Bleeding

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Bleeding is the loss of blood from the circulatory system.^[1] Bleeding can occur internally, where blood leaks from blood vessels inside the body or externally, either through a natural opening such as the vagina, mouth or rectum, or through a break in the skin. The complete loss of blood is referred to as exsanguination,^[2] and desanguination is a massive blood loss. Loss of 10-15% of total blood volume can be endured without clinical sequelae in a healthy person, and blood donation typically takes 8-10% of the donor’s blood volume.^[3]

For AEGIS-II inclusion criteria #5, multivessel disease criteria can be met by findings on the cardiac catheterization for the index MI, a prior cardiac catheterization, or both:

• Index MI cardiac catheterization: 50% or greater stenosis of the left main or at least 2 coronary artery territories (LAD, LCX, RCA) (prior to any interventions performed)
• Prior cardiac catheterization: 50% or greater stenosis of left main or at least 2 coronary artery territories (LAD, LCx, RCA) (prior to any interventions performed)
• Both: Index MI cardiac catheterization with 1 vessel with 50% or greater stenosis (prior to any interventions performed) AND prior PCI of at least 1 vessel different from index MI vessel
• Prior multivessel CABG

Multivessel disease requires a 50% or greater stenosis in at least 2 of the 3 major epicardial artery territories (LAD, LCx, RCA) or the left main vessel. Branch vessel disease may qualify as part of the territory of that branch vessel (for example, a diagonal vessel is considered part of the LAD territory). For the purpose of this study, the ramus is considered part of the Left Circumflex artery territory. If a branch vessel is used as a qualifying vessel, that branch should be of large enough size to potentially undergo revascularization if clinically indicated, e.g. >2mm vessel size.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

There are a variety of classification schemes that are designed to characterize the severity of bleeding. Some are used in clinical practice, others are used to quantitate bleeding in clinical trials.

Quantitating the incidence of bleeding is critical to characterize the side effects of new drugs, surgical procedures and devices. The incidence of bleeding complications varies from 1% to 10% during treatment of acute coronary syndromes (ACS) and PCI (Percutaneous coronary intervention). This is in part due to use of combination of multiple drugs like aspirin, heparin, warfarin, platelet P2Y12 inhibitors, glycoprotein IIb/IIIa inhibitors, direct thrombin inhibitor and also the invasive procedures (percutaneous coronary intervention, Coronary artery bypass graft) during this period. Also, the bleeding complications have been found to be associated with increase in incidence of short and long term adverse outcomes like death, non-fatal MI (myocardial infarction), stroke and stent thrombosis. The exact mechanism underlying this is not clearly defined but may be due to the cessation of evidence based therapies (like antiplatelet, Beta blockers, statin), effect ofblood transfusion, co morbidities and anemia that are seen more in patients with bleeding complications. Therefore, bleeding presents as an important safety endpoint in many of the cardiovascular trials. However, there is a lack of uniformity in the definitions of bleeding that could be used in the cardiovascular trials that in turn make it difficult to conduct and compare the results of different trials. Several bleeding definitions have been used in different clinical trials such as the TIMI, GUSTO, ACUITY, HORIZONS,and PLATO bleeding scales. To reduce the heterogeneity and to adopt standardized bleeding end-point definitions for patients receiving antithrombotic therapy, the Bleeding Academic Research Consortium (BARC) was convened comprising representatives from different fields of medicine. These standardized definitions will help researchers determine the relative safety of different antithrombotic therapies. These definitions are recommended for both clinical trials and registries ^[1]

Hemorrhage is broken down into 4 classes by the American College of Surgeons’ Advanced Trauma Life Support (ATLS).^[2]

• Class I Hemorrhage involves up to 15% of blood volume. There is typically no change in vital signs and fluid resuscitation is not usually necessary.
• Class II Hemorrhage involves 15-30% of total blood volume. A patient is often tachycardic (rapid heart beat) with a narrowing of the difference between the systolic and diastolic blood pressures. The body attempts to compensate with peripheral vasoconstriction. Skin may start to look pale and be cool to the touch. The patient might start acting differently. Volume resuscitation with crystaloids (Saline solution or Lactated Ringer’s solution) is all that is typically required. Blood transfusion is not typically required.
• Class III Hemorrhage involves loss of 30-40% of circulating blood volume. The patient’s blood pressure drops, the heart rate increases, peripheral perfusion, such as capillary refill worsens, and the mental status worsens. Fluid resuscitation with crystaloid and blood transfusion are usually necessary.
• Class IV Hemorrhage involves loss of >40% of circulating blood volume. The limit of the body’s compensation is reached and aggressive resuscitation is required to prevent death.

