Epidemiology

Under normal physiologic conditions, a constant balance exists between clot formation and clot breakdown, with a preference favoring anticoagulation.¹ Hemostasis results from a complex interaction among the vascular endothelium, platelets, the coagulation cascade, and the fibrinolytic system. Any disorder that affects this interplay can alter the equilibrium, thereby producing either excessive thrombosis or excessive hemorrhage.

Broadly speaking, bleeding disorders can be either inherited or acquired. Of the inherited disorders, the von Willebrand syndromes and hemophilia A are the most common, with a prevalence between 1 per 100 individuals and 1 per 100,000 individuals. Less common inherited disorders include deficiencies of factors II, V, VII, X, XIII, and fibrinogen, with a prevalence between 1 and 2 per 100,000 individuals.² The most common acquired bleeding disorders are drug induced, from therapeutic administration of agents expressly intended to decrease the risk of thrombosis. Oral anticoagulants are taken by up to 2% of the population and up to 8% of persons more than 65 years old, and the use of antiplatelet agents is vastly more common than that.³ Patients with inherited bleeding disorders will likely present to the emergency department (ED) for treatment of abnormal bleeding at some point during their lifetime,⁴ and ED visits for bleeding in patients who are taking antithrombotic agents are not uncommon.⁵ The clinician must be familiar with these disease states to provide prompt care because treatment delays can increase morbidity and mortality.^4,⁶

Physiology and Biology of Hemostasis

Coagulation Cascade

The coagulation cascade (Fig. 206.1) is typically thought of as two pathways working separately. In reality, however, the tissue factor pathway (formerly called the extrinsic system) and the contact activation pathway (formerly called the intrinsic system) function intimately with each other to produce thrombin, a critical enzyme in the coagulation system.^1,⁷

Fig. 206.1 Coagulation cascade.

Tissue factor typically resides on smooth muscle cells, fibroblasts, and pericytes.⁸^–¹⁰ Binding of tissue factor to factor VII results in an activated factor VII (factor VIIa). Factor VIIa subsequently catalyzes the conversion of factors IX and X to their active forms (factors IXa and Xa, respectively).

The contact activation pathway begins with the activation of factor XII by the high-molecular-weight enzymes kininogen and prekallikrein.¹ This activation subsequently triggers a series of reactions leading to the conversion of X to Xa, the first step of the common pathway. The exact relevance of the contact activation pathway is debatable, however, because its activation is not needed in trauma-initiated coagulopathy.¹ Furthermore, with the exception of a deficiency of factor XI, deficiencies in enzymes involved in the contact activation pathway generally do not produce substantial coagulopathies.¹

The common pathway starts with the conversion of factor X to Xa, which, in turn, converts prothrombin to thrombin. Ultimately, thrombin catalyzes the conversion of fibrinogen to fibrin.

Platelet Function

Following injury to the vascular endothelium, endothelin is released, resulting in vasoconstriction. In addition, injury to the vascular endothelium results in tissue factor exposure, with subsequent binding of platelets to the endothelium.^8,¹⁰ Platelet adhesion primarily involves the binding of platelets to damaged endothelium by von Willebrand factor (vWF).^11,¹² Additional platelet activation occurs through the release of numerous mediators including adenosine diphosphate (ADP), epinephrine, thromboxane A₂, and thrombin.¹¹ Ultimately, platelet activation and aggregation require glycoprotein IIb/IIIa.¹¹ Thrombus stability, however, requires fibrin, which is formed from the coagulation cascade on the surface of platelets.¹¹

Presenting Signs and Symptoms

The optimal management of the patient with a bleeding disorder involves, as always, aggressive resuscitative measures (e.g., focus on ensuring adequate airway, breathing, and circulation). However, those patients with bleeding disorders also require specific therapies targeted toward the underlying disease state. Diagnostic laboratory tests and factor or product replacement should be administered on an individualized basis.

A careful history must be obtained from the patient, including the exact nature of the bleeding disorder, if known. A history regarding xenobiotic usage and past bleeding episodes should be obtained, including a history of previous bleeding with mild procedures (e.g., prolonged bleeding following tooth extractions), menstrual history (e.g., particular heavy or prolonged bleeding), and prior transfusion history. In addition, the clinician should question the patient regarding current bleeding, including the presence of dermal (petechiae, purpura, or ecchymosis), gastrointestinal (melena, hematochezia, or hematemesis), genitourinary (hematuria), mucosal membrane (gingival or epistaxis), and musculoskeletal (hemarthrosis) hemorrhage.

