Chapter 25

Congenital 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 risk to the patient; however, the patient whose ability to control bleeding has been altered by congenital defects in coagulation factors, platelets, or blood vessels may be in grave danger unless the dentist identifies the problem before performing any dental procedure. In most cases, once the patient with a congenital bleeding problem has been identified, steps can be taken to greatly reduce the risks associated with dental procedures. The following disorders are discussed in this chapter: hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome), von Willebrand disease, Bernard-Soulier disease, Glanzmann’s thrombasthenia, hemophilia A, hemophilia B (Christmas disease), and congenital hypercoagulability disorders.

Definition

Inherited (congenital) bleeding disorders are genetically transmitted. They may involve a deficiency of one of the coagulation factors, abnormal construction of platelets, deficiency of von Willebrand factor, or malformation of vessels (< ?xml:namespace prefix = "mbp" />Box 25-1). They are not nearly as prevalent as acquired bleeding disorders. In a typical dental practice of 2000 patients, at the most 10 to 20 patients will have a congenital bleeding disorder. Inherited hypercoagulability disorders increase the risk for thromboembolism due to a genetic deficiency of an antithrombotic factor or increasing a prothrombotic factor. They are more common than the inherited bleeding disorders.

Box 25-1 Classification of Congenital Bleeding and Thrombotic Disorders

Nonthrombocytopenic Purpuras

Vascular Wall Alterations

Hereditary hemorrhagic telangiectasia

Disorders of Platelet Function

von Willebrand’s disease (may have secondary factor VIII deficiency)

Bernard-Soulier disease*

Glanzmann’s thrombasthenia

Others

Thrombocytopenic Purpuras (all are very rare)

Gray platelet syndrome

May-Hegglin anomaly

Hereditary thrombocytopenia, deafness, and renal disease

Fechtner syndrome

Alport’s syndrome

Sebastian platelet syndrome

Others

Disorders of Coagulation

Hemophilia A (factor VIII deficiency)

Hemophilia B (factor IX deficiency)

Other coagulation factor deficiencies

Hypercoagulable States

Antithrombin III deficiency

Protein C deficiency

Protein S deficiency

Factor V Leiden mutation

Prothrombin G2021A mutation

Hyperchomocysteinemia

^* Bernard-Soulier disease also has been classified as a thrombocytopenic disorder.

Epidemiology: Incidence and Prevalence

The most common inherited bleeding disorder is von Willebrand disease. It affects about 1% of the U.S. population. The disease usually is inherited as an autosomal dominant trait. Hemophilia A, factor VIII deficiency, is the most common of the inherited coagulation bleeding disorders. It occurs in about 1 of every 5000 male births. More than 20,000 individuals in the United States have hemophilia A.^1,² Because of its genetic mode of transfer, certain areas of the United States contain higher concentrations of people with hemophilia. Hemophilia B (Christmas disease), a factor IX deficiency, is found in about 1 of every 30,000 male births.¹ About 80% of all genetic coagulation disorders are hemophilia A, 13% are hemophilia B, and 6% are factor XI deficiency.¹ Bernard-Soulier disease and Glanzmann’s thrombasthenia are rare inherited platelet disorders.³ Hereditary hemorrhagic telangiectasia (HHT) is a rare (1 : 8000 to 1 : 50,000) vascular disorder.⁴ Ehlers-Danlos disease, osteogenesis imperfecta, pseudoxanthoma elasticum, and Marfan syndrome are rare hereditary connective tissue disorders that may be associated with bleeding problems but are not covered in this chapter.⁴ An inherited hypercoagulable state has been reported in more than 60% of patients presenting with idiopathic venothromboembolism.⁵

Etiology

Patients may be born with a deficiency of one of the factors needed for blood coagulation—for example, factor VIII deficiency as in hemophilia A or factor IX deficiency as in hemophilia B or Christmas disease. Congenital deficiencies of the other coagulation factors have been reported but are rare (Table 25-1). When congenital deficiency of a coagulation factor occurs, only a single factor is affected.^1,⁶

