Acquired Bleeding and Hypercoagulable Disorders


A number of procedures that are performed in dentistry may cause bleeding. Under normal circumstances, these procedures can be performed with little clinical risk; however, in patients whose ability to control bleeding has been altered by drugs or disease, such procedures may be associated with potentially catastrophic outcomes unless the dental practitioner identifies the problem before initiation of treatment. In most instances, after a patient with a bleeding problem due to drugs or disease has been identified, appropriate dental management will greatly reduce the associated risks. This chapter presents an overview of the physiologic mechanisms involved in the control of bleeding and the pathophysiology of acquired bleeding disorders and hypercoagulable states. Congenital bleeding disorders and genetic hypercoagulable conditions are covered in Chapter 25 .

Bleeding disorders are conditions that alter the ability of blood vessels, platelets, and coagulation factors to maintain hemostasis. Acquired bleeding disorders may occur as the result of diseases, drugs, radiation, or chemotherapy for cancer in which vascular wall integrity, platelet production or function, or coagulation factors are impaired.

Most bleeding disorders are iatrogenic. Every patient who receives coumarin (brand names: Warfarin, Coumadin) to prevent recurrent thrombosis has a potential bleeding problem. Most of these patients are receiving anticoagulant medication because they have had a recent myocardial infarction, a cerebrovascular accident, or thrombophlebitis. Patients who have atrial fibrillation ; had open heart surgery to correct a congenital defect, replace diseased arteries, or repair or replace damaged heart valves; or had recent total hip or knee replacement also may be receiving long-term anticoagulation therapy. Patients treated with antiplatelet medications to prevent cardiovascular complications also may have a potential bleeding problem. Advanced age increases the risk for bleeding and bleeding complications. Some people treated with aspirin for chronic illnesses, such as rheumatoid arthritis, may have potential bleeding problems.

COMPLICATIONS: Patients who have acquired bleeding disorders and experience trauma or invasive procedures are at risk for excessive bleeding, severe blood loss, and potentially death.


Patients with acute or chronic leukemia may have clinical bleeding tendencies because of thrombocytopenia, which may result from overgrowth of malignant cells in the bone marrow that leaves no room for red blood cells (RBCs) or platelet precursors. In addition, patients with leukemia may develop thrombocytopenia from the toxic effects of the various chemotherapeutic agents used to treat the disease. The etiology and incidence of leukemia are reviewed in Chapter 23 .

It is difficult to obtain accurate information about the incidence of other systemic conditions, such as liver disease, renal failure, thrombocytopenia, and drug-induced vascular wall defects, that may render the patient susceptible to prolonged bleeding after injury or surgery. However, when the prevalence of drug-influenced or disease-produced defects in the normal control of blood loss is considered, a busy dental practice will contain a large number of patients who may be potential “bleeders.” It is estimated that in a dental practice of 2000 adults, about 100 to 150 patients may have a possible bleeding problem.


Patients with acute or chronic leukemia may have clinical bleeding tendencies because of thrombocytopenia, which may result from overgrowth of malignant cells in the bone marrow that leaves no room for red blood cells (RBCs) or platelet precursors. In addition, patients with leukemia may develop thrombocytopenia from the toxic effects of the various chemotherapeutic agents used to treat the disease. The etiology and incidence of leukemia are reviewed in Chapter 23 .

It is difficult to obtain accurate information about the incidence of other systemic conditions, such as liver disease, renal failure, thrombocytopenia, and drug-induced vascular wall defects, that may render the patient susceptible to prolonged bleeding after injury or surgery. However, when the prevalence of drug-influenced or disease-produced defects in the normal control of blood loss is considered, a busy dental practice will contain a large number of patients who may be potential “bleeders.” It is estimated that in a dental practice of 2000 adults, about 100 to 150 patients may have a possible bleeding problem.


A pathologic alteration of blood vessel walls, a significant reduction in the number of platelets, defective platelets 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.

The classification given in Box 24.1 is based on bleeding problems in patients with normal numbers of platelets (nonthrombocytopenic purpura), decreased numbers of platelets (thrombocytopenic purpura), disorders of coagulation, and hypercoagulable states.

Box 24.1
Classification of Acquired Bleeding and Thrombotic Disorders

Nonthrombocytopenic Purpuras

Vascular Wall Alteration

  • Scurvy

  • Infections

  • Chemicals

  • Allergy

Disorders of Platelet Function

  • Drugs

  • Aspirin, other NSAIDs

  • Other antiplatelet drugs

  • Dipyridamole and aspirin (Aggrenox)

  • Ticlopidine (Ticlid)

  • Clopidogrel (Plavix)

  • Abciximab (ReoPro)

  • Eptifibatide (Integrilin)

  • Tirofiban (Aggrastat)

  • Alcohol

  • β-Lactam antibiotics

  • Cephalothins

  • Herbal medications

  • Vitamin E allergy

  • Autoimmune disease

  • Uremia

Thrombocytopenic Purpuras


  • Idiopathic


  • Chemicals

  • Physical agents (radiation)

  • Systemic disease (leukemia and others)

  • Metastatic cancer to bone

  • Splenomegaly

  • Drugs

    • Alcohol

    • Thiazide diuretics

    • Estrogens

    • Gold salts

  • Vasculitis

  • Mechanical prosthetic heart valves

  • Viral or bacterial infections

Disorders of Coagulation

  • Liver disease

  • Vitamin K deficiency

    • Biliary tract obstruction

    • Malabsorption

    • Excessive use of broad-spectrum antibiotics

  • Anticoagulation drugs

    • Heparin

    • Low-molecular-weight heparins

      • Enoxaparin (Lovenox)

