Hemostasis is a process that maintains normal blood flow through healthy vessels but, when a vessel is damaged, rapidly generates a clot at the site of vascular injury. The major components of the hemostatic mechanism are the platelets, the anticoagulant proteins, the procoagulant proteins, and the various components of the vascular wall. Normal hemostasis is an interactive process in which each element cooperates closely to generate a rapid, cohesive, focused reaction. An abnormality of 1 element destabilizes the system, but significant clinical symptoms often manifest only when 2 components are affected. Typical examples include the patient with hemophilia who bleeds after sustaining trauma and the antithrombin (AT) 3–deficient woman in whom thrombosis develops during pregnancy. The astute clinician is aware of situations that may exacerbate preexisting conditions. Pretreatment of known predisposing conditions can prevent complications, as exemplified by infusion of factor 8 concentrate before and after surgery to a patient with hemophilia A to prevent excessive bleeding. Table 38.1 shows common bleeding symptoms and the most common disorders that trigger these symptoms.
| Mucocutaneous Bleeding |
| Immune thrombocytopenic purpura |
| Child abuse |
| Trauma |
| Poisoning with anticoagulants (rat poison) |
| Chronic/insidious |
| von Willebrand disease |
| Platelet function defect |
| Marrow infiltration/aplasia |
| Deep/Surgical Bleeding |
| Hemophilia |
| Vitamin K deficiency |
| von Willebrand disease |
| Generalized Bleeding |
| Disseminated intravascular coagulation |
| Vitamin K deficiency |
| Liver disease |
| Uremia |
Coagulation Cascade
Two opposing systems generate local clots but limit the clot to the area of vascular damage. Fig. 38.1 shows the sequence of activation of coagulation. The cascade is capable of rapid response because generation of a small number of activated factors at the “top” of the cascade leads to thousands of molecules of thrombin. Deficiencies of proteins at or below factors 11 or 7 in the coagulation cascade sequence result in clinical bleeding symptoms, whereas deficiencies of factor 12, prekallikrein, and high–molecular-weight kininogen do not. The coagulation mechanism is continuously generating a small amount of thrombin. If there is trauma, tissue factor and factor 7 combine to activate factor 10 to factor 10a both directly and indirectly via factor 9. Factor 10a then forms a complex on a membrane surface (provided by the activated platelet) with factor 5 and calcium, which results in more thrombin generation. Platelets stick to areas of vessel injury, thus restricting thrombin generation and clot formation to the area of damage.
Thrombin exerts positive feedback on the system by acting on factor 11 to trigger the intrinsic system, cleaving factors 5 and 8 to activate them, further accelerating thrombin generation, aggregating platelets, and activating factor 13. In this model, coagulation is always “turned on” and therefore, reacts faster than if it were static and suddenly had to initiate a series of reactions to trigger clot formation. This dynamic concept underscores the impact of deficiencies in anticoagulant protein as the system is continuously generating thrombin. A deficiency of an inhibitory enzyme or a cofactor removes part of the “brakes” on the system and causes increased thrombin generation.
Coagulation Inhibitors
Four key systems interact to inhibit the coagulation mechanism:
- •
AT
- •
Protein C/S system
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Fibrinolytic system
- •
Tissue factor pathway inhibitor (TFPI)
Antithrombin
AT is a member of the serine protease inhibitor family (serpins) that inhibits thrombin, factor 10a, and, less efficiently, factors 9a and 11a. When AT is bound to heparin, this reaction is accelerated 1000-fold. AT is the active anticoagulant operative during heparin therapy; if AT is deficient, heparin therapy may fail. Heparin-like molecules are synthesized by endothelial cells and interact with AT on the vessel wall to inhibit coagulation. Both congenital and acquired AT deficiencies are associated with a predisposition toward thrombosis. AT is consumed during clotting.
