Chapter 3: Bleeding and Thrombosis

APPROACH TO THE PATIENT: Bleeding and Thrombosis CLINICAL PRESENTATION

Disorders of hemostasis may be either inherited or acquired. A detailed personal and family history is key in determining the chronicity of symptoms and the likelihood of the disorder being inherited, as well as providing clues to underlying conditions that have contributed to the bleeding or thrombotic state. In addition, the history can give clues as to the etiology by determining (1) the bleeding (mucosal and/or joint) or thrombosis (arterial and/or venous) site and (2) whether an underlying bleeding or clotting tendency was enhanced by another medical condition or the introduction of medications or dietary supplements.

A history of bleeding is the most important predictor of bleeding risk. In evaluating a patient for a bleeding disorder, a history of at-risk situations, including the response to past surgeries, should be assessed. Does the patient have a history of spontaneous or trauma/surgery-induced bleeding? Spontaneous hemarthroses are a hallmark of moderate and severe factor VIII and IX deficiency and, in rare circumstances, of other clotting factor deficiencies. Mucosal bleeding symptoms are more suggestive of underlying platelet disorders or Von Willebrand disease (VWD), termed disorders of primary hemostasis or platelet plug formation. Disorders affecting primary hemostasis are shown in Table 3-1.

A bleeding score has been validated as a tool to predict patients more likely to have type 1 VWD (International Society on Thrombosis and Haemostasis Bleeding Assessment Tool [www.isth.org/resource/resmgr/ssc/isth-ssc_bleeding_assessment.pdf]). This is most useful tool in excluding the diagnosis of a bleeding disorder, and thus avoiding unnecessary testing. One study found that a low bleeding score (≤3) and a normal activated partial thromboplastin time (aPTT) had 99.6% negative predictive value for the diagnosis of VWD. Bleeding symptoms that appear to be more common in patients with bleeding disorders include prolonged bleeding with surgery, dental procedures and extractions, and/or trauma, menorrhagia or postpartum hemorrhage, and large bruises (often described with lumps).

Easy bruising and menorrhagia are common complaints in patients with and without bleeding disorders. Easy bruising can also be a sign of medical conditions in which there is no identifiable coagulopathy; instead, the conditions are caused by an abnormality of blood vessels or their supporting tissues. In Ehlers-Danlos syndrome, there may be posttraumatic bleeding and a history of joint hyperextensibility. Cushing’s syndrome, chronic steroid use, and aging result in changes in skin and subcutaneous tissue, and subcutaneous bleeding occurs in response to minor trauma. The latter has been termed senile purpura.

Epistaxis is a common symptom, particularly in children and in dry climates, and may not reflect an underlying bleeding disorder. However, it is the most common symptom in hereditary hemorrhagic telangiectasia and in boys with VWD. Clues that epistaxis is a symptom of an underlying bleeding disorder include lack of seasonal variation and bleeding that requires medical evaluation or treatment, including cauterization. Bleeding with eruption of primary teeth is seen in children with more severe bleeding disorders, such as moderate and severe hemophilia. It is uncommon in children with mild bleeding disorders. Patients with disorders of primary hemostasis (platelet adhesion) may have increased bleeding after dental cleanings and other procedures that involve gum manipulation.

Menorrhagia is defined quantitatively as a loss of >80 mL of blood per cycle, based on the quantity of blood loss required to produce iron-deficiency anemia. A complaint of heavy menses is subjective and has a poor correlation with excessive blood loss. Predictors of menorrhagia include bleeding resulting in iron-deficiency anemia or a need for blood transfusion, passage of clots >1 inch in diameter, and changing a pad or tampon more than hourly. Menorrhagia is a common symptom in women with underlying bleeding disorders and is reported in the majority of women with VWD, women with factor XI deficiency, and symptomatic carriers of hemophilia. Women with underlying bleeding disorders are more likely to have other bleeding symptoms, including bleeding after dental extractions, postoperative bleeding, and postpartum bleeding, and are much more likely to have menorrhagia beginning at menarche than women with menorrhagia due to other causes.

