Patrick F. Fogarty
APPROACH TO THE BLEEDING PATIENT
Abnormalities of the activity of coagulation proteins and related molecules, decreased platelet function, or disruption of the vasculature (as by surgery or trauma) can lead to bleeding. Careful assessment of both the clinical history and laboratory testing are necessary to establish the reason for bleeding.
Initial laboratory studies in a patient with new-onset or recent bleeding include a platelet count, activated partial thromboplastin time (aPTT), prothrombin time (PT), and fibrinogen. If the bleeding is moderate to severe, a hemoglobin level and specimen for red cell cross-matching should also be sent.
The character, timing, and location of the bleeding should be considered. Is the bleeding spontaneous, or associated only with invasive procedures or trauma? If peri-procedural, is the bleeding immediate or delayed? Mucocutaneous bleeding (epistaxis, gingival hemorrhage, petechiae/ecchymoses, gastrointestinal, and urinary tract bleeding) are more characteristic of a defect in the activity of platelets, whereas soft-tissue bleeding or hemarthrosis suggests a deficiency in the activity of coagulation factors.
The clinical context is very important in determining the reason for bleeding. Hemorrhage in a patient who has been receiving heparin or warfarin may indicate excess anticoagulation or presence of a previously undetected lesion. A lifelong history of excessive bleeding may occur due to an inherited disorder of hemostasis. Bleeding in an individual who is in septic shock may point to disseminated intravascular coagulation (DIC). New-onset, diffuse bleeding in a patient who is pregnant or post-partum may signify the HELLP syndrome or other entities. Postsurgical bleeding may stem from a number of causes, but an initial consideration should be deficient hemostasis due to a traumatized, bleeding vessel, as well as a coagulation factor defect or deficits.
A family history of bleeding raises the clinical suspicion for heritable disorders such as hemophilia A or B (X-linked recessive inheritance) or von Willebrand disease (VWD) (autosomal dominant inheritance in most cases).
Importantly, bleeding does not necessarily indicate an intrinsic abnormality of hemostasis. Individuals with normal coagulation and platelet function will bleed given a sufficient hemostatic challenge (trauma, surgery, invasive malignancy).
THE COAGULATION SYSTEM
Coagulation Factors: Background
Coagulation factors (clotting factors) are synthesized in the liver.
Factors II, VII, IX, X, XI, and XII are serine proteases that are inactive as synthesized and acquire enzymatic capability when cleaved (activated) by other proteins. A post-synthetic step in the production of factors II, VII, IX, and X and the natural anticoagulant proteins C and S requires the activity of a vitamin K–dependent carboxylase that modifies the amino-terminus of each factor, enabling it to function.
Tissue factor (TF) and factors V and VIII serve as cofactors for coagulation reactions.
The activity of all clotting factors culminates in a principal event: the generation of thrombin at sites of vascular injury. Thrombin activates platelets (primary hemostasis) and cleaves fibrinogen to form fibrin (secondary hemostasis) at sites of blood vessel compromise.
The normal laboratory range of factor activity levels is ˜50% to 150% and is derived from plasma activity as observed in a reference pool of normal donors. The hemostatic level of a given clotting factor (the level of factor necessary to maintain normal hemostasis) typically is much lower. For instance, 5% activity of factor VIII is well below the laboratory reference range but usually is sufficient to prevent spontaneous bleeding.
The Coagulation Cascade
The coagulation cascade illustrates the activation of coagulation factors in the formation of a fibrin clot. It comprises the tissue injury (also known as extrinsic), contact (also known as intrinsic), and common pathways of coagulation (Fig. 20.1). The pathways within the coagulation cascade probably best reflect the activity of clotting factors in vitro, whereas in vivo the pathways not only interact at multiple points but also function in concert with the activation and aggregation of platelets to achieve hemostasis.