TABLE 25-1 Blood Coagulation Components

Factor	Deficiency	Function
Factor II (prothrombin)	Congenital—rare	Protease zymogen
Factor X	Congenital—rare	Protease zymogen
Factor IX	Congenital—rare	Protease zymogen
Factor VII	Congenital—very rare	Protease zymogen
Factor VIII	Congenital—more common	Cofactor
Factor V	Congenital—rare	Cofactor
Factor XI	Congenital—rare	Protease zymogen
Factor XII	Deficiency reported but does not cause bleeding; aPTT will be prolonged	Protease zymogen
Factor I (fibrinogen)	Congenital—rare	Structural
von Willebrand factor	Congenital—most common	Adhesion
Tissue factor	Not applicable	Cofactor initiator
Factor XIII	Congenital—rare; will cause bleeding, but aPTT and PT will be normal	Fibrin stabilization
High-molecular-weight kininogen	Deficiency does not cause bleeding; will prolong aPTT	Coenzyme
Prekallikrein	Deficiency does not cause bleeding; will prolong aPTT	Coenzyme

Data from McVey JH: Coagulation factors. In Young NS, Gerson SL, High KA, editors: Clinical hematology, St. Louis, 2006, Mosby.

In von Willebrand disease, the primary problem involves lack of various sizes of von Willebrand factor (vWF), which are needed to attach platelets to damaged vascular wall tissues and to carry factor VIII in circulation.⁷ In the most severe form of the disease, bleeding occurs as a consequence of lack of platelet adhesion and deficiency of factor VIII.⁷ Bernard-Soulier disease is a disorder of platelet adhesion to vWF due to the lack of glycoprotein Ib on the platelet membrane.⁴ These platelets are unable to bind to vWF and thus are unable to adhere to the subendothelium. Glanzmann’s thrombasthenia is a disorder of platelet aggregation due to abnormality of the platelet membrane complex glycoprotein IIb/IIIa.⁴ The platelets can adhere to the subendothelium but cannot bind to fibrinogen.

HHT is a disorder consisting of multiple telangiectatic lesions involving the skin and mucous membranes.⁴ Bleeding occurs because of the inherent mechanical fragility of the affected vessels. Problems with the construction of connective tissue components of the vessel wall are the underlying weakness in Ehlers-Danlos disease, osteogenesis imperfecta, pseudoxanthoma elasticum, and Marfan syndrome.^4,⁸ The reader is referred to other sources for further information on these latter diseases.

Pathophysiology

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. These hemostatic mechanisms are discussed in detail in Chapter 24, on acquired bleeding disorders.

Clinical Presentation

Signs and Symptoms

The most common objective findings in patients with genetic coagulation disorders are ecchymoses, hemarthrosis, and dissecting hematomas (Figures 25-1 and 25-2).^1,^6,⁹ The signs seen most commonly in patients with abnormal platelets or thrombocytopenia are petechiae and ecchymoses (Figure 25-3).^2,^10,¹¹ The signs seen most commonly in patients with vascular defects are petechiae and bleeding from the skin or mucous membrane.⁴

FIGURE 25-1 Large Area of Subcutaneous Ecchymoses Due to Trauma in a Patient with Hemophilia.

(From Hoffbrand AV, Pettit JE: Color atlas of clinical hematology, ed 4, London, 2010, Mosby.)

FIGURE 25-2 Acute Hemarthrosis of the Knee is a Common Complication of Hemophilia.

It may be confused with acute infection unless the patient’s coagulation disorder is known, because the knee is hot, red, swollen, and painful.

(From Forbes CD, Jackson WF: Color atlas and text of clinical medicine, ed 3, London, 2003, Mosby.)

FIGURE 25-3 Purpura (Petechiae)- in this Case Throbocytopenia Purpura (TP).

The patient was a 15-year-old boy whose antiepileptic treatment regimen had recently been modified to include sodium valproate. This is just one of a number of drugs that may induce TP, but the disorder is almost always reversible if the drug therapy is stopped.

(From Forbes CD, Jackson WF: Color atlas and text of clinical medicine, ed 3, London, 2003, Mosby.)

