Jul 18, 2017 Hematology Case Review is a comprehensive text that covers the expansive knowledge about the study of blood cells. After collecting blood smears and bone marrow aspirates for over 40 years, Dr. Doll has created the most up to date and comprehensive compilation of hematology case studies.
![]() Goals and Objectives
During this rotation, the resident will demonstrate the following competencies:
Patient Care
Residents must be able to provide patient care that is compassionate, appropriate, and effective for the treatment of health problems and the promotion of health. Residents are expected to:
Medical Knowledge
Practice-Based Learning and Improvement
Interpersonal and Communication Skills
Professionalism
System-Based Practice
Duration
The Coagulation rotation is taught as a one-month rotation.
Duties and Responsibilities by Year
Teaching Staff
Katharine A. Downes, M.D., Rotation Director
Robert Maitta, MD, PhD
Hollie Reeves, DO
Molly Klima, MT (ASCP)
Supervision and Evaluation
Faculty attendings supervise all aspects of the Coagulation rotation. The pathologist with significant resident contact during the rotation evaluates the rotating residents addressing the above six competency areas. Evaluations are based on daily interaction with residents and 'sign-out' activities. In this way, residents receive daily feedback on their interpretations of case material. Residents are assisted by attending staff in preparation of coagulation presentations for laboratory rounds and for the technical staff and receive feedback on their presentations. Residents are evaluated on a monthly basis with regard to competency areas. Evaluations are reviewed with the resident and then forwarded to the Residency Program Director, where they are available for review.
Angiogenesis Generates New Blood Vessels: Blood vessel with an erythrocyte (red blood cell) within its lumen, endothelial cells forming its tunica intima or inner layer, and pericytes forming its tunica adventitia (outer layer). VasoconstrictionIntact blood vessels are central to moderating blood’s clotting tendency. The endothelial cells of intact vessels prevent clotting by expressing a fibrinolytic heparin molecule and thrombomodulin, which prevents platelet aggregation and stops the coagulation cascade with nitric oxide and prostacyclin. When endothelial injury occurs, the endothelial cells stop secretion of coagulation and aggregation inhibitors and instead secrete von Willebrand factor, which causes platelet adherence during the initial formation of a clot. The vasoconstriction that occurs during hemostasis is a brief reflexive contraction that causes a decrease in blood flow to the area. Platelet Plug FormationPlatelets create the “platelet plug” that forms almost directly after a blood vessel has been ruptured.
Within twenty seconds of an injury in which the blood vessel’s epithelial wall is disrupted, coagulation is initiated. It takes approximately sixty seconds until the first fibrin strands begin to intersperse among the wound. After several minutes, the platelet plug is completely formed by fibrin.Contrary to popular belief, clotting of a skin injury is not caused by exposure to air, but by platelets adhering to and being activated by collagen in the blood vessels’ endothelium. The activated platelets then release the contents of their granules, which contain a variety of substances that stimulate further platelet activation and enhance the hemostatic process.When the lining of a blood vessel breaks and endothelial cells are damaged, revealing subendothelial collagen proteins from the extracellular matrix, thromboxane causes platelets to swell, grow filaments, and start clumping together, or aggregating. Von Willebrand factor causes them to adhere to each other and the walls of the vessel. This continues as more platelets congregate and undergo these same transformations. This process results in a platelet plug that seals the injured area.
If the injury is small, the platelet plug may be able to form within several seconds. Coagulation CascadeIf the platelet plug is not enough to stop the bleeding, the third stage of hemostasis begins: the formation of a blood clot. Platelets contain secretory granules. When they stick to the proteins in the vessel walls, they degranulate, thus releasing their products, which include ADP (adenosine diphosphate), serotonin, and thromboxane A2 (which activates other platelets).First, blood changes from a liquid to a gel. At least 12 substances called clotting factors or tissue factors take part in a cascade of chemical reactions that eventually create a mesh of fibrin within the blood. Each of the clotting factors has a very specific function. Prothrombin, thrombin, and fibrinogen are the main factors involved in the outcome of the coagulation cascade.