      • Ardeparin (Normiflo)

      • Dalteparin (Fragmin)

      • Nadroparin (Fraxiparine)

      • Reviparin (Clivarine)

      • Tinzaparin (Innohep)

  • Synthetic heparin

    • Fondaparinux (Arixtra)

    • Idraparinux

  • Coumarin (warfarin), oral

  • Direct thrombin inhibitors

    • Lepirudin (Reflucan)

    • Desirudin (Revasc)

    • Argatroban (Acova)

    • Bivalirudin (Angiox)

    • Dabigatran (Pradaxa), oral

  • Disseminated intravascular coagulation

  • Primary fibrinogenolysis

Hypercoagulable States

  • Old age

  • Immobilization

  • Obesity

  • Infection

  • Hospitalization

  • Major surgery

  • Hormonal therapy

  • Atherosclerosis

  • Malignancy

  • Hyperhomocysteinemia

  • Antiphospholipid antibody syndromes

    • Lupus erythematosus

    • Rheumatoid arthritis

    • Sjögren syndrome

NSAID, Nonsteroidal antiinflammatory drug.

Infections, chemicals, collagen disorders, or certain types of allergies can alter the structure and function of the vascular wall to the point that the patient may have a clinical bleeding problem. A patient may have normal numbers of platelets, but they may be defective or unable to perform their proper function in the control of blood loss from damaged tissues. If the total number of circulating platelets is reduced to below 50,000/µL of blood, the patient may be a bleeder. In some cases, the total platelet count is reduced by unknown mechanisms; this is called primary or idiopathic thrombocytopenia. Chemicals, radiation, and various systemic diseases (e.g., leukemia) may have a direct effect on the bone marrow, potentially resulting in secondary thrombocytopenia.

Acquired coagulation disorders are the most common cause of prolonged bleeding. Liver disease and disseminated intravascular coagulation (DIC) can lead to severe bleeding problems. Many of the other acquired coagulation disorders may become apparent in patients only after trauma or surgical procedures. In contrast with the congenital coagulation disorders, in which only one factor is affected, the acquired coagulation disorders usually have multiple factor deficiencies.

Acquired hemophilia is an uncommon finding that can be caused by autoantibody inhibitors directed against “self”-clotting, which is mostly commonly factor VIII. About half of cases of acquired hemophilia are associated with autoimmune diseases, lymphoproliferative disorders, idiosyncratic drug reactions, pregnancy, and advanced age.

The liver produces all of the protein coagulation factors; thus, any patient with significant liver disease may have a bleeding problem. In addition to having a possible disorder in coagulation, a patient with liver disease who develops portal hypertension and hypersplenism may be thrombocytopenic as a result of splenic overactivity, which leads to increased sequestration of platelets in the spleen.

Any condition that so disrupts the intestinal flora that vitamin K is not produced in sufficient 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, malabsorption 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.

Drugs, such as heparin and coumarin derivatives, can cause a bleeding disorder because they may disrupt the coagulation process. Antiplatelet medications, aspirin, other nonsteroidal antiinflammatory drugs (NSAIDs), penicillin, cephalosporins, and alcohol also may interfere with platelet function.

Many herbal supplements can impair hemostatic function for the control of bleeding. Fish oil or concentrated omega-3 fatty acid supplements may impair platelet activation. Diets naturally rich in omega-3 fatty acids can result in a prolonged bleeding time and abnormal platelet aggregation. Fish oil supplements prolong bleeding time, inhibit platelet aggregation, and decrease thromboxane A 2 (TXA 2 ) production. Vitamin E appears to inhibit protein kinase C–mediated platelet aggregation and nitric oxide production. The following herbal supplements 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.


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 coagulation phase is secondary. The coagulation phase is followed by the fibrinolytic phase, during which the clot is dissolved ( Box 24.2 ).

Box 24.2
Normal Control of Bleeding

  • 1.

    Vascular phase

    • a.

      Vasoconstriction occurs in area of injury.

    • b.

      Begins immediately after injury.

  • 2.

    Platelet phase

    • a.

      Platelets and vessel wall become “sticky.”

    • b.

      Mechanical plug of platelets seals off openings of cut vessels.

    • c.

      Begins seconds after injury.

  • 3.

    Coagulation phase

    • a.

      Blood lost into surrounding area coagulates through extrinsic and common pathways.

    • b.

      Blood in vessels in area of injury coagulates through intrinsic and common pathways.

    • c.

      Takes place more slowly than other phases.

  • 4.

    Fibrinolytic phase

    • a.

      Release of antithrombotic agents

    • b.

      Destruction of antithrombotic agents by spleen and liver

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. Vascular wall integrity is important for maintaining the fluidity 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.

Vascular endothelial cells also are involved in antithrombotic 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 thrombin 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 fibrinolysis.

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 contribute to normal homeostasis and vascular integrity through synthesis of type IV collagen, fibronectin, and vWF.

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. 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.

Adenosine diphosphate released by damaged endothelial cells initiates aggregation of platelets (primary wave), and when platelets 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. Box 24.3 summarizes the functions of platelets.

Box 24.3
Platelet Functions and Activation

  • 1.

