Chapter 27. Blood: IV. Bleeding Disorders

The normal vascular system maintains a delicate balance between clotting mechanisms and clot lysis, with the result that internal or external bleeding is controlled and pathologic thrombosis prevented (see Chapter 9: Abnormalities of Blood Supply).

Several factors acting in concert maintain this equilibrium:

1.  Blood vessels maintain anatomic integrity and a smooth endothelium. Following minor injuries, the blood vessels undergo vasoconstriction, thereby preventing bleeding from the injured site and permitting repair. Vasoconstriction is an effective method of hemostasis in small vessel injuries but is not adequate when large vessels are damaged.

2.  Platelets form the initial hemostatic plug that seals a site of vascular injury. Platelets also play a major role in forming the permanent thrombus that seals the injury.

3.  Blood coagulation is the formation of fibrin from plasma precursors. Fibrin and platelets constitute the permanent hemostatic plug.

4.  Fibrinolysis is the production of factors such as plasmin from plasma precursors that lyse and remove fibrin thrombi which have formed in the circulation.

Disturbance of any one of these mechanisms may produce abnormal bleeding on the one hand (Table 27-1) or abnormal thrombosis on the other. Pathologic thrombosis is discussed in Chapter 9: Abnormalities of Blood Supply.

The clinical effects of abnormal bleeding disorders (Table 27-2) are similar regardless of the mechanisms. Laboratory testing is generally required to reach a precise clinical diagnosis, following which appropriate therapy may be selected.

Along with thrombocytopenia, vascular defects represent the most common cause of bleeding diathesis. In certain vascular disorders, the underlying defect relates to production of abnormal collagen or elastin (Table 27-1); in vasculitis, inflammation is the cause.

Henoch-Schönlein purpura (anaphylactoid purpura) deserves special mention as a poststreptococcal disease of childhood. It occurs 1–3 weeks after streptococcal infection and is thought to be mediated by deposition of cross-reactive IgA or immune complexes plus complement on the endothelium. Occasional cases have been reported with apparent hypersensitivity to other bacteria, insect bites, or food (milk, eggs, crab, strawberries). Clinically, there is purpura, abdominal pain (due to mucosal involvement in the gut, often with frank bleeding), arthralgia or arthritis, and glomerulonephritis. Fever is often present. The prognosis is determined by the severity of the renal lesion (focal glomerulonephritis with deposition of IgA and complement; see Chapter 48: The Kidney: II. Glomerular Diseases).

Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease) is inherited as an autosomal dominant trait and manifested by multiple capillary microaneurysms in the skin and mucous membranes. The lesions tend to become more conspicuous with age and are exceedingly fragile, predisposing both to episodes of acute severe bleeding and to chronic blood loss from the intestinal tract with resulting iron deficiency anemia.

Normal Structure & Function

Platelets are anucleate cytoplasmic fragments 2–4 μm in diameter derived from megakaryocytes. The normal platelet count in peripheral blood is 150,000–400,000/μL. The platelets have a clear outer zone and an inner zone containing cytoplasmic organelles (Figure 27-1), which include contractile microfilaments and several types of granules that contain a variety of enzymes, phospholipid, adenosine diphosphate (ADP), adenosine triphosphate (ATP), serotonin, calcium, and thromboplastic substances. Platelets have a life span of 8–10 days in the peripheral blood.

In peripheral blood smears, platelets appear as small granular cytoplasmic fragments about one-fourth the size of an erythrocyte. Platelets that have exited the marrow recently are larger, and a finding of many large forms is evidence that the rate of release of platelets from the marrow is increased.

The main function of platelets is in hemostasis. In the early phase of hemostasis after vascular injury, platelets plug and seal injured areas in the wall of the blood vessel (Figure 27-2). The process of formation of the platelet plug involves two mechanisms: adhesion and aggregation.

1.  Platelet adhesion: Platelets in the blood are attracted to collagen exposed by endothelial damage. Effective adhesion requires the presence of von Willebrand factor (vWF), which is secreted by the endothelial cells into the serum. Adherence is followed by clumping and release of cytoplasmic granules (activation). Degranulation is an active phenomenon that involves contraction of the platelet microskeleton; it is dependent on the presence of prostaglandins and is inhibited by aspirin. Platelet adhesion is a function of the outer zone of the platelet cytoplasm, with the glycoprotein Ib (GPIb) receptors binding to large multimers of vWF at the injury site.