Differential Diagnosis and Medical Decision Making

The initial assessment of a patient with a known or suspected bleeding disorder begins with a thorough history and physical examination. Laboratory studies can be used to assess the severity of the disorder and to support a diagnosis. The initial laboratory studies that should be obtained when evaluating such patients include a complete blood count, prothrombin time (PT; a measure of the tissue factor pathway), and an activated partial thromboplastin time (aPTT; a measure of the contact activation pathway). A fibrinogen count can also assist in the initial management. These laboratory tests can help screen for clinically significant factor deficiencies, such as hemophilia A or B, as well as hypofibrinogenemic states. Additional tests may be indicated, depending on the condition of interest. For example, the concentration of D-dimers may be helpful in establishing the diagnosis of disseminated coagulation (DIC), whereas factor concentrations may be useful in assessing the severity of hemophilia. Patients with acute fulminant hepatic failure may demonstrate abnormalities similar to those seen in DIC. In such cases, factor V, VII, and VIII levels can be obtained. Although factor V levels are likely to be decreased in both DIC and liver failure, factor VIII levels are normal or elevated in liver failure–induced coagulopathy, yet markedly decreased in DIC-induced coagulopathy. Factor VII levels are also reduced in coagulopathy resulting from hepatic failure. Mixing studies can be performed to determine whether a factor deficiency or inhibitor is present in patients with prolonged aPTT.¹³ Examination of the peripheral blood film can be very helpful in patients with unexplained bleeding disorders.

Coagulation Cascade Defects

Hereditary Defects

Hemophilia A and B

Hemophilia A and hemophilia B are X-linked recessive disorders involving factors VIII and IX, respectively. Clinically, hemophilia B is indistinguishable from hemophilia A. However, nearly half of all cases of hemophilia A, the most common form of hemophilia, represent de novo mutations, in which boys are born to parents without the disease.¹ These disorders can be classified as mild, moderate, or severe, corresponding to a plasma coagulation factor concentration of 6% to 30%, 2% to 5%, or 1% or lower, respectively.¹⁴ Those patients with a mild form of the disease generally have bleeding only after trauma or surgery. In contrast, patients with the severe form of the disease have an average of 20 to 30 bleeding episodes annually, and bleeding occurs spontaneously or after minor trauma.¹⁴ Hemarthrosis is one of the most common forms of bleeding in severe forms of hemophilia.¹ Historically, treatment involved transfusions of plasma concentrates of coagulation factors.¹⁴ However, such an approach was associated with the acquisition of numerous infectious diseases, including human immunodeficiency virus infection or hepatitis, as well as the development of inhibitors to the clotting factors.^14,¹⁵ Now, both plasma and recombinant-derived factor VIII and IX exist. Treatment can be administered as an on-demand regimen, in which therapy is given based on bleeding, or in a prophylactic regimen. Because the plasma half-life of factor IX is longer than of factor VIII (18 to 24 hours versus 8 to 12 hours), dosing of factor replacement is less frequent for hemophilia B than for hemophilia A.¹⁶ Table 206.1 shows a common treatment regimen. Minor bleeding requires factor replacement to achieve factor concentrations of 30% of normal (typically 30 units/kg). In contrast, major hemorrhagic events, including hemarthrosis and large muscle bleeding, requires factor replacement to achieve factor concentrations of at least 50% (typically 50 units/kg). Life-threatening hemorrhage requires factor replacement to achieve factor concentrations of at least 80% (typically 80 units/kg).¹⁶ In general, each unit per kilogram of body weight of factor VIII increases plasma factor VIII concentrations by 2%, whereas each unit per kilogram of body weight of factor IX increases plasma factor IX concentrations by 1%.¹⁶ In patients with life-threatening bleeding, however, in vivo factor concentrations should be followed to ensure adequate replacement. When patients with hemophilia A have developed inhibitors to factor VIII, recombinant factor VIIa (rFVIIa) (90 mcg/kg) has been used.⁴

Table 206.1 Common Treatment Strategics for coagulopathies *

	TREATMENT OPTIONS	NOTES
Disease-Induced Coagulopathy
Factor V deficiency	FFP
Factor VIII deficiency	Recombinant factor VIIIa	1 U/kg IV increases plasma factor VIII concentrations by 2%. A typical dose will be 40 U/kg for severe bleeding.
Factor VIII deficiency	Recombinant factor VIIa can be used for those with inhibitors to factor VIII	90 mcg/kg IV
Factor IX deficiency	Recombinant factor IXa	1 U/kg IV increases plasma factor IX concentrations by 1%. A typical dose will be 80 U/kg for severe bleeding.
Factor X deficiency	FFP or PCC
Factor XI deficiency	FFP
von Willebrand disease	DDAVP Aminocaproic acid Tranexamic acid	0.3 mcg/kg IV 50-60 mg/kg IV q4-6h 10-15 mg/kg IV q8-12h
Congenital fibrinogen disorders	FFP Cryoprecipitate Fibrinogen concentrates†
Coagulopathy of trauma	FFP Platelets
Disseminated intravascular coagulation	Cryoprecipitate Platelets	Primary treatment is to treat the underlying cause
Transfusion-related coagulopathy	FFP Platelets
Drug/toxin–Induced Coagulopathy
Heparin	Protamine	1 Unit reverses 100 U UFH
Factor Xa inhibitors	rFVIIa FFP	90 mcg/kg IV
Warfarin	Vitamin K, FFP, PCC
Crotalid envenomation	Crotalidae polyvalent immune Fav (ovine); CroFab