Hemophilia, one of the oldest known genetic disorders, can be classified into types A, B, or C. Hemophilia A (congenital factor VIII deficiency) is the most common form, accounting for 85% of all patients with hemophilia. It involves reduced protein levels related either to reduced protein synthesis or accelerated clearance related to a neutralizing acquired factor VIII inhibitor (i.e., either related to exposure to animal sources of factor VIII or
spontaneous development of an autoantibody to factor VIII that occurs in 1:1,000,000 individuals). It is an X-linked recessive disorder and therefore occurs predominately in men and on occasion in homozygous women. Approximately 30% of patients have no family history of this disease; presumably, their disease is caused by a new somatic mutation that results in reduced hepatic protein synthesis. The clinical disease severity (i.e., bleeding diathesis) generally directly correlates both with the factor VIII activity level as well as the presence and efficacy of a neutralizing inhibitor. Patients with less than 1% activity generally express a severe form of the disease, which may manifest as spontaneous bleeding into joints, muscles, and vital organs and involve life-threatening bleeding events (e.g., central nervous system [CNS], retroperitoneum). Patients with between 6% and 40% activity generally have mild disease and may go undiagnosed until they face hemostatic stress. A screening test for hemophilia A is the activated partial thromboplastin time (aPTT), which will be prolonged in all patients except those with mild disease depending on the sensitivity of the coagulation methods/reagents used. Measuring factor VIII activity will generally provide a diagnosis, but reproducibly normal levels do not exclude carrier status because factor VIII concentrations may become elevated in times of stress. Genetic testing provides a definitive diagnosis in the setting of an inherited disorder of protein synthesis.

Patients with hemophilia B present with either deficient or defective factor IX; this entity represents approximately 14% of hemophilia patients. This X-linked genetic disorder has an inheritance pattern and clinical features that are similar to those of hemophilia A but can be diagnosed by measuring both the concentration and function of factor IX. Factor IX is a vitamin K-dependent factor.

The remaining 1% of hemophiliac patients have a deficiency in factor XI and is classified as hemophilia C, an autosomal disorder that is extremely rare except in Ashkenazi Jews. Hemophilia C can be distinguished from A and B by the absence of bleeding into joints and muscles. In addition, the degree of factor XI deficiency may not predict a patient’s bleeding tendency in the postoperative period.

vWD is the most common congenital bleeding disorder; it is characterized by either protein deficiency and/or defects in von Willebrand factor (vWF). vWF plays a role in hemostasis by catalyzing the binding of platelets to the subendothelium (i.e., via glycoprotein [GP] Ib receptors) or to other platelets (i.e., via GP IIb/IIIa receptors) and additionally acting as the predominate carrier for factor VIII. vWF is synthesized by endothelial cells, but there is substantial posttranslational modification of the protein monomers within the Golgi apparatus that leads to high molecular weight (HMW) and very high molecular weight (VHMW) forms that have the highest capacity to activate platelets. The most common form of the disease (i.e., type 1) is inherited as an autosomal dominant trait and has an incidence cited as high as 2% to 3% of northern European populations while probably is 0.1% in the general population. Patients with vWD can have a prolonged bleeding time (BT), which is rarely performed, as well as other test abnormalities (e.g., increased aPTT or prolonged platelet function analyzer [PFA]-100 values). vWD manifests clinically as bruising, epistaxis, mucocutaneous bleeding, and menorrhagia in women. Because vWD is an assortment of various forms (e.g., type 1, 2, and 3 as outlined in Table 31.1), there is frequently heterogeneity in its clinical manifestations and relative risk of bleeding. The diagnosis may be suggested by the patient’s history of a bleeding diathesis and the presence of a prolonged BT, prolonged aPTT (i.e., in 50% of patients), or abnormal PFA-100 result despite a normal platelet count and no drug effect. Laboratory analysis is useful for classifying the types and subtypes of vWD to guide therapy. Acquired forms of vWD have also been described, associated with lymphoproliferative disease, tumors, cardiac valvular lesions, as well as others. Six different
vWD types and subtypes exist (type 1, type 2A, type 2B, type 2N, type 2M, and type 3). Type 1 and type 3 represent quantitative deficiency of normal vWF related to either modest (type 1) or severe (type 3) reductions in vWF levels due to reduced synthesis. Type 2 includes qualitative defects that are subdivided based on the levels and function of HMW forms of vWF and the corresponding mechanistic defects on platelet adhesion, platelet activation/aggregation, or factor VIII binding. Type 1 vWD represents most afflicted patients (e.g., 85%) and is marked by decreased levels of normal vWF. First-line treatment for type 1 disease is with desmopressin (L-deamino-8-D-arginine-vasopressin [DDAVP]). DDAVP has been shown to frequently normalize vWF and factor VIII levels due to release of vWF from the endothelium as well as other hemostatic factors (i.e., tissue plasminogen activator [tPA], prostacyclin, etc.). Type 2A vWD represents 15% to 30% of type 2 patients and is a qualitative defect in platelet-vWF platelet adhesion. Accordingly, vWF protein levels can be normal, but the absence of HMW vWF multimers results in reduced platelet activation, as reflected by reduced ristocetin induced cofactor activity. Type 2B vWD represents that subset of patients with enhanced affinity for platelet GP Ib, related to a structural abnormality in HMW forms of vWF that result in a more pronounced degree of platelet activation leading to spontaneous platelet aggregation and resultant thrombocytopenia. In these patients, thrombocytopenia may be aggravated by administration of desmopressin. Subtype 2B can be assessed by evaluating the exaggerated response to an antibiotic ristocetin, which stimulates the binding of vWF to platelet GP Ib and resultant platelet aggregation. In the absence of HMW forms of vWF, no agglutination will occur with the ristocetin cofactor activity assay. In type 2N, there is a decreased affinity of vWF for factor VIII based on the absence of the factor VIII binding receptors on vWF. These patients are often misdiagnosed as having hemophilia A. In type 2M, there is a decrease in vWF-dependent platelet adhesion due to an abnormality of HMW multimers. Type 3 vWD is inherited in a recessive fashion and represents virtually complete absence of vWF, and many of these patients die in utero on within a few days after birth. DDAVP is not beneficial in type 3 because these patients have no endogenous production of vWF. Type 2B and type 3 are extremely rare. It is important to distinguish the subtypes of vWD because the use of DDAVP in type 2B may cause worsening of the degree of thrombocytopenia. DDAVP does not increase vWF in type 3 because there are no stores of vWF in endothelial cells.

