UNITED INTERNATIONAL MEDICAL SCHOOLS
Coagulation -Stopping an unstoppable force
- Muhammad Yaseen Nivas
What does it take to stop an unstoppable force? Are there any immovable objects at all? In this article we look at how the body pulls an immovable object out of the air to stop an unstoppable force it usually doesn't want to stop.
Blood
Maybe it wasn’t hard to guess what that attempt at a joke was about. But it is very cool, at least to me, how the blood meant to be in constant motion can be suddenly stopped when needed.
Hemostatic mechanisms
There are a couple of ways blood flow can be stopped (e.g. when there is a breach in the vessel wall).
1.Vasoconstriction: less blood into the region of injury. But won’t a small diameter mean faster blood flow, due to volume conservation? Good point, but since the vessels are in parallel, the blood is rerouted.
2.Platelet plug: Imagine you just discover a third hole in your garden hose and close it with your finger while fetching some duct tape to seal it firmly. That’s somewhat comparable to a platelet plug. The tiny cytoplasmic fragments aggregate and close the site of injury, waiting for the final boss to walk in.
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3.Clot formation: The duct tape is finally here and you can let go. A protein called fibrin forms a molecular mesh which traps platelets, RBCs and everything else in it, securing the site of injury, preventing blood loss.
The details
Obviously, you didn't expect a medical article to be so simple, did you? Let's go into the nitty-gritty
I. Vasoconstriction
When the vessel wall is injured, the smooth muscle cells reflexively contract. Endothelin is a very potent vasoconstrictor involved. Also involved are serotonin and thromboxane A2.
II. Platelet Plug Formation
Platelets are fragments of megathrombocytes and contain granules filled with substances required for hemostasis. They are activated in many ways, one of which is by binding to subendothelial ECM (especially a molecule called vWF). Activated platelets release a plethora of substances, like thromboxane A2 and ADP which activate even more platelets. Prevention of ADP-induced activation of platelets is used by the drug Clopidogrel.
Caption: ADP leads to the activation of the Gp IIb/IIIa receptor, required for the cross-linking of platelets and fibrinogen. Clopidogrel, by inactivating ADP receptor (P2Y12 specifically), inactivates GpIIb/IIIa, thereby reducing aggregation. Platelets bind to vWF via a membrane protein called GpIIb/IIIa. The absence of vWF is referred to as von Willebrand disease (vWD). Deficiency of GpIIb/IIIa protein leads to Bernard Soulier syndrome (pseudo-vWD).
III. Clot formation
To put it in short, a couple reactions ending with fibrin formation is referred to as the ‘coagulation cascade’. There are two ways, intrinsic (where the damage occurs inside the vessel) and extrinsic (where the damage is caused by external trauma). There are 12 ‘clotting factors’ all of which are produced in its inactive form. They’re activated by each other, as shown in the diagram (which is daunting to look at first, but becomes simple as you go through it step by step)
Caption: The coagulation cascade
Both - the extrinsic and intrinsic pathways culminate in activating clotting factor 10, which activates the enzyme thrombin, which cleaves fibrinogen into fibrin. Fibrin forms a large mesh
The main player is thrombin. It plays a variety of roles, like activating platelets (via the platelet receptor PAR-1), activating a couple clotting factors (primarily fibrinogen) and inhibiting clot lysis. Thrombin is inhibited by the enzyme antithrombin-III, which uses heparin as a cofactor (this is why heparin is an anticoagulant).
Hemophilia is a genetic disease caused by the absence of 3 clotting factors (each responsible for a different variant of the disease). Hemophilia A, B, and C are caused by the absence of factors 8,9,11. Acquired hemophilia occurs when factor 8 is suppressed by antibodies.
Vitamin K is important for the activation of factors 2,7,9,10 and therefore, vitamin K deficiency, or inhibition of the enzymes responsible for the vitamin K based activation of the factors can lead to bleeding disorder. This vitamin K dependency is exploited by anti-clot drugs like warfarin and dicumarol.
Caption: The red lines show the steps inhibited by the anticoagulant warfarin. Gamma carboxylation at glutamyl residues increases the number of chelating sites for calcium, which activates the factors.
IV. Fibrinolysis: Healing
Once everything’s okay, we don't need the clot (and when a clot is formed at a site of injury, we don’t want it everywhere).
The main mechanism is by breaking down the fibrin mesh (into fibrin degradation products (FDP). Blood levels of D-dimer, one type of FDP, can be used to check for clots. The D-dimer test is important in diagnosing clot-related diseases like Deep Vein Thrombosis and Pulmonary embolism) The enzyme responsible for this is plasmin (usually inactive as plasminogen) and is activated by tissue plasminogen (t-PA). t-PA itself can be inhibited by Plasminogen activator inhibitor.
Caption: Reteplase is a modified version of tPA that is administered as a fibrinolytic drug.
Takeaway
How the dissolved blood elements can quickly cause cessation of blood flow reminds one of how plain-clothed bodyguards can quickly immobilize an assassin. So what do you think prevails? The unstoppable force or the immovable object?