Roger S. Riley, M.D., Ph.D.
Diseases of coagulation can be inherited or acquired and include defects in blood coagulation and excessive fibrinolysis. Defects in blood coagulation may be due to the failure of synthesis of a coagulation factor, the production of an abnormal coagulation factor molecule, excessive destruction of coagulation factors, or due to the presence of circulating coagulation inhibitors. Excessive fibrinolysis usually arises from the sudden release of tissue activators into the blood stream, with a variable contribution from impaired removal of the activators by the liver.
Inherited Diseases of Coagulation
Inherited defects in blood coagulation factors are most commonly due to the synthesis of a biologically inactive coagulation factor; reduced synthesis of normal molecules occurs less frequently. Hereditary deficiencies of all of the coagulation factors have been described. Factor VIII deficiency, factor IX deficiency, and von Willebrand's disease are uncommon, and the other deficiencies are very rare. The common inherited and acquired factor deficiencies are summarized in Table 1 and described below.
Von Willebrand's Disease
von Willebrand disease (vWD) is due to inherited deficiency in von Willebrand factor (vWF). vWD is the most common inherited bleeding disorder of humans. Using sensitive laboratory testing, abnormalities in vWF can be detected in approximately 8000 people per million. Clinically significant vWD occurs in approximatley 125 people per million. This is a frequencey at least twice that of hemophilia A. Deficiency of vWF results in defective platelet adhesion and causes a secondary deficiency in factor VIII. The result is that vWF deficiency can cause bleeding that appears similar to that caused by platelet dysfunction or hemophilia. vWD is an extremely heterogeneous disorder that has been classified into several major subtypes. Type I vWD is the most common and is inherited as an autosomal dominant trait. This variant is due to simple quantitative deficiency of all vWF multimers. Type 2 vWD is also subdivided further dependent upon whether the dysfunctional protein has decreased or paradoxically increased function in certain laboratory tests of binding to platelets. Type 3 vWD is clinically severe and is characterized by recessive inheritence and virtual absence of vWF.
Normal or decreased FVIII Unbound FVIII has short half-life Normal vWF levels, activity, and multimer structure Decreased vWF activity Absence of high molecular weight multimers Absence of high molecular weight multimers Presents early in life Very low FVIII levels (3-10%)
Normal or decreased FVIII
Unbound FVIII has short half-life
Normal vWF levels, activity, and multimer structure
Decreased vWF activity
Absence of high molecular weight multimers
Absence of high molecular weight multimers
Presents early in life
Very low FVIII levels (3-10%)
Von Willebrand's disease (vWD), which may be the most common hereditary procoagulant disorder, is caused by deficient or defective plasma von Willebrand factor.
Inherited Factor Deficiencies
The characteristics of the congenital and acquired coagulation factor deficiencies are listed in Table II.
Factor I (Fibrinogen) Deficiency
Inherited disorders in fibrinogen (factor I) are rare, and include afibrinogenemia (a complete lack of fibrinogen), hypofibrinogenemia (decreased levels of fibrinogen) and dysfibrinogenemia (dysfunctional fibrinogen molecule). Afibrinogenemia is a severe autosomal recessive disease characterized by neonatal umbilical cord hemorrhage, ecchymoses, mucosal hemorrhage, internal hemorrhage, and recurrent abortion. Both inherited and acquired forms of hypofibrinogenemia (fibrinogen levels < 100mg/dL, normal 250-350mg/dL) have been descrivbed. Symptoms of hypofibrinogememia are similar to, but less severe than, afibrinogenemia. The inherited forms are usually autosomal dominant. Many patients with abnormal, dysfunctional fibrinogen molecules have also been reported and more than 70 different types of dysfibrinogenemia have been described. The clinical manifestations of dysfibrinogenemia are variable, but may include hemorrhage, spontaneous abortion, and thromboembolism. Most of the dysfibrinogenemisa are inherited in an autosomal dominant manner. Bleeding episodes in patients with dysfibrinogenemia are treated with cryoprecipitate or fresh frozen plasma, and anticoagulants are often indicated for those with thrombosis.
Factor II Deficiency
Patients with an inherited deficiency of prothrombin (hypoprothrombinemia) or a dysfunctional prothrombin molecule (dysprothrombinemia) are unusual, with only about 30 cases reported to date. All cases have shown autosomal recessive inheritence. The clinical manifestations of these diseases are variable, with bruising, excessive menstrual bleeding, postoperative hemorrhage, and even muscle hematomas reported in patients with the most severe disease. Symptomatic disease is treated with prothrombin complex concentrate (PCCs) or fresh frozen plasma.