Protein C/Protein S System
The protein C/protein S system is complex and limits clot extension by inactivating the rate-limiting coenzymes of the coagulation cascade, factors 5 and 8. To prevent extension of the clot, the anticoagulant mechanism must limit thrombin formation to areas of vascular damage. As a 1st step, thrombin binds to the protein thrombomodulin on intact endothelial cells. Thrombomodulin-bound thrombin then converts protein C into its activated form, activated protein C (APC). APC then combines with protein S to inactivate factors 5 and 8. In addition, APC may promote fibrinolysis. Thrombin itself is inactivated when bound to thrombomodulin and simultaneously augments the anticoagulant response by generating APC. APC limits the amount of thrombin that can be generated subsequently.
AT3, protein C, and protein S are important inhibitors of clotting because deficiencies of each of these proteins, either inherited or acquired, are associated with an increased risk for thrombosis. A mutation in factor 5 (factor 5 Leiden) that makes it less susceptible to proteolysis by APC (resistance to APC) is the most common hereditary predisposition to thrombosis. TFPI is an inhibitor of factor 7a ( Fig. 38.2 ).
Fibrinolytic System
The fibrinolytic system dissolves and removes clots from the vascular system so that normal flow through vessels can be restored. Endothelial cells synthesize 2 activators of plasminogen: tissue-type plasminogen activator (TPA) and urokinase, both of which convert plasminogen to plasmin, the enzyme that degrades fibrin. Normally, plasminogen activator and its inhibitor, plasminogen activator inhibitor, are synthesized in equimolar amounts and are released from endothelial cells in parallel, leading to minimal amounts of active fibrinolysis. Increased activation or damage to the vascular system can alter this balance and result in increased TPA release, thus generating plasmin and lysing local clots. Plasminogen activator has been synthesized in a recombinant form (rTPA) and is an effective pharmacologic fibrinolytic agent in vivo.
Platelet-Endothelial Cells Axis
Clotting is initiated when platelets adhere to damaged endothelium ( Fig. 38.3 ). In areas of vascular damage, the adhesive protein, von Willebrand factor (VWF), binds to the exposed subendothelial collagen matrix and undergoes a conformational change. VWF then binds to its platelet receptor, glycoprotein Ib, and activates platelets. Activated platelets secrete adenosine diphosphate (ADP), which induces nearby circulating platelets to aggregate. Platelet-to-platelet cohesion is mediated by the binding of fibrinogen to its platelet receptor, glycoprotein IIb/IIIa. Therefore, both VWF and fibrinogen play essential roles in normal platelet function in vivo . Simultaneously with the platelet adhesion-aggregation response, coagulation is being activated. The platelet membrane brings the reactants of the cascade into close proximity, promoting rapid, effective factor catalysis and accelerating the reactions 1000-fold faster than would occur in the absence of the appropriate surface.
Normally, endothelial cells provide an antithrombotic surface through which blood flows without interruption. The endothelial cell is capable of a rapid change in function and character so that it can augment coagulation after stimulation with a variety of modulating agents, including lymphokines and cytokines, as well as noxious agents such as endotoxin and infectious viruses ( Fig. 38.4 ). Widespread alteration of endothelial cell function can shift and dysregulate the hemostatic response and promote activation of clotting, which is the probable mechanism by which sepsis induces the clinical syndrome of disseminated intravascular coagulation (DIC).
Developmental Hemostasis
Hemostatic disorders in newborns are more common than at any other pediatric age. The neonate is relatively deficient in most procoagulant and anticoagulant proteins. Platelet function may also be impaired. Blood flow characteristics in the newborn are unique because of the high hematocrit, small-caliber vessels, low blood pressure, and special areas of vascular fragility. Table 38.2 presents the normal values for coagulation screening tests and procoagulant proteins in preterm and full-term infants, as well as in older children. Table 38.3 presents age-specific values for the anticoagulant and fibrinolytic proteins.
