книги студ / Color Atlas of Pathophysiology (S Silbernagl et al, Thieme 2000)

A. Compensatory Mechanisms When There Is a Risk of Hypovolemic Shock
	Blood pressure	Blood volume
	falls		reduced
		Chemo-				Stimulus
Anaerobic	PO2	receptors				Signal
						Compensation
glycolysis
					Hypo-	Thirst
	Presso-				thalamus
Lactate	receptors						I
							Shock
pH
Medullary							Circulatory
centers	Volume	Heart			Renin	ADH
	receptors
				Angiotensin II			7.29
						Aldosterone
Sympathetic							Plate
stimulation
	Adrenal				Adrenal
					cortex
	medulla
					Kidney
Epinephrine				Capillaries
						Water
						resorption
Arterial
vasoconstriction,		Capillary
esp. kidneys,		pressure
stomach, intestine
and skin	Venous					Renal
					perfusion
vasoconstriction
		H2O flow			GFR
	Venous	into capillaries
	return
	Heart rate
Peripheral	Cardiac contractility
resistance						Oliguresis
	Blood pressure		Blood volume
	rises		increases				231

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7 Heart and Circulation

232

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increased sympathetic tone. Arterial vasoconstriction (not in shock caused by vascular distension) directs the reduced cardiac output away from the skin (pallor), the abdominal organs, and the kidneys to vital organs (coronary arteries, the brain), bringing about centralization of the circulation. Vasoconstriction of the venous capacitance vessels (increased cardiac filling), tachycardia, and positive inotropy, all the result of sympathetic nervous activity, raise the previously reduced cardiac output slightly. Epinephrine released from the adrenal medulla supplements this nervous system mechanism.

Volume compensation (→ A, right). The fall in blood pressure and arteriolar constriction with incipient shock diminishes the effective capillary filtration pressure, and thus interstitial fluid flows into the blood compartment. In addition, atrial pressure receptors recognize the volume deficit (decreased atrial pressure), which inhibits the secretion of atriopeptin and reflexly brings about ADH secretion (Hen- ry–Gauer reflex). ADH acts as a vasoconstrictor and to retain water. The reduction in renal blood pressure increases the release of renin, more angiotensin II is formed, the latter stimulating thirst and also having a vasoconstrictor effect. In addition, it increases the secretion of aldosterone, which in turn diminishes salt elimination, and thus water elimination, via the kidney (→ p.122ff.). If the risk of shock can be averted, the lost erythrocytes will be replaced later (raised renal erythropoietin formation; → p. 30ff.) and the plasma proteins will be replenished in the liver by increased synthesis.

If the organism is not able, without outside help (infusions etc.), to prevent the shock with the above-mentioned homeostatic compensatory mechanisms, manifest (or decompensated) shock will develop (→ B). If the systolic blood pressure remains < 90 mmHg or the mean pressure < 60 mmHg for a prolonged period (which can happen despite volume replacement [protracted shock]), the consequences of hypoxia will lead to organ damage that may culminate in extremely critical multiorgan failure. Frequent organ damage includes acute respiratory failure (= shock lung = adult respiratory distress syndrome [ARDS]) with hypoxemia, acute renal failure (glomerular fil-

tration rate [GFR] < 15 mL/min, despite normalization of blood pressure and volume), liver failure (plasma bilirubin is elevated, prothrombin decreased), brain damage (loss of consciousness, increasing degree of coma), disseminated intravascular coagulation, acute ulcers in the gastrointestinal tract with bleeding.

Several mechanisms are involved in shock, some of them self-reinforcing.They aggravate the shock until it can no longer be favorably influenced, whatever the therapeutic measures (irreversible or refractory shock). The follow-

ing	vicious circles	develop,	among others:
1.	Vasoconstriction	flow	velocity	↓
	blood viscosity	↑ flow	resistance	↑
	flow velocity ↓↓ etc. until complete flow

arrest (stasis with sludge phenomenon) (→ C1).

2a. Volume ↓ blood pressure ↓ peripheral vasoconstriction → hypoxia → arteriolar opening → fluid loss into interstitial spaces → volume ↓↓ blood pressure ↓↓hypoxia ↑ (→ C2a).

2b.Volume ↓ hypoxia capillary damage

clot formation disseminated intravascular coagulation bleeding into tissues

volume ↓↓ (→ C2b).

2 c. Hypoxia capillary damage thrombus formation hypoxia ↑ (→ C2 c).