Prothrombin and fibrinogen are proteins that are produced and deposited in the blood by the liver.When blood vessels are damaged, vessels and nearby platelets are stimulated to release a substance called prothrombin activator, which in turn activates the conversion of prothrombin, a plasma protein, into an enzyme called thrombin. This reaction requires calcium ions. Thrombin facilitates the conversion of a soluble plasma protein called fibrinogen into long, insoluble fibers or threads of the protein, fibrin. Fibrin threads wind around the platelet plug at the damaged area of the blood vessel, forming an interlocking network of fibers and a framework for the clot. This net of fibers traps and helps hold platelets, blood cells, and other molecules tight to the site of injury, functioning as the initial clot. This temporary fibrin clot can form in less than a minute and slows blood flow before platelets attach.Next, platelets in the clot begin to shrink, tightening the clot and drawing together the vessel walls to initiate the process of wound healing. Usually, the whole process of clot formation and tightening takes less than a half hour.
Key Takeaways Key Points. Vasoconstriction is the narrowing of the blood vessels, which increases blood pressure but can decrease blood flow and loss. Vasoconstriction is mediated by contraction of the smooth muscles lining a blood vessel. Vasoconstriction is caused by thromboxane A 2 from activated platelets and injured epithelial cells, nervous system reflexes from pain, and direct injury to vascular smooth muscle. Vasopressins are drugs that may induce vasoconstriction and increase blood pressure. Vasonstriction only lasts for a few minutes during hemostasis.
Vasoconstriction during hemostasis: Blood vessel experiencing vasoconstriction as its smooth muscle contracts while the blood clot forms. Mechanisms of VasoconstrictionThe vasoconstriction response is triggered by factors such as a direct injury to vascular smooth muscle, signaling molecules released by injured endothelial cells and activated platelets (such as thromboxane A 2), and nervous system reflexes initiated by local pain receptors. The spasm response becomes more effective as the amount of damage is increased. Vascular spasm is much more effective at slowing the flow of blood in smaller blood vessels. Vasoconstriction also causes an increase in blood pressure for affected blood vessels.Smooth muscle in the vessel wall goes through intense contractions that constrict the vessel. If the vessels are small, spasms compress the inner walls together and may be able to stop the bleeding completely. If the vessels are medium to large-sized, the spasms slow down immediate outflow of blood, lessening the damage but still preparing the vessel for the later steps of hemostasis.
The spasm response becomes stronger and lasts longer in more severe injuries. Vasoconstriction may be induced by drugs called vasopressins, which increase blood pressure and can help treat certain conditions.
Injury and InflammationDuring injury, vasoconstriction is brief, lasting only a few minutes while the platelet plug and coagulation cascade occur. This is because as tissues are damaged during an injury, inflammation occurs as a result of inflammatory mediator release from immune system cells (such as mast cells or NK cells) that receive cell stress cytokines from damaged enothelial cells or vasoactive amines (serotonin) that are secreted by activated platelets. During inflammation, vasodilation occur, along with increased vascular permeability and leukocyte chemotaxis, ending the spasm of vasoconstriction and hemostasis as wound healing begins. Platelets: A blood slide of platelets aggregating or clumping together. The platelets are small, bright purple fragments.Normally, the endothelial cells express molecules that inhibit platelet adherence and activation while platelets circulate through the blood vessels. These molecules include nitric oxide, prostacylcine (PGI 2) and endothelial ADP-ase.During an injury, subendothelial collagen from the extracellular matrix beneath the endothelial cells is exposed on the epithelium as the normal epithelial cells are damaged and removed, which releases von Willebrand Factor (VWF).
VWF causes the platelets to change form with adhesive filaments (extensions) that adhere to the subendothelial collagen on the endothelial wall. Platelet ActivationAfter platelet adherence occurs, the subendothelial collagen binds to receptors on the platelet, which activates it. During platelet activation, the platelet releases a number of important cytokines and chemical mediators via degranulation. The released chemicals include ADP, VWF, thromboxane A2, platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), serotonin, and coagulation factors.