FIGURE 20.1. The coagulation cascade.The tissue injury pathway of coagulation begins with the binding of activated factor VII (VIIa) to tissue factor (TF), which is provided by cell membranes.VIIa converts X to Xa.The prothrombinase complex, formed by the binding of Xa to Va in the presence of PL and Ca2+, converts II (prothrombin) to IIa (thrombin).The contact pathway of coagulation begins with the activation of factor XII to XIIa by kallikrein. XIIa cleaves XI to XIa; XIa cleaves IX to IXa. IXa forms a complex with VIIIa in the presence of PL and Ca2+(tenase complex), and converts X to Xa. Xa, in the presence of Va, PL, and Ca2+, then cleaves II (prothrombin) to IIa (thrombin).The common pathway involves the cleavage of II by prothrombinase to yield thrombin, and thrombin cleavage of fibrinogen to form fibrin, which is then cross-linked via the action of XIIIa. Activation of coagulation usually begins with the tissue injury system, which provides feedback to the contact system by IIa-mediated activation of factor XI.There are additional points of interaction between the pathways (not indicated).
Tissue injury pathway. The tissue injury pathway of coagulation begins with the binding of activated factor VII (VIIa) to TF. The TF-VIIa complex mediates the conversion of X to Xa. The prothrombinase complex, formed by the binding of Xa to Va on a phospholipid (PL) surface (usually platelet membranes) in the presence of Ca2+, converts II (prothrombin) to IIa (thrombin).
Contact pathway. Activation of contact factors at the site of vascular injury leads to the conversion of Factor XII to XIIa, and the sequential conversion of XI to XIa and IX to IXa. IXa complexes with VIIIa, PL, and Ca2+, forming the tenase complex, which converts X to Xa. Xa, in a complex with Va, PL, and Ca2+ then cleaves II (prothrombin) to IIa (thrombin). The TF-VIIa complex can also activate IX leading to the subsequent formation of the tenase complex.
Common pathway. The tissue injury and contact pathways converge in the common pathway, where X is converted to Xa, and prothrombin (II) is cleaved to form thrombin. Thrombin then cleaves fibrinogen to form fibrin, which is then cross-linked via the action of XIII.
Common Coagulation Tests
An understanding of the basic laboratory tests for coagulation assists in the evaluation of bleeding disorders.
The PT is performed by adding thromboplastin (TP), composed of crude or recombinant TF plus Ca2+, to plasma that has been anti-coagulated with citrate, and the time to formation of a fibrin clot is measured. Because the PT comprises reactions of coagulation that occur in the tissue injury and common pathways of coagulation, deficiencies in the activity of II, V, VII, X, or fibrinogen may prolong the PT.
The International Normalized Ratio (INR) was developed to standardize the reporting of PT values in warfarin-anticoagulated patients. Standardization is necessary because commercially available TP reagents have varying potencies that directly impact the PT; one TP may yield a different PT result than another when the same sample is tested. The potency of a given TP is expressed in terms of the International Sensitivity Index (ISI).
Because the INR was developed to report factors measured by the PT that are decreased by warfarin impairment of vitamin K–mediated synthesis (the INR is not standardized for abnormalities of factor V and fibrinogen), the INR should be used only to describe anticoagulation in patients who are receiving warfarin. In all other patients (such as patients with liver disease), the PT should be referenced.
The formula for the INR is (PTpatient/PTmean normal)ISI.
The aPTT begins with the addition of a contact activating agent to citrate-anticoagulated plasma. PL and Ca2+ are added, and the time for formation of a fibrin clot is measured. Because the aPTT reflects reactions of coagulation that occur in the contact and common pathways of coagulation, deficiencies in the activity of factors II, V, VIII, IX, X, XI, or XII may prolong the aPTT. A deficiency of other contact factors, such as prekallikrein or high molecular weight kininogen (HMWK), may also prolong the aPTT. Isolated abnormalities of fibrinogen rarely impact the aPTT.
