Are HUS and TTP related?


Q. Is there a relationship between hemolytic-uremic syndrome and thrombotic thrombocytopenic purpura? I see them lumped together a lot. (more…)

DDAVP and von Willebrand disease

Q. I’m confused about DDAVP. Why do you use it in von Willebrand disease? I read that it raises VIII and VWF, but that doesn’t really make sense since the factor VIII is already there, there is no need to make more of it? (more…)

Antiphospholipid antibody syndrome

Q. Can you write a post about antiphospholipid syndrome? I could not find good source which explains its pathophysiology and laboratory results

A. First, before we get into the antiphospholipid syndrome, we need to talk about antiphospholipid antibodies. As you might expect from their name, antiphospholipid antibodies are autoantibodies in the patient’s plasma that are directed against various phospholipids (there are lots of phospholipid surfaces in the body – including the phospholipid surface upon which the coagulation factors interact). There are a bunch of different types of antiphospholipid antibodies, including anticardiolipin antibodies, anti-glycoprotein antibodies, and the so-called lupus anticoagulants (which were discovered in patients with lupus).

In addition to binding to various phospholipid surfaces in the body, these autoantibodies also just happen to bind to the phospholipid part of the PTT reagent (and sometimes, the PT reagent). Then there’s not enough usable reagent in the test tube, and the patient’s specimen doesn’t clot! The coagulation tests are therefore falsely prolonged.

Antiphospholipid antibodies are sometimes called “inhibitors” because they appear to inhibit coagulation in the test tube. But here’s a weird thing: in the body, they can be associated with thrombosis!

You may be asking yourself: how do you get these antiphospholipid antibodies? And are they dangerous?

It turns out there are different answers for different patients. Children, for example, sometimes develop antiphospholipid antibodies after an infection. In this setting, the risk of thrombosis is only slightly increased; it’s usually not a big deal clinically. Adults sometimes develop antiphospholipid antibodies as part of an autoimmune disorder like lupus (in fact, antiphospholipid antibodies – in whatever clinical setting – are often called “lupus inhibitors” because of this association). In these patients, the risk of thrombosis is moderately increased. Finally, elderly adults may develop antiphospholipid antibodies in association with drugs. This is virtually always a harmless event with no increased risk of thrombosis.

Okay, so here’s where we get to the antiphospholipid antibody syndrome part. This term is used when a patient with an antiphospholipid antibody has thromboses or pregnancy-related complications (like recurrent miscarriage, pre-term labor, or pre-eclampsia). This syndrome is a serious thing. In a small number of patients, the thromboses can be widespread, leading to multi-organ system damage and death. The term is reserved for patients who are symptomatic; you wouldn’t use the term in patients who have an antiphospholipid antibody but no symptoms.

So what would you do if you think your patient might have an antiphospholipid antibody? Well, you’d need to confirm this suspicion with laboratory tests. First, order a PTT (in fact, that’s how a lot of these patients get picked up – they present with an abnormally prolonged PTT in the face of clinical evidence of thrombosis).

Then, order up a mixing study. Remember what a mixing study is? You do this test when you have a patient with a prolonged PTT and you want to know why. It’s performed by taking the patient’s (probably abnormal) plasma and mixing it with some pooled (normal) plasma – then running the PTT on this new mixed sample.

If the new PTT value is within the normal range (if it “corrects”), then you know the pooled human plasma must have supplied something to the patient’s plasma to make it clot normally. The “something” is usually a coagulation factor that the patient is missing.

If the new PTT value is still abnormal (if it’s still prolonged, and doesn’t “correct”), then you know that even though you added a bunch of normal plasma to the mix, the patient’s plasma still couldn’t clot normally. There must be some other problem with the patient’s plasma. The “other problem” is usually an inhibitor.

One caveat: some antiphospholipid antibodies do not prolong the PTT. It all depends on the particular PTT reagent your lab is using (some reagents are just more easily swayed by the antiphospholipid antibodies). So if you really feel your patient may have an antiphospholipid antibody, you shouldn’t stop investigating that possibility just because the PTT comes back normal! There are plenty of fancy lab tests that can be done to detect antiphospholipid antibodies. Just call your friendly neighborhood pathologist and see what he/she has to offer.

Phospholipids, tissue factor and the platelet plug

plug

Q. I have a question about forming the platelet plug. Where are the phospholipids that get exposed, and how does platelet aggregation affect that? If this is in the subendothelium why weren’t they exposed upon ripping or whatever caused the endothelial damage? Also, what is tissue factor?

A. The phospholipids you’re referring to are part of the platelet cell membrane. The platelet membrane contains many different kinds of phospholipids on its surface. This is important because many of the coagulation factors (for example, the factor Xa-Va complex) require a phospholipid surface to exert their effects. During platelet aggregation, some of the phospholipids undergo important changes, making them more available to the coagulation factors.

Here is how a platelet plug is formed:

1. The endothelium gets ripped up, which exposes subendothelial proteins (like collagen) to the blood.

2. The platelets see these subendothelial proteins, and they stick to them using von Willebrand factor (this step is called platelet adhesion).

3. As the platelets adhese, they flatten out and release their granules (which have a lot of functions, one of which is to attract other platelets).