The extra ADP and VWF is especially important because it causes nearby platelets to adhere and activate, as well as release more ADP, VWF, and other chemicals. Platelet plug formation is considered a positive feedback process because ADP and VWF levels are successively increased as more and more platelets activate to form the plug.
The other factors released during platelet activation perform other important functions. Thromboxane is an arachidonic acid derivative (similar to prostaglandins) that activates other platelets and maintains vasoconstriction. Serotonin is a short-lived inflammatory mediator with a vasoconstrictive effect that contributes to vascular changes associated with inflammation during an injury. PDGF and VEGF are involved in angiogenesis, the growth of new blood vessels and cell cycle proliferation (division) following injury. The coagulation factors include factor V and VIII, which are involved in the coagulation cascade that converts fibrinogen into fibrin mesh after platelet plug formation. Platelet AggregationThe final step of platelet plug formation is aggregation of the platelets into a barrier-like plug.
Receptors on the platelet bind to VWF and fibrinogen molecules, which hold the platelets together. Platelets may also bind to subendothelial VWF to anchor them to the damaged endothelium. The completed plug will cover the damaged components of the endothelium and will stop blood from flowing out of it, but if the wound is large enough, blood will not coagulate until the fibrin mesh from the coagulation cascade is produced, which strengthens the platelet plug. If the wound is minor, the platelet plug may be enough to stop the bleeding without the coagulation cascade. CoagulationCoagulation is the process by which a blood clot forms to reduce blood loss after damage to a blood vessel. Key Takeaways Key Points.
The coagulation cascade is a series of reactions, which is classically divided into three pathways: the contact (also known as the intrinsic) pathway, the tissue factor (also known as the extrinsic pathway), and the common pathway. The intrinsic pathway occurs when negatively charged molecule contact causes a cascade of factors that produce factor X. The extrinsic pathway occurs when tissue damage causes the release of tissue factor, creating a smaller cascade that produces factor X. The common pathway merges both pathways as factor X is used to create thrombin from prothrombin. Secondary hemostasis involves factors of the coagulation cascade, which collectively strengthen the platelet plug. Coagulation can be harmful if blood clots embolize and obstruct other blood vessels. Coagulation Pathway Secondary HemostasisHemostasis can either be primary or secondary.
Primary hemostasis refers to platelet plug formation, which forms the primary clot. Secondary hemostasis refers to the coagulation cascade, which produces a fibrin mesh to strengthen the platelet plug. Secondary hemostasis occurs simultaneously with primary hemostasis, but generally finishes after it. The coagulation factors circulate as inactive enzyme precursors, which, upon activation, take part in the series of reactions that make up the coagulation cascade. The coagulation factors are generally serine proteases (enzymes).
Coagulation Cascade Intrinsic PathwayThe intrinsic pathway (contact activation pathway) occurs during exposure to negatively charged molecules, such as molecules on bacteria and various types of lipids. It begins with formation of the primary complex on collagen by high-molecular-weight kininogen (HMWK), prekallikrein, and factor XII (Hageman factor). This initiates a cascade in which factor XII is activated, which then activates factor XI, which activated factor IX, which along with factor VIII activates factor X in the common pathway. Extrinsic PathwayThe main role of the extrinsic (tissue factor) pathway is to generate a “thrombin burst,” a process by which large amounts of thrombin, the final component that cleaves fibrinogen into fibrin, is released instantly. The extrinsic pathway occurs during tissue damage when damaged cells release tissue factor III. Tissue factor III acts on tissue factor VII in circulation and feeds into the final step of the common pathway, in which factor X causes thrombin to be created from prothrombin. Common PathwayIn the final common pathway, prothrombin is converted to thrombin.
When factor X is activated by either the intrinsic or extrinsic pathways, it activates prothrombin (also called factor II) and converts it into thrombin using factor V. Thrombin then cleaves fibrinogen into fibrin, which forms the mesh that binds to and strengthens the platelet plug, finishing coagulation and thus hemostasis. It also activates more factor V, which later acts as an anticoagulant with inhibitor protein C, and factor XIII, which covalently bonds to fibrin to strengthen its attachment to the platelets. Coagulation ProblemsWhile the coagulation cascade is critical for hemostasis and wound healing, it can also cause problems.