2.  Platelet aggregation: The release of platelet granules containing ADP, various biogenic amines, and thromboxane A2 induces accumulation and aggregation of large numbers of platelets to form the hemostatic plug that prevents bleeding from the injured zone. Aggregation involves another glycoprotein receptor (GPIIb–IIIa) binding with fibrinogen to initiate the fibrin plug (see Table 27-4).

Platelets secrete other factors that also play a role: platelet-derived growth factor (PDGF), which stimulates repair), platelet factor 4 (PF4), chemotactic for neutrophils), and serotonin (a vasoconstrictor).

Abnormalities of Blood Platelets

Abnormalities of blood platelets include (1) decreased numbers (thrombocytopenia), (2) increased numbers (thrombocytosis), and (3) abnormal platelet function. There are numerous causes for such abnormalities (Table 27-3). In general, thrombocytopenia and abnormal platelet function impair the normal hemostatic mechanism and cause increased bleeding. Thrombocytosis is associated with an increased tendency to thrombosis.

Idiopathic Thrombocytopenic Purpura

Incidence & Etiology

Idiopathic thrombocytopenic purpura (ITP) is a common disease in which severe reduction of platelet numbers in the blood is caused by immune destruction of platelets. It occurs in two clinical forms:

1.  Acute ITP: Acute is seen mainly in children. About 50% of cases are associated with a history of viral infection 2–3 weeks before onset. It is believed that immune complexes bind to the surface of platelets, resulting in phagocytosis by splenic mac rophages. Acute ITP is characterized by spontaneous recovery in the majority of patients; 80% are normal after 6 months; many recover within 6 weeks.

2.  Chronic ITP: Chronic ITP occurs mainly in adults, with a predilection for females (3:1) and frequent occurrence of relapse during pregnancy. Thrombocytopenia is the result of peripheral destruction of platelets that have bound an IgG antiplatelet autoantibody on their surface. Chronic ITP is a long-standing disorder characterized by multiple relapses and remissions.

3.  Neonatal thrombocytopenic purpura: Neonatal disease occurs in children born to mothers with chronic ITP. It results from transfer of the IgG antibodies across the placenta.

Pathology

Platelet survival is impaired. The platelet count is markedly decreased, often to the 10,000–50,000/μL range. The bone marrow typically shows increased numbers of megakaryocytes (compensatory hyperplasia).

The spleen is the major site of destruction of antibody-coated platelets. It is usually either normal in size or slightly enlarged and shows sinusoidal congestion and hyperplasia of macrophages.

As with any patient with severe thrombocytopenia, the bleeding time is prolonged and capillary fragility (tourniquet test) is increased. Tests of coagulation (clotting time, partial thromboplastin time, and prothrombin time) are normal. Clot retraction, which depends on platelets, is defective.

Clinical Features & Treatment

Patients present with a bleeding tendency. Clinical bleeding occurs when the platelet count falls to very low levels (< 40,000/μL). The most common clinical feature is purpura. Bleeding may also occur from mucosal surfaces, leading to hematuria, melena, menorrhagia, and hemoptysis. Rarely, intracerebral hemorrhage occurs—a complication associated with a high mortality rate.

The diagnosis of ITP is one of exclusion, reached by ruling out all other causes of thrombocytopenia.

Treatment with high-dose corticosteroids suppresses splenic phagocytic activity. There is evidence that autoantibody synthesis is also decreased. The response to steroids has a lag phase of several days during which platelet transfusions are frequently necessary to provide adequate hemostasis. Splenectomy is effective in treatment by removing the main site of platelet destruction but does nothing to correct the basic abnormality.

Abnormalities of Platelet Function

Platelet function abnormalities are characterized by symptoms and signs of platelet deficiency (ie, abnormal bleeding) but with a normal platelet count. Tests of platelet function such as clot retraction, platelet adhesion, and aggregation in response to different agents are abnormal and are valuable in separating the different disease processes (Table 27-4).

