Diseases or drugs that affect the production of platelets or plasma proteins responsible for clotting cause excessive bleeding problems. The most common are diseases of the bone marrow and chemotherapy, both of which deplete platelets by inhibiting the production of megakaryocytes. In addition, liver disease, commonly caused by chronic alcoholism or viral infections, inhibits the production of the proteins responsible for blood coagulation. Less commonly, genetic mutations of these proteins cause life-long excessive bleeding (hemophilia). Finally, although chronic inflammation such as that associated with chronic periodontitis enhances clotting systemically, it often inhibits blood clotting locally (Sects. 13.2.3 and 13.3.1). Any of the above conditions may cause an unexpectedly large amount of bleeding from a tooth extraction and it is advisable to take a medical history and ensure that local inflammation is reduced as much as possible beforehand (Sect.13.5.1).

Capillaries are fragile. Continuous movement of the heart or intermittent movements and pressure changes around the cartilage between the bones stresses the capillaries, predisposing them to wear and tear that can activate the clotting system. Micro-size clots continually form and dissolve. A more severe injury such as bumping into a hard object causes bruising from bleeding beneath the skin. Although bleeding stops after a few minutes because a clot forms, the bruise lasts for a day or longer while leukocytes attracted by proinflammatory cytokines released by the damaged tissues (Sect. 13.3.2) digest the extravascular erythrocytes (Sect. 13.2.4). As the bruise disappears and the damaged tissue begins to be repaired, the clot is gradually lysed.

In older adults, there is a predisposition to clotting because of blood vessel degeneration or a decreased blood flow. The clots may obstruct a small artery or detach as an embolus that obstructs a arteries or veins elsewhere. Possible consequences are heart attack, stroke, pulmonary obstruction, or peripheral necrosis (Sect. 13.4.3). A tooth extraction in an elderly individual can cause an embolism elsewhere in the body. Elderly patients and patients on medication should be readied for oral surgery only after taking a history to elicit potential bleeding problems and consulting their attending physician. Rarely, acute disseminated intravascular blood clotting may be induced in any individual by a severe crushing injury, a severe allergic reaction to an insect bite or drug, or uncontrolled systemic bacterial or viral infections.

Platelets initiate coagulation by interacting with von Willebrand Factor (VWF), a multidomain protein (Fig. 11.2) synthesized and secreted by healthy endothelial cells. Following loss of signal peptide in the endothelial cell endoplasmic reticulum (ER), the proVWF molecule dimerizes by disulfide bonding at the C-terminal cysteine knot domain, which is homologous to the domain in TGF-β (Sect. 3.2.2). The dimers are transported to the Golgi, where propeptide domains D1 and D2 are cleaved, permitting large multimers to assemble by disulfide bond exchange between the dimer D3 domains. Sites of stress or injury expose subendothelial stromal collagen that binds to A3 domains in the multimer. The collagen interaction exposes A1 domains that tether platelets from the blood flow by binding to a platelet surface glycoprotein (Gp) called GpIbα. Tethering activates the platelets to aggregate into a platelet plug or soft clot which temporarily stops the bleeding and provides a surface for the more permanent blood clot. Platelet plug formation is enhanced mildly by epinephrine and ADP (Sect. 11.6.6), and strongly if thrombin is already activated (Sect. 11.3.4). Epinephrine is released into the blood as a response to injury, and ADP is released passively from injured endothelial cells and erythrocytes prior to activation. The activated platelets form a plug in three ways: First, an integrin on the platelet surface (α_IIbβ₃) is activated and binds to an RGD sequence (Sect. 3.2.1) on the VWF C1 domain (Fig. 11.2), but is displaced by fibrinogen (1.5 – 3.0 mg/ml in blood plasma, 100 – 300 times greater than multimeric VWF); Second, phosphatidylserine is moved from inner to outer leaflet of the platelet membrane; Third, granules whose contents stimulate thrombosis (blood clotting) and wound healing are secreted. One secreted component is thromboxane A ₂ (TXA₂), an eicosanoid (Fig. 13.13.) that stimulates thrombosis. TXA₂ recruits and activates additional platelets from blood without VWF binding. Fibrinogen binds to the activated α_IIbβ₃ integrin, enlarging the soft clot (plug) at the injured site (Fig. 11.3). The activated platelets further seal capillaries by contracting actin in the pericyte cytosol, and the many platelets in the soft clot provide a large phosphatidylserine surface for coagulation. Multimeric VWF is therefore the sensor of blood vessel injury; it aggregates and activates platelets to plug the wound and launch the blood coagulation system.