Postpartum hemorrhage (PPH) is a common symptom in women with underlying bleeding disorders. In women with type 1 VWD and symptomatic carriers of hemophilia A in whom levels of VWF and factor VIII usually normalize during pregnancy, PPH may be delayed. Women with a history of PPH have a high risk of recurrence with subsequent pregnancies. Rupture of ovarian cysts with intraabdominal hemorrhage has also been reported in women with underlying bleeding disorders.

Tonsillectomy is a major hemostatic challenge, because intact hemostatic mechanisms are essential to prevent excessive bleeding from the tonsillar bed. Bleeding may occur early after surgery or after approximately 7 days postoperatively, with loss of the eschar at the operative site. Similar delayed bleeding is seen after colonic polyp resection. Gastrointestinal (GI) bleeding and hematuria are usually due to underlying pathology, and procedures to identify and treat the bleeding site should be undertaken, even in patients with known bleeding disorders. VWD, particularly types 2 and 3, has been associated with angiodysplasia of the bowel and GI bleeding.

Hemarthroses and spontaneous muscle hematomas are characteristic of moderate or severe congenital factor VIII or IX deficiency. They can also be seen in moderate and severe deficiencies of fibrinogen, prothrombin, and factors V, VII, and X. Spontaneous hemarthroses occur rarely in other bleeding disorders except for severe VWD, with associated factor VIII levels <5%. Muscle and soft tissue bleeds are also common in acquired factor VIII deficiency. Bleeding into a joint results in severe pain and swelling, as well as loss of function, but is rarely associated with discoloration from bruising around the joint. Life-threatening sites of bleeding include bleeding into the oropharynx, where bleeding can obstruct the airway, into the central nervous system, and into the retroperitoneum. Central nervous system bleeding is the major cause of bleeding-related deaths in patients with severe congenital factor deficiencies.

Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) that inhibit cyclooxygenase 1 impair primary hemostasis and may exacerbate bleeding from another cause or even unmask a previously occult mild bleeding disorder such as VWD. All NSAIDs, however, can precipitate GI bleeding, which may be more severe in patients with underlying bleeding disorders. The aspirin effect on platelet function as assessed by aggregometry can persist for up to 7 days, although it has frequently returned to normal by 3 days after the last dose. The effect of other NSAIDs is shorter, as the inhibitor effect is reversed when the drug is removed. Thienopyridines (clopidogrel and prasugrel) inhibit ADP-mediated platelet aggregation and, like NSAIDs, can precipitate or exacerbate bleeding symptoms.

Many herbal supplements can impair hemostatic function (Table 3-2). Some are more convincingly associated with a bleeding risk than others. Fish oil or concentrated omega-3 fatty acid supplements impair platelet function. They alter platelet biochemistry to produce more PGI₃, a more potent platelet inhibitor than prostacyclin (PGI₂), and more thromboxane A₃, a less potent platelet activator than thromboxane A₂. In fact, diets naturally rich in omega-3 fatty acids can result in a prolonged bleeding time and abnormal platelet aggregation studies, but the actual associated bleeding risk is unclear. Vitamin E appears to inhibit protein kinase C–mediated platelet aggregation and nitric oxide production. In patients with unexplained bruising or bleeding, it is prudent to review any new medications or supplements and discontinue those that may be associated with bleeding.

Acquired bleeding disorders are commonly secondary to, or associated with, systemic disease. The clinical evaluation of a patient with a bleeding tendency must therefore include a thorough assessment for evidence of underlying disease. Bruising or mucosal bleeding may be the presenting complaint in liver disease, severe renal impairment, hypothyroidism, paraproteinemias or amyloidosis, and conditions causing bone marrow failure. All coagulation factors are synthesized in the liver, and hepatic failure results in combined factor deficiencies. This is often compounded by thrombocytopenia from splenomegaly due to portal hypertension. Coagulation factors II, VII, IX, and X and proteins C, S, and Z are dependent on vitamin K for posttranslational modification. Although vitamin K is required in both procoagulant and anticoagulant processes, the phenotype of vitamin K deficiency or the warfarin effect on coagulation is bleeding.