Individuals in excellent physical and cardiovascular shape may have more effective compensatory mechanisms before experiencing cardiovascular collapse. These patients may look deceptively stable, with minimal derangements in vital sounds, while having poor peripheral perfusion (shock). Elderly patients or those with chronic medical conditions may have less tolerance to blood loss, less ability to compensate and take medications, such as betablockers, which may blunt the cardiovascular response. Care must be taken in the assessment of these patients.

The World Health Organization (WHO) standardized grading scale to measure the severity of bleeding is as follows:

• Grade 0: no bleeding

• Grade 1: petechial bleeding;

• Grade 2: mild blood loss (clinically significant);

• Grade 3: gross blood loss, requires transfusion(severe;

• Grade 4: debilitating blood loss, retinal or cerebral associated with fatality

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]}

For AEGIS-II inclusion criteria #5, multivessel disease criteria can be met by findings on the cardiac catheterization for the index MI, a prior cardiac catheterization, or both:

• Index MI cardiac catheterization: 50% or greater stenosis of the left main or at least 2 coronary artery territories (LAD, LCX, RCA) (prior to any interventions performed)
• Prior cardiac catheterization: 50% or greater stenosis of left main or at least 2 coronary artery territories (LAD, LCx, RCA) (prior to any interventions performed)
• Both: Index MI cardiac catheterization with 1 vessel with 50% or greater stenosis (prior to any interventions performed) AND prior PCI of at least 1 vessel different from index MI vessel
• Prior multivessel CABG

Multivessel disease requires a 50% or greater stenosis in at least 2 of the 3 major epicardial artery territories (LAD, LCx, RCA) or the left main vessel. Branch vessel disease may qualify as part of the territory of that branch vessel (for example, a diagonal vessel is considered part of the LAD territory). For the purpose of this study, the ramus is considered part of the Left Circumflex artery territory. If a branch vessel is used as a qualifying vessel, that branch should be of large enough size to potentially undergo revascularization if clinically indicated, e.g. >2mm vessel size.

• Hematemesis – vomiting fresh blood
• Hemoptysis – coughing up blood from the lungs
• Hematochezia – rectal blood
• Hematuria – blood in the urine from urinary bleeding
• Intracranial hemorrhage – bleeding in the skull.
• Cerebral hemorrhage – a type of intracranial hemorrhage, bleeding within the brain tissue itself.
• Intracerebral hemorrhage – bleeding in the brain caused by the rupture of a blood vessel within the head. See also hemorrhagic stroke.
• Subarachnoid hemorrhage (SAH) implies the presence of blood within the subarachnoid space from some pathologic process. The common medical use of the term SAH refers to the nontraumatic types of hemorrhages, usually from rupture of a berry aneurysm or arteriovenous malformation(AVM). The scope of this article is limited to these nontraumatic hemorrhages.
• Pulmonary hemorrhage
• Vaginal bleeding
• Postpartum hemorrhage
• Breakthrough bleeding
• Ovarian bleeding. This is a potentially catastrophic and not so rare complication among lean patients with polycystic ovary syndrome undergoing transvaginal oocyte retrieval.^[1]
• Upper gastrointestinal bleed
• Suicide: Exsanguination is a suicide method caused by cutting of arteries, notably: carotid, radial, ulnar, and femoral arteries.
• Trauma: Injury or trauma can cause exsanguination if bleeding is not stymied. It is the most common cause of deaths on the battlefield (though the most common cause of death from battle is infection). Non-battlefield causes can include partial or complete amputation from use of circular saws (e.g., hand-held circular saw, radial arm saw, table saw).
• Internal hemorrhage: Patients can develop catastrophic internal hemorrhages, such as from a bleeding peptic ulcer or splenic hemorrhage, which can cause exsanguination even without any external bleeding. It is a relatively common cause of unexpected, sudden death in patients who seemed previously well.
• Alcoholism: Alcoholics can also suffer from exsanguination. Thin-walled dilated veins just below the lower esophageal mucosa called esophageal varices may ulcerate or be torn (“Mallory-Weiss syndrome“) during the violent retching of the alcoholic leading to massive bleeding and sometimes exsanguination.
• Retroperitoneal hematoma
• Ruptured aortic aneurysm
• Ruptured abdominal aortic aneurysm

Traumatic bleeding is caused by some type of injury. There are different types of wounds which may cause traumatic bleeding. These include:

