bleeding disorders, hemophilia, (handout: Bleeding Disorders) (Von Willebrand’s) Flashcards
Define hemostasis and provide a brief outline.
Hemostasis is the process that causes bleeding to stop. The 3 phases of hemostasis are:
- Vascular Phase: Vasoconstriction occurs immediately in the area of injury.
- Platelet Phase: Platelets and vessel walls become “sticky” which forms a mechanical plug of platelets to seal off the openings of the vessel. This begins seconds after injury.
- Coagulation Phase: Blood coagulates through the extrinsic, intrinsic, and common pathways. This phase takes place more slowly than the other phases.
what is the etiology of acquired bleeding and hypercoagulable disorders?
A pathologic alteration of blood vessel walls, a signi - cant reduction in the number of platelets, defective plate- lets or platelet function, a deficiency of one or more coagulation factors, the administration of anticoagulant or antiplatelet drugs, a disorder of platelet release, or the inability to destroy free plasmin can result in significant abnormal clinical bleeding. This may occur even after minor injuries and may lead to death in some patients if immediate action is not taken.q
what does the liver have to do with coagulation? and the spleen?
The liver produces all of the protein coagulation factors; thus, any patient with signi cant liver disease may have a bleeding problem. In addition to having a possible disorder in coagulation, the patient with liver disease who develops portal hypertension and hyper- splenism may be thrombocytopenic as a result of splenic overactivity, which leads to increased sequestration of platelets in the spleen.10
how does the intestinal flora have to do with coagulation?
Any condition that so disrupts the intestinal ora that vitamin K is not produced in suf cient amounts will result in a decreased plasma level of the vitamin K–dependent coagulation factors. Vitamin K is needed by the liver to produce prothrombin (factor II) and factors VII, IX, and X. Biliary tract obstruction, malab- sorption syndrome, and excessive use of broad-spectrum antibiotics all can lead to low levels of prothrombin and factors VII, IX, and X on this basis.10
meidcation, herbal supplements and diet
Drugs, such as heparin and coumarin derivatives, can cause a bleeding disorder because they may disrupt the coagulation process. Antiplatelet medications, aspirin, other nonsteroidal antiin ammatory drugs (NSAIDs), penicillin, cephalosporins, and alcohol also may interfere with platelet function.11
Many herbal supplements can impair hemostatic function for the control of bleeding. Fish oil or concen- trated omega-3 fatty acid supplements may impair plate- let activation. Diets naturally rich in omega-3 fatty acids can result in a prolonged bleeding time and abnormal platelet aggregation.1 Fish oil supplements prolong bleeding time, inhibit platelet aggregation, and decrease thromboxane A2 (TXA2) production.12 Vitamin E appears to inhibit protein kinase C–mediated platelet aggregation and nitric oxide production.1 The following herbal sup- plements have potential antiplatelet activity: ginkgo, garlic, bilberry, ginger, dong quai, Asian ginseng, tumeric, meadow sweet, willow, coumarin-containing herbs, chamomile, horse chestnut, red clover, and fenugreek. In patients with unexplained bruising or bleeding, it is prudent to review any new medications or supplements and discontinue those that may be associated with bleeding.1
what are the three phases of homeostasis again?
The three phases of hemostasis for controlling bleeding are vascular, platelet, and coagulation. The vascular and platelet phases are referred to as primary, and the coagu- lation phase is secondary. The coagulation phase is fol- lowed by the fibrinolytic phase, during which the clot is dissolved (Box 24-2).
what happens in the vascular phase?