4. Other platelets come to the adhesion site, and they stick down onto the platelets that are already there (this step is called aggregation).

5. Now the platelet plug is formed. One cool thing about the platelet plug – in addition to its function of plugging the hole in the vessel – is that the platelet membrane provides a phospholipid surface which is essential for many of the coagulation factors. In fact, when platelets aggregate, certain phospholipids in their membranes become even more available to be used by the coagulation factors.

Tissue factor is a separate thing. It is the substance that initiates the whole coagulation cascade in vivo. It’s present in different areas of the body (in the subendothelium, in some inflammatory cells, and perhaps even in little locked-up microparticles in the blood). It is not present in active form in the blood until it’s needed for coagulation. So when the endothelium is ripped up (or when inflammatory cells decide to release it, or when the little microparticles get a signal to open up), tissue factor is exposed to the blood, and it binds to factor VIIa, and the cascade proceeds along the extrinsic pathway.

A different kind of plug: the image of Claes Oldenberg’s giant three-way plug at the Tate was taken by jovike (http://www.flickr.com/photos/49503078599@N01/54082836/), under cc license.

What’s the deal with ADAMTS 13?

Adam

Q. We learnt about a pretty rare disorder called thrombotic thrombocytopenic purpura (TTP) in which super-huge von Willebrand Factor (vWF) multimers are made which lead to occlusion of microcirculation. (more…)

Microangiopathic hemolytic anemia

MAHA

We’ve talked about a whole bunch of different hemolytic anemias over the past few weeks.

We’ve gone through the main hereditary hemolytic anemias: hereditary spherocytosis (and its less-common counterpart, hereditary elliptocytosis), glucose-6-phosphate dehydrogenase deficiency, the hemoglobinopathies (like sickle cell anemia) and the thalassemias.

We’ve also talked about immune-related hemolytic anemia (warm and cold), which is an acquired hemolytic anemia.

The last main type of hemolytic anemia on our list is microangiopathic hemolytic anemia, or MAHA for short, which falls under the acquired group of hemolytic anemias. In this type of hemolytic anemia, the red cells are ripped apart by physical trauma. Often the trauma results from red cells getting snagged as they try to pass through vessels laden with fibrin strands (there are a ton of situations in which this occurs, as we’ll see). Sometimes the trauma is due to other types of trauma (like an artificial heart valve that busts a few red cells each time it closes).

Let’s take a look at the other-types-of-trauma group first because it’s a little easier to conceptualize. There are two main causes of MAHA in this group: artificial heart valves and coarctation of the aorta. They really should call this group “macroangiopathic hemolytic anemia” because the problem is in big (macro) not tiny (micro) vessels, but they didn’t ask me. In both of these causes, red cells are getting ripped up in large spaces – either by the smashing of cells within an artificial heart valve (the old ball-and-socket valves were the worst for this; the newer models are much kinder to red cells), or by the ripping apart of red cells in turbulent blood flow (as you would get in coarctation of the aorta).

The remaining cases of MAHA are due to red cells getting snagged as they try to traverse thrombus-laden vessels. There are tons of situations in which the patient starts forming fibrin at an increased rate. If you look at Robbins, or any hematology textbook, you’ll be quickly overwhelmed by the sheer number of disorders and conditions that are associated with a microangiopathic hemolytic anemia, such as:

  1. Disseminated intravascular coagulation (DIC) – a nasty condition in which there is bleeding and clotting at the same time in the patient. Lots of things can cause DIC (like malignancy, obstetric complications, trauma, and sepsis) – and it’s complicated enough that we’ll get into it in a future post.
  2. Thrombotic thrombocytopenic purpura (TTP) – a syndrome in which the patient gets little thrombi within the microvasculature anywhere in the body, but especially the CNS and kidneys. We’ve talked a little about TTP before.
  3. Hemolytic-uremic syndrome (HUS) – a disorder often related to ingestion of food (especially raw hamburger, but also spinach, other vegetables, you name it) containing E. coli 0157:H7. The bug makes a toxin that damages endothelial cells, and for some reason, the kidneys are hit the hardest.

The blood smear is where the action is in MAHA. If you look carefully at a blood smear from a patient with MAHA, you’ll see fragmented red cells, or schistocytes. Schistocytes are smaller than normal red cells, and they have points on them. There are all kinds of permutations on this theme – some schistocytes have just one point, some look like they have little horns, some just look like little ragged red cell shards. If you look at the image above, you’ll see a whole bunch of schistocytes of varying shapes.

The most specific type of schistocyte is the “triangulocyte” (that’s really the name; would I make that up?), which is, as the name suggests, a triangular fragment of a red cell. These aren’t as common as the other types of schistocytes (there isn’t a triangulocyte in the above image). If you see one of those puppies, you better figure out what’s going on with the patient.

And that’s the main point I want to make about this type of hemolytic anemia. Given all the causes of this anemia – many of which carry a high mortality – you can’t just say the patient has MAHA, and move on to the next blood smear. You have to figure out what’s causing the hemolysis (or, rather, the clinician needs to figure it out); don’t miss this one. It could be a matter of life and death.

Photo credit: Ed Uthman at http://commons.wikimedia.org/ (DIC_With_Microangiopathic_Hemolytic_Anemia_(301920983).jpg)