3.Cardiac output ↓ blood pressure ↓ coronary perfusion ↓ myocardial hypox-

ia myocardial acidosis and ATP deficiency cardiac contractility ↓ cardiac output ↓↓ (→ C3,4).

4a. Cardiac contractility ↓ blood flow ↓ thrombosis pulmonary embolism hypoxia cardiac contractility ↓↓ (→ C4a).

4b. Hypoxia cardiac contractility ↓ pulmonary edema hypoxia ↑ (→ C4b).

4 c. Cardiac contractility ↓ blood pressure ↓coronary perfusion ↓ cardiac contractility ↓↓ (C4 c).

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B. Causes, Symptoms, and Consequences of Shock

Loss of blood or fluid

Sepsis, anaphylaxis,

Pulmonary edema

Myocardial infarct,

hyperthermia

AV block, etc.

Hypovolemia Vasodilation

Symptoms:

Cardiac filling

thirst								II
		Cardiac output			Cardiac			Shock
					contractility
hypotonia		Blood pressure						Circulatory
					Hypoxia
rapid
	Heart rate	Sympathetic tone
heart rate					Organ damage,			7.30
cold					esp.:
sweat		Vasoconstriction			lung		gastro-	Plate
pallor	Skin						intestinal
				kidney			tract
(not in
sepsis etc.)	Counterregulation
C. Vicious circles (1–4) which Lead to Irreversible Shock
Vasoconstriction			Blood pressure
			Vasoconstriction
	Blood
				Hypoxia		a
	flow velocity
					Capillary	Precapillary
					damage		dilation
Blood			Thrombi		b
viscosity			c		Consumption
		Stasis			coagulopathy
					Volume
				Bleeding
					outflow
1	Circulatory failure		2 Hypovolemia	Circulatory failure
			Cardiac			a
Hypoxia			contractility
	Myocardial acidosis
				Pulmonary edema
							Thrombi
			Blood
Blood		Myocardial	pressure		b
						Pulmonary
pressure		damage		c
						emboli
			Coronary
				Respiratory
		Cardiac	blood flow
				failure
CO		contractility
			Hypoxia
3	Circulatory failure		4	Circulatory failure				233

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7 Heart and Circulation

234

Edemas

Functional pores in the capillary endothelium allow largely protein-free plasma fluid to filter into the interstitial spaces. About 20 L/d are filtered through all capillaries of the body (excluding the kidneys), of which 90% are immediately reabsorbed. The remaining 2 L/d reach the blood compartment only via the lymph (→ A).

The filtration or reabsorption rate Qf is determined by the filtration coefficient Kf (= water permeability · exchange area) of the capillary wall, as well as by the effective filtration

pressure Peff (Qf = Peff · Kf). Peff is the difference between the hydrostatic pressure difference P

and the oncotic (colloidal osmotic) pressure difference Δπ across the capillary wall (Starling’s law), where P = blood pressure in the capillaries (Pcap) – interstitial pressure (Pint, normally ≈ 0 mmHg). Δπ arises due to the protein concentration being higher in plasma than in the interstitial space by Cprot (≈ 1 mmol/L), and it is the greater, the closer the reflexion coeffi-

cient for plasma proteins (σprot) is to 1.0, i.e., the smaller the endothelial permeability for

plasma proteins (Δπ = σprot · R · T · Cprot). At heart level, P at the arterial end of the capil-

laries is ca. 30 mmHg; at the venous end it falls to ca. 22 mmHg. Δπ (ca. 24 mmHg; → A, right) counteracts these pressures so that the intially high filtration (Peff = + 6 mmHg) is turned into reabsorption when Peff becomes negative. (In

the lungs P is only 10 mmHg, so that Peff is very low.)

Below the level of the heart the hydrostatic pressure of the column of blood is added to the pressure in the capillary lumen (at foot level ca. + 90 mmHg). It is especially on standing still that the filtration pressure is very high in the legs. It is compensated by self-regulation in that because of the outflow of water, the protein concentration and thus Δπ is increased along the capillaries. It is also part of self-regu- lation that Pint rises when filtation is increased (limited compliance of the interstitial space), and as a result P decreases.