The normal blood platelet count is 150,000–450,000/μL. Thrombocytopenia results from decreased production, increased destruction, and/or sequestration. Although the bleeding risk varies somewhat by the reason for the thrombocytopenia, bleeding rarely occurs in isolated thrombocytopenia at counts <50,000/μL and usually not until <10,000–20,000/μL. Coexisting coagulopathies, as is seen in liver failure or disseminated coagulation; infection; platelet-inhibitory drugs; and underlying medical conditions can all increase the risk of bleeding in the thrombocytopenic patient. Most procedures can be performed in patients with a platelet count of 50,000/μL. The level needed for major surgery will depend on the type of surgery and the patient’s underlying medical state, although a count of approximately 80,000/μL is likely sufficient.

The risk of thrombosis, like that of bleeding, is influenced by both genetic and environmental influences. The major risk factor for arterial thrombosis is atherosclerosis, whereas for venous thrombosis, the risk factors are immobility, surgery, underlying medical conditions such as malignancy, medications such as hormonal therapy, obesity, and genetic predispositions. Factors that increase risks for venous and for both venous and arterial thromboses are shown in Table 3-3.

The most important point in a history related to venous thrombosis is determining whether the thrombotic event was idiopathic (meaning there was no clear precipitating factor) or was a precipitated event. In patients without underlying malignancy, having an idiopathic event is the strongest predictor of recurrence of VTE. In patients who have a vague history of thrombosis, a history of being treated with warfarin suggests a past DVT. Age is an important risk factor for venous thrombosis—the risk of DVT increases per decade, with an approximate incidence of 1/100,000 per year in early childhood to 1/200 per year among octogenarians. Family history is helpful in determining if there is a genetic predisposition and how strong that predisposition appears to be. A genetic thrombophilia that confers a relatively small increased risk, such as being a heterozygote for the prothrombin G20210A or factor V Leiden mutation, may be a minor determinant of risk in an elderly individual undergoing a high-risk surgical procedure. As illustrated in Fig. 3-5, a thrombotic event usually has more than one contributing factor. Predisposing factors must be carefully assessed to determine the risk of recurrent thrombosis and, with consideration of the patient’s bleeding risk, determine the length of anticoagulation. Similar consideration should be given in determining the need, if any, to test the patient and family members for thrombophilias.

Careful history taking and clinical examination are essential components in the assessment of bleeding and thrombotic risk. The use of laboratory tests of coagulation complement, but cannot substitute for, clinical assessment. No test exists that provides a global assessment of hemostasis. The bleeding time has been used to assess bleeding risk; however, it does not predict bleeding risk with surgery and it is not recommended for this indication. The PFA-100, an instrument that measures platelet-dependent coagulation under flow conditions, is more sensitive and specific for VWD than the bleeding time; however, it is not sensitive enough to rule out mild bleeding disorders. PFA-100 closure times are prolonged in patients with some, but not all, inherited platelet disorders. Also, its utility in predicting bleeding risk has not been determined.

For routine preoperative and preprocedure testing, an abnormal prothrombin time (PT) may detect liver disease or vitamin K deficiency that had not been previously appreciated. Studies have not confirmed the usefulness of an aPTT in preoperative evaluations in patients with a negative bleeding history. The primary use of coagulation testing should be to confirm the presence and type of bleeding disorder in a patient with a suspicious clinical history.

Because of the nature of coagulation assays, proper sample acquisition and handling is critical to obtaining valid results. In patients with abnormal coagulation assays who have no bleeding history, repeat studies with attention to these factors frequently results in normal values. Most coagulation assays are performed in sodium citrate anticoagulated plasma that is recalcified for the assay. Because the anticoagulant is in liquid solution and needs to be added to blood in proportion to the plasma volume, incorrectly filled or inadequately mixed blood collection tubes will give erroneous results. Vacutainer tubes should be filled to >90% of the recommended fill, which is usually denoted by a line on the tube. An elevated hematocrit (>55%) can result in a false value due to a decreased plasma-to-anticoagulant ratio.