Binding of factor VIII to vWF is required for optimal factor VIII survival and for transport of factor VIII to areas of endothelial injury to enable approximation with factor IX (i.e., the factor VIII and IX complex leads to activation of factor X on the platelet surface). Factor VIII is one of the largest and least stable coagulation factors. It forms a noncovalent complex with vWF. By binding factor VIII, vWF reduces the inactivation of factor VIII by protein C. The half-life of factor VIII is about 2 hours in the absence of vWF. vWF only binds factor VIII prior to cleavage by thrombin to activated factor VIII (fVIIIa). Although vWF is important in maintaining adequate levels of factor VIII, less than 10% of vWF multimers bind factor VIII.

Platelet adhesion occurs via interaction of collagen-bound HMW vWF at subendothelial sites of injury with platelet GP Ib-V-IX and platelet GP VI. Not only does GP VI play a role in adhesion, but it is also the major agonist for initial platelet activation and granule release. Platelet activation via collagen is independent of thrombin activation. Tissue factor (TF) is another stimulus for activation of platelets that are exposed to vascular subendothelium. When platelets are activated to a certain threshold, the release reaction ensues which involves release of alpha and dense granule contents (i.e., thromboxane A2 and adenosine diphosphate [ADP]), which are agonists for expression of additional surface receptors for further platelet activation and ultimately aggregation. Platelet aggregation involves cross-linking of platelets to each other (clumping) using the critical GP IIb/IIIa receptors that are bound by either vWF or fibrinogen. The degree of platelet aggregation is also influenced by varying shear rates in vascular beds and more importantly the local concentration of thrombin.

The small size of platelets relative to other blood components, such as red or white cells, results in their slower transit in the blood vessel with resultant margination. Platelet diffusivity or margination is the process in which the faster moving, larger cellular components within blood push the platelets toward the walls of the blood vessel; accordingly, in the setting of anemia, reduced margination of platelets may result in a lower concentration of platelets in close proximity to the vessel wall. As a result of margination, platelets are in contact with the surface of the blood vessel and can immediately respond to potential endothelial defects. Any endothelial break exposes platelets to subendothelial structures, including collagens and other proteins that activated the hemostatic system (e.g., TF), which promote adhesion between GP Ib receptors on platelets to the subendothelium as well as generation of thrombin. In addition to the generation of thrombin, platelet adhesion also initiates platelet activation, in which the shape of the platelet is altered and the contents of the cytoplasmic granule are
released. The substances inside the alpha and dense granules include factors such as ADP and serotonin, and factor Va, which further promote platelet activation and aggregation. The platelet plug formed in this process provides initial hemostasis. The degree of platelet activation, release, and ultimate aggregation is in large part predicated by the concentration of thrombin (IIa) in the local milieu. The final stage of platelet plug formation is driven by IIa mediated expression of IIb/IIIa receptors that enables fibrinogen (fibrin) and vWF to crosslink platelets (aggregation). Thrombin also converts fibrinogen to fibrin to strengthen the platelet matrix. Finally, activation of factor XIII produces cross-polymerization of the loose fibrin to produce a firm and stable platelet—coagulation factor cross-linked matrix resulting in a clot.

