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Chapter 69: Bleeding and Thrombosis

Chapter 69 | Part 2: Cardiovascular Diseases · Part 2 – Cardinal Manifestations & Presentation

Detailed clinical reference synthesised from Harrison's Principles of Internal Medicine, 22nd Edition

🔑 Key Clinical Points

  1. Hemostasis is a balance between procoagulant forces (platelet adhesion, fibrin clot) and anticoagulant forces (natural inhibitors).
  2. Macrophage Activation Syndrome (MAS-HLH) is defined in children as febrile patient with ferritin >684 µg/L and any two of: platelet count ≤181 × 10^9/L, AST >48 U/L, triglycerides >1.76 mmol/L, fibrinogen ≤3.6 g/L.
  3. d-Dimer assays are sensitive markers of blood clot formation and validated to exclude deep venous thrombosis (DVT) and pulmonary embolism in selected populations.
  4. The International Normalized Ratio (INR) is determined by INR = (PT / PT_normal_mean)^ISI and is used to assess stable anticoagulation.
  5. Bleeding score (ISTH Bleeding Assessment Tool) is recommended for screening von Willebrand disease (VWD) in primary care to avoid unnecessary testing.
  6. Heavy menstrual bleeding is quantitatively defined as >80 mL of blood per cycle and is a common symptom in women with underlying bleeding disorders.
  7. NSAIDs impair primary hemostasis by inhibiting cyclooxygenase 1 and can precipitate GI bleeding, particularly in patients with underlying bleeding disorders.
  8. Thrombotic risk increases with age, and a history of idiopathic venous thromboembolism (VTE) is the strongest predictor of recurrence in patients without underlying malignancy.
  9. Proper sample acquisition for coagulation assays requires filling citrate tubes to >90% of recommended volume to avoid erroneous results due to incorrect plasma-to-anticoagulant ratio.
  10. Activated protein C (APC) acts as an anticoagulant by cleaving and inactivating activated factors V and VIII, accelerated by cofactor protein S.

📑 Table of Contents

📋 Figures in This Chapter

# Type Description
1 🖼 Figure Coagulation is initiated by tissue factor (TF) exposure, which, with factor which...
2 🖼 Figure Thrombotic risk over time
3 🖼 Figure The plasminogen activators, tissue type plasminogen activator FIGURE 69-2 Fibrin formation and...

1. DEFINITION & OVERVIEW

The human hemostatic system provides a natural balance between procoagulant and anticoagulant forces. The procoagulant forces include platelet adhesion and aggregation and fibrin clot formation; anticoagulant forces include the natural inhibitors of coagulation and fibrinolysis. Under normal circumstances, hemostasis is regulated to promote blood flow; however, it is also prepared to clot blood rapidly to arrest blood flow and prevent exsanguination. After bleeding is successfully halted, the system remodels the damaged vessel to restore normal blood flow. The major components of the hemostatic system, which function in concert, are (1) platelets and other formed elements of blood, such as monocytes and red cells; (2) plasma proteins (the coagulation and fibrinolytic factors and inhibitors); and (3) the vessel wall.

1.1 Hemophagocytic Lymphohistiocytosis (HLH) & Macrophage Activation Syndrome (MAS)

Macrophage activation syndrome (MAS) is a life-threatening hyperinflammatory complication of rheumatic disease and other autoimmune diseases. It is characterized by an uncontrolled activation and proliferation of T lymphocytes and macrophages and classified among the secondary, acquired forms of HLH because it shares many clinical and laboratory features with both primary and secondary HLH, hence the term MAS-HLH. MAS-HLH is the third most common form of HLH in adults and the second most common in children. In children, it occurs most frequently in individuals with systemic juvenile idiopathic arthritis (sJIA), affecting 10% of these patients, and with systemic lupus erythematosus. In adults, systemic lupus erythematosus is the most common cause, followed by adult-onset Still's disease, affecting about 5% and 10–15% of these patient groups, respectively. Other causes include systemic vasculitis and inflammatory bowel disease. Clinically, MAS-HLH manifests as fever, liver dysfunction, cytopenia, hyperferritinemia, coagulopathy, CNS abnormalities, and, more rarely, hemophagocytosis. Fibrinogen and platelet levels are often higher than in other forms of HLH, due to the inflammatory nature of sJIA. In 2016, MAS-HLH in sJIA patients was defined as a febrile patient with ferritin >684 µg/L and any two of the following: platelet count ≤181 × 10^9/L, aspartate aminotransferase >48 U/L, fasting triglycerides >1.76 mmol/L (156 mg/dL), and fibrinogen ≤3.6 g/L. Most MAS-HLH flares are reported to be triggered by active disease, but about a third have an infectious trigger. The cytokine pattern in MAS-HLH is characterized by high serum levels of IL-18, distinguishing it from other forms of HLH such as FHL. The mortality rate in MAS-HLH is about 5–10% in children and 10–15% in adults. CNS involvement is frequent and may lead to irreversible neurologic damage. Early diagnosis and treatment are therefore crucial. Patients with MAS-HLH may also develop severe pulmonary disease with a high fatality rate, reported to be about 50%, for which the best treatment and prevention still is unknown. The predominant pathology is pulmonary alveolar proteinosis and/or endogenous lipoid pneumonia, but the underlying cause is unknown.