Laboratory Tests

Three tests are recommended for use in initial screening for possible bleeding disorders¹²^–¹⁴: activated partial thromboplastin time (aPTT), prothrombin time (PT), and platelet count (Figure 25-4). If no clues are evident as to the cause of the bleeding problem, and the dentist is ordering the tests through a commercial laboratory, an additional test can be added to the initial screen: thrombin time (TT).¹²^–¹⁴

FIGURE 25-4 Organization of the coagulation system based on current screening assays. The intrinsic coagulation system consists of the protein factors XII, XI, IX, and VIII and prekallikrein (PK) and high-molecular-weight kininogen (HK). The extrinsic coagulation system consists of tissue factor and factor VII. The common pathway of the coagulation system consists of factors X, V, and II and fibrinogen (I). The activated partial thromboplastin time requires the presence of every protein except tissue factor and factor VII. The prothrombin time (PT) requires tissue factor; factors VII, X, V, and II; and fibrinogen. The thrombin clotting time only tests the integrity of fibrinogen.

(From McPherson RA, Pincus MR, editors: Henry’s clinical diagnosis and management by laboratory methods, ed 22, London, 2012, Saunders.)

Patients with positive results on screening tests should be evaluated further so that 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. The screening laboratory tests are discussed in detail in Chapter 24.

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 and/or fibrin-degradation products, consist of staphylococcal clumping assay, agglutination of latex particles coated with antifibrinogen antibody, and euglobulin clot lysis time.¹²^–¹⁴

Medical Management

In this section, congenital conditions that may cause clinical bleeding are considered. The emphasis is placed on identification of patients with a potential bleeding problem and management of these patients if surgical procedures are needed.

Table 25-2 summarizes the nature of the defects and the medical treatment available for excessive bleeding in patients with the disorders covered in this section. Tables 25-3 and 25-4 list the commercial products that are available to treat bleeding problems in these disorders.

TABLE 25-2 Medical Treatment of Congenital Bleeding Disorders

Condition	Defect	Medical Management
Hereditary hemorrhagic telangiectasia	Multiple telangiectasias with mechanical fragility of the abnormal vessels	Laser Surgery Estrogen Estrogen plus progesterone Thalidomide
von Willebrand disease	Deficiency or defect in vWF causing poor platelet adhesion and in some cases deficiency of F-VIII	Desmopressin Aminocaproic acid Factor VIII replacement that retains vWF
Hemophilia A	Deficiency or defect in F-VIII	Desmopressin Aminocaproic acid Factor VIII
Hemophilia A	Some patients develop antibodies (inhibitors) to F-VIII	Porcine factor VIII, PCC, aPCC, factor VIIa, and/or steroids for patients with inhibitors
Hemophilia B	Deficiency or defect in F-IX	Desmopressin Aminocaproic acid Factor IX
Hemophilia B	Development of antibodies (inhibitors) to F-IX is much less common than with hemophilia A	PCC, aPCC, factor VIIa,* and/or steroids for patients with inhibitors
Bernard-Soulier disease	Genetic defect in platelet membrane, absence of glycoprotein Ib (GP-Ib) causes disorder in platelet adhesion	Platelet transfusion Desmopressin Factor VIIa
Glanzmann’s thrombasthenia	Genetic defect in platelet membrane, absence of glycoprotein IIb/IIIa (GPIIb/IIIa)	Platelet transfusion Desmopressin Factor VIIa

aPCC, Activated prothrombin complex concentrates; PCC, Prothrombin complex concentrates; vWF, von Willebrand factor.

* Factor VIIa is activated factor VII.