Normal Blood Coagulation

Coagulation represents the method of permanent healing of a vascular injury. It follows vasoconstriction and formation of the platelet plug and maintains hemostasis when normal blood flow is restored. Coagulation is achieved by the interaction of several plasma protein factors (Table 27-5) that ultimately results in formation of fibrin when they are activated sequentially (Figure 27-2).

Disorders of Blood Coagulation

Etiology

There are three principal groups of coagulation disorders.

Deficiency of Coagulation Factors

Deficiencies of individual coagulation factors may occur as inherited diseases (Table 27-6). Of these, factor VIII deficiency (hemophilia A and von Willebrand's disease) and factor IX deficiency (Christmas disease) are the most common. Acquired deficiencies of coagulation factors occur in severe liver disease (affects all factors produced by the liver) and in vitamin K deficiency (prothrombin and factors VII, IX, and X).

Presence of Circulating Anticoagulants

Factor deficiencies may also be induced by anticoagulant therapy with coumarin derivatives (which interfere with vitamin K, thereby inhibiting synthesis of prothrombin and of factors VII, IX, and X). Directly acting anticoagulants that antagonize some of the coagulation cascade include (a) drugs such as heparin (an antithrombin), (b) antibodies (factor VIII inhibitor and lupus anticoagulant, an antibody in systemic lupus erythematosus), and (c) natural anticoagulants (antithrombin and fibrin degradation products).

Fibrinolytic Activity

Increased fibrinolytic activity in the blood results from increased activation of the plasmin system.

Clinical Features

Patients with disorders of coagulation tend to bleed excessively following minor trauma such as dentistry. In severe cases, spontaneous bleeding occurs (ie, bleeding without evident trauma)—commonly into joints (hemarthrosis) and muscles. Bleeding is usually slow but persistent and can be halted by replacement of the deficient factor.

All coagulation disorders have similar clinical manifestations. Determination of the cause of the abnormality requires bleeding and coagulation testing (Figure 27-3 and Tables 27-7 and 27-8).

Factor VIII Deficiency

Factor VIII circulates as a covalently linked complex of two distinct molecules (Figure 27-4): (1) Factor VIII coagulant (VIII:c) is a critical component of the intrinsic coagulation pathway (Figure 27-3) and is also known as antihemophilic globulin (deficiency produces hemophilia A). Factor VIII:C is measured by bioassay or by immunoassay (factor VIII:c antigen). (2) Factor VIII von Willebrand factor (VIII:vWF) is by much the larger part of the factor VIII complex. Factor VIII:vWF serves two functions. First, it plays a critical role in platelet aggregation. Second, it enhances factor VIII:C activity at the site of injury and serves as a carrier of circulating VIII:c. Deficiency of factor VIII:vWF produces von Willebrand's disease. Factor VIII:vWF is measured by a function assay (ristocetin test) or by an immunoassay (factor VIII: related antigen; VIII:R Ag).

Hemophilia A

Incidence & Etiology

Hemophilia A (classic hemophilia) is inherited as an X-linked recessive trait, occurring mainly in males. Females develop hemophilia only when they have the abnormal gene on both X chromosomes (homozygous)—a rare event that occurs when a hemophiliac male mates with a carrier female or when a single functional X chromosome carries the abnormal gene. The incidence in the United States is 1:10,000 males. Hemophilia occurs throughout the world.

The presence of the abnormal gene results in deficient synthesis of the coagulant subunit of the factor VIII molecule (VIII:C, Figure 27-4). Factor VIII-related antigen (factor VIII-von Willebrand factor) continues to be present in normal amounts.

The heterozygous female carrier shows a mild decrease in plasma level of the coagulant subunit of factor VIII (VIII:C). Because factor VIII-related antigen level (VIII:RAg) is normal, the ratio of VIII:C to VIII:RAg is less than 0.75 (normal, 1). Observation of a reduced VIII:C to VIII:RAg ratio is a reliable means of detecting heterozygous carriers of the abnormal hemophilia A gene.

Pathology & Clinical Features

Patients with severe hemophilia have less than 1% of factor VIII coagulant activity and bleed spontaneously. Moderately affected patients (1–5% activity) bleed excessively after minor trauma, and mild cases (5–25% activity) are usually asymptomatic. The cause of the variable expression of disease in different patients is not well understood.