    Plasma membrane receptors

    • a.

      Glycoprotein Ib reacts with von Willebrand factor, which attaches to subendothelial tissue.

    • b.

      Glycoprotein Ia/IIa binds to collagen in the injured vessel wall.

    • c.

      Glycoprotein VI binds to collagen in the injured vessel wall.

    • d.

      Glycoproteins IIb and IIIa attach to fibrinogen or fibronectin.

  • 2.

    Platelets contain three types of secretory granules:

    • a.


    • b.

      Alpha granules—contain platelet factor 4; β-thromboglobulin; and several growth factors, including platelet-derived growth factor (PDGF), endothelial cell growth factor (PD-ECGF), and transforming growth factor-βa (TGF-β); also several hemostatic proteins: fibrinogen, factor V, and von Willebrand factor

    • c.

      Dense bodies (electron-dense organelles)—contain ATP, ADP, calcium, and serotonin

  • 3.

    Platelets provide a surface for activation of soluble coagulation factors:

    • a.

      Activated platelets expose specific receptors that bind factors Xa and Va, thus increasing their local concentration, thereby accelerating prothrombin activation.

    • b.

      Factor X also is activated by factors IXa and VIII on the surface of the platelet.

  • 4.

    Platelets contain a membrane phospholipase C:

    • a.

      When activated, it forms diglyceride.

    • b.

      Diglyceride is converted to arachidonic acid by diglyceride lipase.

    • c.

      Arachidonic acid is a substrate for prostaglandin synthetase (COX).

    • d.

      COX formation is inhibited by aspirin and NSAIDs.

    • e.

      The prostaglandin endoperoxide PGG 2 is required for ADP-induced aggregation and release, as is thromboxane A 2 . The formation of both of these agents is dependent on COX.

  • 5.

    The functions of platelets include:

    • a.

      Nurturing endothelial cells

    • b.

      Endothelial and smooth muscle regeneration

    • c.

      Formation of a platelet plug for initial control of bleeding

    • d.

      Stabilization of the platelet plug

ADP, Adenosine diphosphate; ATP, adenosine triphosphate; COX, cyclooxygenase; NSAID, nonsteroidal antiinflammatory drug.

Data from McMillan R: Hemorrhagic disorders: abnormalities of platelet and vascular function. In Goldman L, Ausiello D, editors: Cecil medicine, ed 23, Philadelphia, 2008, Saunders and Baz R, Mekhail T: Disorders of platelet function and number. In Carey WD, et al, editors: Current clinical medicine 2009 Cleveland Clinic, Philadelphia, 2009, Saunders.

A product of platelets, thromboxane, is needed to induce platelet aggregation. The enzyme cyclooxygenase (COX) is essential in the process for generation of thromboxane. Endothelial cells, through a similar process (also dependent on COX), generate prostacyclin, which inhibits platelet aggregation. Aspirin acts as an inhibitor of COX, and this causes irreversible damage to the platelets. However, endothelial cells can, after a short period, recover and synthesize COX; 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 (the time needed for all old platelets to be cleared from the blood).

Coagulation Phase.

The process of the fibrin-forming (coagulation) system is shown in Fig. 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 generated on the surface of the platelets, and bound fibrinogen is converted to fibrin. The end product of coagulation is a fibrin clot that can stop further blood loss from injured tissues ( Figs. 24.2 and 24.3 ).

FIG 24.1
The primary (vascular and platelet) system ( A ), the secondary (coagulation) system for the control of bleeding ( B ), and the coagulation cascade ( C ). The intrinsic coagulation system is triggered by surface contact, the extrinsic system by release of tissue factor from injured tissues, and the common pathway by factor X.
(From Ragni MV: The hemophilias: factor VIII and factor IX deficiencies. In Young NS, Gerson SL, High KA, editors: Clinical hematology, St. Louis, 2006, Mosby.)

FIG 24.2
A blood clot or thrombus, showing blood cells trapped by fibrin strands (scanning electron microscope photograph).
(From Stevens ML: Fundamentals of Clinical Hematology, Philadelphia, WB Saunders, 1997.)

FIG 24.3
A colored scanning electron micrograph of a blood clot or thrombus inside the coronary artery of a human heart.
(Reprinted with permission of P. M. Motta, G. Macchiarelli, S. A. Nottola/Photo Researchers, Inc.)

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. 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, fibrin. Fig. 24.1 shows these coagulation pathways.

TABLE 24.1
Blood Coagulation Components
Factor Deficiency Function
Factor II (prothrombin) Acquired—common Protease zymogen
Factor X Acquired—common Protease zymogen
Factor IX Acquired—common Protease zymogen
Factor VII Acquired—common Protease zymogen
Factor VIII Acquired—rare Cofactor
Factor V Acquired—rare Cofactor
Factor XI Acquired—common Protease zymogen
Factor I (fibrinogen) Acquired—common Structural
von Willebrand Factor Acquired—rare Adhesion
From McVey JH: Coagulation factors. In Young NS, Gerson SL, High KA, editors: Clinical hematology, St. Louis, 2006, Elsevier.

The (faster) extrinsic pathway is initiated through TF (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 TF. The term extrinsic pathway continues to be used today even though 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.

Thrombin generated by the faster extrinsic and common pathway is used to accelerate the slower intrinsic 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 generated; in turn, fibrinogen is converted to fibrin, activates factor XIII, enhances factor V and factor VIII activity, and stimulates aggregation of additional platelets.