2. ETIOLOGY & PATHOPHYSIOLOGY

The hemostatic system functions in concert with three major components: platelets and formed elements, plasma proteins, and the vessel wall. Coagulation is normally initiated through tissue factor (TF) exposure and activation through the classic extrinsic pathway but with critically important amplification through elements of the classic intrinsic pathway. These reactions take place on phospholipid surfaces, usually the activated platelet surface. Coagulation testing in the laboratory can reflect other influences due to the artificial nature of the in vitro systems used. The immediate trigger for coagulation is vascular damage that exposes blood to TF that is constitutively expressed on the surfaces of subendothelial cellular components of the vessel wall, such as smooth muscle cells and fibroblasts. TF is also present in circulating microparticles, presumably shed from cells including monocytes and platelets. Platelet adhesion is mediated primarily by von Willebrand factor (VWF), a large multimeric protein present in both plasma and the extracellular matrix of the subendothelial vessel wall, which serves as the primary 'molecular glue,' providing sufficient strength to withstand the high levels of shear stress that would tend to detach them with the flow of blood. Platelet adhesion is also facilitated by direct binding to subendothelial collagen through specific platelet membrane collagen receptors. Platelet adhesion results in subsequent platelet activation and aggregation. This process is enhanced and amplified by humoral mediators in plasma (e.g., epinephrine, thrombin); mediators released from activated platelets (e.g., adenosine diphosphate, serotonin); and vessel wall extracellular matrix constituents that come in contact with adherent platelets (e.g., collagen, VWF). Activated platelets undergo the release reaction, during which they secrete contents that further promote aggregation and inhibit the naturally anticoagulant endothelial cell factors. During platelet aggregation (platelet-platelet interaction), additional platelets are recruited from the circulation to the site of vascular injury, leading to the formation of an occlusive platelet thrombus. The platelet plug is anchored and stabilized by the developing fibrin mesh. The platelet glycoprotein (Gp) IIb/IIIa (αβ) complex is the most abundant receptor on the platelet surface. Platelet activation converts the normally inactive Gp IIb/IIIa receptor into an active receptor, enabling binding to fibrinogen and VWF. Because the surface of each platelet has about 50,000 Gp IIb/IIIa–binding sites, numerous activated platelets recruited to the site of vascular injury can rapidly form an occlusive aggregate by means of a dense network of intercellular fibrinogen bridges.

2.1 Coagulation Cascade

Plasma coagulation proteins (clotting factors) normally circulate in plasma in their inactive forms. The sequence of coagulation protein reactions that culminate in the formation of fibrin was originally described as a waterfall or a cascade. Two pathways of blood coagulation have been described in the past: the so-called extrinsic, or tissue factor, pathway and the so-called intrinsic, or contact activation, pathway. We now know that coagulation is normally initiated through tissue factor (TF) exposure and activation through the classic extrinsic pathway but with critically important amplification through elements of the classic intrinsic pathway. TF binds the serine protease factor VIIa; the complex activates factor X to factor Xa. Alternatively, the complex can indirectly activate factor X by initially converting factor IX to factor IXa, which then activates factor X. The participation of factor XI in hemostasis is not dependent on its activation by factor XIIa but rather on its positive feedback activation by thrombin. Thus, factor XIa functions in the propagation and amplification, rather than in the initiation, of the coagulation cascade. The role of factor XIIa in activation of factor XI is not fully elucidated, but studies suggest it may be a mechanism to promote thrombosis. Factor Xa can be formed through the actions of either the TF/factor VIIa complex or factor IXa (with factor VIIIa as a cofactor) and converts prothrombin to thrombin, the pivotal protease of the coagulation system. The essential cofactor for this reaction is factor Va, which is produced by thrombin-induced limited proteolysis of factor V. Thrombin is a multifunctional enzyme that converts soluble plasma fibrinogen to an insoluble fibrin matrix. Fibrin polymerization involves an orderly process of intermolecular associations. Thrombin also activates factor XIII (fibrin-stabilizing factor) to factor XIIIa, which covalently cross-links and thereby stabilizes the fibrin clot. The assembly of the clotting factors on activated cell membrane surfaces greatly accelerates their reaction rates and also serves to localize blood clotting to sites of vascular injury. The critical cell membrane components, acidic phospholipids, are not normally exposed on resting cell membrane surfaces. However, when platelets, monocytes, and endothelial cells are activated by vascular injury or inflammatory stimuli, the procoagulant head groups of the membrane anionic phospholipids become translocated to the surfaces of these cells or released as part of microparticles, making them available to support and promote the plasma coagulation reactions.