An embolism is any thrombosis (blood clot) that breaks off without being dissolved and travels through the bloodstream to another site. If it obstructs an artery that supplies blood to a tissue or organ, it can cause ischemia and infarcation to those tissues, leading to a pulmonary embolism, stroke, or heart attack).Coagulation can occur even without injury, as blood pooling from prolonged immobility can cause clotting factors to accumulate and activate a coagulation cascade independently. Additionally, endothelial damage caused by immune system factors like inflammation or hypersensitivity may also cause unnecessary thrombosis and embolism. For example, during severe bacterial infections (septic shock), inflammation-induced tissue damage and the negatively charged molecules of bacteria activate both pathways of the coagulation cascade and cause disseminated intravascular coagulation (DIC), in which many clots form and break off, leading to massive organ failure. AnticoagulantsMany anticoagulants prevent unnecessary coagulation, and those that genetically lack the ability to produce these molecules will be more susceptible to coagulation.
Blood Coagulation Pathways: Blood coagulation pathways in vivo showing the central role played by thrombin. Vitamin KVitamin K is a fat-soluble vitamin necessary for synthesis of coagulation factors involved in the coagulation cascade. Factors II, VII, IX, and X which are all important for the intrinsic and common pathways of coagulation. Vitamin K also synthesizes Protein C, Protein S, and Protein Z, anticoagulant proteins that degrade specific coagulation factors, preventing excessive thrombosis following the initial coagulation cascade.Vitamin K can be inhibited by the anticoagulant drug warfarin, which acts as an antagonist for vitamin K. Warfarin is used in medicine for those at high risk of thromboembolism to prevent the coagulation cascade by reducing vitamin K dependent synthesis of coagulation factors. Warfarin’s effects can be overcome by ingesting more vitamin K to reactivate the coagulation factor synthesis pathway.Vitamin K deficiency is associated with impaired coagulation function and excessive bleeding and hemorrhage (internal bleeding, often severe).
This can be caused by poor diet, malabsorption in the intestines, or liver failure. Those with vitamin K deficiency produce alternative proteins that improperly bind with phospholipids, which also contributes to the lack of coagulant function. Calcium and PhospholipidsCalcium and phospholipids (a platelet membrane constituent) are required cofactors for prothrombin activation enzyme complexes to function. This enzyme is called tenase, and converts prothrombin to thrombin.
Calcium mediates the binding of the tenase enzyme complexes (via the terminal gamma-carboxy residues on FXa and FIXa) to the phospholipid surfaces expressed by platelets, which in turn activates prothrombin to produce thrombin, which then produces fibrin from fibrinogen. Calcium acts as a catalyst for this reaction, speeding up the rate of the reaction to occur within the time frame of the factors involved in the coagulation cascade. Calcium is also required to to synthesize the anticoagulant Protein C (along with vitamin K).Calcium deficiencies inhibit proper blood coagulation. This can be caused by a nutritional deficiency or acute problems in which calcium is allocated elsewhere in the blood. Phosopholipid deficiency is also associated with thrombocytopenia (platelet deficiency) because the phospholipids involved with clotting come from platelets.
Thrombocytopenia causes more severe issues with blood clotting as the platelet plug will not be able to form or activate the coagulation cascade. Key Takeaways Key Points. Clot retraction is dependent on the release of multiple coagulation factors, specifically Factor XIIIa at the end of the coagulation cascade. The formation of blood clots can cause a number of serious diseases. By breaking down the clot, the disease process can be arrested or the complications reduced. Clot retraction is the “shrinking” of a blood clot over a number of days. Thrombus or Blood Clot: Micrograph showing a thrombus (center of image) within a blood vessel of the placenta.As the healing process occurs following blood clot formation, the clot must be destroyed in order to prevent thromboembolic events, in which clots break off from the endothelium and cause ischemic damage elsewhere in the body.
