The discovery of clonal hematopoiesis CH in older individuals has changed the way hematologists and stem cell biologists view aging. Somatic mutations accumulate in stem cells over time. Another aspect of abnormal blood flow, venous stasis, such as in post-operative bed rest, long distance traveling in a car or plane, or immobility due to obesity can lead to endothelial injury thus promoting thrombosis.
Endothelial Injury leads to platelet activation and the formation of a thrombus. This may be a result of inflammation of the endothelial surface of the vasculature. Hypercholesterolemia is an example of a chronic inflammatory condition which progresses into endothelial injury. Hypercoagulability thrombophilia is any disorder of the blood that predisposes a person to thrombosis. This may be a result of inherited clotting disorders such as a Factor V Leiden mutation or an acquired clotting disorder such as disseminated intravascular coagulation.
Clinical Significance In addition to the pathophysiology, a few ideas to keep in mind when you have a patient with clotting mechanism disorders: Patients with: Primary hemostasis defects typically present with small bleeds in the skin or mucosal membranes.
Secondary hemostasis defects typically present with bleeds into soft tissue muscle or joints hemarthrosis. Direct defects in small blood vessels typically present with palpable purpura and ecchymosis. These may collect and become larger to develop a hematoma.
Review Questions Access free multiple choice questions on this topic. Comment on this article. References 1. Thachil J. Semin Thromb Hemost.
Saracoglu A, Saracoglu KT. Coagulopathy during liver transplantation. J Anaesthesiol Clin Pharmacol. Chang JC.
Hemostasis based on a novel 'two-path unifying theory' and classification of hemostatic disorders. Blood Coagul Fibrinolysis. Thromb Res. The role of neutrophils in thrombosis. Complement in the Pathophysiology of the Antiphospholipid Syndrome. Front Immunol. Non-invasive imaging techniques for the differentiation of acute and chronic thrombosis. Ther Drug Monit. Red blood cells: the forgotten player in hemostasis and thrombosis.
HLA system 3. Minor Ag 4. In vivo imaging 5. Engraftment, graft rejection and graft failure 6. Immune regeneration or immune recovery 7. Tumor associated antigens 8. Microbiome Costimulation vs. Inhibition Treg They send nerve im- gus nerves. The bradycardia results from increased parasym- pulses to the NTS and are sensitive to elevated PCO2, as pathetic tone.
Dilation of systemic arterioles and veins is well as decreased pH and PO2. Peripheral chemoreceptors caused by withdrawal of sympathetic tone. This reflex is also exhibit an increased firing rate when 1 the PO2 or pH of elicited by myocardial ischemia and is responsible for the the arterial blood is low, 2 the PCO2 of arterial blood is in- bradycardia and hypotension that can occur in response to creased, 3 the flow through the bodies is very low or acute infarction of the posterior or inferior myocardium.
The increased firing of both peripheral and central The highest levels of organization in the ANS are the chemoreceptors via the NTS and RVL leads to profound supramedullary networks of neurons with way stations in peripheral vasoconstriction.
Arterial pressure is signifi- the limbic cortex, amygdala, and hypothalamus. These cantly elevated. If respiratory movements are voluntarily supramedullary networks orchestrate cardiovascular corre- stopped, the vasoconstriction is more intense and a striking lates of specific patterns of emotion and behavior by their bradycardia and decreased cardiac output occur.
This re- projections to the ANS. As in the case of the baroreceptor reflex, the coro- contribute to the tonic maintenance of blood pressure, nor nary and cerebral circulations are not subject to the sympa- are they necessary for most cardiovascular reflexes, al- thetic vasoconstrictor effects and instead exhibit vasodila- though they modulate reflex reactivity.