If the amount of filtrate exceeds the sum of reabsorbed volume plus lymphatic outflow, edemas develop, ascites develop in the region of portal vein supply, as do pulmonary edemas

in the lungs (→ p. 80). Possible causes of edema are (→ B):

Blood pressure rise at the arterial end due to precapillary vasodilation (Pcap ↑), especially during a simultaneous increase in permeabil-

ity to proteins (σprot ↓ and thus Δπ ↓), for example, in inflammation or anaphylaxis (hista-

mine, bradykinin, etc.).

Rise in venous pressure (Pcap ↑ at the capillary end), which may be caused locally by venous thrombosis or systemically (cardiac edema), for example, by heart failure (→ p. 224ff.). Portal vein congestion leads to ascites (→ p.170).

Reduced plasma concentration of proteins (especially albumin) causes Δπ to fall excessively. This may be the result of renal loss of proteins (proteinuria; → p.104) or of too little hepatic synthesis of plasma proteins (e.g., in liver cirrhosis; → p.172ff.), or of an increased breakdown of plasma proteins to meet amino acid demand if there is a protein deficiency (hunger edema).

Diminished lymphatic flow may also cause local edemas, either by compression (tumors), transection (operations), fibrosis (radiotherapy), or occlusion (Bilharziasis) of the lymphatic vessels.

When edemas form, the interstitial space is enlarged until a new equilibrium is established (filtration = absorption + lymphatic outflow). An increased compliance of the interstitial space encourages edemas to form just as much as a raised hydrostatic pressure in the dependent parts of the body (e.g., ankle edema) does.

As edema fluid originates from blood, the consequence of systemic edema (→ B, bottom) will be a decrease in blood volume, and thus cardiac output. Renal perfusion is reduced not only directly by the fall in CO, but also as a result of sympathetic stimulation. The renal filtration fraction is raised and the renin–angio-

tensin mechanism is initiated. The resulting Na+ retention raises the extracellular fluid vol-

ume which, while increasing the blood volume, actually makes the edema worse. Na+ retention in renal failure also results in edema being formed.

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A. Fluid Exchange at Capillaries
Arteriole			Vein	kPa		mmHg
	Lymph			4.0	P	30
	ca. 10 %
		ca. 90 %		3.5	Δπ	25
pre-			post-	3.0
		Reabsorption	capillary			20
capillary
			resist-	2.5
resist-	Filtration
			ance
ance	(100%)			2.0		15
Interstitial space				Peff = (Pcap – Pint) – σ· R· T·		CProt
Filtration = Reabsorption + Lymphatic drainage				=	P – Δπ (kPa, mmHg)

B. Edema Formation
Circulation	Capillaries	Kidney		Liver		Edemas
						7.31
Systemic:	Systemic:	Glomerular		Liver damage		Plate
heart failure	anaphylaxia,	damage		(e. g. cirrhosis)
etc.	sepsis, etc.	(nephrotic
Local:	Local:	syndrome)
venous thrombosis,	inflammation etc.				Local:
inflammation, etc.
		Protein		Protein	(portal vein)
	Histamine etc.	loss		formation
		Plasma proteins			Congestion
Venous congestion	Precapillary vasodilation
	Pcap	σProt		CProt	Ascites
Na+ metabolism
Na+ uptake high,	P	P
Na+ retention	Δπ	Δπ	=	σProt · R · T ·	CProt
(e. g. renal failure)
				Lymphatic
Na+ balance positive	ECV			drainage
	Edema			Compression of
				lymphatic vessels
Na+ retention	Systemic
				Obliteration
Renin-Angiotensin	Blood volume			(radiotherapy)
					Obstruction
Renal blood flow				Lymph	(bilharziasis)	235
		Pint

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7 Heart and Circulation

236

Atherosclerosis

Atherosclerosis (Ath.; arteriosclerosis) is the cause of more than half of all deaths in the western industrialized nations. It is a slowly progressing arterial disease in which the intima (→ A1) are thickened by fibrous deposits that gradually narrow the lumen and gradually become the site of bleeding and thrombus formation (→ B).

Fatty streaks are the earliest visible sign of Ath. (as early as childhood). They are subendothelial accumulations of large, lipid-contain- ing cells (foam cells; → A2). Later, fibrous plaques or atheroma form (→ A3), which are the cause of the clinical manifestation of Ath. These plaques consist of an accumulation of monocytes, macrophages, foam cells, T lymphocytes, connective tissue, tissue debris, and cholesterol crystals. Plaques are often infected with the bacterium Chlamydia pneumoniae.

The most common site of plaques are the abdominal aorta, coronary arteries, popliteal arteries, and the cerebral circulus arteriosus (in order of frequency).

