Endogenous opioids, such as enkephalins and β-endorphin, can be released into the brain substance and circulation in response to stressors that also trigger circulatory shock. Stressors prompt the release of opioids stored alongside catecholamines in secretory granules in the adrenal medulla and sympathetic nerve terminals. Similarly, the release of β-endorphin and adrenocorticotropic hormone from the anterior pituitary gland is also stimulated by similar factors. Opioids have a depressant effect on the brainstem centers responsible for certain autonomic adaptations in the face of blood loss, endotoxemia, and other stress-induced shocks. Conversely, the opioid antagonist naloxone improves cardiovascular function and survival rates in different types of shock.

The changes in blood clotting following hemorrhage typically occur in two phases. Initially, there is a phase of hypercoagulability followed by a secondary phase of hypocoagulability and fibrinolysis. During the initial phase, platelets and leukocytes adhere to the vascular endothelium, leading to the development of intravascular clots or thrombi shortly after severe bleeding starts. This process, known as disseminated intravascular coagulation (DIC), occurs when thrombin becomes activated and results in widespread fibrin deposition in narrow and medium-sized blood vessels.

The initial phase is further enhanced by the release of thromboxane A2 from ischemic tissues. Thromboxane A2 promotes platelet aggregation, which in turn leads to increased release of thromboxane A2 and further platelet entrapment. This positive feedback loop intensifies and prolongs the tendency to form clots. Inflammatory cytokines such as interleukin-6 and tumor necrosis factor also contribute to DIC. The use of anticoagulants like heparin has significantly reduced mortality rates associated with certain procedures that provoke shock.

In the later stages of hemorrhagic hypotension, clotting time increases and fibrinolysis becomes more prominent. Fibrinolysis occurs when there is depletion of clotting factors and platelets.

Depression of the Mononuclear Phagocytic System﻿
During hemorrhagic hypotension, the function of the Mononuclear Phagocytic System (MPS) becomes depressed. The phagocytic activity of the MPS is regulated by an opsonic protein. In shock, the opsonic activity in plasma decreases, which contributes to the impairment of MPS function. As a result, defense mechanisms against bacteria and toxins become compromised. Hypoperfusion also suppresses the barrier function of adherens junctions and tight junctions in the intestinal epithelium.

Endotoxins from the normal bacterial flora in the intestine enter the circulation but are usually inactivated by the MPS, mainly in the liver. Disruption of the intestinal epithelial barrier, along with MPS depression, allows these endotoxins to enter the bloodstream. Endotoxins induce the synthesis of a specific isoform of nitric oxide synthase in the smooth muscle of blood vessels throughout the body, leading to profound and generalized vasodilation. This vasodilation exacerbates the hemodynamic changes caused by blood loss.
Endogenous opioids, such as enkephalins and βendorphin, may be released into the brain substance and into the circulation in response to the same stresses that provoke circulatory shock. Opioids are stored, along with catecholamines, in secretory granules in the adrenal medulla and in sympathetic nerve terminals, and they are released together in response to stress. Similar stimuli cause the release of β-endorphin and adrenocorticotropic hormone from the anterior pituitary gland. Opioids depress the brainstem centers that mediate some of the compensatory autonomic adaptations to blood loss, endotoxemia, and other shock-provoking stress. Conversely, the opoid antagonist naloxone improves cardiovascular function and rates of survival in various forms of shock.
The alterations in blood clotting after hemorrhage are typically biphasic. An initial phase of hypercoagulability is followed by a secondary phase of hypocoagulability and fibrinolysis. In the initial phase, platelets and leukocytes adhere to the vascular endothelium, and intravascular clots, or thrombi, develop within a few minutes of the onset of severe hemorrhage. This phenomenon, called disseminated intravascular coagulation (DIC), occurs when thrombin is activated and causes widespread deposition of fibrin within narrow and medium-diameter vessels.
The initial phase is further enhanced by the release of thromboxane A2 from various ischemic tissues. Thromboxane A2 aggregates platelets. As more platelets aggregate, more thromboxane A2 is released and more platelets are trapped. This form of positive feedback intensifies and prolongs the clotting tendency. Inflammatory cytokines (interleukin-6, tumor necrosis factor) also contribute to DIC. The rate of mortality from certain standard shock-provoking procedures has been reduced considerably by the administration of anticoagulants such as heparin.
In the later stages of hemorrhagic hypotension, the clotting time is prolonged, and fibrinolysis is prominent. Fibrinolysis occurs when clotting factors and platelets are depleted.
Depression of the Mononuclear Phagocytic System﻿
During the course of hemorrhagic hypotension, MPS function becomes depressed. The phagocytic activity of the MPS is modulated by an opsonic protein. The opsonic activity in plasma diminishes during shock, and this change may account in part for the depression in MPS function. As a result, antibacterial and antitoxin defense mechanisms are impaired. Hypoperfusion also suppresses the barrier function of the adherens junctions and tight junctions in the 1. Two important relationships between cardiac output (Qh) and central venous pressure (Pv) prevail in the cardiovascular system. With regard to the heart, Qh varies directly with Pv (or preload) over a very wide range of Pv. This relationship is represented by the cardiac function curve, and it expresses the Frank-Starling mechanism. In the vascular system, Pv varies intestinal epithelium. Endotoxins from the normal bacterial flora of the intestine constantly enter the circulation. Ordinarily, they are inactivated by the MPS, principally in the liver. Disruption of the intestinal epithelial barrier, together with depression of the MPS, allows these endotoxins to invade the general circulation. Endotoxins produce profound, generalized vasodilation, mainly by inducing the synthesis of an isoform of nitric oxide synthase in the smooth muscle of blood vessels throughout the body. The profound vasodilation aggravates the hemodynamic changes caused by blood loss.