In addition to its importance when arterial blood gases The Fight-or-Flight Response Includes are abnormal, the chemoreceptor reflex is important in the Specific Cardiovascular Changes cardiovascular response to severe hypotension. As blood Upon stimulation of certain areas in the hypothalamus, cats pressure falls, blood flow through the carotid and aortic demonstrate a stereotypical rage response, with spitting, bodies decreases and chemoreceptor firing increases— clawing, tail lashing, back arching, and so on.
Cardiovascular responses include ele- Pain Receptors Produce Reflex Responses vated heart rate and blood pressure. The initial behavioral pattern during the fight-or-flight in the Cardiovascular System response includes increased skeletal muscle tone and gen- Two reflex cardiovascular responses to pain occur. In the eral alertness.
There is increased sympathetic neural activ- most common reflex, pain causes increased sympathetic ac- ity to blood vessels and the heart. When the fight-or-flight response is con- tremities and splanchnic regions when his or her face is summated by fight or flight, arterioles in skeletal muscle di- submerged in cold water. With breath holding during the late because of accumulation of local metabolites from the dive, arterial PO2 and pH fall and PCO2 rises, and the exercising muscles see Chapter This vasodilation may chemoreceptor reflex reinforces the diving response.
The outweigh the sympathetic vasoconstriction in other organs arterioles of the brain and heart do not constrict and, there- and SVR may actually fall. With a fall in SVR, mean arterial fore, cardiac output is distributed to these organs. This pressure returns toward normal despite the increase in car- heart-brain circuit makes use of the oxygen stored in the diac output. Once the diver surfaces, the heart response in humans, but it is usually not accompanied by rate and cardiac output increase substantially; peripheral muscle exercise e.
It seems likely that repeated elevations in arterial trient flow and washing out accumulated waste products. Both classical and operant condition- Vasovagal syncope fainting is a somatic and cardiovascu- ing techniques have been used to raise and lower the blood lar response to certain emotional experiences.
Stimulation pressure and heart rate of animals. Humans can also be of specific areas of the cerebral cortex can lead to a sudden taught to alter their heart rate and blood pressure, using a relaxation of skeletal muscles, depression of respiration, variety of behavioral techniques, such as biofeedback. The cardiovascular events ac- Behavioral conditioning of cardiovascular responses has companying these somatic changes include profound significant clinical implications.
Animal and human studies parasympathetic-induced bradycardia and withdrawal of indicate that psychological stress can raise blood pressure, resting sympathetic vasoconstrictor tone. There is a dra- increase atherogenesis, and predispose to fatal cardiac ar- matic drop in heart rate, cardiac output, and SVR.
The re- rhythmias. These effects are thought to result from an in- sultant decrease in mean arterial pressure results in uncon- appropriate fight-or-flight response. Other studies have sciousness because of lowered cerebral blood flow. The Cardiovascular Correlates of Exercise Require Integration of Central and Peripheral Mechanisms Not All Cardiovascular Responses Are Equal Exercise causes activation of supramedullary neural net- Supramedullary responses can override the baroreceptor re- works that inhibit the activity of the baroreceptor reflex.
For example, the fight-or-flight response causes the The inhibition of medullary regions involved in the barore- heart rate to rise above normal levels despite a simultaneous ceptor reflex is called central command. Central command rise in arterial pressure. In such circumstances, the neurons results in withdrawal of parasympathetic tone to the heart connecting the hypothalamus to medullary areas inhibit the with a resulting increase in heart rate and cardiac output.
Also, during exercise, input from ment for blood flow to exercising muscle. As exercise in- supramedullary regions inhibits the baroreceptor reflex, pro- tensity increases, central command adds sympathetic tone moting increased sympathetic tone and decreased parasym- that further increases heart rate and contractility. It also re- pathetic tone despite an increase in arterial pressure.
