary capillary permeability
• To pulmonary interstitial rapidly - pulmonary effusion changes and leads to hypoxemia and pleural effusion [17]

Second phase - recruitment phase

• Fluids and albumin are reabsorbed from the tissues
• Capillary leak has abated
• Main threat is fluid overload
• Even though the blood pressure may still be low, it is important to avoid overly aggressive intravenous fluid administration
• Massive swelling of the extremities requiring surgical decompression
• Skin of the arm or leg is incised to release the compressive pressure the retained fluid is having on blood flow to and from the extremities [13]
• Excessive intravenous fluids may also cause accumulation of fluid in the lungs and around other vital organs
• Many of the deaths happen during this recruitment phase
• Measurement of central venous or arterial pressure in an intensive care unit is often necessary
• Diuretics
• May be required for excess fluid overload [13]
• Glucocorticoids
• Often used during the acute attack especially early in the recruitment phase
• In an attempt to reduce the capillary leak [13]

Maintenance therapy

• Attempt to reduce the frequency and severity of the acute attacks
• Aimed at decreasing capillary leakage
• Interfering with hormone like cytokines that induce the leakage
• Most commonly used medications are
• Theophylline and terbutaline by mouth [13]
• Antihistamines and beta 2 agonists with terbutaline and theophylline [17]
• Level of theophylline must be maintained in the therapeutic range
• Means of regular blood tests
• Who do not tolerate these drugs may benefit by
• Leukotriene inhibitors - Singulair [13]
• ACE inhibitor such as lisinopril may be of benefit [13]
• Role of glucocorticoids, chemotherapy, thalidomide, and intravenous immunoglobulin is as yet unproven [13]

• Hojivý Detralex a spol. do kombinace nikoho nenapadl ?

• Glukokortikoidy
• It should not be used as a preventive treatment
• Because of the side effects of steroid restrictions [17]
• Indomethacin, spironolactone, cyclosporine (our choice when the etiology is unstable psoriasis ) [31]

Unproven effect

• Theophylline,
• Diuretics,
• Terbutaline,
• Steroids,
• calcium antagonist,
• Ginkgo biloba extracts
• Plasmapheresis as medication for SCLS [23]
• Vascular endothelial cell growth factor (VEGF) inhibitor
• Tumor necrosis factor (TNF)-alpha inhibitor
• Thalidomide
• Prostacyclin [31]
• Pentastarch [31]
• Inhibition of apoptosis by anticaspases or antioxidants
• Inhibitory action on the vascular factor of endothelial growth or on pathways it mediates [31]

Mayo clinic

• Beta agonists such as terbutaline
• Phosphodiesterase-inhibitor theophylline
• Leukotriene-receptor antagonists montelukast sodium [22]
• Because of:
• Ability to increase intracellular cyclic AMP (adenosine monophosphate) levels
• Might counteract inflammatory signaling pathways that induce endothelial permeability
• It was the standard of care until the early 2000s
• Patients frequently experienced renewed episodes of SCLS
• Drugs were poorly tolerated due to their unpleasant side effects [22]
• More recent approach in France early 2000s
• Monthly intravenous infusions of immunoglobulins (IVIG)
• Initial dose of 2 gr/kg/month of body weight
• Proven very successful as per abundant case-report evidence from around the world [22]
• Used for the treatment of autoimmune and MGUS-associated syndromes
• Immunomodulatory and anticytokine properties
• It is likely that it neutralizes their proinflammatory cytokines that provoke endothelial dysfunction
• In 69 mostly European SCLS patients found that preventive treatment with IVIG was the strongest factor associated with their survival
• IVIG prophylaxis is associated with a dramatic reduction in the occurrence of SCLS episodes in most patients, with minimal side effects [22]
• During 1996-2016, the 5- and 10-year survival rates for SCLS patients were 78% and 69% [22]
• Five- and 10-year survival rates in patients treated with IVIG
• 91% and 77%
• Patients not treated with IVIG
• 47% and 37% [22]

Children 2015

• High dose immunoglobulins or theophylline plus verapamil, appears to be safe and efficacious [29]

Diagnoza

• Classic combination of
• Hypotension or shock
• Hemoconcentration
• Hypoalbuminemia
• Sudden and profound capillary leak causes a sharp decrease in serum albumin level (hypoalbuminemia)
• Similarly sharp increase in the level of hemoglobin and hematocrit
• Red blood cells which contribute to measurements of hemoglobin and hematocrit are not actually increased
• Blood becomes concentrated due to the loss of fluid
• Proof is essential for the diagnosis [13]
• Diagnosis of SCLS should rule out
• Infection
• C-1 esterase inhibitor deficiency
• Search for an M protein should be undertaken
• But the absence of an M protein does not exclude the diagnosis [13]
• Significance, if any, of the paraprotein (MGUS) present in most patients with SCLS is unknown [19]
• Other than it has been a precursor to multiple myeloma in a minority (7% in the largest reported cohort) of SCLS patients [19]