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 after it has served its function in homeostasis ( Fig. 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 tPA, which is released by endothelial cells at the site of injury.

FIG 24.4
The coagulation and fibrinolytic pathways with inhibitors. PAI-1 , Plasminogen activator inhibitor-1.
(From Bontempo FA: Hematologic abnormalities in liver disease. In Young NS, Gerson SL, High KA, editors: Clinical hematology, St. Louis, 2006, Mosby.)

The tPA released by injured endothelial cells binds to fibrin as it activates the conversion of fibrin-bound plasminogen 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.

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 vascular permeability and interfere with thrombin-induced fibrin formation; this can provide the basis for clinical bleeding problems. Box 24.4 summarizes the fibrin-lysing system.

Box 24.4
Fibrin-Lysing (Fibrinolytic) System

  • 1.

    Activation of coagulation also activates fibrinolysis.

  • 2.

    Active enzyme: plasmin

  • 3.

    Plasminogen activated to plasmin

    • a.

      Tissue-type plasminogen activator (t-PA)

    • b.

      Prourokinase (scu-PA)

    • c.

      Urokinase (u-PA), streptokinase

  • 4.


    • a.

      t-PA is produced by endothelial cells.

    • b.

      It is released by injury.

    • c.

      It activates plasminogen bound to fibrin.

    • d.

      Circulating plasminogen is not activated.

    • e.

      t-PA will dissolve clot, not cause systemic fibrinolysis.

  • 5.

    Action of plasmin:

    • a.

      Plasmin splits large pieces of alpha and beta polypeptides from fibrin.

    • b.

      It splits small pieces of gamma chains.

    • c.

      First product is X monomer.

    • d.

      Each X monomer splits into one E fragment and two D fragments.

    • e.

      Split products are called fibrin split products (FSPs) and fibrin degradation products (FDPs).

  • 6.

    Action of fibrin degradation products:

    • a.

      Increase vascular permeability

    • b.

      Interfere with thrombin-induced fibrin formation

Data from Lijnen HR, Collen D: Molecular and cellular basis of fibrinolysis. In Hoffman R, et al, editors: Hematology: basic principles and practice, Philadelphia, 2009, Churchill Livingstone and Kessler CM: Hemorrhagic disorders: coagulation factor deficiencies. In Goldman L, Ausiello D, editors: Cecil textbook of medicine, ed 23, Philadelphia, 2008, Saunders.

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 inactivated, 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.

Box 24.5
Physiologic Antithrombotic Systems

  • 1.

    Normal endothelium promotes blood fluidity by inhibiting platelet activation.

  • 2.

    Endothelium also plays a role in anticoagulation by preventing fibrin formation.

  • 3.

    Antithrombin III

    • a.

      It is the major protease inhibitor of the coagulation system.

    • b.

      It inactivates thrombin and other activated coagulation factors.

    • c.

      Heparin acts as an anticoagulant by binding to antithrombin and greatly accelerates the ability of antithrombin to inhibit coagulation proteases.

    • d.

      Heparin and heparin sulfate proteoglycans are naturally present on endothelial cells.

  • 4.

    Activated protein C, with its cofactor protein S, acts as a natural anticoagulant by destroying factors Va and VIIIa.

  • 5.

    Tissue factor pathway inhibitor (TFPI), a plasma protease inhibitor, inhibits factor VIIa and the extrinsic pathway.

  • 6.

    The endogenous fibrinolytic system degrades any fibrin produced despite the above-mentioned antithrombotic mechanisms.

  • 7.

    Inherited deficiencies of antithrombin, protein C, or protein S are associated with a lifelong thrombotic tendency.

  • 8.

    TFPI deficiency has yet to be related to clinical problems.

Data from Dahlback B, Stenflo J: Regulatory mechanisms in hemostasis: natural anticoagulants. In Hoffman R, et al, editors: Hematology: basic principles and practice, ed 5, Philadelphia, 2009, Churchill Livingstone.

Timing of Clinical Bleeding.

A significant disorder that may occur in the vascular or platelet phase leads to an immediate clinical bleeding problem after injury or surgery. These phases are concerned with controlling blood loss immediately after an injury and, if defective, will lead to an early problem. However, if the vascular and platelet phases are normal and the coagulation phase is abnormal, the bleeding problem will not be detected until several hours or longer after the injury or surgical procedure. In the case of small cuts, for example, little bleeding would occur until several hours after the injury, and then a slow trickle of bleeding would start. If the coagulation defect were severe, this slow loss of blood could continue for days. Even with this “trivial” rate, a significant loss of blood might occur (0.5 mL/min or about 3 U/day).

Clinical Presentation

Signs and Symptoms

Signs associated with bleeding disorders may appear in the skin or mucous membranes or after trauma or invasive procedures. Jaundice ( Fig. 24.5 ), spider angiomas ( Fig. 24.6 ), and ecchymoses ( Fig. 24.7 ) may be seen in individuals with liver disease. A fine tremor of the hands when held out also may be observed in these patients. In about 50% of persons with liver disease, a reduction in platelets occurs because of hypersplenism that results from the effects of portal hypertension; these patients may show petechiae on the skin and mucosa.

FIG 24.5
Jaundice of the skin in a patient with chronic liver disease.