Multimeric VWF is degraded by an adamalysin, ADAMTS-13, which is secreted into the blood from endothelial cells along with VWF. ADAMTS-13 resembles procollagen N-peptidase (ADAMTS-2; Fig. 8.7b) except that the C-terminal domain of ADAMTS-2 is replaced by four additional thrombospondin-1 repeats (TS-1 repeats) and terminates in two CUB repeats (like those found on procollagen C-terminal peptidase, PCP, Fig. 8.7a). Mutations of ADAMTS-13 prevent the degradation of VWF. The concentration of multimeric VWF is increased, oversensitizing the blood to minor injuries at sites such as the heart where capillaries are stressed. The result is thrombotic thrombocytopenic purpura, a life-threatening disease in which small clots form, break loose, and block arterioles in the body. In contrast, mutations of VWF prevent it from binding collagen and do not stimulate platelets. The blood clotting system is underactivated and injuries cause excessive bleeding (hemophilia).

Activated platelets possess a phosphatidylserine surface that binds calcium ions (as in matrix vesicles; Sect. 9.3.3). This surface attaches various proteins that circulate in the blood and possess a negatively charged Ca⁺² binding domain of up to nineγ-carboxyglutamate (gla) residues (Fig. 11.4). Osteocalcin (Sect. 9.4.2.) also possesses this gla domain.

A gla protein is secreted into the endoplasmic reticulum (ER) of the liver where its N-terminal domain binds to and activates an enzyme that converts glutamic acid residues in the gla domain to γ-carboxyglutamic acid. The activated carboxylase enzyme then binds to a reduced form of vitamin K, a diphenol (KH₂) to which it adds molecular oxygen. The product is an epoxide which reacts with a catalytic amine (N:) on the carboxylase (Fig. 11.5a), converting it to a strong epoxide base (K⁻) that abstracts a proton from the γ-carbon of a glutamyl residue in the gla domain. The resulting γ-carbanion spontaneously binds to carbon dioxide, converting it to a carboxyglutamate residue (Fig. 11.5b). Simultaneously, the proton (Fig. 5.11a) converts K⁻ into a stable quinone epoxide, KO (Fig. 11.5b). Vitamin K oxidoreductase, a separate enzyme from the carboxylase in the ER membrane, completes the cycle by regenerating KH² from KO. The carboxylase and oxidoreductase iteratively convert all the glutamate residues in a gla-domain. The carboxylase then catalyzes a proteolysis reaction that cleaves the N-terminal propeptide, releasing both carboxylated protein and propeptide separately. Carboxylation of glu to gla resembles oxidation of proline to hydroxyproline by vitamin C during collagen synthesis (Sect. 7.3.1.). The electrons may be obtained from glutathione and passed through an unknown reductase to a cystine disulfide bond in a small hydrophilic loop of vitamin K oxidoreductase protruding into the ER lumen. The electrons are relayed to a second cystine disulfide bond in the membrane of the oxidoreductase before being passed to KO.

Wafarin is one of a family of vitamin K mimics (coumarins) that successfully compete for the KH₂ binding site on vitamin K oxidoreductase. The diphenol cannot be regenerated from KO, and glutamate is not carboxylated. The coumarins are therefore anticoagulants because the gla proteins are secreted into blood as precursors (Coumarins and problems associated with their use are discussed in Sect. 11.6.3) The clotting factor pro-proteases that possess a gla domain are factors II, VII, IX, and X (Table 11.1). These and other factors are carried around in the blood until they touch an activated platelet. The negative charge on the gla domain of the pro-protease completes a calcium sandwich with phosphatidylserine on the platelet aggregate. The negative lipid is on one side, the γ-carboxyglutamate is on the other, and the Ca²⁺ ions are in the middle (Fig. 11.4). Binding alters the conformation of the pro-protease factors and activates proteolysis.

Following the recruitment and activation of platelets by injured capillaries, their soft clot aggregates provide a surface for plasma proteins to interact and activate thrombin, which transforms soluble fibrinogen to a fibrin clot. Thrombin is activated by two blood coagulation pathways, extrinsic and intrinsic. A defective extrinsic path is incompatible with life, whereas defects of the intrinsic path cause hemophilia.

The extrinsic pathway is mediated by tissue factor (TF), also known as thromboplastin or factor III (Fig. 11.6a). Tissue factor is not present in blood plasma, i.e., it is extrinsic or outside of the vascular system. TF is a membrane protein that becomes exposed to the blood by trauma to the endothelial surface of blood vessels. It is especially rich in the membranes of pericytes, platelets, and leukocytes, but present in lesser amounts in most cells. It is absent from striated muscle cells and chondroblasts.

When TF is exposed to blood, it spontaneously binds factor VII, a serine protease of the coagulation system that possesses a gla domain (Table 11.1). The TF–VII complex therefore adheres to the negatively charged surface of activated platelets. About 0.4% of factor VII is activated in blood by fatty acid- or triglyceride-mediated activation of factor IX and binds similarly to TF. The TF–VIIa complex (Fig. 11.6a