| Test | 19–27 Wk Gestation † | 28–31 Wk Gestation † | 30–36 Wk Gestation | Full Term | 1–5 Yr | 6–10 Yr | 11–18 Yr | Adult |
|---|---|---|---|---|---|---|---|---|
| PT (sec) | — | 15.4 (14.6–16.9) | 13.0 (10.6–16.2) | 13.0 (10.1–15.9) | 11 (10.6–11.4) | 11.1 (10.1–12.0) | 11.2 (10.2–12.0) | 12 (11.0–14.0) |
| INR | — | — | 1.0 (0.61–1.7) | 1.00 (0.53–1.62) ‡ | 1.0 (0.96–1.04) | 1.01 (0.91–1.11) | 1.02 (0.93–1.10) | 1.10 (1.0–1.3) |
| APTT (sec) | — | 108 (80–168) | 53.6 (27.5–79.4) ‡ § | 42.9 (31.3–54.3) ‡ | 30 (24–36) | 31 (26–36) | 32 (26–37) | 33 (27–40) |
| Fibrinogen | 1.00 (±0.43) | 2.56 (1.60–5.50) | 2.43 (1.50–3.73) ‡ § | 2.83 (1.67–3.99) | 2.76 (1.70–4.05) | 2.79 (1.57–4.0) | 3.0 (1.54–4.48) | 2.78 (1.56–4.0) |
| Bleeding | — | — | — | — | 6 (2.5–10) ‡ | 7 (2.5–13) ‡ | 5 (3.8) ‡ | 4 (1–7) time (min) |
| Factor 2 | 0.12 (±0.02) | 0.31 (0.19–0.54) | 0.45 (0.20–0.77) ‡ | 0.48 (0.26–0.70) ‡ | 0.94 (0.71–1.16) ‡ | 0.88 (0.67–1.07) ‡ | 0.83 (0.61–1.04) ‡ | 1.08 (0.70–1.46) |
| Factor 5 | 0.41 (±0.10) | 0.65 (0.43–0.80) | 0.88 (0.41–1.44) § | 0.72 (0.34–1.08) ‡ | 1.03 (0.79–1.27) | 0.90 (0.63–1.16) ‡ | 0.77 (0.55–0.99) ‡ | 1.06 (0.62–1.50) |
| Factor 7 | 0.28 (±0.04) | 0.37 (0.24–0.76) | 0.67 (0.21–1.13) ‡ | 0.66 (0.28–1.04) ‡ | 0.82 (0.55–1.16) ‡ | 0.86 (0.52–1.20) ‡ | 0.83 (0.58–1.15) ‡ | 1.05 (0.67–1.43) |
| Factor 8 procoagulant | 0.39 (±0.14) | 0.79 (0.37–1.26) | 1.11 (0.5–2.13) | 1.00 (0.50–1.78) | 0.90 (0.59–1.42) | 0.95 (0.58–1.32) | 0.92 (0.53–1.31) | 0.99 (0.50–1.49) |
| VWF | 0.64 (±0.13) | 1.41 (0.83–2.23) | 1.36 (0.78–2.10) | 1.53 (0.50–2.87) | 0.82 (0.60–1.20) | 0.95 (0.44–1.44) | 1.00 (0.46–1.53) | 0.92 (0.50–1.58) |
| Factor 9 | 0.10 (±0.01) | 0.18 (0.17–0.20) | 0.35 (0.19–0.65) ‡ § | 0.53 (0.15–0.91) † ‡ | 0.73 (0.47–1.04) ‡ | 0.75 (0.63–0.89) ‡ | 0.82 (0.59–1.22) ‡ | 1.09 (0.55–1.63) |
| Factor 10 | 0.21 (±0.03) | 0.36 (0.25–0.64) | 0.41 (0.11–0.71) ‡ | 0.40 (0.12–0.68) ‡ | 0.88 (0.58–1.16) ‡ | 0.75 (0.55–1.01) ‡ | 0.79 (0.50–1.17) | 1.06 (0.70–1.52) |
| Factor 11 | — | 0.23 (0.11–0.33) | 0.30 (0.08–5.2) ‡ § | 0.38 (0.40–0.66) ‡ | 0.97 (0.52–1.50) ‡ § | 0.86 (0.52–1.20) | 0.74 (0.50–0.97) ‡ | 0.97 (0.67–1.27) |
| Factor 12 | 0.22 (±0.03) | 0.25 (0.05–0.35) | 0.38 (0.10–0.66) ‡ § | 0.53 (0.13–0.93) ‡ | 0.93 (0.64–1.29) | 0.92 (0.60–1.40) | 0.81 (0.34–1.37) ‡ | 1.08 (0.52–1.64) |
| PK | — | 0.26 (0.15–0.32) | 0.33 (0.09–0.89) ‡ | 0.37 (0.18–0.69) ‡ | 0.95 (0.65–1.30) | 0.99 (0.66–1.31) | 0.99 (0.53–1.45) | 1.12 (0.62–1.62) |
