Hemostasis and clotting

Positive feedback amplifies: the response strengthens the stimulus that produced it, until some outside event ends the loop.

• It reverses the stimulus:
• Correct: It strengthens the stimulus:
• It keeps the variable at a set point:

Fibrinogen, made by the liver, is the clotting protein that forms the threads of a clot. Serum lacks it because the clot used it up.

• Albumin:
• Gamma globulin:
• Correct: Fibrinogen:

Platelets are nucleus-free fragments broken off megakaryocytes in the marrow. They live 7–10 days.

• Correct: A fragment of a megakaryocyte, with no nucleus:
• A small white blood cell with a round nucleus:
• An immature red blood cell:

Initiation happens on the tissue factor cell and yields a trickle of thrombin. Amplification: that thrombin primes platelets and cofactors. Propagation: the activated platelet surface makes a burst of thrombin, enough to convert fibrinogen to fibrin, which XIIIa cross-links.

• Correct order: 1. Injury exposes tissue factor on cells in the vessel wall 2. Tissue factor and factor VIIa activate factors X and IX 3. Factor Xa with Va makes a small amount of thrombin 4. That thrombin activates platelets and factors V, VIII and XI 5. IXa–VIIIa and Xa–Va on the platelet surface make a burst of thrombin 6. Thrombin converts fibrinogen to fibrin, and XIIIa cross-links it

Vitamin K is needed for four clotting factors. Without it, the liver makes non-working copies, clotting tests lengthen (the PT first) and the person bruises and bleeds easily. Platelets are unaffected.

• Working factors II, VII, IX and X in plasma: down. The liver needs vitamin K to add the calcium-binding groups these factors need. Without it, the factors it makes do not work.
• Prothrombin time (PT): up. The PT depends on factor VII and the common pathway factors X and II. Factor VII has the shortest life in plasma, so the PT lengthens first.
• aPTT: up. The aPTT depends on factor IX and the common pathway factors X and II, all of which need vitamin K.
• Platelet count: no change. Vitamin K is needed for clotting factors, not for making platelets.
• Tendency to bleed: up. With too little working thrombin-making machinery, fibrin forms slowly, and bleeding lasts longer.

Bleeding into a joint is the typical pattern of a clotting factor problem. A long aPTT with a normal PT points to the intrinsic pathway, where factors VIII and IX act. The genes for both lie on the X chromosome, which is why the disease runs in males of a family.

• Correct: Hemophilia A or B: Correct. Hemophilia A or B.
• Thrombocytopenia: His platelet count is normal, and low platelets cause skin and mucous membrane bleeding, not joint bleeds.
• Vitamin K deficiency: Vitamin K deficiency lengthens the PT, often before the aPTT, because factor VII is affected.
• Von Willebrand disease: Von Willebrand disease mainly causes skin and mucous membrane bleeding, such as nosebleeds, rather than joint bleeds.

In a test tube, contact with glass activates factor XII, which starts the intrinsic pathway. In the body, bleeding is stopped by clotting that starts when tissue factor is exposed, so factor XII is not needed. This is one of the observations the cell-based model explains and the lab model does not.

• The aPTT test is unreliable and should not be used: The aPTT measures the test-tube pathway accurately. The long result is real; it just does not predict bleeding here.
• Factor XII is needed for clotting in arteries but not in veins: Factor XII is not needed to stop bleeding in any vessel.
• Correct: Clotting in the body starts with tissue factor: Correct. Tissue factor starts clotting in the body.
• Factor VIII takes over the job of factor XII: Factor VIII does not replace factor XII; they act at different steps.

Aspirin permanently blocks cyclooxygenase, the enzyme platelets use to make thromboxane A2. A platelet has no nucleus and makes almost no new enzyme. The effect lasts until the affected platelets are replaced, which takes their 7–10 day lifespan.

• Aspirin stays in the blood for a week after the last dose: Aspirin itself is cleared from the blood within hours. The effect outlasts the drug.
• Correct: Aspirin disables the platelet enzyme for the platelet's whole life: Correct. The effect lasts as long as the platelets do.
• Aspirin blocks vitamin K, and the liver needs a week to recover: Warfarin works through vitamin K. Aspirin acts on platelets.
• The operation needs extra platelets, and the marrow needs a week to make them: Aspirin does not lower the platelet count; it makes the existing platelets work less well.

Warfarin blocks the recycling of vitamin K. Leafy greens bring in fresh vitamin K, which partly overcomes the block, so the liver makes more working factors II, VII, IX and X. Clotting speeds up and the INR falls.

• It rises, because spinach blocks the vitamin K recycling enzyme too: Spinach supplies vitamin K; it does not block its recycling.
• It stays the same, because diet does not affect clotting: Vitamin K from food directly affects how many working factors the liver makes.
• Correct: It falls: extra vitamin K lets the liver make working factors: Correct. Extra vitamin K works against warfarin.
• It falls, because spinach destroys warfarin in the gut: The effect comes from the vitamin K in the spinach, not from destroying warfarin.

A clot that forms in an unbroken vessel and stays attached is a thrombus. A piece carried along in the blood is an embolus. The blockage it causes where it lodges is an embolism, here a pulmonary embolism.

• Embolus, thrombus, thrombosis: The clot in the calf is attached where it formed, so it is a thrombus, not an embolus.
• Correct: Thrombus, embolus, embolism: Correct. Thrombus, embolus, embolism.
• Thrombus, embolism, embolus: The traveling piece is the embolus; the blockage is the embolism.
• Embolism, thrombus, embolus: The calf clot is a thrombus; an embolism is a blockage, not a clot in place.

Too few platelets cause bleeding from small vessels in the skin and mucous membranes: petechiae and bleeding gums. A clotting factor problem causes deep bleeding into joints and muscles, and bleeding that restarts hours later, because the platelet plug forms but no fibrin reinforces it.

• Both have platelet problems: Patient B's platelet count is normal, and his bleeding pattern is the factor pattern.
• Both have clotting factor problems: Patient A's platelet count of 12,000 per µL is severe thrombocytopenia.
• A has a clotting factor problem; B has a platelet problem: The patterns are the other way round.
• Correct: A has a platelet problem; B has a clotting factor problem: Correct. Skin and mucosa for platelets; joints and delayed bleeding for factors.