TABLE 25-3 FDA-Approved Clotting Concentrates for Hemophilia A and B

Preparation with Virucidal Technique(s)	Type/Manufacturer	Specific Activity (IU/mg Protein)
Ultrapure recombinant factor VIII
Immunoaffinity; ion exchange chromatography	Recombinate (Baxter)	>4000
Ion exchange chromatography, nanofiltration	Refacto (Wyeth)	11,200-15,000
Ion exchange chromatography, ultrafiltration	Kogenate FS (Bayer Inc.)	>4000
No human or animal protein used in culture; immunoaffinity and ion exchange chromatography	Advate (Baxter)	>4000-10,000
Ultrapure human plasma factor VIII
Chromatography and pasteurization	Monoclate P (ZLB Behring)	>3000
Chromatography and solvent detergent	Hemofil M (Baxter)	>3000
High-purity human plasma factor VIII
Chromatography, solvent detergent, dry heating	Alphanate SD (Grifols) vWF	50->400
Solvent detergent, dry heating	Koate-DVI (Bayer) vWF	50-100
Pasteurization (heating in solution)	Humate-P (ZLB-Behring) vWF	1-10
Porcine plasma-derived factor VIII
Solvent detergent viral attenuation	Hyate-C (Ibsen/Biomeasure, Inc.)	>50
Ultrapure recombinant factor IX
Affinity chromatography and ultrafiltration	BeneFix (Wyeth)	>200
Very highly purified plasma factor IX
Chromatography and solvent detergent	AlphaNine SD (Grifols, Inc.)	>200
Monoclonal antibody ultrafiltration	Mononine (ZLB-Behring, Inc.)	>160
Low-purity plasma factor IX complex
Solvent detergent	Profilnine SD (Grifols, Inc.)	<50
Vapor heat	Bebulin VH (Baxter)	<50
Activated plasma factor IX complex concentrate (used primarily for patients with alloantibody and autoantibody factor VIII and IX inhibitor)
Vapor heat	FEIBA VH (Baxter)	<50
Recombinate factor VIIa (indicated for patients with alloantibody and autoantibody factor VIII and IX inhibitors)
Affinity chromatography, solvent detergent	NovoSeven (Novo Nordisk, Inc.)	50,000

FDA, U.S. Food and Drug Administration; vWF, Von Willebrand factor.

Data from Kessler CM: Hemorrhagic disorders: coagulation factor deficiencies. In Goldman L, Ausiello D, editors: Cecil medicine, ed 23, Philadelphia, 2008, Saunders.

TABLE 25-4 FDA-Approved Coagulation Proteins and Replacement Therapies Available in the United States

Vascular Defects

HHT, also referred to as Osler-Weber-Rendu syndrome, is a rare autosomal dominant disorder that is characterized by multiple telangiectatic lesions involving the skin, mucous membranes, and viscera. One form of the disorder, characterized by a high frequency of symptomatic pulmonary arteriovenous malformations and cerebral abscesses, has been identified as being due to abnormalities in the endothelial protein endoglin (ENG), encoded by the gene HHT1, located on chromosome 9. A second form of the disease has been linked to the activin receptor-like kinase 1 gene located on chromosome 12 (HHT2). Other forms of the disease have been linked to loci on chromosome 5q (HHT3), 7p14 (HHT4), and a region of chromosome 3 encoding the TGF-βII receptor (HHT5).⁴

The telangiectasias consist of focal dilation of postcapillary venules with connections to dilated arterioles, initially through capillaries and later directly. Perivascular mononuclear cell infiltrates also are observed. The vessels of HHT show a discontinuous endothelium and an incomplete smooth muscle cell layer. The surrounding stroma lacks elastin. Thus, the bleeding tendencies are thought to be due to mechanical fragility of the abnormal vessels.⁴ Lesions usually appear in affected persons by the age of 40, and they increase in number with age.^4,¹⁵^–¹⁸

Clinical Findings

On clinical examination, venous lakes and papular, punctate, matlike, and linear telangiectasias appear on all areas of the skin and mucous membranes, with a predominance of lesions on and under the tongue and on the face, lips, perioral region, nasal mucosa, fingertips, toes, and trunk.⁴ Recurrent epistaxis is a common finding in patients with this disorder; symptoms tend to worsen with age. Thus, the severity of the disorder often can be gauged by the age at which the nosebleeds begin, with the most severely affected patients experiencing recurrent epistaxis during childhood. Cutaneous changes usually begin at puberty and progress throughout life. Bleeding can occur in virtually every organ, with gastrointestinal, oral, and urogenital sites most commonly affected (Figure 25-5). In the gastrointestinal tract, the stomach and duodenum are more frequent sites of bleeding than is the colon. Other features may include hepatic and splenic arteriovenous shunts, as well as intracranial, aortic, and splenic aneurysms. Pulmonary arteriovenous fistulas are associated with oxygen desaturation, hemoptysis, hemothorax, brain abscess, and cerebral ischemia due to paradoxical emboli. Cirrhosis of the liver has been reported in some families.^4,^15,¹⁶

FIGURE 25-5 Hereditary Haemorrhagic Telangiectasia (HHT).