The vascular phase begins immediately after injury and involves vasoconstriction of arteries and veins in the area of injury, retraction of arteries that have been cut, and buildup of extravascular pressure by blood loss from cut vessels. This pressure aids in collapsing the adjacent capillaries and veins in the area of injury. Vas- cular wall integrity is important for maintaining the flu- idity of blood. The smooth endothelial lining consists of a nonwettable surface that, under normal conditions, does not activate platelet adhesion or coagulation. In fact, the endothelial cells synthesize and secrete three potent antiplatelet agents: prostacyclin, nitric oxide, and certain adenine nucleotides.8,13-15
Vascular endothelial cells also are involved in anti- thrombotic and prothrombotic activities. The major antithrombotic activity consists of secretion of heparin- like glycosaminoglycans (heparin sulfate) that catalyze inactivation of serine proteases such as thrombin and factor Xa by antithrombin III. Endothelial cells also produce thrombomodulin, which combines with throm- bin to form a complex that activates protein C. Activated protein C (APC) then binds to endothelially released protein S, causing proteolysis of factor Va and factor VIIIa that inhibits coagulation. Tissue-type plasminogen activator (tPA) is released by injured endothelial cells to initiate brinolysis.8,13-15
Vessel wall components contribute prothrombotic activities. Exposure of vessel wall subendothelial tissues, collagen, and basement membrane through chemical or traumatic injury serves as a tissue factor (TF)—for which the old term was tissue thromboplastin—and initiates coagulation by way of the extrinsic pathway. The extrinsic pathway can be turned off by tissue factor pathway inhibitor (TFPI). An inducible endothelial cell prothrombin activator may directly generate thrombin. Injured endothelial cells release adenosine diphosphate (ADP), which induces platelet adhesion. Vessel wall injury also promotes platelet adhesion and thrombus formation through exposure of subendothelial tissues to von Willebrand factor (vWF). Endothelial cells also con-
tribute to normal homeostasis and vascular integrity
through synthesis of type IV collagen, bronectin, and vWF.8,13-15
What happens in the platelet phase?
Platelets are cellular fragments from the cytoplasm of megakaryocytes that last 8 to 12 days in the circulation. About 30% of platelets are sequestered in the microvasculature or spleen and serve as a functional reserve. Platelets do not have a nucleus; thus, they are unable to repair inhibited enzyme systems through drugs such as aspirin. Aged or nonviable platelets are removed and destroyed by the spleen and liver.8,13,16 Functions of platelets include maintenance of vascular integrity, formation of a platelet plug to aid in initial control of bleeding, and stabilization of the platelet plug through involvement in the coagulation process. About 10% of platelets are used to nurture endothelial cells, allowing for endothelial and smooth muscle regeneration.
Subendothelial tissues are exposed at the site of injury and, through contact activation, cause the platelets to become sticky and adhere to subendothelial tissues, platelet membrane glycoprotein Ib (GPIb) binds with vWF, which is attached to the subendothelial tissue, and glycoprotein Ia/IIa (GPIa/IIa) and glycoprotein VI (GPVI) bind to collagen in the injured vessel wall.
ADP released by damaged endothelial cells initiates aggregation of platelets (primary wave), and when plate- lets release their secretions, a second wave of aggregation results. Platelets bind with fibrinogen by the membrane glycoprotein IIb (GPIIb) the fibrinogen is then converted to fibrin, which stabilizes the platelet plug. The result of the preceding processes is a clot of platelets and fibrin attached to the subendothelial tissue.8,13,16 Box 24-3 sum- marizes the functions of platelets.
A product of platelets, thromboxane, is needed to induce platelet aggregation. The enzyme cyclooxygenase is essential in the process for generation of thromboxane. Endothelial cells, through a similar process (also depen- dent on cyclooxygenase), generate prostacyclin, which inhibits platelet aggregation. Aspirin acts as an inhibitor of cyclooxygenase, and this causes irreversible damage to the platelets. However, endothelial cells can, after a short period, recover and synthesize cyclooxygenase; thus, aspirin has only a short effect on the availability of prostacyclin from these cells. The net result of aspirin therapy is to inhibit platelet aggregation. This effect can last up to 9 days (time needed for all old platelets to be cleared from the blood).8,13,16
how long do platelets last ?
Platelets are cellular fragments from the cytoplasm of megakaryocytes that last 8 to 12 days in the circulation
what destroys platelets?
Aged or nonviable platelets are removed and destroyed by the spleen and liver.
what’s the result of aspirin therapy? how long can the effect last?
The net result of aspirin therapy is to inhibit platelet aggregation. This effect can last up to 9 days (time needed for all old platelets to be cleared from the blood).8,13,16
what happens in the coagulation phase?
The process of the fibrin-forming (coagulation) system is shown in Figure 24-1. The overall time involved from injury to a fibrin-stabilized clot is about 9 to 18 minutes. Platelets, blood proteins, lipids, and ions are involved in the process. Thrombin is gener- ated on the surface of the platelets, and bound fibrinogen is converted to fibrin.8,16 The end product of coagulation is a fibrin clot that can stop further blood loss from injured tissues (Figures 24-2 and 24-3).