| HMWK | — | 0.32 (0.19–0.52) | 0.49 (0.09–0.89) ‡ | 0.54 (0.06–1.02) ‡ | 0.98 (0.64–1.32) | 0.93 (0.60–1.30) | 0.91 (0.63–1.19) | 0.92 (0.50–1.36) |
| Factor 13a | — | — | 0.70 (0.32–1.08) ‡ | 0.79 (0.27–1.31) ‡ | 1.08 (0.72–1.43) | 1.09 (0.65–1.51) | 0.99 (0.57–1.40) | 1.05 (0.55–1.55) |
| Factor 13b | — | — | 0.81 (0.35–1.27) ‡ | 0.76 (0.30–1.22) ‡ | 1.13 (0.69–1.56) ‡ | 1.16 (0.77–1.54) ‡ | 1.02 (0.60–1.43) | 0.98 (0.57–1.37) |
* All factors except fibrinogen are presented as U/mL (fibrinogen in mg/mL), where pooled normal plasma contains 1 U/mL. All data are expressed as the mean followed by the upper and lower boundaries encompassing 95% of the normal population.
† Levels for 19–27 wk and 28–31 wk are from multiple sources and cannot be analyzed statistically.
‡ Values are significantly different from those of adults.
§ Values are significantly different from those of full-term infants.
| Inhibitor | 19–27 Wk Gestation † | 28–31 Wk Gestation † | 30–36 Wk Gestation | Full Term | 1–5 Yr | 6–10 Yr | 11–18 Yr | Adult |
|---|---|---|---|---|---|---|---|---|
| AT3 | 0.24 (±0.03) ‡ | 0.28 (0.20–0.38) ‡ | 0.38 (0.14–0.62) ‡ § | 0.63 (0.39–0.87) ‡ | 1.11 (0.82–1.39) | 1.11 (0.90–1.31) | 1.06 (0.77–1.32) | 1.0 (0.74–1.26) |
| Protein C | 0.11 (±0.03) ‡ | — | 0.28 (0.12–0.44) ‡ § | 0.35 (0.17–0.53) ‡ | 0.66 (0.40–0.92) ‡ | 0.69 (0.45–0.93) ‡ | 0.83 (0.55–1.11) ‡ | 0.96 (0.64–1.28) |
| Protein S | — | — | — | — | — | — | — | — |
| Total (U/mL) | — | — | 0.26 (0.14–0.38) ‡ § | 0.36 (0.12–0.60) ‡ | 0.86 (0.54–1.18) | 0.78 (0.41–1.14) | 0.72 (0.52–0.92) | 0.81 (0.61–1.13) |
| Free (U/mL) | — | — | — | — | 0.45 (0.21–0.69) | 0.42 (0.22–0.62) | 0.38 (0.26–0.55) | 0.45 (0.27–0.61) |
| Plasminogen (U/mL) | — | — | 1.70 (1.12–2.48) ‡ | 1.95 (1.25–2.65) ‡ | 0.98 (0.78–1.18) | 0.92 (0.75–1.08) | 0.86 (0.68–1.03) | 0.99 (0.77–1.22) |
| TPA (ng/mL) | — | — | 8.48 (3.00–16.70) | 9.6 (5.0–18.9) | 2.15 (1.0–4.5) ‡ | 2.42 (1.0–5.0) ‡ | 2.16 (1.0–4.0) ‡ | 1.02 (0.68–1.36) |
| α 2 AP (U/mL) | — | — | 0.78 (0.40–1.16) | 0.85 (0.55–1.15) | 1.05 (0.93–1.17) | 0.99 (0.89–1.10) | 0.98 (0.78–1.18) | 1.02 (0.68–1.36) |
| PAI–1 | — | — | 5.4 (0.0–12.2) ‡ | 5.42 (1.0–10.0) | 5.42 (1.0–10.0) | 6.79 (2.0–12.0) ‡ | 6.07 (2.0–10.0) ‡ | 3.60 (0–11.0) |
* All values are expressed in U/mL, where pooled plasma contains 1 U/mL, with the exception of free protein S, which contains a mean of 0.4 U/mL. All values presented as the mean by the upper and lower boundaries encompassing 95% of the population.