The long-incubation aPTT is performed by incubating the sample with activating agents for 10 minutes prior to the addition of PL and Ca2+. If the contact factor prekallikrein is deficient, this extra incubation time allows activation of factor XII and correction of the aPTT.
Mixing studies are performed using a mixture of 50% patient plasma and 50% normal control plasma; the PT or aPTT is then performed as usual. Correction of a prolonged PT or aPTT with mixing generally implies a qualitative or quantitative abnormality of one or more clotting factors in the patient plasma. In contrast, failure of the PT or aPTT to correct completely upon mixing suggests the presence of an inhibitor in the patient plasma that neutralizes a component of the patient and normal plasma. Both lupus anticoagulants (LAs; see below) and inhibitors to specific clotting factors can result in a prolonged aPTT or PTT that does not correct upon mixing.
When evaluating a prolonged aPTT, an aPTT is performed on the mixture, then the mixture is allowed to incubate for an hour and the aPTT is repeated; some inhibitors of factor VIII are maximally inhibitory at an hour or more post-mix. For instance, the aPTT on a 1:1 mixture of normal and patient plasma containing a factor VIII inhibitor may show correction initially but demonstrate a prolongation at 1 hour.
Occasionally, a weak LA may produce a prolonged aPTT or PT that corrects on mixing.
The bleeding time (BT) involves making a controlled incision in soft tissue (usually at a site on the forearm) and measuring the time to cessation of bleeding. Anemia and abnormalities of coagulation factors, platelets, or the vasculature may prolong the BT. The BT does not correlate with risk of surgical bleeding in most patients,1 and is no longer widely used or recommended.
The thrombin time (TT) involves the addition of exogenous thrombin to patient plasma, inducing cleavage of fibrinogen to fibrin and the formation of a fibrin clot.
The most common cause of a prolonged TT is the presence of heparin in the sample, which can be confirmed by documentation of a normalization of the TT when the test is repeated using a heparin-binding agent such as protamine or Heparsorb®.
Abnormalities of fibrinogen and circulating heparin-like anticoagulants also cause a prolonged TT.
The reptilase time is also used to assess abnormalities of fibrinogen (reptilase cleaves fibrinogen to fibrin). Unlike thrombin, however, reptilase is not inhibited by the presence of heparin. Thus, a prolonged TT in conjunction with a normal reptilase time usually indicates heparin contamination, whereas prolongation of both tests indicates a qualitative abnormality of fibrinogen.
The functional fibrinogen assay assesses fibrinogen concentration by addition of an excess of thrombin to a sample of diluted plasma.
Specialized Coagulation Tests
The anti-Xa assay provides information about the degree of anticoagulation that has occurred in the patient plasma due to the effect of heparin (unfractionated or low molecular weight) on factor Xa in the sample. By convention, samples should be drawn 4 to 6 hours after low molecular weight heparin (LMWH) administration to estimate anticoagulation.
Tests for LAs distinguish an inhibitor of a specific clotting factor from an LA as the cause of a prolongation in the aPTT that does not correct with mixing. Most tests for LAs involve addition of excess PLs to the reaction system to neutralize the LA and result in a correction of a prolonged clotting time. One such test is the Russell’s viper venom time; other systems for the diagnosis of LAs are available. 2
The Bethesda Assay is a special type of mixing study that involves incubation of dilutions of patient plasma with normal (control) plasma to assess the potency of an inhibitor (generally, to factor VIII) in the patient’s plasma. After a 2-hour incubation phase, a factor VIII assay (or other appropriate factor assay, as indicated) is performed on each dilution (and on samples used to create a control curve); as the proportion of patient plasma in the mixture decreases, the effect of the inhibitor decreases, and the factor assay clotting time shortens. The Nijmegen modification to the Bethesda assay includes slightly different buffers to stabilize the proteins during the incubation period.3
The potency of the inhibitor is expressed in Bethesda units (BU). The reciprocal of the dilution of the mixture of patient and normal control plasma that contains ˜50% of normal factor VIII activity is the inhibitor titer in BU. For instance, if 50% inhibition of normal FVIII activity occurred at a 1:40 dilution, the inhibitor titer would be said to be 40 BU.