HHT is a condition in which occult blood loss in the gut may lead to severe iron deficiency anemia. The diagnosis usually is clear from a careful clinical examination, although the telangiectases are not always as obvious, as in this patient with multiple lesions on the face, lip, and tongue. The patient had received multiple blood transfusions over many years because of HHT-associated gastrointestinal blood loss, and he had developed cirrhosis associated with hepatitis B antigen positivity—probably as a result of transmission of hepatitis B in transfused blood.

(From Forbes CD, Jackson WF: Color atlas and text of clinical medicine, ed 3, London, 2003, Mosby.)

Laboratory Tests

There are no reliable laboratory tests to determine the tendency for bleeding to occur in affected persons. The Ivy bleeding time is not useful. Clinical findings and a history of bleeding problems are the only effective means to identify patients at risk.

Treatment

Therapy for HHT remains fragmented and problematic, consisting of laser treatment for cutaneous lesions; split-thickness skin grafting, embolization of arteriovenous communications, or hormonal therapy (estrogen or estrogens plus progesterone) for epistaxis; pulmonary resection or embolization for pulmonary arteriovenous malformations; and hormonal therapy and laser coagulation for gastrointestinal lesions.⁴ Estrogen or progesterone treatment has been advised, but no benefit has been demonstrated in a placebo-controlled randomized trial.¹⁵ A recent study suggested that treatment with thalidomide reduced the severity and frequency of nosebleeds (epistaxis) in subjects with HHT.¹⁹

The nasal vasculature pattern may help to predict the response to laser therapy versus septodermaplasty. Resurfacing the nasomaxillary cavity with radial forearm fasciocutaneous free flaps has been reported to be effective in patients with refractory epistaxis. The antifibrinolytic agents aminocaproic acid and tranexamic acid have been reported to be beneficial in controlling hemorrhage, but negative results with antifibrinolytic therapy also have been reported. Improvement in lesions has been reported in cases using an antagonist to vascular endothelial growth factor and sirolimus and aspirin. Patients with gastrointestinal bleeding should receive supplemental iron and folate; red blood cell transfusions and parenteral iron may be required in some patients.^4,^15,¹⁶

Platelet Disorders

von Willebrand Disease

The most common inherited bleeding disorder is von Willebrand disease, which is caused by an inherited defect involving platelet adhesion. The vWF gene and protein and points of mutation are shown in Figure 25-6. The cause of platelet dysfunction in von Willebrand disease is a deficiency or a qualitative defect in vWF, which is made from a group of glycoproteins produced by megakaryocytes and endothelial cells. They are formed into a single monomer that polymerizes into huge complexes, which are needed to carry (bind) factor VIII and to allow platelets to adhere to surfaces. Unbound factor VIII is destroyed in the circulation.^2,^7,^10,¹¹

FIGURE 25-6 The structure of the vWF gene and protein. The structures of the vWF gene and pseudogene are indicated schematically at the top of the figure. The corresponding protein also is depicted, including the homologous repeat domain structure. The localization within vWF of point mutations associated with VWD variants also is indicated. AA, Amino acids; vWD, von Willebrand disease; vWF, von Willebrand factor.

(From Hoffman R, et al, editors: Hematology: basic principles and practice, ed 5, Philadelphia, 2009, Churchill Livingstone.)

The disease has several variants, depending on the severity of genetic expression (Table 25-5). Most of the variants are transmitted as autosomal dominant traits (types 1 and 2). These variants of the disease tend to result in mild to moderate clinical bleeding problems. Type 1 is the most common form of von Willebrand disease. It accounts for about 70% to 80% of the cases. The greater the deficiency of vWF in type 1 disease, the more likely it is that signs and symptoms of hemophilia A will be found. Type 2A is responsible for 15% to 20% of cases. The other variants of the disease are uncommon.⁶ Type 3, which is rare, is transmitted as an autosomal recessive trait that leads to severe deficiency of vWF and FVIII.^2,^7,^10,¹¹ Variants of von Willebrand disease with a significant reduction in vWF or with a vWF that is unable to bind factor VIII may show signs and symptoms of hemophilia A, in addition to those associated with defective platelet adhesion. In mild cases, bleeding occurs only after surgery or trauma. In the more severe cases—type 2N and type 3—spontaneous epistaxis or oral mucosal bleeding may be noted.^2,^7,^10,¹¹

TABLE 25-5 Multimeric Patterns of von Willebrand Disease and Laboratory Diagnosis by Type