FIG 24.6
A, Spider angioma on the skin of a patient with chronic liver disease. B, Note how the spider legs of the angioma blanch with pressure on the central arteriole.
(From Forbes CD, Jackson WF: Color atlas and text of clinical medicine, ed 3, Edinburgh, 2003, Mosby.)

FIG 24.7
Ecchymoses on the mucosa of the hard and soft palate in a patient with chronic liver disease.

Petechiae ( Fig. 24.8 ) and ecchymoses are the signs seen most commonly in patients with abnormal platelets or thrombocytopenia.

FIG 24.8
The arm of a patient with thrombocytopenia showing numerous petechiae.

Patients with acute or chronic leukemia may reveal one or more of the following signs: ulceration of the oral mucosa, hyperplasia of the gingivae ( Fig. 24.9 ), petechiae of the skin or mucous membranes ( Fig. 24.10 ), ecchymoses of skin or mucous membranes, and lymphadenopathy. Chapter 23 discusses these findings in greater detail.

FIG 24.9
Hyperplastic gingiva in a patient with leukemia.

FIG 24.10
Palatal petechiae in a patient with leukemia.
(From Hoffbrand AV: Color atlas of clinical hematology, ed 3, St. Louis, 2000, Mosby.)

A number of patients with bleeding disorders may show no objective signs that suggest the underlying problem. Severe or chronic bleeding can lead to anemia with features of pallor, fatigue, and so forth. Anemia is discussed in detail in Chapter 22 .

Laboratory and Diagnostic Findings

Several tests are available to screen patients for bleeding disorders and to help pinpoint the specific deficiency. In general, screening is done in dentistry when the patient reveals a history of a bleeding problem or a family member with a history of a bleeding problem or when signs of bleeding disorders are found during the clinical examination. The dentist can order the screening tests, or the patient can be referred to a hematologist for screening. In medicine, routine screening is done for patients before major surgical procedures such as open heart surgery are performed.

The Ivy bleeding time (BT) has been used to screen for disorders of platelet function and thrombocytopenia. It has been found to be unreliable and is no longer used as a screening test. The platelet function analyzer (PFA-100), an instrument that measures platelet-dependent coagulation under flow conditions, is more sensitive and specific for platelet disorders and von Willebrand disease than the bleeding time; however, it is not sensitive enough to rule out underlying mild bleeding disorders. The relationship between bleeding time test and postextraction bleeding in a healthy control population was evaluated by Brennan et al in 2002. The mean cutaneous BT was 5.9 minutes (range, 1.5–10.0 minutes). The mean oral BT was 7.5 minutes (range, 0–20 minutes). Cutaneous BT did not correlate with oral BT or any measures of postoperative bleeding. Therefore, the BT and PFA-100 are not recommended as screening tests to be used by dentists.

Three tests are recommended for use in initial screening for possible bleeding disorders: activated partial thromboplastin time (aPTT), prothrombin time (PT), and platelet count ( Fig. 24.11 ). In the absence of clues to the cause of the bleeding problem, if the dentist is ordering the tests through a commercial laboratory, an additional test can be added to the initial screen: the thrombin time (TT).

FIG 24.11
Coagulation cascade indicating the intrinsic pathway measured by activated partial thromboplastin time (aPTT); the extrinsic pathway measured by prothrombin time (PT); and the conversion of fibrinogen to fibrin, which is measured by thrombin time (TT). Other proteins—prekallikrein and high-molecular-weight (HMW) kininogen—participate in the contact activation phase but are not considered coagulation factors. Ca 2+ , Calcium; PL, phospholipid.
(From Rick ME: Coagulation testing. In Young NS, Gerson SL, High KA, editors: Clinical hematology, St. Louis, 2006, Mosby.)

Patients with positive screening test results should be evaluated further so the specific deficiency can be identified and the presence of inhibitors ruled out. A hematologist orders these tests, establishes a diagnosis that is based on the additional testing, and makes recommendations for treatment of the patient who is found to have a significant bleeding problem.

Screening Tests.

Partial Thromboplastin Time. The 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 activator, 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 prolonged in cases of mild to severe deficiency of factor VIII or IX. The test result is abnormal when a given factor is 15% to 30% below its normal value.

Prothrombin Time.

The PT is used to check the extrinsic pathway (factor VII) and the common pathway (factors V and X, prothrombin, and fibrinogen). 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 laboratory 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 international normalized ratio (INR) format is recommended. INR, a method that standardizes PT assays, is defined later in this chapter. In this book, the term INR is used only for PT tests from patients taking coumarin-like drugs.

Platelet Count.

The platelet count is used to screen for possible bleeding problems caused by thrombocytopenia. A normal platelet count is 150,000 to 450,000/µL of blood. Patients with a platelet count of between 50,000 and 100,000/µL manifest excessive bleeding only with severe trauma. Patients with counts below 50,000/µL demonstrate skin and mucosal purpura and bleed excessively with minor trauma. Patients with platelet counts below 20,000/µL may experience spontaneous bleeding.

Thrombin Time.

In this test, thrombin is added to the patient’s blood sample as the activating agent. It converts fibrinogen in the blood to insoluble fibrin, which makes up the essential portion of a blood clot. Again, a control must be run, and results vary from laboratory to laboratory. This test bypasses the intrinsic, extrinsic, and most of the common pathway. For example, patients with hemophilia A or factor V deficiency have a normal TT. Generally, the normal range for the TT test is 9 to 13 seconds, and results in excess of 16 to 18 seconds are considered abnormal or prolonged. Abnormal test results usually are caused by excessive plasmin or fibrin split products.