Assays for specific clotting factors. Factor activity levels can be assessed by clot-based reaction, which employ modifications of the aPTT or PT, and some factors by chromogenic systems.
Factor activity levels are generally reported as percentages (of “normal” activity) or in units per milliliter (U/mL), with 1 U/mL corresponding to 100% of the factor found in 1 mL of normal plasma.
Usually, levels of 25% to 40% are necessary to prolong the PT or aPTT. Mild or moderate deficiencies of a given clotting factor may lead to an elevated PT or aPTT, but may be adequate for hemostasis.
The euglobulin clot lysis time (ECLT) measures time for dissolution of a fibrin clot; a shortened ECLT indicates activation of the fibrinolytic system. The most common cause of a shortened ECLT is DIC, in which fibrinolysis is activated in response to an activation of coagulation. Deficiencies in the activity of plasminogen activator inhibitor or alpha-2-antiplasmin also shorten the ECLT (see below).
Thromboelastography is measurement of various parameters of clot formation in whole blood, which captures functional data on the activity of both platelets and coagulation factors.4 This test is used clinically mostly in cardiovascular surgical settings although other applications have been explored. 5
DIFFERENTIAL DIAGNOSIS OF ABNORMAL COAGULATION TESTS
Conditions that predispose to bleeding or produce abnormal coagulation test results can be divided into those entities that prolong the aPTT, PT, or both (Table 20.1 and Figs. 20.2, 20.3, and 20.4).
Conditions Associated with a Prolonged aPTT
LAs2 are a very common cause of a prolongation in the aPTT that does not correct completely on mixing.
LAs were so named due to their frequent presence in patients with systemic lupus erythematosus and tendency to prolong coagulation tests by interacting with PL in the test sample. In contradistinction to their name, however, LAs are not physiologic anticoagulants; additionally, over one-half of patients with LAs do not have connective tissue disease (see Chapter 22).
LAs are diagnosed using the methods described above.
Hemophilia A and B. More frequently than with any other factor essential to the aPTT reaction, a deficiency of factor VIII causes a prolongation in the aPTT that corrects completely on mixing. Congenital factor VIII deficiency is referred to as hemophilia A. (Factor VIII is also decreased in moderate and severe VWD; see below.) Congenital deficiency of factor IX is hemophilia B.
Hemophilia A is estimated to occur in one per 5,000 to 10,000 live male births; hemophilia B is about a fifth as common. The disorders are inherited in an X-linked recessive fashion: males are affected, whereas females are carriers and are generally not affected unless significant lyonization has occurred favoring the X chromosome bearing the abnormal copy of the FVIII gene. There is no race predilection.
The presentation of the disease relates to the level of residual factor activity in the plasma. Severe hemophilia (<1% factor activity) typically presents in infancy with bleeding at circumcision, or in early childhood with spontaneous bleeding into soft tissues (muscles) or joints, and intracranial, gastrointestinal, or urinary bleeding. Moderate hemophilia (1%–5% factor activity) is typified by less severe bleeding than that observed in severe disease, whereas individuals with mild hemophilia (>5% activity) usually do not experience spontaneous bleeding but may bleed upon significant hemostatic challenges such as trauma or surgery.
FIGURE 20.2. Laboratory diagnostic algorithm for a prolonged aPTT and normal PT. aPTT, activated partial thromboplastin time; LA, lupus anticoagulant.
* Some LAs escape detection, even after performing two tests. If all relevant coagulation factor activities are demonstrated to be hemostatic, an LA may be the explanation for the aPTT prolongation.