Of the important risk factors of Ath. (→ C1), five can be influenced, namely hyperlipidemia, hypertension, smoking, diabetes mellitus, and hyperhomocysteinemia. It is not clear whether chlamydia infection plays an important part in the pathogenesis of Ath., or whether it perhaps even triggers its development. Risk factors that cannot be influenced are age, male sex, and a genetic predisposition (→ p. 246ff.). Subordinate factors are overweight and a sedentary or stressful lifestyle.

Hyperlipidemia. Serum cholesterol levels higher than 265 mg/dL (6.85 mmol/L) in those aged 35 – 40 years increase the risk of coronary heart disease fivefold compared to values of < 220 mg/dL (5.7 mmol/L). 70% of this cholesterol is transported in low-density lipoproteins (LDLs) and the development of Ath. correlates closely with increased LDL levels. A defect in LDL receptors leads to very early Ath. (→ p. 246ff.). A special risk factor seems to be lipoprotein(a) (= LDL that contains apolipoprotein Apo(a)). Apo(a) resembles plasminogen and binds to fibrin so that Apo(a) may have an antifibrinolytic and thus thrombogenic effect. (On the role of triglyceride and high-density lipoproteins [HDL], → p. 246ff.).

Smoking increases the risk of dying from the effects of coronary heart disease 1.4 to 2.4fold (even light smoking), and in heavy smokers up to 3.5fold. Smoking low tar and low nicotine cigarettes does not lower this risk, but it is significantly lowered if smoking is stopped altogether. It is not clear how smoking promotes Ath. Possible causes are sympathetic nervous system stimulation by nicotine,

displacement of O2 in the Hb molecule by carbon monoxide, increased platelet adhesiveness, and raised endothelial permeability, induced by constituents in smoke.

Hyperhomocysteinemia (> 14 µg/L plasma, e.g., due to a lack of methylenetetrahydrofolate reductase [MTFR]), increases the risk of Ath., a rise of 5 µmol/L corresponding to the risk of a 20 mg/dL increase in cholesterol concentration. Homocystein (HoCys) favors plaque formation, probably in several ways (see below). In the commonly occurring thermolabile gene polymorphism of MTFR, folate deficiency develops (→ p. 34). If the latter is removed, the HoCys level becomes normal.

The pathogenesis of Ath. remains unexplained, but endothelial damage (and chlamydia infection?, see above) could be the primary event and the reaction to it may eventually lead to plaque formation (response to injury hypothesis; → C). Plaques usually develop at sites of high mechanical stress (vessel bifurcation); in this way also hypertension becomes a risk factor. Among the reactions are an increased lipid uptake in the vessel wall as well as adhesion of monocytes and thrombocytes

(→ C2,3), helped by HoCys. The monocytes penetrate into the intima and are transformed into macrophages (→ C4). These liberate reac-

tive O2 radicals, especially the superoxide anion ·O2– (also helped by HoCys), which have a general damaging effect on endothelial cells and inactivate endothelium-formed NO on its

way to the endothelium and the vascular musculature: ·NO + ·O2– → ·ONOO– (→ C5). This results in the loss of NO action, namely inhibition of platelet and monocyte adhesion to the endothelium as well as antiproliferative and vasodilating effects on the vascular musculature. The latter favor spasms (→ B and C7). Even in the early stages of Ath., O2 radicals

!

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A. Vascular Wall Changes on Atherosclerosis
Endothelium			Necrotic nucleus
			(foam cells, cell debris,
Intima		Fibrous cover plate
			cholesterol crystals)
Media		(connective tissue,
Adventitia		immigrant muscle cells)
		Endothelial damage
	Lumen	and dysfunction
		Foam cells
		(lipid deposits)
		in the intima
1
Normal			3
vascular wall
	2		Fibrous plaque
			(atheroma)
	Fatty streaks

B. Consequences of Atherosclerosis

Plaque	Plaque
Residual	enlargement
lumen	Ischemia
	(→infarction)
	Spasm

Hypertension

Media damage

Nonatherosclerotic

causes

Thrombosis

True aneurysm

Dissecting aneurysm

Embolism

	Rupture	Ischemia
		(→infarction)

Thromboembolism

Rupture, occlusion of side branches, pericardial tamponade, aortic regurgitation, thromboembolism