Localization of coagulation and control of primary/secondary hemostasis are controlled by many factors. Circulating heparin or endothelial glycosaminoglycans and low levels of thrombin can result in release of tissue factor pathway inhibitor (TFPI) which inhibits TF activation of factor X. Additionally, lower levels of factor IIa result in activation of protein C (along with its cofactor protein S) which inactivate activated factors Va and VIIIa along the endothelium via thrombomodulin, which along with other coagulation inhibiting substances are present on the intact endothelial glycocalyx. The heparin-antithrombin complex binds and inhibits activated clotting factors, including factors XIIa, XIa, IXa, Xa, and IIa. Finally, the intact endothelial surface secretes many mediators, which have a platelet-inhibiting (e.g., triphosphate dephosphorylases, prostacyclin or PGI2, nitric oxide) or clot-lysing effect (e.g., tPA). tPA initiates the physiologic process of fibrinolysis and digests factors V/VIII and fibrinogen and fibrin resulting in fibrin degradation (split) products (fibrin split products [FSPs]) and D-dimers (cross-linked fibrin), respectively, which are removed by the liver via mononuclear phagocyte system. Accumulation of these by-products (FSPs and D-dimer) in the setting of substantial liver dysfunction can lead to abnormal hemostasis secondary to platelet dysfunction.

After an extended period of time, when normal blood is placed in an empty test tube, a clot will form without adding any agents. The clotting factors involved in this process were originally classified as the “intrinsic” factors because everything necessary for blood to clot was “intrinsic” to the test tube. The “extrinsic” path is another potent stimulus for thrombin formation and is initiated by exposure of tissue thromboplastin (TF) to factor VIIa. The extrinsic and intrinsic pathways converge as the both result in activation of factor X to form the common pathway.

This classic separation of procoagulant factors into extrinsic, intrinsic, and common coagulation cascades, although a convenient framework, is not necessarily the most ideal way to describe the hemostatic system because of the crosstalk of many factors other than coagulation proteins (e.g., endothelium, platelets, and leukocytes). In fact, the current paradigm of coagulation uses a cell-based model and takes into account many in vivo pathways and, importantly, the contribution of the endothelium and the cellular components. Although the classic intrinsic and extrinsic coagulation pathways do lead to the formation and activation
of thrombin (and hence the amplification of coagulation), its failure to take into account the cellular components, which play a vital role in hemostasis, limits their usefulness in a complete understanding of the hemostatic system.

The cell-based theory consists of three stages: initiation, amplification, and propagation. Each stage represents a different aspect of hemostasis at a cellular level, with a pivotal point predicated on a spike or “burst” in the concentration of thrombin that ultimately results in the formation of a stable clot. An appreciation of thrombin’s role in the coagulation cascade is critical, and the coagulation cascade is the reason that the majority of all therapeutic anticoagulation strategies are directed at the inhibition of either Xa and/or thrombin. In addition to the effects of thrombin activation secondary to platelet adhesion, the initiation phase of the cell-based model is marked by the exposure of TF to circulating factor VIIa that leads to generation of thrombin as the essential step. This thrombin generation leads to amplification via factor XI and the generation of even more thrombin, thereby activating the other two phases, serving as a potent catalyst for hemostasis. An understanding of these mechanisms helps to illustrate how the drug NovoSeven (activated factor VII) is such an effective hemostatic agent predominately related to its ability to lead to thrombin generation. This agent is ideally suited for settings that involve local sites of injury which express TF (e.g., localized, not traumatic CNS bleeds). Untoward events can occur in situations (e.g., disseminated intravascular coagulation [DIC], extracorporeal devices) that potentially involve the presence of high systemic levels of TF, which can lead to systemic activation of thrombin and resultant thrombosis. The classic coagulation cascade is shown in Figure 31.1.