By reducing the size of and breaking down the clot, the disease process can be arrested or the complications reduced.Clot retraction refers to a regression in size of the blood clot over a number of days. During this process, the edges of the endothelium at the point of injury are slowly brought together again to repair the damage. Clot retraction is dependent on the release of multiple coagulation factors released at the end of the coagulation cascade, most notably factor XIIIa crosslinks. These factors cause the fibrin mesh to contract by forming twists and knots that condense the size of the clot.
Clot retraction generally occurs within 24 hours of initial clot formation and decreases the size of the clot by 90%. Following clot retraction, a separate process called fibrinolysis occurs which degrades the fibrin of the clot while macrophages consume the expended platelets, thus preventing possible thromboembolism. Wound HealingWhile the clot retracts, the wound begins to heal.
The first step of wound healing is epithelial cell migration, which forms a scab before the clot retracts. This occurs due to the stimulus of platelet-derived growth factor (PDGF). After clot retraction, true repair begins as tissue proliferation starts and collagen from the extracellular matrix is deposited in the wound while granulation tissue forms. Then new blood vessels grow into the healing tissue in a process called angiogenesis, which is stimulated by vascular endothelial growth factor (VEGF).
The wound itself contracts, reducing in size. After these steps occur, new epithelial cells grow to cover the wound. If the wound was severe or unevenly shaped, or if healing takes too long, scarring may occur from collagen deposition. Most scarring on the skin is benign, but scarring inside the tissues of organs such as the heart or the lungs can cause health problems. Key Takeaways Key Points.
Fibrinolysis is the breakdown of a fibrin clot. Plasmin is the enzyme that breaks down fibrin. Fibrinolysis: Blue arrows denote stimulation and red arrows inhibition.T-PA is released into the blood very slowly by the damaged endothelium of the blood vessels. T-PA and urokinase are themselves inhibited by plasminogen activator inhibitor-1 and plasminogen activator inhibitor-2 (PAI-1 and PAI-2). In contrast, plasmin further stimulates plasmin generation by producing more active forms of both tissue plasminogen activator (tPA) and urokinase.
Following fibrin degradation by plasmin, old activated platelets from the platelet plug are phagocytized and destroyed by macrophages.Alpha 2-antiplasmin and alpha 2-macroglobulin inactivate plasmin. Plasmin activity is also reduced by thrombin -activatable fibrinolysis inhibitor (TAFI), which modifies fibrin to make it more resistant to the tPA-mediated plasminogen. Plasmin operates on a negative feedback process because it is reduced when the fibrin clot is fully degraded.
Mechanisms of Secondary FibrinolysisSecondary fibrinolysis generally refers to treatment of pathological thromboembolism. If blood clots embolize to different parts of the body, they can cause tissue death by blocking off blood flow to those tissues. This is a common cause of heart attacks, pulmonary embolism, and strokes. Several medications exist to help treat and prevent these conditions.Fibrinolytic drugs include synthesized tissue plasminogen activator and streptokinase, a bacterial enzyme that has degrades fibrin directly. Clots may also be prevented or kept from worsening through the use of blood thinners ( anticoagulants ).
Aspirin has anticoagulant properties because it inhibits cyoclo-oxygenase dependent pathways of platelet activation, which can prevent clotting from worsening. Heparin is a fast-acting anticoagulant produced by the body and used as a drug which inhibits the activity of thrombin. Warfarin inhibits vitamin K cofactor activation during the coagulation cascade, and citrates chelate calcium to prevent prothrombin activation into thrombin.All of these treatments have been shown to have tremendous therapeutic benefit in treating those with thromboembolic diseases; however, they can make injury much more difficult to treat by disrupting the clotting process. For example, patients thought to be suffering from a stroke (obstructed artery in the brain ) must be screened through imaging before given aspirin or a fibrinolytic drug, because if they have an aneurysm or hemorrhage (burst blood vessel or bleeding in the brain), administering fibrinolytic treatment would make their condition worse and possibly fatal by inhibiting the clotting that could save their lives. CC licensed content, Specific attribution. Human Physiology/Blood physiology.
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