2.2 Antithrombotic Mechanisms

Several physiologic antithrombotic mechanisms act in concert to prevent clotting under normal circumstances. These mechanisms operate to preserve blood fluidity and to limit blood clotting to specific focal sites of vascular injury. Endothelial cells have many antithrombotic effects. They produce prostacyclin, nitric oxide, and ectoADPase/CD39, which act to inhibit platelet binding, secretion, and aggregation. Endothelial cells produce anticoagulant factors including heparan proteoglycans, TF pathway inhibitor, and thrombomodulin. They also activate fibrinolytic mechanisms through the production of tissue plasminogen activator, urokinase, plasminogen activator inhibitors, and annexin-2. Antithrombin is the major plasma protease inhibitor of thrombin and other clotting factors in coagulation. Antithrombin neutralizes thrombin and other activated coagulation factors by forming a complex between the active site of the enzyme and the reactive center of antithrombin. The rate of formation of these inactivating complexes increases by a factor of several thousand in the presence of heparin. Inherited quantitative or qualitative deficiencies of antithrombin lead to a lifelong predisposition to venous thromboembolism (VTE). Protein C is a plasma glycoprotein that becomes an anticoagulant when it is activated by thrombin. The binding of protein C to its receptor on endothelial cells places it in proximity to the thrombin-thrombomodulin complex, thereby enhancing its activation efficiency. Moreover, partial degradation of fibrin by plasmin exposes new plasminogen and tPA-binding sites in carboxy-terminus lysine residues of fibrin fragments to enhance these reactions further. This creates a highly efficient mechanism to generate plasmin locally on the fibrin clot, which then becomes plasmin's substrate for digestion to fibrin degradation products. Activated protein C acts as an anticoagulant by cleaving and inactivating activated factors V and VIII. This reaction is accelerated by a cofactor, protein S, which, like protein C, is a glycoprotein that undergoes vitamin K–dependent posttranslational modification. Quantitative or qualitative deficiencies of protein C or protein S, or resistance to the action of activated protein C by a specific variant at its target cleavage site in factor Va (factor V Leiden), lead to hypercoagulable states. Tissue factor pathway inhibitor (TFPI) is a plasma protease inhibitor that regulates the TF-induced extrinsic pathway of coagulation. TFPI inhibits the TF/factor VIIa/factor Xa complex, essentially turning off the TF/factor VIIa initiation of coagulation, which then becomes dependent on the 'amplification loop' via factor XI and factor VIII activation by thrombin. TFPI is bound to lipoprotein and can also be released by heparin from endothelial cells, where it is bound to glycosaminoglycans, and from platelets. The heparin-mediated release of TFPI may play a role in the anticoagulant effects of unfractionated and low-molecular-weight heparins.