Chronic form of SCLS

• Manifest by swelling of the extremities and sometimes fluid accumulation around the heart and lungs.
• The characteristic occur due to loss of fluid in the tissues
• Increase in hemoglobin and hematocrit
• Decrease in albumin
• Low blood volume with decrease in blood pressure or shock are uncommon in the chronic form
• These patients may respond to
• glucocorticoids
• diuretics
• aminophylline [13]

Další nálezy

• More than one half of patients have a monoclonal or M protein detected in the blood.
• Level of M protein is usually low
• Produced by what usually amount to small numbers of plasma cells in the marrow
• Itself does not appear to cause the attacks
• Capillary lining cells may be damaged by a factor in the blood, which is produced during the acute attack [13]

Epidemiologie

• Less than 100 patients reported in the world literature since its first description in 1960 by Clarkson
• Seems to occur more often in males and older adults
• May be more frequent than the literature suggests
• Diagnosis is often missed or delayed.
• May be mistaken for a severe infection such as septic shock or toxic shock syndrome
• Features often lead to misdiagnosis:
• Heart failure or kidney disease
• C-1 esterase inhibitor deficiency syndrome in angioedema
• Hemoconcentration and resulting high hematocrit and hemoglobin level have been mistaken for polycythemia [13]
• Well-defined events that occurred before attacks could be identified in only 22% of patients
• Seropositive influenza
• Seropositive West Nile virus infection
• Chronic SCLS
• Noncyclical peripheral edema and hypoalbuminemia in the absence of secondary causes of edema [18]
• Cohort and 8 of 15 reported cases overall (53%) had a documented infectious trigger
• None of the pediatric patients tested to date had a monoclonal gammopathy (n = 10)
• 75% to 95% of adults with classic acute SCLS have monoclonal gammopathy of undetermined significance [29]

TNF

• Can accelerate the occurrence of CLS [17]

Teplo

• Nevhodná je
• Horká koupel
• Saunování
• Přehřívání organizmu dlouhým opalováním
• Zbytečným pobytem v teplém prostředí

VE-cadherin narušení

• Vascular endothelial-specific transmembrane proteins
• calcium-mediated homotypic interactions between adjacent cells are indispensable for endothelial barrier function
• Episodic serum of SCLS patients
• Attenuated the junctional localization of VE-cadherin [18]

ZO-1 narušení

• Vascular endothelial-specific transmembrane proteins
• calcium-mediated homotypic interactions between adjacent cells are indispensable for endothelial barrier function
• Episodic serum of SCLS patients
• Disrupted paracellular junctions [18]

Expression of anti-lymphangiogenic cytokines

TGF-B1, interferon gamma, IL4, IL13

• Decrease lymphatic endothelial proliferation
• Increase lymphatic leakiness.

Kataru et al., 2011; Gardenier et al., 2017; Gousopoulos et al., 2017; Park et al., 2018

• Can directly decrease responsiveness of lymphatic endothelial cells to VEGF-C
• Thus decreasing the efficacy of exogenous VEGF-C delivery for the treatment of lymphedema.

Savetsky et al., 2015; Shin et al., 2015; Ogata et al., 2016

• www.frontiersin.org/articles/10.3389/fphar.2022.828513/full

LTB4

• Bimodal effect on lymphangiogenesis:
• Low doses of LTB4 increased lymphangiogenesis
• High concentrations - as found in lymphedema —inhibited lymphangiogenesis
• www.frontiersin.org/articles/10.3389/fphar.2022.828513/full

Markers of inflammation

• In 1-2 patients being associated SLCE episodes with elevated markers of inflammation
• Modestly increased TNFalpha levels in acute SCLS serum samples
• Relative to the basal and control groups
• Neither IL-2 nor IL-8 was elevated in patients with SCLS compared with controls [18]

Neurogenní edém

Neuropatie

Poradiační

• Může vzniknout i po několika letech od radioterapie

NK cells

• In mice study prooved to be involved in the pathological process of CLS [17]