Factor V Deficiency
Congenital factor V deficiency (Owrens disease, parahaemophilia, proaccelerin deficiency) is a rare disorder (incidence approximately 1:1,000,000) that usually shows an autosomal recessive inheritance pattern. Many patients are asymptomatic, but delayed bleeding after trauma or surgery, epistaxis, excessive menstral bleeding, or bruising can occur. Hemarthroses are unusual. Most patients have <5% plasma factor V activity and antigen levels. However, a few patients with a suspected factor V dysfunctional molecule have been found. The clinical severity of the disease does not correlate well with factor V levels, but does appear to correlate with the level of platelet alpha-granule factor V. Fresh frozen plasma stored for less than 1-2 months is given for symptomatic bleeding.
Combined Factor V-Factor VIII Deficiency
Factor VII Deficiency
Factor VII deficiency (proconvertin deficiency ) may be inherited or acquired. This disease is usually autosomal recessive in nature, and affects approximately 1:500,000 individuals. Bleeding in severely affected patients (<1% factor VII levels) can be serious, with intracranial hemorrhage at birth or severe bleeding with circumcision. Epistaxis, gastrointestinal bleeding, and/or menstrual bleeding may occur in moderately affected patients. The diagnosis is confirmed by measurement of plasma factor VII antigen levels. Treatment is with infusion of fresh frozen plasma or prothrombin complex concentrates (PCCs). Frequent treatment is required in factor VII deficient patients due to the short half-life of factor VII (3-6 hours). Plasma-derived factor VII concentrate and recombinant factor VIIa is available in some countries but not licensed in the United States.
Factor VIII Deficiency (Hemophilia A)
Congenital factor VIII deficiency (hemophilia A, classic hemophilia,) is a rare hereditary hemorrhagic disorder, with an incidence of approximately one in 5,000 live male births. Since the factor VIII gene is localized on the X chromosome, the disease is manifested only in hemizygous males (X-linked recessive), although all daughters of a hemophiliac male are disease carriers. More than 600 point mutations and other alterations in the factor VIII gene have been identified in patients with factor VIII deficiency. The clinical severity of the disease varies with the plasma level of factor VIII in comparison with the normal level (mild 5-50%, moderate 1-4%, severe <1%). Patients with severe factor VIII deficiency are at risk for easy bruising, prolonged bleeding from wounds or trauma, spontaneous hemorrhage into the muscles and joints, and excessive bleeding at the time of circumcision. Patients with mild disease are usually not at risk for spontaneous hemorrhage, but may bleed excessively after trauma or surgery.
Factor IX Deficiency (Hemophilia B)
Hereditary factor IX deficiency (Christmas disease, hemophilia B) is a sex-linked disorder that is clinically indistinguishable from hemophilia A. However, the disease is much less common, with a frequency about 1/10 that of factor VIII deficiency. Genetically, the disease is very heterogenous, with more than 300 point mutations, short nucleotide deletions or insertions, and other gene abnormalities identified to date. The aPTT is prolonged, with normal vWF levels. Diagnostic confirmation requires a factor IX assay.
Factor X Deficiency
Congenital factor X deficiency is a very disorder, with approximately 50 reported cases. Cases due to absent or reduced synthesis have been reported, as well as various dysfunctional molecular forms. Most cases show autosomal recessive inheritance. Severe bleeding may be found in patients with the severe form of the disease (<1% factor X), with muscle bleeding and intracranial hemorrhage. Gastrointestinal bleeding, bruising, and epistaxis are also seen. And women with Factor X deficiency are prone to excessive menstrual bleeding and first-trimester miscarriage. FFP or OCCs with high factor X content are administered for symptomatic bleeding.
Factor XI Deficiency
Congenital factor XI deficiency (Rosenthal syndrome, hemophilia C) is primarily a disease of Ashkenazi Jews, and most cases in the United States have been reported in New York and Los Angeles. The overall frequency of the disease is approximately 1:100,000. The bleeding manifestations of homozygous factor XI deficiency are highly variable, even in the same patient, and do not correlate well with the plasma level of factor XI. However, significant postoperative or post-traumatic bleeding are most often encountered in homozygous patients with severe deficiency (<15%). Bleeding is usually slow and delayed, although vigorous bleeding requiring transfusion has been reported. Spontaneous bleeding is uncommon, but epistaxis, menorrhagia, hematuria, retinal hemorrhage, and subarachnoid bleeding can occur. Excessive bruising has only been seen in a few patients, and spontaneous hemorrhage into the muscles and joints has not been reported. Patients with factor XI deficiency suffer an increased incidence of myocardial infarction and thromboembolism. Patients with heterozygous factor XI deficiency are usually asymptomatic. Preoperative administration of FFP or cryoprecipitate is warrented for elective surgical procedures, with the goal of achieving a plasma factor level of 20-30% of normal. Factor XI concentrate is available in Europe, but is not licensed for use in the United States.