2.3 The Fibrinolytic System

Any thrombin that escapes the inhibitory effects of the physiologic anticoagulant systems is available to convert fibrinogen to fibrin. In response, the endogenous fibrinolytic system is then activated to dispose of intravascular fibrin and thereby maintain or reestablish the patency of the circulation. Just as thrombin is the key protease enzyme of the coagulation system, plasmin is the major protease enzyme of the fibrinolytic system, acting to digest fibrin to fibrin degradation products. The plasminogen activators, tissue type plasminogen activator (tPA) and the urokinase-type plasminogen activator (uPA), cleave the Arg560-Val561 bond of plasminogen to generate the active enzyme plasmin. The lysine-binding sites of plasmin (and plasminogen) permit it to bind to fibrin, so that physiologic fibrinolysis is 'fibrin specific.' Both plasminogen (through its lysine-binding sites) and tPA possess specific affinity for fibrin and thereby bind selectively to clots. The assembly of a ternary complex, consisting of fibrin, plasminogen, and tPA, promotes the localized interaction between plasminogen and tPA and greatly accelerates the rate of plasminogen activation to plasmin. Partial degradation of fibrin by plasmin exposes new plasminogen and tPA-binding sites in carboxy-terminus lysine residues of fibrin fragments to enhance these reactions further. This creates a highly efficient mechanism to generate plasmin locally on the fibrin clot, which then becomes plasmin's substrate for digestion to fibrin degradation products. Plasmin cleaves fibrin at distinct sites of the fibrin molecule, leading to the generation of characteristic fibrin fragments during the process of fibrinolysis. The sites of plasmin cleavage of fibrin are the same as those in fibrinogen. However, when plasmin acts on covalently cross-linked fibrin, d-dimers are released; hence, d-dimers can be measured in plasma as a relatively specific test of fibrin (rather than fibrinogen) degradation. d-Dimer assays can be used as sensitive markers of blood clot formation and have been validated for clinical use to exclude the diagnosis of deep venous thrombosis (DVT) and pulmonary embolism in selected populations. d-Dimer levels increase with age. Use of an age-adjusted d-dimer threshold for risk stratification results in less additional testing for VTE. Physiologic regulation of fibrinolysis occurs primarily at three levels: (1) plasminogen activator inhibitors (PAIs), specifically PAI-1 and PAI-2, inhibit the physiologic plasminogen activators; (2) the thrombin-activatable fibrinolysis inhibitor (TAFI) limits fibrinolysis; and (3) α-antiplasmin inhibits plasmin. PAI-1 is the primary inhibitor of tPA and uPA in plasma. TAFI cleaves the N-terminal lysine residues of fibrin, which aid in localization of plasmin activity. α-Antiplasmin is the main inhibitor of plasmin in human plasma, inactivating any nonfibrin clot–associated plasmin.

3. CLINICAL FEATURES

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. Easy bruising and heavy menstrual bleeding 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 connective 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. Heavy menstrual bleeding 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 heavy menstrual bleeding 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. Heavy menstrual bleeding is a common symptom in women with underlying bleeding disorders and is reported in the majority of women with VWD, factor XI deficiency, platelet function disorders, and hemophilia, including genetic carriers with borderline-normal factor levels. Women with underlying bleeding disorders are more likely to have other bleeding symptoms, including bleeding after dental extractions and postoperative and postpartum bleeding, and are much more likely to have heavy menstrual bleeding beginning at menarche than women with heavy menstrual bleeding due to other causes. Heavy menstrual bleeding may result in iron deficiency and is documented to have significant adverse effects on quality of life. Postpartum hemorrhage is a common symptom in women with underlying bleeding disorders. In women with type 1 VWD or hemophilia A in whom levels of VWF and factor VIII often normalize during pregnancy, postpartum hemorrhage may be delayed. Women with a history of postpartum hemorrhage may have a higher risk of recurrence with subsequent pregnancies. Women with underlying bleeding disorders are at risk for other reproductive tract bleeding, including rupture of ovarian cysts with intraabdominal hemorrhage. 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, is 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 very low factor VIII levels. 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.

3.1 Medications and Supplements

Prohemorrhagic Effects of Medications and Dietary Supplements. 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 lasts for the life of the platelet; however, in individuals with typical platelet turnover, the functional defect reverts to near-normal within 2–3 days after the last dose. The effect of other NSAIDs is shorter, as the inhibitor effect is reversed when the drug is removed. Inhibitors of the ADP P2Y receptor (clopidogrel, prasugrel, and ticagrelor) inhibit ADP-mediated platelet aggregation and, like all NSAIDs, can precipitate or exacerbate bleeding symptoms. The risk of bleeding with these drugs is higher than with NSAIDs. Many herbal supplements can impair hemostatic function. 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 PGI, a more potent plate inhibitor than prostacyclin (PGI), and more thromboxane A, a less potent platelet activator than thromboxane A. 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. Many supplements have been associated with increased bleeding with surgery and anticoagulant-related bleeding. In patients with unexplained bruising or bleeding, it is prudent to review any new medications or supplements and discontinue those that have been associated with bleeding.