Finally, afferent impulses from ex- scribed. Many response patterns interact, reflecting the ex- ercising skeletal muscle terminate in the RVL where they tensive neural interconnections between all levels of the further augment sympathetic tone. CNS and interaction with various elements of the local During exercise, blood flow of the skin is largely influ- control systems. For example, the baroreceptor reflex inter- enced by temperature regulation, as described in Chapter Cutaneous sympa- thetic nerves participate in body temperature regulation The Diving Response Maintains Oxygen see Chapter 29 , but also serve the baroreceptor reflex.
At Delivery to the Heart and Brain moderate levels of heat stress, the baroreceptor reflex can cause cutaneous arteriolar constriction despite elevated The diving response is best observed in seals and ducks, core temperature. However, with severe heat stress, the but it also occurs in humans. An experienced diver can ex- baroreceptor reflex cannot overcome the cutaneous vasodi- hibit intense slowing of the heart rate parasympathetic lation; as a result, arterial pressure regulation may fail.
In Various hormones play a role in the control of the cardio- contrast, epinephrine causes vasodilation in skeletal muscle vascular system. Important sites of hormone secretion in- and splanchnic beds. SVR may actually fall and mean arte- clude the adrenal medulla, posterior pituitary gland, kid- rial pressure does not rise. The baroreceptor reflex is not ney, and cardiac atrium.
Changes in the circulating NE concentration are nephrine. This increased sensitivity to neurotransmitters is small relative to changes in NE resulting from the direct re- referred to as denervation hypersensitivity. Several factors lease from nerve endings close to vascular smooth muscle contribute to denervation hypersensitivity, including the and cardiac cells.
Increased circulating epinephrine, how- absence of sympathetic nerve endings to take up circulating ever, contributes to skeletal muscle vasodilation during the norepinephrine and epinephrine actively, leaving more fight-or-flight response and exercise.
In these cases, epi- transmitter available for binding to receptors. In ceptors in target cells. Because of their adrenergic receptors and reinforces the effect of NE re- enhanced response to circulating catecholamines, trans- leased from sympathetic nerve endings. A comparison of the responses to infusions of epineph- rine and norepinephrine illustrates not only the different effects of the two hormones but also the different reflex re- The Renin-Angiotensin-Aldosterone System sponse each one elicits Fig.
Epinephrine and norep- Helps Regulate Blood Pressure and Volume inephrine have similar direct effects on the heart, but NE The control of total blood volume is extremely important elicits a powerful baroreceptor reflex because it causes sys- in regulating arterial pressure. Because changes in total blood volume lead to changes in central blood volume, the long-term influence of blood volume on ventricular end-di- Epinephrine Norepinephrine astolic volume and cardiac output is paramount.
Cardiac output, in turn, strongly influences arterial pressure. Reduced arterial pressure and blood volume cause the 5 5 release of renin from the kidneys. Renin release is mediated 0 4 8 12 16 0 4 8 12 16 by the sympathetic nervous system and by the direct effect of lowered arterial pressure on the kidneys.
Renin is a pro- Systemic vascular 15 19 teolytic enzyme that catalyzes the conversion of an- resistance giotensinogen, a plasma protein, to angiotensin I Fig.
Angiotensin I is then converted to angiotensin II by angiotensin-converting enzyme ACE , primarily in 10 14 the lungs. Angiotensin II directly stimulates contrac- infusions of epinephrine and norepineph- rine. See text for details. Modified from Rowell LB. New York: Ox- lease from sympathetic nerves and sensitizes vascular ford University Press, This system plays an important role in the regu- lation of arterial blood pressure and blood volume. If an ACE inhibitor is given stretched.
By increasing sodium excretion, it decreases to such individuals, blood pressure falls. Renin is released blood volume see Chapter It also inhibits renin release during blood loss, even before blood pressure falls, and the as well as aldosterone and AVP secretion.