Factor XII Deficiency
Factor XII deficiency (Hageman trait) is a rare autosomal recessive disease. Most patients do not exhibit clinical bleeding tendencies, although menorrhagia and recurrent subarachnoid hemorrhage have been reported in isolated patients. However, the disease is associated with thromboembolic disease, including myocardial infarction, venous thromboembolism, pulmonary embolism, and moya-moya disease.
Factor XIII Deficiency
Hereditary deficiencies of factor XIII are autosomal recessive diseases, with <1000 cases reported since 1960. In patients with severe homozygous factor XIII deficiency, fibrin crosslinking does not occur, and a clinical disease of moderate to severity results. The disease is manifested shortly after birth in about 80% of affected patients with severe disease (<1% factor XIII) due to bleeding from the umbilical stump. A lifelong history of bruising, hematomas, and bleeding after trauma follows, and there is a high incidence of intracranial hemorrhage which often results in death. Soft tissue and joint hemorrhage is seen after trauma, but spontaneous hemorrhage is not characterisstic. Typically, bleeding is delayed for 24 hours or more after the traumatic event, when the primary clot breaks down. Poor wound healing and abnormal scar formation is observed, and women with factor XIII deficiency undergo spontaneous abortion if they become pregnant. The infusion of FFP or cryoprecipitate is used to treat bleeding episodes in the United States, and a factor XIII concentrate prepared from the placenta is available in Europe. Prophylactic administration of factor XIII is effective due to the long plasma half-life of the molecule (about 8 days) and the low concentration required for the prevention of bleeding. Spontaneous abortion can be prevented only by plasma replacement throughout pregnancy.
Congenital prekallikrein deficiency (Fletcher trait) is a rare autosomal recessive disease identified in a number of families and individuals of several nationalities. Clinical bleeding has not been reported, but there is a predilection for myocardial infarction, venous thromboembolism, and cerebral thrombosis. A markedly prolonged aPTT is found. Therapy is not indicated.
Congenital Deficiency of High- and Low Molecular Weight Kininogen
Rare individual patients and several families with autosomal recessive deficiency of high and/or low molecular weight kininogen have been identified, and variously reported as the Fitzgerald trait, Flaujeac trait, and Williams trait. None of these patients have shown bleeding tendencies, although thrombotic disease is common.
Two congenital hemorrhagic disorders have been ascribed to abnormalities of fibrinolysis. A deficiency of alpha-antiplasmin, the major plasmin inhibitor, leads to uncontrolled plasmin activity with consequent hemorrhage. An excess of circulating plasminogen activator causes a post-traumatic hemorrhagic disorder.
Acquired Disorders of Coagulation
Acquired disorders which cause generalized hemorrhage are much more commonly encountered in clinical practice than the inherited syndromes (except in pediatrics).
Disseminated Intravascular Coagulation
Disseminated intravascular coagulation (DIC, consumption coagulopathy) is one of the most common and clinically important acquired disorders of hemostasis. In DIC, intravascular activation of the coagulation system results in the widespread deposition of fibrin microthrombi in the microcirculation, the consumption of platelets and clotting factors, and activation of the fibrinolytic system. DIC is not a specific disease, but a sequalae of many pathologic conditions, including acute intravascular hemolysis, hemolytic transfusion reactions, shock, hyperthermia, extensive tissue damage, malignancies, obstetric complications, hyperthermia, snake bites, and other conditions.
In DIC, massive coagulation depletes procoagulants and platelets, causing bleeding, while the uncontrolled generation of thrombin results in thromboses in the arterial and venous beds (Fig. 17). Ischemic infarction and necrosis produced by the thromboses intensify the damage, release tissue factor, and further activate the hemostatic system. Tissue damage and the deposition of fibrin also result in the release and activation of plasminogen activators and the generation of plasmin in amounts that overwhelm its inhibitor, (alpha-2-antiplasmin. Plasmin degrades factors VIII, V, and I and produces fibrin/fibrinogen degradation products. These substances, as well as the products of incompletely polymerized fibrin, impair platelet function and normal fibrin polymerization.
The clinical consequences of disseminated intravascular coagulation depend on its cause and the rapidity of the initiating event. Slow or chronic activation (compensated DIC, chronic DIC) causes an excess of activated products, predisposing to thrombosis, and leading to vascular infarctions or venous thrombosis. Rapid activation of coagulation is dominated by intravascular coagulation, with depletion of platelets and the procoagulant factors I, II, V, VIII, and XIII (and perhaps factor VII), and the production of fibrin degradation products. Hemorrhage into wound sites, intravenous lines, and catheters, as well as bleeding into deep tissues is the usual clinical consequence. The intravascular fibrin strands produce microangiopathic hemolytic anemia. Nonspecific signs and symptoms such as fever, hypotension, acidosis, proteinuria, and hypoxia may also occur.