4. DIFFERENTIAL DIAGNOSIS

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 bleeding score has been validated as a tool to predict patients more likely to have an inherited bleeding disorder, particularly type 1 VWD (International Society on Thrombosis and Haemostasis Bleeding Assessment Tool [www.isth.org/resource/resmgr/ssc/isth-ssc_bleeding_assessment.pdf]), and a self-administered form has been validated. This is the most useful tool in excluding the diagnosis of a bleeding disorder, thus avoiding unnecessary testing, and is recommended by 2021 guidelines for screening for VWD in primary care. Bleeding symptoms that are more common in patients with bleeding disorders include prolonged bleeding with surgery, dental procedures and extractions, and/or trauma; heavy menstrual bleeding or postpartum hemorrhage; and large bruises (often described with lumps). Postpartum hemorrhage is a common symptom in women with underlying bleeding disorders. Easy bruising and heavy menstrual bleeding 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 connective 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.

4.1 Thrombosis Risk Factors

The risk of thrombosis, like that of bleeding, is influenced by both genetic and environmental factors. 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 69-2. 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. Underlying Systemic Diseases That Cause or Exacerbate a Bleeding Tendency. 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 and 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 increase the risk of bleeding in the thrombocytopenic patient. Most procedures can be performed in patients with a platelet count of 50,000/μL or greater.

Table 1 — Table 69-2 Some Risk Factors for Thrombosis

VENOUS VENOUS AND ARTERIAL
Inherited Inherited
Factor V Leiden Homocystinuria
Prothrombin G20210A Dysfibrinogenemia
Antithrombin deficiency Acquired
Protein C deficiency Malignancy
Protein S deficiency Antiphospholipid antibody syndrome
Acquired Hormonal therapy
Age Polycythemia vera
Previous thrombosis Essential thrombocythemia
Immobilization Paroxysmal nocturnal hemoglobinuria
Major surgery Thrombotic thrombocytopenic purpura
Pregnancy and puerperium Heparin-induced thrombocytopenia
Hospitalization Disseminated intravascular coagulation
Obesity Infection
Infection Unknowna
Smoking Elevated factor II, VIII, IX, XI
Elevated TAFI levels Low levels of TFPI

5. INVESTIGATIONS & DIAGNOSIS

Careful history taking and clinical examination are essential components in the assessment of bleeding and thrombotic risk. The use of laboratory tests of coagulation complements, but cannot substitute for, clinical assessment. No test exists that provides a global assessment of hemostasis. Thrombin generation assays have not generally provided reproducible results across laboratories. The bleeding time does not predict bleeding risk, and it is not recommended for this indication. Thromboelastography can be useful in guiding intraoperative transfusion and is being explored in other settings but is not broadly applicable for the diagnosis of disorders of hemostasis and thrombosis. 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 activated partial thromboplastin time (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. These 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. Screening Assays. 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. 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 69-3. 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 expressed as the International Sensitivity Index (ISI). The international normalized ratio (INR) is determined based on the formula: INR = (PT / 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. PT reagents have variable sensitivity to the direct Xa inhibitors, and the PT is usually normal in patients on apixaban. 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. 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 necessitates 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. Chromogenic assays may also be used. Testing for Antiphospholipid Antibodies. Antibodies to phospholipids (cardiolipin) or phospholipid-binding proteins (β-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) is a modification of a standard test with the phospholipid reagent decreased, thus increasing the sensitivity to antibodies that interfere with the phospholipid component. These tests, 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 increase the risk of bleeding in the thrombocytopenic patient. Most procedures can be performed in patients with a platelet count of 50,000/μL or greater.

5.1 Coagulation Test Interpretation

The relationship between defects in secondary hemostasis (fibrin formation) and coagulation test abnormalities is shown in Table 69-3. 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. Chromogenic assays may also be used.

Table 2 — Table 69-3 Hemostatic Disorders and Coagulation Test Abnormalities

Prolonged Activated Partial Thromboplastin Time (aPTT) No clinical bleeding—↓ factor XII, high-molecular-weight kininogen, prekallikrein Variable, but usually mild, bleeding—↓ factor XI, mild ↓ factor VIII and factor IX Frequent, severe bleeding—severe deficiencies of factors VIII and IX Heparin and direct thrombin inhibitors
Prolonged Prothrombin Time (PT) Factor VII deficiency Vitamin K deficiency—early Warfarin anticoagulation Direct Xa inhibitors (rivaroxaban, edoxaban, apixaban—note PT may be normal)
Prolonged aPTT and PT Factor II, V, X, or fibrinogen deficiency Vitamin K deficiency—late Direct thrombin inhibitors
Prolonged Thrombin Time Factor II, V, X, or fibrinogen deficiency Vitamin K deficiency—late Direct thrombin inhibitors