† Occasionally, weak LAs can cause a prolongation in the aPTT that corrects completely on mixing. In this scenario, factor assays may be indicated in addition to LA testing, especially if demonstration of hemostatic factor levels is regarded as important (e.g., in a preoperative patient).
Factor concentrates are the mainstay of treatment (Table 20.2); both plasma-derived and recombinant products are commercially available. For acute major bleeding (e.g., intracranial) or prophylaxis prior to major surgery, doses of 50 U/kg (FVIII) or 100 to 120 U/kg (FIX) are administered by IV bolus infusion every 8 to 12 hours for 1 to 14 days, depending on the anatomic location and severity of the bleeding.6 Longer-acting FVIII and FIX molecules are in clinical development.7 Less severe bleeding (hemarthrosis) or prophylaxis prior to moderately invasive procedures (such as endoscopy with biopsy) may be addressed with lower doses of factor. Patients with mild hemophilia A may respond to infusion of DDAVP (0.3 mcg/kg/dose),8 but a trial should be done in the non-bleeding state to document a rise of the FVIII activity level into the hemostatic range.
FIGURE 20.3. Laboratory diagnostic algorithm for a prolonged PT and normal aPTT. LA, lupus anticoagulant; PT, prothrombin time; TT, thrombin time.
* Decreased functional fibrinogen in conjunction with a normal immunologic fibrinogen indicates an abnormal fibrinogen (dysfibrinogenemia), whereas decreased functional and immunologic assays are typical of hypofibrinogenemia.
† Occasionally, LAs can cause a prolongation in the PT that corrects on mixing.
The oral antifibrinolytic agent aminocaproic acid (Amicar®), given at a dose of 1 to 2 g every 4 to 6 hours, may be useful for patients with mucosal or oral bleeding, or bleeding associated with dental procedures.
Prophylactic factor replacement therapy (twice or thrice weekly infusions) is routinely used as a means of preventing the morbidity incurred from recurrent joint bleeding.9 It is more common among children than adults; generally, the practice is begun by the age of 4 years.
Inhibitors. Patients with congenital hemophilia (usually with severe disease) who have received factor concentrates as treatment for bleeding are at risk for inhibitor formation. Over 25% of patients with hemophilia A and less than 5% of patients with hemophilia B will develop inhibitors to factor VIII or IX, respectively. The potency of the inhibitor is expressed in BU. Low-titer inhibitors (<5 BU) often may be overcome by increasing the dose or frequency of infused factor concentrate. It is usually not possible to overcome high-titer inhibitors (>5 BU) using this approach, however, and administration of activated prothrombin complex concentrates and/or recombinant factor VIIa is necessary (Table 20.2). 10
Acquired hemophilia occurs at an incidence of approximately 1 per million per year, typically in elderly persons or in those with underlying lymphoproliferative conditions, cancer, autoimmunity, or prior pregnancy. Anti-FVIII IgG antibodies neutralize FVIII, leading to a prolonged aPTT that does not correct upon mixing. The clinical presentation commonly features extensive ecchymoses and soft-tissue hematomas. Bypassing agents (see Table 20.2) are used to treat acute bleeding, whereas a variety of immunosuppressive agents, typically incorporating corticosteroids initially, may produce a response. The mortality of this condition is considerable.11
FIGURE 20.4. Laboratory diagnostic algorithm for a prolonged aPTT and PT. aPTT, activated partial thromboplastin time; DIC, disseminated intravascular coagulation; FDP, fibrin degradation products; LA, lupus anticoagulant; PT, prothrombin time.
* Co-existing conditions, such as vitamin K deficiency (leading to a prolonged PT) and a concomitant LA (leading to an elevated aPTT), are possible.
† Rarely, co-inheritance of deficiencies in multiple coagulation factors (such as factors V and VIII) can occur.
VWD, due to the lack of adequate VWF to bind and protect circulating factor VIII from clearance, can lead to low VIII levels and a prolongation in the aPTT (see Chapter 21, Disorders of Hemostasis II). The prolongation in the aPTT corrects on mixing.
