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Diseases of Coagulation

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.

Table II
Classification of von Willebrand's Disease
Color
Type
Frequency
Clinical
Severity
Inheritance
Etiology
Laboratory
Features
Type 1
70-80% Mild - moderate Usually autosomal dominant
Rarely compound recessive
Quantititative defect in vWF proteins, no structural abnormalities Mild to moderately decreased vWF:Ag and FVIII
Type 2A
15-20% Decreased platelet-dependent function of vWF Absence of high and middle weight vWF multimers

Normal or decreased FVIII

Type 2N
Rare Mild to moderate Autosomal dominant Functional abnormality of vWF prevents complexes with FVIII

Unbound FVIII has short half-life

Moderate to severe decrease in FVIII

Normal vWF levels, activity, and multimer structure

Type 2B
Rare Structural defect of vWF with increased affinity for platelet GPIb receptor Thrombocytopenia

Decreased vWF activity

Absence of high molecular weight multimers

Platelet-type pseudo-vWD
Rare Resembles wWD Type 2B Structural defect of platelet GPIb receptor with increased affinity for vWF Decreased vWF activity

Absence of high molecular weight multimers

Type 3
Very Rare (1/Million) Severe

Presents early in life

Variable, homozygotes or compound heterozygotes Failure of vWF synthesis Virtual absence of all multimers

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.

Since there are several variants (subtypes) of von Willebrand disease that differ in their clinical and laboratory manifestations. If the history is suggestive of vWD, the first step is to perform an aPTT, platelet count, and bleeding time. Since vWF is the Factor VIILC carrier protein, low vWF levels are usually accompanied by low factor Vlll:C level and a prolonged aPTT. The platelet count is usually normal and the bleeding time is frequently prolonged. However, laboratory testing in vWD is notoriously variable, particularly in mild cases, and the assays on several different occasions may be necessary to demonstrate an abnormality. In addition, the patient's blood group affects the vWF level (patients with blood group 0 have lower vWF levels than those with blood group A or B) and the other laboratory manifestations.

If the initial tests confirm the presence of an abnormality, vWF levels are next measured by immunologic techniques, and vWF multimeric composition is determined by electrophoretic procedures, and the functional capabilities of vWF are determined by the ristocetin cofactor test. Ristocetin is an antibiotic, which causes platelets to express the GPIb receptor in a form in which it can be linked by vWF to cause platelet agglutination. In the assay, patient plasma is added in incremental amounts to a standard mixture of ristocetin and normal platelets and platelet agglutination is measured.

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 (Owren’s 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.

The gray platelet syndrome is a separate but related disease characterized by thrombocytopenia, mild bleeding, reduced platelet alpha-granule factor V, and normal plasma levels of factor V. See platelet section for additional information.

Combined Factor V-Factor VIII Deficiency

This rare disease clinically resembles congenital factor V deficiency, and is primarily found in Sephardic Jews. 0

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.

Acquired factor VII deficiency most commonly results from oral anticoagulation therapy with warfarin but can be caused by liver disease, dietary vitamin K deficiency, antibiotic administration, or gastrointestinal malabsorption diseases. Mucosal bleeding can result from severe acquired factor VII deficiency.

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.

The diagnosis of an inherited Factor VIII deficiency is made on the basis of the clinical manifestations, family history, and laboratory assays (bleeding time, aPTT, factor VIII:C). In most cases, a normal bleeding time and a classic family history rule out vWD, which, unlike hemophilia A, is autosomally transmitted. In addition, all patients with hemophilia A have normal levels of vWF. Women who are carriers can be recognized because their VIII:C level is about half of normal, whereas their vWF level is normal. Prenatal assays for factor VIII deficiency are under investigation.

Patients with mild hemophilia often benefit from treatment with desmopressin (DDAVP). Desmopressin induces release of stored FVIII and vWF, and is usually administered prophylactically prior to surgery or dental procedures. Aspirin and other drugs which affect platelet function are contraindicated in these patients, and they should avoid occupations, hobbies, or sports which may induce physical trauma. Factor VIII concentrates prepared from either human plasma or recombinant DNA technology are administered during serious bleeding episodes when DDAVP is insufficient.