The most commonly used screening tests are the PT, aPTT, and platelet count. The PT assesses the factors I (fibrinogen), II (prothrombin), V, VII, and X (Fig. 3-6). The PT measures the time for clot formation of the citrated plasma after recalcification and addition of thromboplastin, a mixture of TF and phospholipids. The sensitivity of the assay varies by the source of thromboplastin. The relationship between defects in secondary hemostasis (fibrin formation) and coagulation test abnormalities is shown in Table 3-4. To adjust for this variability, the overall sensitivity of different thromboplastins to reduction of the vitamin K–dependent clotting factors II, VII, IX, and X in anticoagulation patients is now expressed as the International Sensitivity Index (ISI). An inverse relationship exists between ISI and thromboplastin sensitivity. The international normalized ratio (INR) is then determined based on the formula: INR = (PT_patient/PT_{normal mean})^ISI.

The INR was developed to assess stable anticoagulation due to reduction of vitamin K–dependent coagulation factors; it is commonly used in the evaluation of patients with liver disease. Although it does allow comparison between laboratories, reagent sensitivity as used to determine the ISI is not the same in liver disease as with warfarin anticoagulation. In addition, progressive liver failure is associated with variable changes in coagulation factors; the degree of prolongation of either the PT or the INR only roughly predicts the bleeding risk. Thrombin generation has been shown to be normal in many patients with mild to moderate liver dysfunction. Because the PT only measures one aspect of hemostasis affected by liver dysfunction, we likely overestimate the bleeding risk of a mildly elevated INR in this setting.

The aPTT assesses the intrinsic and common coagulation pathways; factors XI, IX, VIII, X, V, and II; fibrinogen; prekallikrein; high-molecular-weight kininogen; and factor XII (Fig. 3-6). The aPTT reagent contains phospholipids derived from either animal or vegetable sources that function as a platelet substitute in the coagulation pathways and includes an activator of the intrinsic coagulation system, such as nonparticulate ellagic acid or the particulate activators kaolin, celite, or micronized silica.

The phospholipid composition of aPTT reagents varies, which influences the sensitivity of individual reagents to clotting factor deficiencies and to inhibitors such as heparin and lupus anticoagulants. Thus, aPTT results will vary from one laboratory to another, and the normal range in the laboratory where the testing occurs should be used in the interpretation. Local laboratories can relate their aPTT values to the therapeutic heparin anticoagulation by correlating aPTT values with direct measurements of heparin activity (anti-Xa or protamine titration assays) in samples from heparinized patients, although correlation between these assays is often poor. The aPTT reagent will vary in sensitivity to individual factor deficiencies and usually becomes prolonged with individual factor deficiencies of 30–50%.

Mixing studies are used to evaluate a prolonged aPTT or, less commonly PT, to distinguish between a factor deficiency and an inhibitor. In this assay, normal plasma and patient plasma are mixed in a 1:1 ratio, and the aPTT or PT is determined immediately and after incubation at 37°C for varying times, typically 30, 60, and/or 120 min. With isolated factor deficiencies, the aPTT will correct with mixing and stay corrected with incubation. With aPTT prolongation due to a lupus anticoagulant, the mixing and incubation will show no correction. In acquired neutralizing factor antibodies, notably an acquired factor VIII inhibitor, the initial assay may or may not correct immediately after mixing but will prolong or remain prolonged with incubation at 37°C. Failure to correct with mixing can also be due to the presence of other inhibitors or interfering substances such as heparin, fibrin split products, and paraproteins.

Decisions to proceed with specific clotting factor assays will be influenced by the clinical situation and the results of coagulation screening tests. Precise diagnosis and effective management of inherited and acquired coagulation deficiencies necessitate quantitation of the relevant factors. When bleeding is severe, specific assays are urgently required to guide appropriate therapy. Individual factor assays are usually performed as modifications of the mixing study, where the patient’s plasma is mixed with plasma deficient in the factor being studied. This will correct all factor deficiencies to >50%, thus making prolongation of clot formation due to a factor deficiency dependent on the factor missing from the added plasma.