Factor XI deficiency (sometimes called hemophilia C) typically results in a prolonged aPTT that corrects on mixing. It is inherited in an autosomal recessive manner and is most prevalent among individuals of Ashkenazi Jewish descent. It typically causes a mild bleeding tendency that is worsened by trauma or surgery. Levels of factor XI do not correlate well with bleeding symptoms.12 Fresh frozen plasma (FFP) may be used prophylactically or for treatment of bleeding, and adjunctive aminocaproic acid decreases unmitigated fibrinolysis, making it useful for chronic prophylaxis, oral bleeding, dental work, or minor surgical procedures. In some locales, a plasma-derived FXI concentrate is available.
Factor XII deficiency and deficiencies of prekallikrein and HMWK. Although they may lead to a prolonged aPTT, these conditions do not cause bleeding.
Acquired inhibitors to coagulation proteins. Occasionally, adults without a prior history of hemophilia develop high-titer inhibitors to factor VIII; not infrequently, a concomitant lymphoproliferative or immune disorder is present. Immunosuppressive treatment with corticosteroids or chemotherapy usually is effective. 13
Heparin contamination. The presence of heparin in the sample used for the aPTT determination may be verified by documenting normalization of the aPTT after the test is repeated using a heparin-binding agent.
Warfarin may mildly prolong the aPTT due to depletion of factors II, X, or XI.
Occasionally, traumatic venipuncture may cause the aPTT to be prolonged, due to the direct activation of coagulation at the site of venipuncture, leading to depletion of crucial coagulation proteins in the collected specimen. The blood should be redrawn with careful technique during phlebotomy and the aPTT repeated to document normalization. (Traumatic venipuncture may also lead to a shortening of the aPTT due to small amounts of thrombin generation.)
Conditions Associated with a Prolonged Prothrombin Time
Vitamin K deficiency can cause an elevated PT that typically corrects completely on mixing. The vitamin K–dependent factors that are measured by the PT are II, VII, and X.
Malabsorption or deficient dietary intake of vitamin K (from green leafy vegetables such as cabbage, cauliflower, and spinach, cereals, soybeans, and other foods) or decreased production by intestinal bacteria (which may be destroyed by antibiotics) may lead to vitamin K deficiency.
For treatment, vitamin K (phytonadione) may be administered via parenteral or oral routes. Intravenous administration (1 mg/day) results in faster normalization of a prolonged PT than subcutaneous dosing, but occasionally has been associated with anaphylaxis; therefore, intravenous doses should be administered slowly (over 30 minutes) while the patient is monitored. Subcutaneous administration should be avoided due to erratic absorption. 14
At least partial correction of the PT is expected within 24 hours after parenteral administration of vitamin K if vitamin K deficiency is the only reason for the prolongation in the PT.
Coagulopathy of liver disease. Hepatic insufficiency leads to decreased synthesis of clotting factors, such as the vitamin K–dependent factors and, with more severe disease, factors V, VIII, XI, XII, and fibrinogen, resulting in a prolonged PT (and with severe disease, aPTT) that correct(s) on mixing.
In contradistinction to coagulopathy due to isolated vitamin K deficiency, liver disease may feature a reduced factor V level in addition to decreased levels of factors II, VII, IX, and X.
Patients with prolonged clotting times due to liver disease paradoxically may be prone to thrombosis.15
Warfarin. Warfarin inhibits the vitamin K–dependent carboxylase that is important for the synthesis of factors II, VII, IX, and X. Decreased functional levels of factors II, VII, and X may prolong the PT and produce an elevated INR.
Supratherapeutic INRs that are not associated with bleeding generally are managed by temporary withholding of warfarin to allow the INR to descend into the desired range, and restarting the warfarin at a lower dose.