When central blood vol- fluid. Retention of sodium paves the way for increasing ume and atrial stretch are increased, ANP secretion rises, blood volume. Renin, angiotensin, aldosterone, and the leading to higher sodium excretion and a reduction in factors that control their release and formation are dis- blood volume. The RAAS is important in the normal maintenance of blood volume and blood pressure. It is crit- ical when salt and water intake is reduced. Erythropoietin Increases the Production Rarely, renal artery stenosis causes hypertension that of Erythrocytes can be attributed solely to elevated renin and angiotensin II The final step in blood volume regulation is production of levels.
In addition, the renin-angiotensin system plays an erythrocytes. In patients with congestive heart failure, renin cells. The stimuli for erythropoietin release include hy- and angiotensin II are increased and contribute to elevated poxia and reduced hematocrit. An increase in circulating SVR as well as sodium retention. AVP and aldosterone enhances salt and water retention and results in an elevated plasma volume. The increased plasma Arginine Vasopressin Contributes volume with a constant volume of red blood cells results to the Regulation of Blood Volume in a lower hematocrit.
The decrease in hematocrit stimu- lates erythropoietin release, which stimulates red blood cell Arginine vasopressin AVP is released by the posterior pi- synthesis and, therefore, balances the increase in plasma tuitary gland controlled by the hypothalamus. Three pri- volume with a larger red blood cell mass. Short-term con- vessels. However, in special circumstances e. AVP exerts its major effect on the cardiovascular system by Long-term control depends on salt and water excretion causing the retention of water by the kidneys see Chapter by the kidneys.
Excretion of salt and water by the kidneys 24 —an important part of the neural and humoral mecha- is regulated by some neural and hormonal mechanisms, nisms that regulate blood volume. However, it is also regulated by arterial pressure. Increased Atrial Natriuretic Peptide Helps Regulate arterial pressure results in increased excretion of salt and water—a phenomenon known as pressure diuresis Fig.
Blood Volume Consid- Plasma volume eration of the responses to standing erect provides an op- portunity to explore these elements in detail. Figure When a person is recumbent, pressure in the veins of the legs is only a few mm Hg above the pressure in 8 the right atrium. The pressure distending the veins—trans- mural pressure—is equal to the pressure within the veins of the legs because the pressure outside the veins is atmos- Output of salt and water 6 pheric pressure the zero-reference pressure.
A higher output of salt and water in response to increased arterial pressure reduces blood volume. Blood volume is reduced until pressure returns to its normal level. The curve on the left shows the relationship in a person with normal blood pressure. The curve on the right shows the same relationship in an individual who is hypertensive.
Note that the hypertensive individual has an elevated arterial pres- sure at a normal output of salt and water. Medical Physiology. Philadelphia: WB Saunders, , p. As discussed earlier in this chapter and in Chapter 15, a decrease in blood volume reduces stroke volume by lowering the end-diastolic filling of the ventricles. Decreased stroke volume lowers cardiac output and arterial pressure.
Pressure diuresis persists until it lowers blood volume and cardiac output sufficiently to return mean arterial pressure to a set level. A decrease in mean arterial pressure has the opposite effect on salt and water excretion.
Reduced pressure diuresis increases blood volume and cardiac output until mean arterial pressure is re- turned to a set level. Pressure diuresis is a slow but persistent mechanism for regulating arterial pressure. In this example, standing rial pressure is above or below a set level, it will eventually places a hydrostatic pressure of approximately 80 mm Hg on the return pressure to that level. In hypertensive patients, the feet. Right atrial pressure is lowered because of the reduction in curve shown in Figure The negative pressures above the heart with salt and water excretion are normal at a higher arterial pres- standing do not actually occur because once intravascular pressure sure.
If this were not the case, pressure diuresis would inex- drops below atmospheric pressure, the veins collapse. These are orably bring arterial pressure back to normal. It follows that an adequate cardiovascular re- pressure is still zero atmospheric. Because the veins are sponse to the changes caused by upright posture—or- highly compliant, such a large increase in transmural pres- thostasis—is absolutely essential to our lives as bipeds see sure is accompanied by an increase in venous volume.
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