• Abrasion – Also called a graze, this is caused by transverse action of a foreign object against the skin, and usually does not penetrate below the epidermis
• Excoriation – In common with Abrasion, this is caused by mechanical destruction of the skin, although it usually has an underlying medical cause
• Hematoma – (also called a blood tumor) – caused by damage to a blood vessel that in turn causes blood to collect under the skin.
• Laceration – Irregular wound caused by blunt impact to soft tissue overlying hard tissue or tearing such as in childbirth. In some instances, this can also be used to describe an incision.
• Incision – A cut into a body tissue or organ, such as by a scalpel, made during surgery.
• Puncture Wound – Caused by an object penetrated the skin and underlying layers, such as a nail, needle or knife
• Contusion – Also known as a bruise, this is a blunt trauma damaging tissue under the surface of the skin
• Crushing Injuries – caused by a great or extreme amount of force applied over a long period of time. The extent of a crushing injury may not immediately present itself.
• Gunshot wounds – Caused by a projectile weapon, this may include two external wounds (entry and exit) and a contiguous wound between the two

The pattern of injury, evaluation and treatment will vary with the mechanism of the injury. Blunt trauma causes injury via a shock effect; delivering energy over an area. Wounds are often not straight and unbroken skin may hide significant injury. Penetrating trauma follows the course of the injurious device. As the energy is applied in a more focused fashion, it requires less energy to cause significant injury. Any body organ, including bone and brain, can be injured and bleed. Bleeding may not be readily apparent; internal organs such as the liver, kidney and spleen may bleed into the abdominal cavity. The only apparent signs may come with blood loss. Bleeding from a bodily orifice, such as the rectum, nose, ears may signal internal bleeding, but cannot be relied upon. Bleeding from a medical procedure also falls into this category.

Medical bleeding is that associated with an increased risk of bleeding due to an underlying medical condition. It will increase the risk of bleeding related to underlying anatomic deformities, such as weaknesses in blood vessels (aneurysm or dissection), arteriovenous malformation, ulcerations. Similarly, other conditions that disrupt the integrity of the body such as tissue death, cancer, or infection may lead to bleeding.

The underlying scientific basis for blood clotting and hemostasis is discussed in detail in the articles, Coagulation, haemostasis and related articles. The discussion here is limited to the common practical aspects of blood clot formation which manifest as bleeding.

Certain medical conditions can also make patients susceptible to bleeding. These are conditions that affect the normal “hemostatic” functions of the body. Hemostasis involves several components. The main components of the hemostatic system include platelets and the coagulation system.

Platelets are small blood components that form a plug in the blood vessel wall that stops bleeding. Platelets also produce a variety of substances that stimulate the production of a blood clot. One of the most common causes of increased bleeding risk is exposure to non-steroidal anti-inflammatory drugs (or “NSAIDs”). The prototype for these drugs is aspirin, which inhibits the production of thromboxane. NSAIDs inhibit the activation of platelets, and thereby increase the risk of bleeding. The effect of aspirin is irreversible; therefore, the inhibitory effect of aspirin is present until the platelets have been replaced (about ten days). Other NSAIDs, such as “ibuprofen” (Motrin) and related drugs, are reversible and therefore, the effect on platelets is not as long-lived.

There are several named coagulation factors that interact in a complex way to form blood clots, as discussed in the article on coagulation. Deficiencies of coagulation factors are associated with clinical bleeding. For instance, deficiency of Factor VIII causes classic Hemophilia A while deficiencies of Factor IX cause “Christmas disease”(hemophilia B). Antibodies to Factor VIII can also inactivate the Factor VII and precipitate bleeding that is very difficult to control. This is a rare condition that is most likely to occur in older patients and in those with autoimmune diseases. von Willebrand disease is another common bleeding disorder. It is caused by a deficiency of or abnormal function of the “von Willebrand” factor, which is involved in platelet activation. Deficiencies in other factors, such as factor XIII or factor VII are occasionally seen, but may not be associated with severe bleeding and are not as commonly diagnosed.

In addition to NSAID-related bleeding, another common cause of bleeding is that related to the medication, warfarin (“Coumadin” and others). This medication needs to be closely monitored as the bleeding risk can be markedly increased by interactions with other medications. Warfarin acts by inhibiting the production of Vitamin K in the gut. Vitamin K is required for the production of the clotting factors, II, VII, IX, and X in the liver. One of the most common causes of warfarin-related bleeding is taking antibiotics. The gut bacteria make vitamin K and are killed by antibiotics. This decreases vitamin K levels and therefore the production of these clotting factors.

Deficiencies of platelet function may require platelet transfusion while deficiciencies of clotting factors may require transfusion of either fresh frozen plasma of specific clotting factors, such as Factor VIII for patients with hemophilia.

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