Critically elevated INRs (>9) may be addressed with temporary discontinuation of warfarin, plus administration of vitamin K14 or FFP if the patient is felt to be at very high risk for bleeding.
For treatment of warfarin-associated major bleeding,16 the warfarin should be discontinued and FFP (4 units), prothrombin complex concentrate (such as Bebulin®, 35 units/kg/dose), or rhVIIa (NovoSeven®; 15–90 μg/kg/dose ) should be administered along with intravenous or oral vitamin K.
LAs can cause a mild prolongation in the PT (see above).
Hypofibrinogenemia/Dysfibrinogenemia. Quantitative or qualitative abnormalities of fibrinogen typically produce a long TT and reptilase time (see above), but the PT also may be prolonged (Fig. 20.3). The PT is much more sensitive to hypofibrinogenemia/dysfibrinogenemia than is the aPTT.
Defects in the function of fibrinogen are more commonly acquired (as with cirrhosis or active liver disease) than congenital. For instance, DIC characteristically produces a consumptive hypofibrinogenemia.
Replacement of fibrinogen in a bleeding patient with hypofibrinogenemia/dysfibrinogenemia may be accomplished by administration of cryoprecipitate or a plasma-derived fibrinogen concentrate; for major surgery or bleeding, a plasma fibrinogen level of 80 to 100 mg/dL is targeted.
Deficiencies of individual clotting factors. Congenital deficiencies of isolated coagulation factors (for example, VII) leading to a prolonged PT are extremely rare and typically are inherited in autosomal recessive pattern.
Antibodies to bovine factor V and thrombin may develop after exposure to topical bovine thrombin (used in orthopedic, neurologic, and vascular surgery). The antibodies cross react with human factor V and/or thrombin, resulting in prolongation of the PT and bleeding in some patients. 17
Conditions Associated with a Prolonged Activated Partial Thromboplastin Time and Prothrombin Time
Coagulopathy of liver disease. If hepatic insufficiency is extreme, multiple factor deficiencies can result in a prolonged PT and aPTT.
Deficiencies of individual clotting factors. Isolated deficiencies of factors II, V, or X are rare,18 but may prolong both the PT and aPTT.
DIC. Depletion of coagulation factors via diffuse activation of coagulation may cause a prolongation in both the PT and aPTT (see Chapter 21).
LAs can prolong both the PT and aPTT (discussed previously).
Conditions Associated with Bleeding and Normal Coagulation Tests
Factor XIII deficiency. Activated factor XIII cross-links fibrin strands, stabilizing the fibrin clot. Individuals with a deficiency of factor XIII characteristically develop delayed bleeding several hours to days following surgery or trauma. Traumatic soft tissue and joint bleeds, recurrent pregnancy loss, and spontaneous intracranial hemorrhages also have been described. 12
Clot lysis or enzymatic assays and sequencing of either of the two genes that encode the molecule may be diagnostic.
Treatment of bleeding consists of infusion of cryoprecipitate or FFP.
Alpha-2-antiplasmin deficiency or plasminogen activator I (PAI-1) deficiency leads to accelerated digestion of fibrinogen and fibrin clots and (in some patients) increased bleeding.19 Infusion of FFP may be clinically useful.
Congenital and acquired abnormalities of the vasculature and integument can cause increased fragility of blood vessels and bruising or bleeding, despite normal coagulation, fibrinolysis, and platelet function.20 Such conditions include hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease), heritable defects of collagen (Ehlers-Danlos syndrome, osteogenesis imperfecta), acquired collagen-associated conditions (scurvy, prolonged glucocorticoid administration, the normal aging skin), and other anomalies (Marfan syndrome, amyloidosis, vasculitis). There is no effective treatment for bruising associated with the congenital disorders; preventative measures to reduce the risk of trauma should be followed. Repletion of vitamin C (scurvy) and reduction of corticosteroids (glucocorticoid excess) ameliorate bruising associated with those acquired processes.
References