6. MANAGEMENT & TREATMENT

A common first-line approach is glucocorticoids in high doses, such as intravenous pulse methylprednisolone 30 mg/kg per dose up to a maximum of 1000 mg/dose once daily for 3–5 days followed by high-dose oral or intravenous glucocorticoids. Cyclosporin A (2–7 mg/kg/d) can be added. IL-1–blocking therapy is also effective, such as with anakinra in a dose of 2–6 mg/kg up to 10 mg/kg per day in divided doses. Experience with other immunomodulating agents, including tocilizumab, emapalumab, and ruxolitinib, is increasing. In patients with severe disease or CNS involvement despite glucocorticoids, cyclosporin A, and/or anakinra, a moderate dose of etoposide (50–100 mg/m2 once weekly) can be very effective. Other HLH-directed immunomodulatory agents, such as anakinra, may also be valuable, but results of studies on such therapies are limited. Data on treatment results are limited, but anakinra with or without glucocorticoids is suggested as first-line therapy. As second- and third-line therapy, ruxolitinib, emapalumab, and low-dose etoposide have been suggested. A two-step approach is suggested: First, target the cytokine storm and T-cell proliferation with moderately dosed etoposide (75–100 mg/m2), glucocorticoids, and possibly IVIG, and then target the neoplastic disease by specific treatment as soon as organ function has improved to an acceptable degree. Other HLH-directed immunomodulatory agents, such as anakinra, may also be valuable, but results of studies on such therapies are limited. Data on treatment results are limited, but anakinra with or without glucocorticoids is suggested as first-line therapy. As second- and third-line therapy, ruxolitinib, emapalumab, and low-dose etoposide have been suggested. Increasing use of CAR T-cell therapy and other immune effector cell-based therapies has led to an increasing number of cases with a clinical picture resembling secondary HLH that is distinct from cytokine release syndrome. This HLH-like complication is more frequent when using CD22 CAR T cells, affecting about a third of these patients. The survival and biological understanding of primary and secondary HLH have increased dramatically over the past decade(s), but much remains to be learned. Despite being life-threatening and now also treatable, HLH is still markedly underdiagnosed. Numerous lives might be saved by increased awareness of HLH.

6.1 HLH Treatment Algorithm

A two-step approach is suggested: First, target the cytokine storm and T-cell proliferation with moderately dosed etoposide (75–100 mg/m2), glucocorticoids, and possibly IVIG, and then target the neoplastic disease by specific treatment as soon as organ function has improved to an acceptable degree. Other HLH-directed immunomodulatory agents, such as anakinra, may also be valuable, but results of studies on such therapies are limited. Data on treatment results are limited, but anakinra with or without glucocorticoids is suggested as first-line therapy. As second- and third-line therapy, ruxolitinib, emapalumab, and low-dose etoposide have been suggested. In patients with severe disease or CNS involvement despite glucocorticoids, cyclosporin A, and/or anakinra, a moderate dose of etoposide (50–100 mg/m2 once weekly) can be very effective.

7. PROGNOSIS & COMPLICATIONS

The mortality rate in MAS-HLH is about 5–10% in children and 10–15% in adults. CNS involvement is frequent and may lead to irreversible neurologic damage. Early diagnosis and treatment are therefore crucial. Patients with MAS-HLH may also develop severe pulmonary disease with a high fatality rate, reported to be about 50%, for which the best treatment and prevention still is unknown. The predominant pathology is pulmonary alveolar proteinosis and/or endogenous lipoid pneumonia, but the underlying cause is unknown. The survival and biological understanding of primary and secondary HLH have increased dramatically over the past decade(s), but much remains to be learned. Despite being life-threatening and now also treatable, HLH is still markedly underdiagnosed. Numerous lives might be saved by increased awareness of HLH.

8. SPECIAL CONSIDERATIONS

Underlying Systemic Diseases That Cause or Exacerbate a Bleeding Tendency. 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 and 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 increase the risk of bleeding in the thrombocytopenic patient. Most procedures can be performed in patients with a platelet count of 50,000/μL or greater. Many supplements have been associated with increased bleeding with surgery and anticoagulant-related bleeding. In patients with unexplained bruising or bleeding, it is prudent to review any new medications or supplements and discontinue those that have been associated with bleeding.