Plate 7.32 Atherosclerosis I

237

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7 Heart and Circulation

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modify by oxidation of those LDLs that have entered the endothelium (→ C7). Oxidized LDLs damage the endothelium and there induce the expression of adhesion molecules which allow vessel musculature to proliferate. Oxidation also results in altered binding of LDLs. They can no longer be recognized by ApoB 100 receptors (→ p. 246ff.), but rather by so-called scavenger receptors that are contained in large amounts within the macrophages. Consequently, these now phagocytize large amounts of LDLs and are transformed into sedentary foam cells (→ C9). Lipoprotein(a) can be oxidized and phagocytized in a similar fashion. Simultaneously, chemotactic factors of monocytes and thrombocytes trigger the migration of smooth muscle cells from the media into the intima (→ C6). Here they are stimulated to proliferate by PDGF and other growth-promot- ing factors (from macrophages, thrombocytes, damaged endothelium, and the muscle cells themselves). They, too, are transformed into

foam cells by uptake	of oxidized	LDLs
(→ C10). They form an	extracellular	matrix

(collagen, elastin, proteoglycans) that also contributes to atheroma formation.

The consequences of plaque deposition (→ B) are narrowing of the lumen that can lead to ischemia. Coronary heart disease (→ p. 218ff.) as well as chronic occlusive arterial disease of the limbs with painful ischemia on exercise (intermittent claudication) are examples of this. Other consequences of plaque formation are stiffening of the vessel wall (calcification), thrombus formation that obstructs the residual lumen and can cause peripheral emboli (e.g., cerebral infarction, stroke) as well as bleeding into the plaques (additional narrowing by the haematoma) and the vessel wall. Thus weakened, the wall may be stretched (aneurysm; see below) and even rupture, with dangerous bleeding into the surrounding tissues, for example, from the aorta (see below) or cerebral vessels (massive intracerebral bleeding, stroke; → p. 360).

An aneurysm is a circumscribed bulging of an arterial vessel due to congenital or acquired wall changes. It takes on the following forms:True aneurysm (→ B, left) with extension to all three wall layers (intima, media, and adventitia). In 90– 95% of cases it is caused by atherosclerosis with hypertension. Frequently the abdominal aorta is affected. In rare cases it may be congenital or caused by trauma, cystic medial necrosis (Marfan’s, Ehlers–Danlos, or Gsell–Erdheim syndrome), or infection (syphilis, mycosis in immune-deficient patients).

False aneurysm (pseudoaneurism), consisting of a perivascular hematoma over a tear in the intima and media, connected with the vessel lumen. It is caused by trauma or infection (accident, operation, arterial catheterization).

Dissecting aneurysm (→ B, middle), usually in the ascending aorta in which, after perforation of the intima, blood under high (arterial) pressure “burrows” a path within the (usually degenerative) media so that intima and adventitia become separated along an advancing length of wall.

Arteriovenous aneurysm occurs when an aneurysm ruptures into a vein, producing an arteriovenous fistula.

One of the catastrophic complications of an aneurysm is rupture. If it occurs in a large vessel, hemorrhagic shock will dominate the clinical picture (→ p. 230ff.). Rupture of an intracranial artery (often the anterior communicating artery) together with subarachnoid bleeding is an acute risk to cerebral function. Rupture of an aneurism near the heart (especially a dissecting aneurism) can cause acute pericardial tamponade (→ p. 228) and, if the aortic root is involved, aortic regurgitation (→ p. 200). Other complications are thrombosis in the aneurism, occlusion at the orgin of an artery as well as emboli to distal vessels (ischemia or infarction, respectively; → B, right).

238

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C. Response to Injury Hypothesis of Atherosclerosis Genesis
Smoking		Diabetes mellitus	Hyperhomo-	Age
			cysteinemia
Hypertension
		Lumen		Genetic risk factors
Hyperlipidemia (LDL)				Male
Endothelium		1
Intima
		Endothelial damage		Chlamydia infection ?
Media
					II
2				3	Atherosclerosis
Lipid permeability		Monocyte adhesion		Thrombocyte aggregation
		and immigration
	Monocyte
		Macrophage
LDL			4		7.33
		Transformation in			Plate
		macrophages		Chemotactic and
				growth factors
		Release of
		O2 radicals		Immigration and
	O2–
				proliferation of
NO				myocytes in the intima
		NO + O2– → ONOO–		6
		5		Proliferation
LDL oxidation		Lack of NO action
8				Myocytes
				Vasodilation
Oxidized LDL				7
				Spasm
		Changed
		receptor behavior
LDL phagocytosis			9
				10
Scavenger
receptor
		Foam cell	Foam cell
			Plaque (atheroma)		239