† Levels for 19–27 wk and 28–31 wk are from multiple sources and cannot be analyzed statistically.
‡ Values are significantly different from those of adults.
§ Values are significantly different from those of full-term infants.
Levels of factors 5 and 8, fibrinogen, VWF, and platelets become normal by 28 weeks of gestation. Protein S levels are also normal at birth, but levels of other anticoagulant proteins, especially protein C, AT3, and plasminogen, are low in full-term infants and are even lower in premature neonates. The levels of most procoagulant and anticoagulant proteins increase throughout gestation; therefore, the most immature infant has the lowest levels of these proteins and is at the highest risk for either bleeding or thrombotic complications.
Vitamin K deficiency is a particular problem of the newborn. Vitamin K is a fat-soluble vitamin that induces the post-translational γ-carboxylation of the vitamin K-dependent substances (factors 2, 7, 9, and 10; protein C; and protein S). This carboxylation step occurs after the protein is synthesized in the liver and must occur for the vitamin K-dependent coagulation factor to bind calcium, the bridge to the membrane surface on which these proteins form complexes with other members of the clotting cascade and catalyze subsequent reactions. Vitamin K deficiency effectively renders these proteins unable to bind to a surface. Most of the vitamin K in adults originates from the diet and from bacterial production in the intestine. The breast-fed neonate is at high risk for vitamin K deficiency because human milk is relatively deficient in vitamin K, the neonatal liver itself is immature, and the newborn’s gut requires several days to develop normal bacterial flora.
Severe vitamin K deficiency in neonates, hemorrhagic disease of the newborn (HDN), occurs in breast-fed infants who have not received intramuscular vitamin K prophylaxis. Such infants may experience diffuse bleeding and even central nervous system hemorrhage at 3-5 days of life. HDN is an extraordinarily rare event in the United States because of nearly universal neonatal administration of vitamin K. In the evaluation of bleeding in a newborn, the clinician should confirm that vitamin K has been administered. Patients with disorders of the gastrointestinal tract, those taking broad-spectrum antibiotics, those born of mothers who received phenobarbital or phenytoin during pregnancy (very–early-onset HDN), and those with cholestasis and malabsorption (late-onset HDN) are at higher risk for vitamin K deficiency.
Clues From History and Physical Examination
History
Table 38.4 is an outline of historical questions that are important for the diagnosis of bleeding disorders as it is critical to obtain quantifiable, precise information. Easy bruising and nosebleeds are common in children, although the presence of large (>2 inches in diameter) bruises at multiple sites, prolonged nosebleeds (>15-30 minutes), and hematoma formation are seen in up to 20-40% of children with a bleeding disorder. Bleeding post-circumcision should raise the suspicion of hemophilia, while bleeding from the umbilical cord stump is associated with factor 13 deficiency. Some helpful questions include “What was the biggest bruise you ever had, and what caused it?” and “Have you ever noted little red dots [petechiae] on your skin?”
Draw family tree. The items just listed should be applied to immediate family members, especially a history of easy bruising, epistaxis, excessive bleeding after surgery, menorrhagia, excessive bleeding after childbirth, or a family history of others with diagnosed or suspect bleeding disorders. Attempt to deduce inheritance pattern. |
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