Severe Hepatic Disease
In severe liver disease there may be a significant impairment in the synthesis of procoagulants and other substances involved in coagulation, as well as the synthesis of dysfunctional procoagulants. Plasminogen survival is shortened in cirrhosis, and the plasminogen levels fall. Platelet survival is distinctly shortened, and platelet splenic sequestration is increased. In addition to mucosal hemorrhage and tissue bleeding, bleeding varices, gastritis, and peptic ulcer can result. The PT, platelet count, and bleeding time should be used to screen for a hepatic coagulopathy, but the results of these assays cannot be directly correlated with the severity of liver disease.
Circulating Inhibitors of Coagulation (Anticoagulants)
Specific inhibitors are directed against a specific coagulation factor (i.e., VIII, IX, XI, etc) while non-specific inhibitors exert an effect independent of a single coagulation factor. Inhibitors vary in their clinical significance. Although most patients with a specific inhibitor show clinically significant bleeding or thrombosis, many nonspecific inhibitors do not cause clinical problems and are discovered incidentally during a routine coagulation workup. Coagulation inhibitors are one of the most common problems encountered in the coagulation laboratory.
Acquired Factor V Inhibitors
Antibodies specific for factor V have primarily been associated with operative procedures, drug ingestion, blood transfusion, infections, and the intraoperative use of bovine thrombin ("fibrin glue"). Factor V inhibitors are usually transient, and vary considerably in their ability to cause clinical bleeding. The variability in clinical symptomatology is attributed to the antibody titer, specificity, and avidity, as well as the presence of "protected" intracellular platelet factor.
Anti-Phospholipid Antibody Syndrome
The SLE-like inhibitor, or lupus anticoagulant (LA), is the most common type of nonspecific coagulation inhibitor. These inhibitors were first identified in patients with systemic lupus erythematosus and their presence correlates with the appearance of the biologic false positive Wassermann reaction for syphilis in such patients. LAs are immunoglobulins (IgG, IgM, both) directed against certain phospholipid epitopes, including the phospholipid added as a surrogate source of phospholipid in the aPTT. As a result, the in vitro formation of phospholipid containing coagulation complexes is inhibited, and a prolonged aPTT results. If washed platelets are substituted for cephalin, the PTT usually becomes normal in patients with the LA, since LAs do not react with platelet phospholipids. In addition to SLE (only 20% occur in SLE), LAs have been reported in patients with other autoimmune diseases, malignancies, infections, AIDS, drug-induced diseases, and otherwise normal individuals. In children, LAs most frequently occur in association with tonsillitis and infected adenoids.
Non-Specific, Non-Lupus Inhibitors
Vitamin K Deficiency
The synthesis of gamma-carboxyglutamic acid, a substance required for the biologic function of factors II, VII, IX, and X, requires a vitamin K-dependent carboxylase. In the absence of vitamin K, functionally coagulation factors are synthesized that lack gamma-carboxyglutamic residues are synthesized in the liver. In the settings of severe malnutrition, intestinal malabsorption, obstructive jaundice, and the chronic administration of oral antibiotics, mucosal bleeding and ecchymoses occur when procoagulant levels fall below 10 to 15% of normal.
Drugs that alter hemostasis or interfere with hepatic function may cause coagulopathy if administered in excess. Most commonly, these include heparin, warfarin, and thrombolytic agents.
The monoclonal proteins produced in patients with multiple myeloma and macroglobulinemia can interfere with platelet function and cause clinical bleeding. Coagulation tests may be abnormal because of these antibodies or the underlying disease.
Bleeding after Cardiopulmonary Bypass
Intraoperative and postoperative episodes of life-threatening hemorrhage sometimes occur in patients undergoing heart surgery with cardiopulmonary bypass. The cause appears to be an acquired platelet function disorder, probably caused by contact between the platelets and the oxygenator apparatus. Frequently have in the absence of significant procoagulant consumption or heparin overdose. In addition to the release of platelet alpha-granule contents, activation of fibrinolysis may occur together with modest procoagulant factor depletion. The administration of DDAVP may cause an increase in vWF, which will compensate the platelet function defect.
Since fibrinogen is an acute-phase reactant, elevated plasma levels occur in a variety of infectious diseases. The mechanism leading to increased plasma fibrinogen in a number of other diseases is less well understood. These diseases include: coronary artery disease, diabetes, hypertension, peripheral artery disease, hyperlipoproteinemia, hypertriglyceridemia, pregnancy, menopause, hypercholesterolemia, use of oral contraceptives, and smoking.