Diagnostic Tests Performed by the Hematologist.

When one or more of the screening tests yield an abnormal result, the hematologist runs additional tests to pinpoint the specific defect of the bleeding disorder.

Platelet Disorders.

The platelet count is very effective for identifying patients with thrombocytopenia. It is not effective for identifying patients with disorders of platelet function such as von Willebrand disease, Bernard-Soulier disease, Glanzmann disease, uremia, and drug-induced platelet release defects. BT may be prolonged in these patients, but test results are inconsistent. Platelet aggregation tests, ristocetin-induced agglutination, platelet release reaction, and other tests may have to be performed for the nature of the clinical bleeding problem to become apparent.

Additional laboratory tests are needed to establish the diagnosis and to identify the type of von Willebrand disease. These consist of ristocetin cofactor activity, ristocetin-induced platelet aggregation, immunoassay of vWF, multimeric analysis of vWF, and specific assays for factor VIII.

Disorders of the Intrinsic Pathway. Screening tests show prolonged aPTT, normal PT, and normal platelet count (except in some cases of von Willebrand disease). The next step is to mix (mixing tests) the patient’s blood with a sample of pooled plasma and repeat the aPTT. If this test is normal, then the specific missing factor is identified by specific assays. If the mixing test result is abnormal, tests for inhibitor activity (antibodies to the factor) are performed. Some acquired coagulation disorders can produce prolonged aPTT along with normal PT. These include the lupus inhibitor, antibodies to factor VIII, and heparin therapy.

Disorders of the Extrinsic Pathway. A normal aPTT and a prolonged PT suggest a factor VII deficiency, which is very rare, or inhibitors to factor VII. Factor VII deficiency is confirmed by specific assay. Mixing studies are used to rule out factor VII inhibitors.

Disorders of the Common Pathway. A prolonged aPTT and a prolonged PT in a patient with a history of a congenital bleeding disorder indicate a common pathway factor deficiency. Congenital deficiency of factors V and X, prothrombin, or fibrinogen is rare. When both of these test results are prolonged, an acquired common pathway factor deficiency is usually indicated. Often, multiple factors are found to be deficient. Conditions that can cause both tests to be abnormal are vitamin K deficiency, liver disease, and DIC. When both test results are prolonged in a patient with a history suggestive of a congenital bleeding problem, the next step is to exclude or identify an abnormality of fibrinogen in the laboratory. This involves measuring the plasma fibrinogen level and performing tests for D-dimer of FDPs. After a problem involving fibrinogen has been ruled out, the next step is to perform mixing studies to rule out inhibitor activity. If these test result are negative, then specific assays for deficiency of factor V or X or prothrombin are performed.

Degradation Products of Fibrin or Fibrinogen. In patients with prolonged aPTT, PT, and TT, the defect involves the last stage of the common pathway, which is the activation of fibrinogen to form fibrin to stabilize the clot. The plasma level of fibrinogen is determined, and if it is within normal limits, then tests for fibrinolysis are performed. These tests, which detect the presence of fibrinogen, FDPs, or both, consist of staphylococcal clumping assay, agglutination of latex particles coated with antifibrinogen antibody, and euglobulin clot lysis time.

Disorders with Normal Primary Screening Results. Patients with vascular abnormalities that can cause clinical bleeding may not be identified through the use of recommended screening tests. BT is the only finding that might be abnormal in these patients. However, it has clearly been shown that BT is inconsistent in these patients. Thus, this test is not reliable for identifying these patients. In most cases, the diagnosis must be based on history and clinical findings.

Three known defects in the coagulation system do not affect PT, aPTT, or TT. These are rare and include factor XIII deficiency, α 2 plasmin inhibitor deficiency, and plasminogen activator inhibitor-1 deficiency (major inhibitor of plasminogen activators). Patients with a strong clinical history of bleeding and normal coagulation test results (PT, aPTT, and TT) require additional testing, such as the use of 5M urea.

Another small group of patients with a history of significant bleeding problems will have negative test results when screened by means of currently recommended methods. It appears that current methods are unable to reveal whatever disorder these patients may have. A clear-cut history of prolonged bleeding after trauma or surgical procedures is always more significant than negative laboratory data.

Medical Management

In this section, conditions that may cause clinical bleeding are considered. The emphasis is on detection of patients with potential bleeding problems and management of such patients if surgical procedures are needed. Disorders affecting the vascular, platelet, coagulation, and fibrinolytic phases are discussed. DIC, disorders of platelet release, and primary fibrinogenolysis are described to show the nature of acquired bleeding disorders. These diseases reflect the roles of various factors involved in the control of excessive bleeding after injury, and they reveal what happens when these factors are defective. Table 24.2 summarizes the nature of the defects and the medical treatments available for excessive bleeding in patients with several of the more common acquired disorders covered in this section.