Patients with moderate or severe factor VIII deficiency are administered factor VIII concentrates at the earliest sign of bleeding since stored factor VIII is usually insufficient. Although the amount of administered factor VIII and the duration of treatment depends on the severity of the bleeding event, patients with a major bleeding event from trauma or surgery require maintanence of 50-100% factor VIII levels for 10 days or longer. The commerically available factor VIII preparations vary in activity, purity, and cost. Unfortunately, there is a high incidence of transfusion-acquired HIV, hepatitis B, and other viral infections in older patients with factor VIII deficiency who received factor VIII infusions in the early and mid-1980’s. Recombinant factor VIII has the greatest specific activity (4000-6000), but it is expensive and of limited availability. The cost of medical treatment in patients with severe factor VIII deficiency can easily exceed $100,000. Cryoprecipitate or fresh frozen plasma can be used if factor VIII concentrates are not available. Gene therapy may dramatically improve the outlook for patients with factor VIII deficiency in the future.

The problems of acquired inhibitors in factor VIII deficient patients is discussed below.

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.

Acquired factor X deficiency is seen in some patients with amyloidosis.

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.

Prekallikrein Deficiency

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.

Fibrinolytic Abnormalities

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.

The remaining hereditary coagulation disorders occur very rarely.

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.

The cause of DIC is a disruption in the intricate hemostatic balance, with massive activation of hemostasis ("runaway hemostasis"), which overwhelms the hemostatic regulatory system. An uncontrollable, self-propagating clinical disaster of simultaneous bleeding and clotting can result, with rapid death of the patient if the cycle cannot be interrupted. DIC occurs in a wide variety of clinical settings, which have in common one or a combination of the following features:

  • Massive tissue damage, which liberate tissue thromboplastic materials, causing activation of the extrinsic pathway of coagulation.

  • Extensive alteration of the vascular endothelium, which exposes significant amounts of the intrinsic procoagulants to subendothelial initiators.

  • Shock, associated with reduced blood flow and loss of the beneficial effects of hemodilution.

  • Impaired hepatic perfusion or function, which causes inadequate hepatic removal of circulating particulates and activated procoagulants.

  • Gram-negative septicemia. Endotoxin is released, which enhance the expression of tissue factor, thus accelerating procoagulant activation while suppressing thrombomodulin expression. The protein S-protein C system is also downregulated, further promoting the tendency to DIC.

  • Patients with amniotic fluid emboli, certain snakebites, and hereditary vascular malformations.

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.

Fig. 17. Pathogenesis of DIC.

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.

No laboratory assay is pathognomonic of DIC. However, peripheral smear examination is among the most helpful procedure (Fig. 18). In fulminant cases, this shows a characteristic combination of schistocytes (microangiopathic hemolytic anemia), mild polychromatophilia, and leukocytosis with a left shift, thrombocytopenia, and large young platelets. The platelet count continues to fall in spite of adequate of marrow megakaryocytes. However, schistocytes may be absent in chronic DIC. Fibrinogen levels are decreased, and the PT and aPTT are prolonged, plasmin is low, fibrinolytic activity is enhanced, and elevated levels of plasma fibrin/fibrinogen degradation products and D-dimers. Since DIC is an ongoing process, a single laboratory evaluation can be misleading, and serial coagulation tests may be required to establish the diagnosis, especially in early DIC.

Control of the initiating process is the only definitive therapy for DIC. Until this achieved, blood product support is required, and the judicious use of heparin may reverse the cycle of consumption and clot formation.

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.

Specific Inhibitors

Rare circulating antibody inhibitors specific for any coagulation factor can arise spontaneously, but are usually more common in certain disease settings. Autoantibodies against factor VIII:C which develop in patients with hemophilia A are the most common and widely studied type of specific inhibitor. Most are IgG, noncomplement fixing and directed against either a factor VIII active-site epitope, or against a site which causes shortened molecular half-life or impaired function. Most non-hemophiliac patients with anti-factor VIII antibodies have an associated disease, such systemic lupus erythematosus, a lymphoproliferative disorder, plasma cell malignancies, drug reactions (e.g., reaction to penicillin), or skin disease. The development of mucosal hemorrhages, hematomas, and ecchymoses in these patients lead to their identification.

