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Individuals with Scott syndrome, a rare disorder caused by mutations to scramblase in platelets, have a tendency to bleed because scramblase moves phosphatidylserine (PS) from the cytosolic leaflet to the extracellular leaflet in the plasma membrane of platelets. This disrupts the asymmetrical localization of membrane phospholipids created by ATP-dependent flippases (move PS from extracellular to cytosolic leaflet) and floppases (move phosphatidylcholine [PC] in the opposite direction). When PS is on the outer face of platelet membranes, it provides a site for protein clotting factors to interact and activate thrombin. However, if scramblase is inactive, PS is not available to these factors, resulting in bleeding.

In the case of a 3-year-old girl whose home was treated for a rat infestation, the parents become concerned about her potential ingestion of poison-containing pellets. Blood studies reveal a prolonged prothrombin and activated partial thromboplastin time, as well as a decreased concentration of clotting factors II, VII, IX, and X. The administration of vitamin K is a rational approach to treatment because many rodent poisons are super warfarins, which inhibit γ-carboxylation (production of γ-carboxyglutamate, or Gla, residues). The decreased clotting proteins mentioned are Gla-containing proteases of the clotting cascade, and as warfarin functions as a vitamin K antagonist, providing vitamin K can counteract its effects.

Integrative Cases:
Metabolic pathways, initially presented in isolation, are interconnected to form a network. Four integrative case studies demonstrate how a perturbation in one process can affect other processes in the network.

Case 1: Chest Pain
Patient Presentation: A 35-year-old man named BJ experiences severe substernal chest pain accompanied by dyspnea, diaphoresis, and nausea. He has previously had episodes of exertional chest pain, albeit less severe and of shorter duration. BJ is a smoker, consumes alcohol infrequently, follows a typical diet, and engages in regular walks with his wife. His blood pressure has been normal. Family history reveals that his father and paternal aunt died of heart disease at ages 45 and 39, respectively, while his mother and younger brother (age 31) are reportedly in good health.

Physical Examination (Pertinent Findings): BJ appears pale and clammy, experiencing distress due to chest pain. His blood pressure and respiratory rate are elevated. Lipid deposits are observed on the periphery of his corneas (corneal arcus) and under the skin on and around his eyelids (xanthelasmas). No deposits on his tendons (xanthomas) are found.

Pertinent Test Results: BJ's electrocardiogram indicates a myocardial infarction (MI). Angiography reveals severe stenosis (narrowing) in several coronary arteries. Initial clinical laboratory results show the following:
H = High; L = Low. [Note: BJ had not eaten for approximately 8 hours prior to the blood draw.]

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Correct answer = C. FXIII is a transglutaminase that cross-links fibrin molecules in a soft clot to form a hard clot. Its deficiency does not affect the PT or aPTT tests. [Note: It is evaluated by a clot solubility test.] 5.16. Why do individuals with Scott syndrome, a rare disorder caused by mutations to scramblase in platelets, have a tendency to bleed?
Scramblase moves phosphatidylserine (PS) from the cytosolic leaflet to the extracellular leaflet in the plasma membrane of platelets. This disrupts the asymmetrical localization of membrane phospholipids created by ATP-dependent flippases (move PS from extracellular to cytosolic leaflet) and floppases (move phosphatidylcholine [PC] in the opposite direction). Having PS on the outer face of platelet membranes provides a site for protein clotting factors to interact and activate thrombin. If scramblase is inactive, PS is not available to these factors, and bleeding results.
5.10. Several days after having had their home treated for an infestation of rats, the parents of a 3-year-old girl become concerned that she might be ingesting the poison-containing pellets. After calling the Poison Hotline, they take her to the emergency department. Blood studies reveal a prolonged prothrombin and activated partial thromboplastin time and a decreased concentration of FII, FVII, FIX, and FX. Why might administration of vitamin K be a rational approach to the treatment of this patient?
Many rodent poisons are super warfarins, drugs that have a long half-life in the body. Warfarin inhibits γ-carboxylation (production of γ-carboxyglutamate, or Gla, residues), and the clotting proteins reported as decreased are the Glacontaining proteases of the clotting cascade. [Note: Proteins C and S of anticlotting are also Gla-containing proteins.] Because warfarin functions as a vitamin K antagonist, administration of vitamin K is a rational approach to treatment.
I. I. Integrative Cases
Metabolic pathways, initially presented in isolation, are, in fact, linked to form an interconnected network. The following four integrative case studies illustrate how a perturbation in one process can result in perturbations in other processes of the network.
Case 1: Chest Pain
Patient Presentation: BJ, a 35-year-old man with severe substernal chest pain of ~2 hours’ duration, is brought by ambulance to his local hospital at 5 AM. The pain is accompanied by dyspnea (shortness of breath), diaphoresis (sweating), and nausea.
Focused History: BJ reports episodes of exertional chest pain in the last few months, but they were less severe and of short duration. He smokes (2–3 packs per day), drinks alcohol only rarely, eats a “typical” diet, and walks with his wife most weekends. His blood pressure has been normal. Family history reveals that his father and paternal aunt died of heart disease at age 45 and 39 years, respectively. His mother and younger (age 31 years) brother are said to be in good health.
Physical Examination (Pertinent Findings): BJ is pale and clammy and is in distress due to chest pain. Blood pressure and respiratory rate are elevated. Lipid deposits are noted on the periphery of his corneas (corneal arcus; see left image) and under the skin on and around his eyelids (xanthelasmas; see right image). No deposits on his tendons (xanthomas) are detected.
Pertinent Test Results: BJ’s electrocardiogram is consistent with a myocardial infarction (MI). Angiography reveals areas of severe stenosis (narrowing) of several coronary arteries. Initial results from the clinical laboratory include the following:
H = High; L = Low. [Note: BJ had not eaten for ~8 hours prior to the blood draw.]