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Nonatherosclerotic Peripheral

Vascular Diseases

		As in atherosclerosis (→ p. 236ff.), thrombo-
		embolism of other etiology can cause acute oc-
		clusion of arteries. The emboli usually origi-
		nate in the heart, for example, the left atrium
		(in atrial fibrillation; mitral stenosis, → p.194),
		the left ventricle (dilated cardiomyopathy,
		myocardial infarct), or from the cardiac valves
		(endocarditis, mitral stenosis, valvar prosthe-
		sis). Intracardiac shunts (→ p. 202) allow ve-
	Circulation	nous thrombi (see below) to pass into the arte-
		rial system (paradoxical emboli).
		Several forms of vasculitis are initiated by
		depositions of immune complexes or by cell-
	and	mediated immune reactions	in the arterial
		wall. In polyarteritis nodosa (affecting the small
	Heart	and medium-sized arteries)it is mostly the kid-
		neys, heart, and liver that are affected by the re-
		sulting ischemia. In temporal or giant-cell arter-
	7	itis (large arteries, especially in the head re-
		gion) facial pain and headaches, “claudication”
		of the muscles of mastication and, in some cir-
		cumstances, blindness can occur. Takayasu ar-
		teritis (large arteries in the thorax–neck region)
		can lead to cerebral ischemia, angina pectoris,
		or “claudication” in the arms (pulseless dis-
		ease). Thromboangitis obliterans (Buerger’s dis-
		ease, affecting medium-sized and small arter-
		ies of the limbs) occurs mostly in male smokers.
		In addition to arterial occlusion and migrating
		superficial thrombophlebitis, Raynaud’s phe-
		nomenon occurs, painful vascular spasms (e.g.,
		precipitated by cold) with numbness in the fin-
		gers or toes that at first blanch (ischemia), then
		become cyanotic (hypoxemia), and then turn
		pink again (reactive hyperemia). Raynaud’s
		phenomenon also occurs in some connective
		tissue diseases (scleroderma, systemic lupus
		erythematodes, rheumatoid	arthritis). The
		phenomenon may occur in younger women as
		a primary disease, in the absence of any other
		condition (Raynaud’s disease).

	Venous Disease
240	Because of their thin walls with few muscles,
	the veins are prone to distension, especially in
	the legs where the hydrostatic pressure of the

column of blood increases the transmural pressure. The legs have deep and superficial veins that are connected by perforating veins (→ A, top right). Venous valves ensure orthograde flow against the force of gravity. The alternating contraction and relaxation of the leg musculature and the movement of the joints are essential driving forces for venous return via the deep veins (“joint–muscle pump”). When the leg muscles are relaxed, the valves in the perforating veins ensure blood flow from the surface to the deep veins and also prevent blood flowing in the opposite direction when the muscles contract (→ A1).

Often on the basis of a genetic predisposition

(increased distensibility of the veins), work in a standing or sitting position over many years (lack of “pumping” effect) leads, depending on age, to distension and a winding course of the superficial veins as well as to incompetence of the venous valves and flow reversal (to-and- fro movement of the blood) in both the superficial and the perforating veins (primary varicosis; → A2). Frequently they develop or get worse during pregnancy or in obesity. In addition to cosmetic problems, a feeling of heaviness, burning, pain, and edemas develop in the legs. Inflammation (varicophlebitis) and its spread to the deep veins can lead to chronic venous insufficiency (→ A5; for complications, see below).

If a thrombus forms in the deep veins of the legs (acute phlebothrombosis; → A3), the valves of the perforating veins are torn and blood will drain via the superficial veins, causing secondary varicosis. Causes of phlebothrombosis are damaged veins, immobilization (sitting during long journeys, confinement to bed, paralysis), defective clotting inhibition, operations, trauma or (often undetected) tumors. Contraceptive pills (ovulation inhibitors) increase the risk of phlebothrombosis. A very dangerous acute complication occurs when a thrombus is torn from its attachment, resulting in pulmonary embolism with pulmonary infarction (→ A4). In the long term chronic venous insufficiency develops (→ A5), which through peripheral edema with protein exudation and deposition (including pericapillary fibrin cuff) in the skin, results in fibrosis, dermatosclerosis, tissue hypoxia, and ultimately in leg ulcers (→ A6).

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