TABLE 24.2
Medical Treatment of Acquired Bleeding Disorders
Condition Defect Medical Treatment
Primary thrombocytopenia (idiopathic thrombocytopenia) Platelets destroyed by autoimmune processes Prednisone
Intravenous gamma globulin
Platelet transfusion
Secondary thrombocytopenia Deficiency of platelets due to accelerated destruction or consumption, deficient production, or abnormal pooling Platelet transfusion
Liver disease Multiple coagulation factor defects
Patients with portal hypertension may be thrombocytopenic.
Vitamin K
Replacement therapy only for serious bleeding or before surgical procedures
Desmopressin provides some benefit.
Disseminated intravascular coagulation Multiple coagulation factor defects caused by triggered consumption
Formation of fibrin and fibrinogen degradation products due to fibrinolysis
Treatment of primary disorder
Cryoprecipitate or fresh-frozen plasma for replacement of fibrinogen
Platelet transfusion
Other blood product replacements lead to mixed results.

Vascular Defects

Bleeding disorders caused by vascular abnormalities may be caused by structural malformation of vessels, hereditary disorders of connective tissue, and acquired connective tissue disorders.

Acquired connective tissue disorders that may be complicated by bleeding include scurvy, small vessel vasculitis, and skin disorders. In scurvy, deficiency of vitamin C leads to lack of peptidyl hydroxylation of procollagen, resulting in weakened collagen fibers. The abnormal collagen results in defective perivascular supportive tissues, which can lead to capillary fragility and delayed wound healing. In patients on long-term use of steroids, thinning of connective tissues may result in bleeding after minor trauma.

Small vessel vasculitis may be caused by a variety of conditions that produce inflammation of small vessels, including arterioles, venules, and capillaries. Serum sickness can lead to purpura through immune complex deposits into vessel walls. Drugs such as penicillin, hydralazine, sulfonamides, and thiazide diuretics and hepatitis have been associated with serum sickness–like reactions.

Platelet Disorders

Disorders of Platelet Function.

Platelets participate directly in the clotting cascade by serving as constituents of factor X and prothrombin-converting complexes through the release of platelet factor 3 (PF3). The potency of this release effect is increased by increased participation of platelets in the clotting process. In some cases, platelets may fail to complete the release reaction of PF3. Sometimes this is caused by defective production of thromboxane and other times by a deficiency in the production of dense-granule ADP.

Defective thromboxane production almost always results from the administration of antiinflammatory drugs. The best-known example is aspirin, which inactivates COX, the first enzyme of the prostaglandin–thromboxane synthetic pathway. Other drugs that interfere with thromboxane formation include NSAIDs (indomethacin, phenylbutazone, ibuprofen, sulfinpyrazone), β-lactam antibiotics; calcium channel–blocking drugs (verapamil, diltiazem, and nifedipine), phenytoin, nitrates, phenothiazines, and tricyclic antidepressants. All platelet release defects produce about the same clinical picture.

In otherwise healthy people, the impairment of platelet function that is produced by drugs usually is of no clinical significance. However, in patients with coagulation disorders, uremic or thrombocytopenic patients, and those receiving heparin or coumarin anticoagulants, drug-induced platelet dysfunction can result in serious bleeding. Platelet function studies often show an absence of secondary wave aggregation. Patients can be screened with standard screening tests; if these results are normal, surgical procedures can be performed.

Uremia may interfere with platelet function. This effect can be severe in patients with grossly abnormal platelet function. Such patients are in danger of bleeding to death if injury occurs or surgery is performed. They respond to dialysis, cryoprecipitate, or kidney transplantation but not to platelet replacement. Although β-lactam antibiotics (penicillin and cephalothins) may cause platelet dysfunction, usually no treatment is required. In some undetermined way, alcohol may impair platelet function; this effect may be severe enough to contraindicate surgery unless corrective measures are taken.

Coagulation Disorders

Disseminated Intravascular Coagulation.

Disseminated intravascular coagulation has been reported to occur in about 1 in 1000 hospital admissions. The syndrome is associated with a number of disorders such as infection, obstetric complications, cancer, and snakebites. In fact, worldwide, the most common cause of DIC is snakebite. DIC is a condition that results when the clotting system is activated in all or a major part of the vascular system. Despite widespread fibrin production, the major clinical problem is bleeding, not thrombosis. DIC is caused when large quantities of thromboplastic substances are introduced into the vascular system and “trip” the clotting cascade. Acute DIC may be caused by obstetric complications (abruptio placentae, missed abortion, amniotic fluid embolism), infection, injuries and burns, antigen-antibody complexes, sepsis and septic shock, and acidosis.

Clinical Presentation.

Clinical manifestations of acute DIC include severe bleeding from small wounds; purpura; and spontaneous bleeding from the nose, gums, gastrointestinal tract, or urinary tract ( Fig. 24.12 ). Traumatic hemolytic anemia may occur when RBCs are “sliced” by fibrin strands. On rare occasions, bilateral necrosis of the renal cortex has developed. Chronic DIC may occur in association with certain types of cancer. Malignant cells can release thromboplastic material as they die within the tumor mass. Antigen–antibody complexes associated with systemic lupus erythematosus may cause chronic DIC. In the chronic form of the disease, thrombosis is more common than bleeding.

FIG 24.12
Disseminated intravascular coagulation resulting from staphylococcal septicemia in a 56-year-old man. Note the characteristic skin hemorrhage, ranging in extent from small purpuric lesions to larger ecchymoses. The patient had non–insulin-dependent (type 2) diabetes, and the septicemia originated with an untreated large boil on his thigh.
(From Forbes CD, Jackson WF: Color atlas and text of clinical medicine, ed 3, Edinburgh, 2003, Mosby.)

Laboratory and Diagnostic Findings.