Antibodies to phospholipids (cardiolipin) or phospholipid-binding proteins (β₂-microglobulin and others) are detected by enzyme-linked immunosorbent assay (ELISA). When these antibodies interfere with phospholipid-dependent coagulation tests, they are termed lupus anticoagulants. The aPTT has variability sensitivity to lupus anticoagulants, depending in part on the aPTT reagents used. An assay using a sensitive reagent has been termed an LA-PTT. The dilute Russell viper venom test (dRVVT) and the tissue thromboplastin inhibition (TTI) test are modifications of standard tests with the phospholipid reagent decreased, thus increasing the sensitivity to antibodies that interfere with the phospholipid component. The tests, however, are not specific for lupus anticoagulants, because factor deficiencies or other inhibitors will also result in prolongation. Documentation of a lupus anticoagulant requires not only prolongation of a phospholipid-dependent coagulation test but also lack of correction when mixed with normal plasma and correction with the addition of activated platelet membranes or certain phospholipids (e.g., hexagonal phase).

The thrombin time and the reptilase time measure fibrinogen conversion to fibrin and are prolonged when the fibrinogen level is low (usually <80–100 mg/dL) or qualitatively abnormal, as seen in inherited or acquired dysfibrinogenemias, or when fibrin/fibrinogen degradation products interfere. The thrombin time, but not the reptilase time, is prolonged in the presence of heparin. The thrombin time is markedly prolonged in the presence of the direct thrombin inhibitor, dabigatran; a dilute thrombin time can be used to assess drug activity. Measurement of anti–factor Xa plasma inhibitory activity is a test frequently used to assess low-molecular-weight heparin (LMWH) levels, as a direct measurement of unfractionated heparin (UFH) activity, or to assess activity of the new direct Xa inhibitors rivaroxaban or apixaban. Drug in the patient sample inhibits the enzymatic conversion of an Xa-specific chromogenic substrate to colored product by factor Xa. Standard curves are created using multiple concentrations of drug and are used to calculate the concentration of anti-Xa activity in the patient plasma.

Laboratory assays to detect thrombophilic states include molecular diagnostics and immunologic and functional assays. These assays vary in their sensitivity and specificity for the condition being tested. Furthermore, acute thrombosis, acute illnesses, inflammatory conditions, pregnancy, and medications affect levels of many coagulation factors and their inhibitors. Antithrombin is decreased by heparin and in the setting of acute thrombosis. Protein C and S levels may be increased in the setting of acute thrombosis and are decreased by warfarin. Antiphospholipid antibodies are frequently transiently positive in acute illness. Testing for genetic thrombophilias should, in general, only be performed when there is a strong family history of thrombosis and results would affect clinical decision making.

Because thrombophilia evaluations are usually performed to assess the need to extend anticoagulation, testing should be performed in a steady state, remote from the acute event. In most instances, warfarin anticoagulation can be stopped after the initial 3–6 months of treatment, and testing can be performed at least 3 weeks later. As a sensitive marker of coagulation activation, the quantitative d-dimer assay, drawn 4 weeks after stopping anticoagulation, can be used to stratify risk of recurrent thrombosis in patients who have an idiopathic event.

The bleeding time has been used to assess bleeding risk; however, it has not been found to predict bleeding risk with surgery, and it is not recommended for use for this indication. The PFA-100 and similar instruments that measure platelet-dependent coagulation under flow conditions are generally more sensitive and specific for platelet disorders and VWD than the bleeding time; however, data are insufficient to support their use to predict bleeding risk or monitor response to therapy, and they will be normal in some patients with platelet disorders or mild VWD. When they are used in the evaluation of a patient with bleeding symptoms, abnormal results, as with the bleeding time, require specific testing, such as VWF assays and/or platelet aggregation studies. Because all of these “screening” assays may miss patients with mild bleeding disorders, further studies are needed to define their role in hemostasis testing.

For classic platelet aggregometry, various agonists are added to the patient’s platelet-rich plasma and platelet aggregation is measured. Tests of platelet secretion in response to agonists can also be measured. These tests are affected by many factors, including numerous medications, and the association between minor defects in aggregation or secretion in these assays and bleeding risk is not clearly established.