Most specific inhibitors cause elevations in the aPTT, PT, and/or thrombin, depending on the inhibitor's site of action, biologic potency, and other features. Further evaluation reveals a positive "inhibitor screen" and negative dRVVT. Factor assays show decreased functional activity of the factor against which the inhibitor is directed.

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.

Non-Specific Inhibitors

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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.

Paradoxically, clinical bleeding is not associated with the presence of LA alone because the platelet membranes provide an alternative phospholipid surface for in vivo coagulation complexes, which are not inhibited by LA. If bleeding does occur in a patient with LA, an associated abnormality, such as hypothrombinemia, thrombocytopenia, platelet dysfunction, uremia, abnormalities of von Willebrand's factor, specific factor inhibitors (usually factors II and VIII), or drug-induced coagulopathies (chlorpromazine or procainamide) is responsible. In spite of the lack of bleeding manifestations, patients with LAs develop other clinical problems, including thrombosis, recurrent pregnancy loss, thrombocytopenia, cutaneous lesions (livido reticularis, leg ulcers (erythema nodosum-like nodules), neurologic problems, and hemolytic anemia. Thrombosis (venous and/or arterial) occurs in about 25% of patients with LA, irrespective of the presence of SLE. The lower extremities are the most frequent sites of venous thrombosis, while arterial thrombosis most often involves the cerebral arteries. The incidence of intrauterine death has varied between 10% and 50% in different studies. The mechanism of fetal wastage is unknown, although a thrombotic mechanism has been implicated in some studies.

The similarity in clinical presentation between patients with lupus anticoagulants and anticardiolipin antibodies has led to much recent interest in the interrelations between these antibodies. Both are now considered to be overlapping subsets of a larger group of autoantibodies, the antiphospholipid antibodies. Patients with lupus anticoagulants and/or anticardiolipin antibodies in the presence of one or more clinical manifestations are now considered to have the "antiphospholipid antibody syndrome."

The presence of a LA may be suspected from the clinical development of thromboembolic events or recurrent pregnancy loss. However, a prolonged aPTT discovered during routine coagulation screening is the most presentation of a LA. Once a prolonged aPTT is identified, the dRVVT or laboratory assays are necessary to confirm the presence of an inhibitor, and to differentiate LA from other inhibitors.

Non-Specific, Non-Lupus Inhibitors

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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.

Vitamin K deficiency can be suspected in a patient with a prolonged PT, normal or slightly prolonged aPTT, normal fibrinogen level (unless severe liver disease from another cause is present), and negative screen for anticoagulants. Correction of the PT in 24 to 36 hours with oral vitamin K therapy confirms the diagnosis. However, the administration of fresh frozen plasma (FFP) may be required in the interim in the presence of severe bleeding.


Drug-induced Hemorrhage

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.

Heparin overdose may not be obvious. It causes subcutaneous hemorrhages and deep tissue hematomas. The PTT, PT, and TT are vastly prolonged, but assays that test clotting independent of heparin are normal. Warfarin overdose is usually iatrogenic, and due to a misadministered dose of warfarin or the simultaneous ingestion of an drug that potentiates the anticoagulant action of warfarin (i.e., fluoroquinolone, ciprofloxacin). In addition, self or surreptitious administration of warfarin should always be suspected in patients with unexplained mucosal bleeding, ecchymosis, or subserosal bleeding into the gut wall, since warfarin is commercially available as a rotent poison.

Thrombolytic therapy is widely used for the treatment of acute myocardial infarction and for some cases of pulmonary embolism. Bleeding is usually confined to relatively trivial oozing at vascular invasion sites, but subdural hematomas, cerebral infarction, and intracranial bleeding have also occurred. In addition to hypofibrinogenemia, thrombolytic agents destroy factor VIII and factor V, and generate FDPs, which interfere with clot formation and platelet function. If thrombolytic therapy is suspected as the cause of bleeding, an aPTT, thrombin time,

Fibrinogen level, and (alpha-2-antiplasmin level should be obtained as rapidly as possible. If thrombolytic therapy is the cause, the aPTT is prolonged, the fibrinogen level is usually below 50 mg/dl, the thrombin time is prolonged (as a result of the fibrin degradation products), and a2-antiplasmin is depleted.

Dysproteinemias

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.

Acquired Hypofibrinogenemia

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.