A physiologic host defense mechanism, hemostasis focuses on arrest of bleeding by forming hemostatic plugs composed of platelets and fibrin at sites of vessel injury. In contrast, thrombosis reflects a pathologic process associated with intravascular thrombi that occlude the lumens of arteries or veins. Disorders are typically caused by disruption of one of the three axes of Virchow’s triad: the vasculature, blood flow, or hypercoagulability of the blood. These processes are inter dependent and integrated, and their dysregulation leads to immunothrombosis.
Hemostatic Disorders
Bleeding can occur if there is abnormal platelet plug formation and/ or reduced thrombin generation and subsequent fibrin clot formation at the site of vascular injury, disorders of primary and secondary hemostasis, respectively. Bleeding also can occur if the platelet/ fibrin clot is prematurely degraded because of excessive fibrinolysis; a disorder of tertiary hemostasis. The features distinguishing disorders of primary, secondary, and tertiary hemostasis are outlined in Table 1. Hemorrhagic disorders can be inherited or acquired, and the clinical and laboratory evaluation of such disorders is detailed in Chapters 126 and 127, respectively.
Table1. Comparison of the Features of Disorders of Primary, Secondary, or Tertiary Hemostasis
Disorders of Primary Hemostasis
Platelet plug formation, the first step in the arrest of bleeding at sites of injury, requires three key components: (a) an adequate number of functional platelets, (b) vWF, the molecular glue that mediates plate let adhesion to the damaged vessel wall even in the face of high shear, and (c) a normal blood vessel that constricts in response to injury (Table2). Because the platelet plug provides the first line of defense against bleeding, patients with disorders of primary hemostasis often present with immediate bleeding after injury, and petechiae (pinpoint hemorrhages) may be noted. In addition to skin bleeding, mucocutaneous bleeding, which may manifest as epistaxis, bleeding gums, or hematochezia, is common as is excessive menstrual bleeding in women.
Table2. Disorders of Primary Hemostasis
Disorders of primary hemostasis may be inherited or acquired. Thrombocytopenia, or congenital or acquired disorders of platelet function, are common causes of bleeding. Thrombocytopenia can be the result of decreased production, which can occur because of failure, infiltration, or fibrosis of the bone marrow, increased platelet destruction, or abnormal distribution because of platelet pooling in the spleen . Increased destruction of platelets can occur via immune mechanisms, such as immune thrombocytopenic purpura (ITP), alloimmune thrombocytopenia, posttransfusion purpura, and drug-induced thrombocytopenia including heparin-induced thrombocytopenia, or nonimmune mechanisms, which include microangiopathic disorders, such as thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, as well as consumption because of activation of coagulation, such as occurs with disseminated intravascular coagulation.
Platelet function disorders include disorders of platelet (a) adhesion, such as von Willebrand disease and Bernard-Soulier syndrome; (b) thromboxane synthesis; (c) secretion, such as alpha or dense granule deficiency, or aspirin-like secretion defects; (d) aggregation, such as Glanzmann thrombasthenia; or (e) procoagulant activity (Scott syndrome) where the platelets fail to support clotting factor complex assembly. Acquired disorders of platelet function can occur in patients taking drugs that impair platelet function, such as aspirin or nonsteroidal anti-inflammatory drugs, or in patients with uremia, paraproteins, myelodysplastic, or myeloproliferative disorders .
Bleeding can also occur with inflammation or malformations of the blood vessels, or abnormalities of the connective tissue sup porting the blood vessels. Inflammatory disorders include Henoch Schonlein purpura and the vasculitis that occurs with paraproteins or cryoglobulins, or in patients with systemic lupus erythematosus or other immune disorders. Hereditary hemorrhagic telangiectasia is an inherited disorder associated with malformations of the capillaries. Telangiectatic vessels can often be seen in the oral and nasal cavities of patients with this disorder and bleeding episodes, primarily from the nose and gastrointestinal tract, are common. Abnormalities of the connective tissue matrix supporting the blood vessels include Marfan syndrome, Ehlers-Danlos syndrome, and pseudoxanthoma elasticum. Patients with these disorders frequently report easy bruising.