Nitric oxide

• Could lead to vascular endothelial cell injury and increase capillary permeability [17]

p190BRhoGAP mutation

• Prolonged RhoB activation in fatal systemic capillary leak syndrome [24]
• TNF transiently activates RhoB in ECs
• Developing leak
• Inactivation of RhoB
• Correlates with barrier recovery
• Mutation in p190BRhoGAP impairs RhoB inactivation
• Mutant phenotype may also be important in acquired systemic capillary leak associated with critical illness in humans [24]
• SNV, adenosine 2,285 to thymidine, in one copy of the ARHGAP5 gene on chromosome 14 (position 32,562,160 of genome build 37) [24]
• Single amino acid change, changing aspartic acid 762 to valine
• Predicted to be very deleterious to protein function by PolyPhen2 (0.55, P), SIFT (0.04, D), LRT (0, D), and MutationTaster (1, D) scores
• Occurs at a site that is highly conserved among humans and other species [24]
• Rho GTPase activating proteins (RhoGAPs) stimulate GTP hydrolysis
• By and inactivation of one or more of the three Ras homologue gene family members expressed in humans (RhoA, RhoB, and RhoC)
• RhoA has been implicated in alterations of barrier function by thrombin
• Abundance of RhoB transcript and activation of RhoB protein
• Increased by TNF treatment
• Unique C-terminal region - may have specialized functions not shared by RhoA or RhoC
• Inhibitor of EC barrier recovery
• By sequestering Rac1 away from intercellular junctions in human umbilical vein ECs stimulated by thrombin (Marcos-Ramiro et al., 2016)
• Increased active RhoB and prolonged activation of RhoB in response to TNF in SCLS x control
• Correlates with the defective recovery of barrier function [24]

Parézy se stázou krevního toku

• se stejnostrannou angioparézou
• Nebývají postiženy šlachy
• U roztroušené sklerózy
• Stavy po poliomyelitidě
• Hemiparézy končetiny po cévní mozkové příhodě [8]
• Stavy s poškozením autonomníno nervstva, které reguluje tonus kapilár
• Takže i některé neuropatie

Povrchní dýchání

• Příliš nízký krátký nasávací podtlak v hrudníku při nádechu

Psychological stressors

• Also influence VEGF and Ang2 levels [18]

Selektiny sP a sL zvýšené koncentrace

• Adhezivní molekuly přítomné na všech leukocytech
• Při jejich zvýšených koncentracích dochází ke snadnější adhezi leukocytů na kapilární endotel [12]

Shear stress

• Also influence VEGF and Ang2 levels [18]

Systemic inflammatory response syndrome - SIRS

Infekce / trauma

• Excessive activation of mononuclear macrophage system
• Release of inflammatory mediator
• Endothelial cell and capillary walls damage
• Cell junction separation
• Cracks appear
• Capillary transport channel diameter and vascular permeability increase
• Small protein in the blood leaks into the interstitial space
• Interstitial colloid osmotic pressure
• Interstitial edema [17]

Operation after Cardiopulmonary Bypass

• Systemic inflammatory response
• Blood surface contact with the pump pipe
• Non-physiological perfusion
• Surgical trauma
• Ischemia reperfusion injury
• Changes in body temperature [17]
• Related to perioperative capillary leak
• Independent factors of CLS in 310 cases were:
• Infection cycle time
• Type of cardiac malformation
• Lowest temperature of operation
• Age [17]

Komplikace

• ARDS
• Renal injury
• Pancreatitis
• Brain oedema, intracranial hypertension, herniation
• Hepatic edema and injury
• GIT toxin translocation
• Hearth arrytmiha and filure (ion dysbalance, ...)

Dlouhodobé stání, sezení, či chůze

• I u zcela zdravých lidí mohou nohy otéci, pokud jsou namáhány dlouhodobým stáním nebo dlouhou chůzí u netrénovaného jedince
• Kombinuje se zde více faktorů
• Otlačení nohou v botách
• Horší odtok žilní krve z nohou ve vertikální poloze apod.

Statické otoky

• U osob s oslabením svalově-žilní pumpy lýtek
• U starších nepohyblivých osob s artrózami kloubů dolních končetin
• Někdy se tyto otoky označují jako otoky geriatrické nebo artrotické
• U lidí se sedavým zaměstnáním
• Po delší cestě autobusem či letadlem apod. [8]
• Všechny otoky dolních končetin se zhoršují nedostatkem pohybu, dlouhodobým stáním a sezením
• Naopak ustupují při chůzi a zvednutí dolních končetin

Aktivace sympatiku

• Perimaleolární otoky
• Souvisí s aktivací sympatického nervového systému cestou
• Baroreceptorů,
• Konstrikcí postkapilárních venul,
• Tím zvýraznění tlakového gradientu na kapilární úrovni
• Vzniká z prekapilární arteriolodilatace a postkapilární venokonstrikce
• Hydrostatický tlak zhoršuje fenomén kapilární transudace