8.1 Pregnancy and Reproductive Health

Heavy menstrual bleeding is a common symptom in women with underlying bleeding disorders and is reported in the majority of women with VWD, factor XI deficiency, platelet function disorders, and hemophilia, including genetic carriers with borderline-normal factor levels. Women with underlying bleeding disorders are more likely to have other bleeding symptoms, including bleeding after dental extractions and postoperative and postpartum bleeding, and are much more likely to have heavy menstrual bleeding beginning at menarche than women with heavy menstrual bleeding due to other causes. Heavy menstrual bleeding may result in iron deficiency and is documented to have significant adverse effects on quality of life. Postpartum hemorrhage is a common symptom in women with underlying bleeding disorders. In women with type 1 VWD or hemophilia A in whom levels of VWF and factor VIII often normalize during pregnancy, postpartum hemorrhage may be delayed. Women with a history of postpartum hemorrhage may have a higher risk of recurrence with subsequent pregnancies. Women with underlying bleeding disorders are at risk for other reproductive tract bleeding, including rupture of ovarian cysts with intraabdominal hemorrhage.

9. KEY PEARLS & CLINICAL TRAPS

A bleeding score has been validated as a tool to predict patients more likely to have an inherited bleeding disorder, particularly type 1 VWD (International Society on Thrombosis and Haemostasis Bleeding Assessment Tool [www.isth.org/resource/resmgr/ssc/isth-ssc_bleeding_assessment.pdf]), and a self-administered form has been validated. This is the most useful tool in excluding the diagnosis of a bleeding disorder, thus avoiding unnecessary testing, and is recommended by 2021 guidelines for screening for VWD in primary care. Bleeding symptoms that are more common in patients with bleeding disorders include prolonged bleeding with surgery, dental procedures and extractions, and/or trauma; heavy menstrual bleeding or postpartum hemorrhage; and large bruises (often described with lumps). Postpartum hemorrhage is a common symptom in women with underlying bleeding disorders. Easy bruising and heavy menstrual bleeding 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 connective 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. d-Dimer assays can be used as sensitive markers of blood clot formation and have been validated for clinical use to exclude the diagnosis of deep venous thrombosis (DVT) and pulmonary embolism in selected populations. d-Dimer levels increase with age. Use of an age-adjusted d-dimer threshold for risk stratification results in less additional testing for VTE. The bleeding time does not predict bleeding risk, and it is not recommended for this indication. Thromboelastography can be useful in guiding intraoperative transfusion and is being explored in other settings but is not broadly applicable for the diagnosis of disorders of hemostasis and thrombosis. 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 activated partial thromboplastin time (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. These 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.

10. WHAT TO LOOK FOR — DIAGNOSTIC CLUES

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. Heavy menstrual bleeding 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 heavy menstrual bleeding 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. Heavy menstrual bleeding is a common symptom in women with underlying bleeding disorders and is reported in the majority of women with VWD, factor XI deficiency, platelet function disorders, and hemophilia, including genetic carriers with borderline-normal factor levels. Women with underlying bleeding disorders are more likely to have other bleeding symptoms, including bleeding after dental extractions and postoperative and postpartum bleeding, and are much more likely to have heavy menstrual bleeding beginning at menarche than women with heavy menstrual bleeding due to other causes. Heavy menstrual bleeding may result in iron deficiency and is documented to have significant adverse effects on quality of life. Postpartum hemorrhage is a common symptom in women with underlying bleeding disorders. In women with type 1 VWD or hemophilia A in whom levels of VWF and factor VIII often normalize during pregnancy, postpartum hemorrhage may be delayed. Women with a history of postpartum hemorrhage may have a higher risk of recurrence with subsequent pregnancies. Women with underlying bleeding disorders are at risk for other reproductive tract bleeding, including rupture of ovarian cysts with intraabdominal hemorrhage. 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, is 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 very low factor VIII levels. 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.

11. WHAT EXCLUDES THE DIAGNOSIS

d-Dimer assays can be used as sensitive markers of blood clot formation and have been validated for clinical use to exclude the diagnosis of deep venous thrombosis (DVT) and pulmonary embolism in selected populations. d-Dimer levels increase with age. Use of an age-adjusted d-dimer threshold for risk stratification results in less additional testing for VTE. The bleeding time does not predict bleeding risk, and it is not recommended for this indication. Thromboelastography can be useful in guiding intraoperative transfusion and is being explored in other settings but is not broadly applicable for the diagnosis of disorders of hemostasis and thrombosis. 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 activated partial thromboplastin time (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. These 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.

Figures & Illustrations

Reproduced from Harrison's 22nd Edition.

Figure 1

Coagulation is initiated by tissue factor (TF) exposure, which, with...