Coagulation of blood involves the components shown in Table 24-1. Many of the coagulation factors are proenzymes that become activated in a “waterfall” or cascade manner—that is, one factor becomes activated, and it, in turn, activates another, and so on in an ordered sequence.17 For example, the proenzyme (zymogen) factor XI is activated to the enzyme factor XIa through contact with injury-exposed subendothelial tissues in vivo to start the intrinsic pathway. In vitro, the intrinsic pathway is initiated by contact activation of factor XII. Coagulation proceeds through two pathways—the intrinsic and the extrinsic. Both use a common pathway to form the end product, brin.8,16 Figure 24-1 shows these coagulation pathways.
The (faster) extrinsic pathway is initiated through tissue factor (an integral membrane protein) and is released or exposed through injury to tissues; this process activates factor VII (VIIa). In the past, the trigger for initiating the extrinsic pathway was referred to as a tissue thromboplastin. It has since been shown that the real activator is the tissue factor (TF). The term extrinsic pathway continues to be used today, despite the fact that it is somewhat outdated. This is because TF is not always extrinsic to the circulatory system but is expressed on the surface of vascular endothelial cells and leukocytes.8,16
Thrombin generated by the faster extrinsic and common pathway is used to accelerate the slower intrin- sic and common pathway. Activation of factor XII acts as a common link between the component parts of the homeostatic mechanism: coagulation, fibrinolytic, kinin, and complement systems. As a result, thrombin is gener- ated; in turn, fibrinogen is converted to fibrin, activates factor XIII, enhances factor V and factor VIII activity, and stimulates aggregation of additional platelets.8,16
what is the fibrinolytic phase?
The fibrin-lysing ( fibrinolytic) system is needed to prevent coagulation of intravascular blood away from the site of injury and to dissolve the clot, once it has served its function in homeostasis (Figure 24-4). This system involves plasminogen, a proenzyme for the enzyme plasmin, which is produced in the liver, and various plasminogen activators and inhibitors of plasmin. The prime endogenous plasminogen activator is tissue-type plasminogen activator (tPA), which is released by endothelial cells at the site of injury.
The tPA released by injured endothelial cells binds to fibrin as it activates the conversion of fibrin-bound plas- minogen to plasmin. Circulating plasminogen (i.e., not fibrin bound) is not activated by tPA. Thus, tPA is
efficient in dissolving a clot without causing systemic fibrinolysis.8,17,18
The effect of plasmin on fibrin and fibrinogen is to split off large pieces that are broken up into smaller and smaller segments. The final smaller pieces are called split products. These split products also are referred to as fibrin degradation products (FDPs). FDPs increase vas- cular permeability and interfere with thrombin-induced fibrin formation; this can provide the basis for clinical bleeding problems.8,19 Box 24-4 summarizes the fibrin- lysing system.
Antiplasmin factors present in circulating blood rapidly destroy free plasmin but are relatively ineffective against plasmin that is bound to fibrin (Box 24-5). Free plasmin is rapidly destroyed and does not interfere with the formation of a clot. Bound plasmin is not inac- tivated, and it is free to dispose of the fibrin clot after its function in homeostasis has been fulfilled. In a sense, the clot is “programmed” at the time of its formation to self-destruct.8,19
what is partial thromboplastin time?
Partial thromboplastin time (PTT) is used to check the intrinsic system (factors VIII, IX, XI, and XII) and the common pathways (factors V and X, prothrombin, and fibrinogen). It also is the best single screening test for coagulation disorders. A phospholipid platelet substitute is added to the patient’s blood to initiate the coagulation process via the intrinsic pathway. When a contact activa- tor, such as kaolin, is added, the test is referred to as activated PTT (aPTT). A control sample must be run with the test sample. In general, aPTT ranges from 25 to 35 seconds, and results in excess of 35 seconds are considered abnormal or prolonged. The aPTT is pro- longed in cases of mild to severe de ciency of factor VIII or IX. The test result is abnormal when a given factor is 15% to 30% below its normal value.1,13,22,23
what is thrombin time?
The prothrombin time (PT) is used to check the extrinsic pathway (factor VII) and the common pathway (factors V and X, prothrombin, and brinogen). For this test, tissue thromboplastin is added to the test sample to serve as the activating agent. Again, a control must be run, and results vary from one labora- tory to another. In general, the normal range is 11 to 15 seconds. PT is prolonged when the plasma level of any factor is below 10% of its normal value. When the test is used to evaluate the level of anticoagulation with coumarin-like drugs the INR format is recommended. INR, a method that standardizes PT assays, is defined later in this chapter.1,13,22,23 In this book the term INR will be used only for PT tests from patients on coumarin- like drugs.24