Disorders of Secondary Hemostasis
Secondary hemostasis depends on rapid generation of sufficient amounts of thrombin to generate a fibrin mesh that not only con solidates the platelet aggregates that form at sites of vascular injury, but also is stable enough to provide a barrier that prevents leakage of blood from the damaged blood vessel. Secondary hemostasis can be compromised by (a) impaired thrombin generation because of con genital or acquired deficiencies of coagulation factors or cofactors or intake of drugs that inhibit one or more steps in the coagulation pathways, (b) congenital or acquired fibrinogen deficiency or dysfunction, and/or (c) impaired cross-linking of fibrinogen because of congenital or acquired deficiency of factor XIII (Table 3).
Table3. Disorders of Secondary Hemostasis
Examples of inherited deficiencies of coagulation factors include hemophilia A and B, deficiencies of factor VIII and factor IX, respectively. Because of redundancy in the coagulation system, only patients with a factor VIII or factor IX level less than 1% have severe disease characterized by spontaneous bleeding or bleeding with minimal trauma. Those with factor levels between 1% and 5% have an intermediate phenotype, whereas patients with factor VIII or IX levels above 5% usually have mild disease and bleed only with trauma or surgery. The frequency of bleeding episodes in patients with severe hemophilia can be reduced with prophylactic administration of the appropriate factor concentrate; such treatment is also administered to hemophiliacs with overt bleeding, or in preparation for surgery or other major interventions. Long-lasting factor VIII and IX molecules have been developed to reduce the frequency of factor replacement. The half-lives of these recombinant full-length or truncated proteins have been prolonged by conjugating them to hydrophilic polymers such as polyethylene glycol, or by fusing them with albumin or the Fc fragment of IgG1. Conjugation to polyethylene glycol protects the proteins from proteolytic degradation, whereas fusion technology creates new recycling pathways that diminish natural protein break down. Management of hemophilia becomes more complicated if patients develop inhibitory antibodies that attenuate or abolish the activity of the infused factor. Emicizumab, the first synthetic clotting factor, is a bispecific antibody that bypasses factor VIII by binding to factor IXa and bridging it to factor X. Emicizumab is now used for treatment of hemophilia A in patients with or without inhibitors.
Congenital deficiencies of prothrombin (factor II), factors V, VII, X, or XI (hemophilia C), or fibrinogen are less common causes of bleeding (see Chapter 135). In contrast, deficiencies of components of the contact pathway—factor XII, high-molecular-weight kininogen, and prekallikrein—are not associated with bleeding.
Acquired deficiencies of coagulation factors can result from decreased synthesis due to severe liver disease, vitamin K deficiency or intake of drugs that interfere with vitamin K metabolism, consumption because of excessive activation of coagulation (e.g., disseminated intravascular coagulation), or accelerated clearance due to adsorption by paraproteins or amyloid, or to autoantibodies that shorten the half-life, attenuate, or abolish clotting factor activity.
Congenital disorders of fibrinogen include absence or low levels of fibrinogen (afibrinogenemia and hypofibrinogenemia, respectively), or synthesis of a dysfunctional protein (dysfibrinogenemia). Acquired disorders of fibrinogen include decreased synthesis or production of an abnormal fibrinogen, increased fibrinogen consumption or the presence of inhibitors that interfere with fibrin polymerization, such as paraproteins, autoantibodies, particularly in patients with systemic lupus erythematosus or other immune disorders or elevated levels of fibrin(ogen) degradation products.
Stabilization of fibrin requires cross-linking of the α and γ chains of adjacent fibrin monomers to yield a polymer that is resistant to pre mature breakdown. Factor XIIIa performs this function by catalyzing the condensation of lysine residues on one chain with glutamic acid residues on another chain. Congenital or acquired deficiency of fac tor XIII can impair cross-linking, resulting in bleeding. The hallmarks of severe factor XIII deficiency include umbilical stump bleeding in the neonatal period, intracranial hemorrhage with little or no trauma, recurrent soft tissue hemorrhages, and, in females, recurrent spontaneous miscarriages.
Disorders of Tertiary Hemostasis
Tertiary hemostasis depends on the generation of plasmin, which degrades fibrin and restores blood flow in damaged vessels. Premature lysis of fibrin in hemostatic plugs can lead to bleeding; this can occur systemically or can be localized (Table 4). Systemic fibrinolysis that occurs in the absence of activation of coagulation, the so-called primary hyperfibrinolysis, is rare but can occur with inherited deficiency of PAI-1 or α2-antiplasmin, the inhibitors of the plasminogen activators and plasmin, respectively, advanced liver disease, and some snakebites. More commonly, systemic hyperfibrinolysis is secondary to activation of coagulation by procoagulants such as tissue factor (e.g., in patients with metastatic cancer) or artificial surfaces (e.g., in cardiopulmonary bypass surgery or with cardiac assist devices). Examples of localized hyperfibrinolysis include menorrhagia or hematuria after prostatectomy triggered by excessive plasmin generation induced by the high concentrations of t-PA and u-PA in the uterus and genitourinary tract, respectively.