Caption: FIGURE 69-1 Coagulation is initiated by tissue factor (TF) exposure, which, with factor which in turn, with FVIII and FV as cofactors, respectively, results in thrombin formation of fibrinogen to fibrin. Thrombin activates FXI, FVIII, and FV, amplifying the coagulation FXa complex is formed, tissue factor pathway inhibitor (TFPI) inhibits the TF/FVIIa dependent on the amplification loop through FIX/FVIII. Coagulation requires calcium (not phospholipid surfaces, usually the activated platelet membrane. — Figure 69-1 Coagulation is initiated by tissue factor (TF) exposure, which, with factor VIIa, activates FIX and FX, that in turn, with FVIII and FV as cofactors, respectively, results in thrombin formation and subsequent conversion of fibrinogen to fibrin. Thrombin activates FXI, FVIII, and FV, amplifying the coagulation signal. Once the TF/FVIIa/FXa complex is formed, tissue factor pathway inhibitor (TFPI) inhibits the TF/FVIIa pathway, making coagulation dependent on the amplification loop through FIX/FVIII. Coagulation requires calcium and takes place on physiologically on phospholipid surfaces, usually the activated platelet membrane.

Figure 2

Thrombotic risk over time

Caption: FIGURE 69-5 Thrombotic risk over time. Shown schematically is an individual’s thrombotic risk over time. An underlying factor V Leiden variant provides a “theoretically” constant increased risk. The thrombotic risk increases with age and, intermittently, with oral contraceptive (OCP) or oral hormone replacement therapy FIGURE 69-6 Coagulation factor activity tested in the activated partial (HRT) use; other events, like major surgery or illness, will increase the risk further. thromboplastin time (aPTT) in red and prothrombin time (PT) in green, or both. F, At some point, the cumulative risk may increase to the threshold for thrombosis factor; HMWK, high-molecular-weight kininogen; PK, prekallikrein. and result in deep venous thrombosis (DVT). Note: The magnitude and duration of risk portrayed in the figure are meant for example only and may not precisely reflect the relative risk determined by clinical study. (Sources: From BA Konkle, A (fibrinogen), II (prothrombin), V, VII, and X (Fig. 69-6). The PT Schafer, in DP Zipes et al [eds]: Braunwald’s Heart Disease, 7th ed. Philadelphia, measures the time for clot formation of the citrated plasma after Saunders, 2005; from FR Rosendaal: Venous thrombosis: A multicausal disease. Lancet 353:1167, 1999.) recalcification and addition of thromboplastin, a mixture of TF — Figure 69-2 Fibrin formation and dissolution. (A) Fibrinogen is a trinodular structure consisting of two D domains and one E domain. Thrombin activation results in an ordered lateral assembly of protofibrils (B) with noncovalent associations. Factor XIIIa cross-links the D domains on adjacent molecules (C). Fibrin and fibrinogen lysis by plasmin occurs at discrete sites and results in intermediary fibrin(ogen) degradation products (not shown). d-Dimers are the product of complete lysis of fibrin (D), maintaining the cross-linked D domains.

Figure 3

The plasminogen activators, tissue type plasminogen activator FIGURE 69-2 Fibrin...

Caption: The plasminogen activators, tissue type plasminogen activator FIGURE 69-2 Fibrin formation and dissolution. (A) Fibrinogen is a trinodular structure consisting of two D domains and one E domain. Thrombin activation results in an (tPA) and the urokinase-type plasminogen activator (uPA), cleave the ordered lateral assembly of protofibrils (B) with noncovalent associations. Factor Arg560-Val561 bond of plasminogen to generate the active enzyme XIIIa cross-links the D domains on adjacent molecules (C). Fibrin and fibrinogen plasmin. The lysine-binding sites of plasmin (and plasminogen) permit (not shown) lysis by plasmin occurs at discrete sites and results in intermediary it to bind to fibrin, so that physiologic fibrinolysis is “fibrin specific.” fibrin(ogen) degradation products (not shown). d-Dimers are the product of Both plasminogen (through its lysine-binding sites) and tPA possess complete lysis of fibrin (D), maintaining the cross-linked D domains. specific affinity for fibrin and thereby bind selectively to clots. The assembly of a ternary complex, consisting of fibrin, plasminogen, and for thrombin on endothelial cell surfaces. The binding of protein C to tPA, promotes the localized interaction between plasminogen and tPA — Figure 69-5 Thrombotic risk over time. Shown schematically is an individual's thrombotic risk over time. An underlying factor V Leiden variant provides a 'theoretically' constant increased risk. The thrombotic risk increases with age and, intermittently, with oral contraceptive (OCP) or oral hormone replacement therapy (HRT) use; other events, like major surgery or illness, will increase the risk further. At some point, the cumulative risk may increase to the threshold for thrombosis and result in deep venous thrombosis (DVT).

Generated from Harrison's Principles of Internal Medicine, 22nd Edition.