Spontaneous bleeding (probably caused by minimal trauma resulting from normal activity) occurs into subcutaneous tissues, skeletal muscle, joints, and mucous membranes. Intracranial hemorrhage is rare but is a major cause of death. Hemorrhage into muscle and joints occurs mainly in the extremities and is followed by organization and fibrosis leading to contractures in affected muscles and to stiffness of joints.

Bleeding after dental surgery is typical. The bleeding is not dramatic but consists of a slow and persistent ooze lasting many days. Oozing commonly begins several hours after surgery and not in the immediate postoperative period.

Acquired immune deficiency syndrome (AIDS) is a major complication in some patient populations due to the presence of human immunodefiency virus (HIV) in factor VIII concentrate.

Diagnosis & Treatment

The partial thromboplastin time is prolonged in almost all patients, and there is a significant decrease in factor VIII coagulant activity (to less than 20% of normal). Factor VIII-related antigen is normal, and the VIII:C to VIII:RAg ratio is markedly decreased. Prothrombin time and bleeding time are normal, indicating that the defect is in the intrinsic pathway. Assays for factor VIII coagulant activity and factor VIII-related antigen are diagnostic and reflect the severity of the disease.

Treatment of hemophilia consists of maintaining plasma factor VIII coagulant activity at a level that permits normal physical activity without bleeding. This may require prophylactic treatment in severe cases. Factor VIII.C is labile and must be provided as fresh plasma, or in concentrated form as cryoprecipitate or as lyophilized factor VIII concentrate. The availability of cryoprecipitate and lyophilized factor VIII concentrate has markedly improved the outlook for patients with hemophilia. Treatment with synthetic vasopressin analogues has been shown to produce elevation of factor VIII levels, producing benefit in mild cases.

Cryoprecipitate is prepared in blood banks from fresh individual plasma units. Lyophilized factor VIII concentrate is made from pooled plasma obtained from a large number of blood donors. As with all such blood components prepared from multiple donors, administration of factor VIII concentrate greatly increases the risk of infections such as hepatitis B, cytomegalovirus infection, and, more recently, HIV. Consequently, hemophiliacs represent a high-risk group for AIDS, and many have developed overt disease. Factor VIII concentrate is now heat-treated, a procedure believed to eliminate these risks.

Von Willebrand's Disease

Von Willebrand's disease is inherited as an autosomal dominant trait characterized by deficiency of the entire circulating factor VIII complex (Figure 27-4). Factor VIII coagulant activity and the von Willebrand factor (factor VIII-related antigen) are decreased to the same extent, so that the ratio of these two components is normal. Variants exist in which factor VIII:C is near normal.

Clinically, patients show bleeding after minor trauma. The onset of symptoms is in childhood and may decrease with age. The most common sites of bleeding are the skin (easy bruising) and mucous membranes (epistaxis). Hemarthrosis, muscle hemorrhage, and intracranial hemorrhage are uncommon.

The diagnosis is made by demonstrating (1) prolonged partial thromboplastin time with normal prothrombin time, (2) decreased factor VIII coagulant activity and Von Willebrand factor (factor VIII-related antigen), and (3) prolonged bleeding time due to platelet dysfunction (Table 27-8). In vitro, there is decreased platelet aggregation after addition of the antibiotic ristocetin, and the ristocetin test is useful for the diagnosis of Von Willebrand's disease. Von Willebrand factor is present in cryoprecipitate, which can therefore be used in treating von Willebrand's disease.

Factor IX Deficiency (Christmas Disease; Hemophilia B)

Christmas disease is uncommon, with an incidence of 1:50,000 population, and results from a deficiency of factor IX.

Christmas disease is characterized by X-linked recessive inheritance, greater prevalence in males, and a clinical picture identical to that of hemophilia A. The diagnosis is made when factor VIII coagulant activity is normal in a patient with symptoms of hemophilia. Plasma factor IX assay shows greatly decreased levels and is diagnostic. Treatment is with fresh plasma or factor IX concentrate; factor IX is not present in cryoprecipitate.

Disseminated Intravascular Coagulation & Fibrinolysis

Disseminated intravascular coagulation (DIC) is an important cause of bleeding that is due to consumption of platelets and several clotting factors during widespread thrombosis in the microcirculation (consumption coagulopathy). DIC and fibrinolysis are discussed in Chapter 9: Abnormalities of Blood Supply.