Conditions, diseases, and abnormalities of platelet function

Now that we have a basic understanding of how platelets form a plug, how the cascade forms a clot, how the cascade is stopped, and how the clot is subsequently removed, let’s get into some conditions, diseases, and abnormalities of platelet function, coagulation, and fibrinolysis. Just like in any biological system, the combinations are essentially endless. (the type of lab results you’ll see for some of these conditions are listed; once we go over tests in the clinical lab, circle back and it will make more sense!)

von Willebrand factor (vWF):
vWF is a glycoprotein made inside of endothelial cells (the cells that line the inside surface of blood vessels). vWF binds to the platelet via GP1b and also binds to exposed collagen so basically it links the platelet to the collagen. vWF is an important player in platelet aggregation.

vWF’s other main function is binding factor 8 in circulation. If factor 8 is not bound to vWF it degrades more rapidly and many people without vWF will have a factor 8 deficiency.

Another side note on vWF; once the common pathway is activated, vWF is released from factor 8 by thrombin. Basically thrombin is saying “all hands on deck” and once released vWF can go help more platelets bind to the damaged site.

von Willebrand’s Disease (vWD):
vWD is a genetic disorder caused by missing or defective vWF. This will cause decreased platelet aggregation, and a slower intrinsic pathway clotting time due to its association with factor 8.

Lab results:
Increased bleeding time, normal PT, prolonged APTT. Why do you see these results? Increased bleeding time is due to the fact that platelets don’t aggregate quickly without vWF. Prolonged APTT is due to the missing factor 8.

Bernard Soulier Syndrome:
This condition is characterized by giant platelets and platelets lacking glycoprotein 1b (GP1b). As you remember GP1b binds to vWF which binds to collagen, so in this condition platelets will not aggregate because they can’t bind vWF.

Memory trick:
Use the phrase “Bernard’s giant Soul is not in room 1b” to quickly recall this condition.

Glanzmann’s thrombasthenia:
In this condition, platelets do not have glycoprotein 2b/3a (GP2b/3a). This is a huge problem because GP2b/3a binds fibrinogen which binds another platelet. Without GP2b/3a, platelets will not link together and will not aggregate.

Lab results:
Normal PT and APTT

Factor 5 Leiden:
Factor 5 Leiden is a mutant version of factor 5. This mutant version resists the action of Protein C and Protein S. Why is this important? People with this mutation are at increased risk for thrombosis because factor 5 Leiden continues to activate thrombin long after it should because Protein C was unable to inactivate it. This can create increased risk for clotting.

Dysfibrinogenemia:
Structural abnormalities in the fibrinogen molecule that cause abnormal results in the PT, APTT, and TT.

Memory trick:
Think disfigured when you think of dysfibrinogenemia

Hypofibrinogenemia:
Fibrinogen concentration of less than 100mg/dL.
Prolonged PT, APTT, and TT due to a lack of fibrinogen. (hypo = low)

Afibrinogenemia:
Rare autosomal recessive condition where no fibrinogen protein is produced.

Make sure to know the meaning of these three fibrinogenemia words!

Disseminated intravascular coagulation (DIC):
This complex condition results when the coagulation inhibitory mechanisms become overwhelmed and platelets and clotting factors are overused or used up. This can result in abnormal clots randomly in the small blood vessels and can lead to disseminated (widespread) bleeding due to the lack of coagulation factors available. DIC is usually caused by another serious underlying condition.

Lab results:
PT, APTT, and TT prolonged due to overused or used up clotting factors, low platelets, schistocytes in peripheral blood smear (RBCs run into fibrin strands); positive D-dimer and fibrin degradation products (FDPs).

Polycythemia:
An increased hemoglobin concentration either due to low plasma volume or increased RBCs. PT and APTT may be prolonged in patients with polycythemia due to the anticoagulant in the blue top sodium citrate tube. The wrong mixture of patient blood and tube anticoagulant will cause excess anticoagulant to bind calcium and prolong coagulation tests. Calcium is required for a few key steps in the cascade. Thrombocytosis can be seen in this condition due to increased precursor cell production. If there are increased RBCs there’s a chance there are increased platelets too.

Thrombotic thrombocytopenic purpura (TTP):
(Thrombotic = clotting, thrombocytopenic = low platelets, purpura = purple rash on the skin caused by internal bleeding of small blood vessels)
This is a rare blood disorder characterized by a low platelet count, renal dysfunction, neurological abnormalities, and microangiopathic hemolytic anemia. The low platelet count is due to clotting.

Lab results:
PT and APTT are normal, schistocytes present due to excess fibrin strands. Why are the PT and APTT normal here? The clotting in this condition does not cause a lack of coagulation factors like in DIC.

Idiopathic thrombocytopenic purpura (ITP):
(Idiopathic = unknown cause)
This condition is also known as immune thrombocytopenia. It is more common in children than adults and can be caused by a viral infection that heals itself in a few weeks.

Storage pool disease:
This condition refers to platelets with defective granules. When granules are defective important proteins aren’t released and platelet aggregation is decreased. Remember granules release their contents during the shape change portion of platelet aggregation.

Lupus anticoagulant:
It’s a bit of a misnomer because only about 5-10% of people with Systemic Lupus Erythematosus (SLE) have Lupus anticoagulant. The Lupus anticoagulant is simply an antibody to phospholipids, your body is attacking itself. The confusion around Lupus anticoagulant can arise because it gives different results in your body versus in a test tube. It’s still doing the same thing just the outcome is different. Huh? Ok, so in a patient with Lupus anticoagulant, clotting is going to be increased (pro-coagulant not anticoagulant!). This is because the antibody is binding to the phospholipids of the platelet membranes and increasing platelet aggregation. However, in a test tube, Lupus anticoagulant binds to the phospholipids in the commercial reagents of the PT and APTT tests and interferes with starting the cascade but only the APTT will show an increased clotting time. Why is this? The PT test uses a much higher concentration of phospholipid and the effect of Lupus anticoagulant is not seen.

Hemophilia:
(hemo = blood, philia = affection for)
Not the greatest name but basically means lack of ability to clot and that’s where the affection for blood comes from.

Hemophilia A:
Sex-linked genetic disorder caused by missing or defective factor 8.
Prolonged APTT, normal bleeding time because platelets still aggregate correctly.

Hemophilia B:
Sex-linked genetic disorder caused by missing or defective factor 9.
Prolonged APTT, normal bleeding time because platelets still aggregate correctly.

Factor 13 deficiency:
This is a very rare condition but worth noting that the PT and APTT will come back normal on this test because a clot is formed, it’s just not stabilized.

Factor 12 deficiency:
Factor 12 deficiency will increase risk of thrombosis and decrease fibrinolytic activity. How does that work? Prekallikrein is also an activator of the fibrinolytic system, factor 11 is the only contact factor that does not activate the fibrinolytic system. It’s good to remember that much like thrombin, it’s possible for the same factor to have multiple jobs.