Consumption and inhibition of the function of clotting factors cause prolongation of the PT, aPTT, and TT. Consumption of platelets causes thrombocytopenia. Secondary fibrinolysis generates increased titers of FDPs, which can be measured by latex agglutination or D-dimer assays. Chronic or compensated forms of DIC are more difficult to diagnose, with highly variable patterns of abnormalities in “DIC screen” coagulation tests. Increased FDPs and a prolonged PT are generally more sensitive measures than abnormalities of the aPTT and platelet count are. Overcompensated synthesis of consumed clotting factors and platelets in some chronic forms of DIC may actually cause shortening of the PT and aPTT or thrombocytosis (or both) even though elevated levels of FDPs indicate secondary fibrinolysis in such cases. The most difficult differential diagnosis of DIC occurs in patients who have coexisting liver disease. The coagulopathy of liver failure is often indistinguishable from that of DIC, partly because advanced hepatic dysfunction is accompanied by a state of DIC. In liver failure, the combination of decreased synthesis of clotting factors, impaired clearance of activated clotting factors, secondary fibrinolysis, and thrombocytopenia from portal hypertension and hypersplenism may make the coagulopathy practically impossible to differentiate from DIC.

Medical Management.

Treatment of patients with DIC consists of an attempt to reverse the cause, control of the major symptom (bleeding or thrombosis), and a prophylactic regimen to prevent recurrence in cases of chronic DIC. Consumed coagulation factors need to be replaced, along with missing platelets. Fibrinogen levels must be restored. Cryoprecipitate is used if bleeding is the major problem. Fresh-frozen plasma (FFP) also may be used. If thrombosis is the major problem (early in the process), intravenous (IV) heparin is used. Long-term heparin infusion is used for prophylaxis in cases of chronic DIC. The use of aminocaproic acid (Amicar), desmopressin, and tranexamic acid preparations is not recommended because increased bleeding may occur.

Fibrinolytic Disorders

Fibrinolysis and Fibrinogenolysis.

Primary fibrinogenolysis may develop if active plasmin is generated in the circulation at a time when the clotting cascade is not in operation. It can occur in patients with liver disease, lung cancer, prostate cancer, or heatstroke. Severe bleeding results from the depletion of fibrinogen (split by plasmin) and the formation of fibrin split products (with their anticoagulant properties) from fibrinogen.

Fibrinogenolysis can be treated with ε-aminocaproic acid or tranexamic acid, which inhibits both plasmin and plasmin activators; however, these drugs may be dangerous if used in patients with DIC because diffuse thromboses may result. Thus, exclusion of the diagnosis of DIC before antifibrinolytic agents are begun is very important. A specific test such as D-dimer measurement can be used for this purpose.

Thrombosis and Antithrombotic Therapy.

Thrombosis is the formation, from components of blood, of an abnormal mass within the vascular system. It involves the interaction of vascular, cellular, and humoral factors within a flowing stream of blood. Thrombosis and the complicating emboli that may result are one of the most important causes of sickness and death in developed countries. Thrombosis is of greater overall clinical importance in terms of morbidity and mortality than are all of the hemorrhagic disorders combined. Excessive activation of coagulation or inhibition of anticoagulant mechanisms may result in hypercoagulability and thrombosis. Injury to the vessel wall, alterations in blood flow, and changes in the composition of blood are major factors leading to thrombosis.

The common causes of acquired venous thrombosis are older age, history of thrombosis, immobilization, obesity, infection, hospitalization, major surgery, and pregnancy. Common causes of both venous and arterial thrombosis are malignancy, hormonal therapy, and DIC. The most common cause of arterial thrombosis is atherosclerosis.

Patients should be considered for laboratory evaluation for inherited thrombotic disorders if they are younger than 45 years of age and have recurrent thrombosis. In addition, patients who have experienced a single thrombotic event and have a family history of thrombosis should be tested. The inherited thrombotic disorders are covered in Chapter 25 .

The pathologic basis for arterial thrombosis involves atherosclerotic vascular disease associated with platelet thrombi. Thrombin is a major mediator in this type of thrombosis. Drug therapy for arterial thrombi involves agents with antithrombin and antiplatelet activity. Venous thrombi usually occur in otherwise normal vessel walls; stasis and hypercoagulability are major predisposing factors. Drugs that prevent thrombin formation or lyse fibrin clots are the main agents used to treat venous thrombi. Antidotes are available for overdosing of heparin (protamine) and warfarin (vitamin K); however, none is available for overdosing of the newer anticoagulant drugs, but significant progress is been made to solve this problem ( Fig. 24.13 ).

FIG 24.13
Subcutaneous heparin is used to reduce the risk of deep vein thrombosis in medical and surgical procedures.
(From Potter PA, Perry AG, Stockert P: Basic nursing, ed 7, St. Louis, 2011, Mosby.)

Clot collectors (inferior vena caval filters [IVCFs]) can be used to prevent large clots from reaching the lungs ( Fig. 24.14 ). The IVCF can be inserted into the vena cava from an incision in the neck area or in the groin area. The IVCF can be permanent or removed when the risk of a large clot traveling to the lung is over. Complications have been reported with the use of IVCFs; these include the breaking off of pieces of the IVCF and the appliance becoming attached to the vessel wall and unable to be removed.

Sep 3, 2018 | Posted by in General Dentistry | Comments Off on Acquired Bleeding and Hypercoagulable Disorders

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