Thrombotic Disorders
Thrombosis may occur in arteries, in the chambers of the heart, or in the veins. Factors contributing to thrombosis in these sites include endothelial injury or activation, reduced blood flow, and hypercoagulability of the blood, the so-called Virchow triad.
Arterial Thrombosis
Most arterial thrombi occur on top of disrupted atherosclerotic plaques. Plaques with a thin fibrous cap and a lipid-rich core are most prone to disruption. Erosion or rupture of the fibrous cap exposes thrombogenic material in the lipid-rich core to the blood, and triggers platelet activation and thrombin generation. The extent of plaque disruption and the content of thrombogenic material in the plaque determine the consequences of the event, regardless of whether it occurs in the cerebral circulation, the coronary circulation, or the major arteries of the legs, but host factors also contribute. Breakdown of regulatory mechanisms that limit platelet activation and inhibit coagulation can augment thrombosis at sites of plaque disruption.
Decreased production of nitric oxide and prostacyclin by diseased endothelial cells can trigger vasoconstriction and platelet activation. Proinflammatory cytokines lower thrombomodulin expression by endothelial cells, thereby sustaining thrombin generation, and stimulate PAI-1 expression, which inhibits fibrinolysis.
Products of blood coagulation contribute to atherogenesis, as well as its complications. Microscopic erosions in the vessel wall trigger the formation of tiny platelet-rich thrombi. Activated platelets release PDGF and TGF-β, which promote a fibrotic response. Thrombin generated at the site of injury not only activates platelets and converts fibrinogen to fibrin, but also activates PAR-1 on smooth muscle cells and induces their proliferation, migration, and elaboration of extracellular matrix. Incorporation of thrombi into plaques promotes plaque growth, and decreased endothelial cell production of heparan sulfate that normally limits smooth muscle proliferation contributes to plaque expansion.2 The multiple links between atherosclerosis and thrombosis have prompted the term atherothrombosis.
Intracardiac Thrombosis
Thrombi can form in the left ventricle after transmural myocardial infarction or with an aneurysm or dyskinetic ventricle, or in the left atrial appendage, particularly in patients with atrial fibrillation. Damage to the endothelium after myocardial infarction and abnormal blood flow are the major triggers for left ventricular thrombus formation. With rapid atrial fibrillation, there also is stasis and turbulent blood flow in the left atrial appendage, which is a long, blind-ended trabeculated pouch. This may lead to localized activation of endothelial cells and subsequent loss of their anticoagulant phenotype, a process amplified by adhesion of leukocytes and subsequent elaboration of proinflammatory cytokines. The generation of thrombin creates a local hypercoagulable state that likely promotes thrombus formation on the abnormal endothelium. Embolization of these thrombi to the brain is a common cause of ischemic stroke and the major cause of mortality and morbidity in patients with atrial fibrillation.
Venous Thrombosis
The causes of venous thrombosis include those associated with hypercoagulability, which can be genetic or acquired, and the mainly acquired risk factors, such as advanced age, obesity, or cancer, which are associated with immobility. Inherited hypercoagulable states and these acquired risk factors combine to establish the intrinsic risk of thrombosis for each individual.38 Superimposed triggering factors, such as surgery, pregnancy, or hormonal therapy, modify this risk, and thrombosis occurs when the combination of genetic, acquired, and triggering forces exceed a critical threshold.
Some acquired or triggering factors entail a higher risk than others. For example, major orthopedic surgery, neurosurgery, multiple trauma, and metastatic cancer (particularly adenocarcinoma) are associated with the highest risk; prolonged bed rest, antiphospholipid antibodies (see Chapter 139), and the puerperium are associated with an intermediate risk; whereas pregnancy, obesity, long-distance travel, or the use of oral contraceptives or hormonal replacement therapy are mild risk factors. Up to half of the patients who present with venous thromboembolism before the age of 45 have inherited hyper coagulable disorders—so-called thrombophilia — particularly those whose event occurred in the absence of risk factors or with minimal provocation, such as after minor trauma or a long haul flight or with estrogen use.
