Pathology Student

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-β₂-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 (hopefully 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.

Q. In liver cirrhosis, why is the PTT not elevated? In all of my review books, it says the PT is used as one of the ways to evaluate liver function. But it seems like the PTT should also be elevated!

A. Both the PT and the PTT can be prolonged in liver failure. The liver makes most of the coagulation factors – including the factors in both the intrinsic and extrinsic pathways. So both the PT (which assesses the extrinsic pathway) and the PTT (which assesses the intrinsic pathway) will be prolonged if the liver is not making coagulation factors like it should.

When you’re using coagulation tests to monitor liver failure, the PT may be a better test than the PTT. The PT assesses factor VII, which is the coagulation factor with the shortest half-life. So the first test to become abnormal if you stop making coagulation factors is the PT; then later, as the other coagulation factors start to become noticeably less abundant, the PTT becomes prolonged too. Perhaps that’s why board review books focus more on the PT (rather than the PTT) in this context.

The same principle holds for people on coumadin. Coumadin affects all the vitamin K dependant coagulation factors (II, VII, IX, X), so eventually, if you’re on a big enough dose, you’ll end up with both a prolonged PT and a prolonged PTT. Usually, though, you use the PT to follow someone as you’re adjusting their coumadin dose, because it’s more sensitive (it will become prolonged before the PTT). That’s important, because when someone is on coumadin, you want to anticoagulate them a little, but not too much. If you only used the PTT, you wouldn’t see an abnormality until factors IX and X dropped below normal levels - and by then the patient would be severely anticoagulated.

Bottom line: you are absolutely correct - both PT and PTT can be prolonged in liver failure.

The image of a cirrhotic liver above is from Wikimedia commons (http://commons.wikimedia.org/wiki/File:Cirrhosis_high_mag.jpg).

Here’s a little coagulation quiz to start your morning. Answers and explanations are in the first comment following this post.

1. Which of the following initiates the coagulation cascade IN VIVO?

A. Factor XII
B. Thrombin
C. Tissue factor
D. Factor X
E. Prekallikrein

2. What does von Willebrand factor do?

A. Binds platelets to each other
B. Binds platelets to the subendothelium
C. Binds platelets to the phospholipid surface
D. Carries factor VII
E. Cleaves factor V

3. Which of the following is true?

A. The intrinsic system is activated first, and then the extrinsic system is turned on later
B. The extrinsic system is weak and short-lived
C. The extrinsic system is only important in vitro
D. Factors V and VII are only important in vitro

4. Which of the following anti-clotting substances acts on factors V and VIII?

A. ATIII
B. Protein C
C. TFPI
D. Plasmin
E. t-PA

5. Which of the following is a cofactor?

A. XII
B. X
C. VIII
D. VII
E. II

6. What are the ingredients in a PTT?

A.  Plasma + phospholipid
B. Plasma + thromboplastin
C. Plasma + calcium
D. Plasma + thrombin
E. Plasma + plasmin

7. Which test evaluates the extrinsic pathway?

A. PT (INR)
B. PTT
C. TT
D. Closure time
E. Bleeding time

8. Which of the following is true regarding the bleeding time?

A. It is a highly reliable and reproducible test
B. The sample is evaluated using an optical densitometer
C. It evaluates platelet function in vivo
D. It is a commonly ordered test
E. It evaluates the coagulation system

9. What is the most common inherited bleeding disorder?

A. von Willebrand’s disease
B. Hemophilia A
C. Hemophilia B
D. Factor V Leiden
E. TTP

10. Which disorders may show “factor-type” bleeding?

A. von Willebrand’s disease
B. Hemophilia A
C. Both
D. Neither

11. Patients with which of the following diseases always have a normal PTT?

A. von Willebrand’s disease
B. Hemophilia A
C. Hemophilia B
D. Factor V Leiden

12. TTP:

A. May present with CNS deficits
B. Is caused by a toxin produced by E. coli
C. Is treated supportively
D. Does not show a microangiopathic blood picture

The gorgeous photo of Leiden (as in Factor V Leiden) was taken by Motumboe (http://www.flickr.com/photos/motumboe/2709667509/).

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.

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. It was explained that this is often due to deficiency of the ADAMTS13 enzyme, which normally inhibits vWF multimers from getting too large. My question is about the normal state of play between vWF and ADAMTS 13. From what I can infer: when no clotting is needed, the ADAMTS13 successfully stops the vWF forming multimers etc. But what happens when we need to clot? What inhibits the ADAMTS 13 protease? What’s that mechanism?

A. First, a little background about von Willebrand factor (VWF). VWF is constitutively released into the blood by endothelial cells as multimers of varying size. A significant amount of VWF is stored in Weibel-Palade bodies, mostly as super-big multimers (called ultra-large VWF, or UL-VWF); this pool is released upon endothelial cell activation. Larger VWF multimers bind circulating platelets more readily than smaller forms. These big multimers also change shape as blood flows faster (normally they circulate in globular forms, but when they are exposed to increased shear forces – like in the microcirculation, or in areas of endothelial injury – they unravel into “stringlike” shapes, which expose more platelet-binding sites on the VWF molecule).  So at sites of endothelial disruption, VWF binds to collagen and unfolds in response to shear forces. This facilitates platelet tethering (adhesion) to the subendothelium, which is necessary for the formation of a good platelet plug.

If we didn’t have a way to keep these large VWF multimers under control, there would be a ton of thrombus formation going on! In fact, that is exactly what happens in the disease you mention, thrombotic thrombocytopenic purpura (we’ve talked about TTP before here and here). Patients have tons of UL-VWF floating around, and they make lots of little thrombi, especially in the microcirculation.

It turns out we do have a way to keep these large VWF from running rampant: it’s an enzyme called ADAMTS13. This enzyme cleaves the UL-VWF, inactivating it.  But if you think about it, you’d need a way to regulate the ADAMTS13 too – which is exactly what you’re asking. If you didn’t have some way to regulate ADAMTS 13 activity,  you’d never make good platelet plugs when you needed to! The ADAMTS 13 would just cleave the VWF as soon as it unraveled, and you’d get no platelet tethering and no thrombus.

The answer to that conundrum is that thrombin, plasmin, and factor XA all cleave ADAMTS 13 and inactivate it. Thrombin, in particular, seems to do a really good job. That’s cool: thrombin actually inactivates an enzyme (ADAMTS 13) in order to promote growth of the thrombus! And on the surface of adjacent uninjured endothelium, any thrombin hanging around would preferentially bind to thrombomodulin (and so be unable to interact with – and inhibit – ADAMTS 13). So in this region of normal endothelium, ADAMTS 13 would be able to act like it normally does, cleaving vWF and preventing thrombus formation.

Whew. The more people find out about coagulation and thrombus formation, the more I think you can just take whatever little coagulation cascade diagram you have and draw arrows from everything to everything else.

Image of Adam (looking fairly inactive at the moment): Michelangelo, Sistine Chapel.

Q. I have a question about von Willebrand Factor – where is it stored? All that I can gather is that it’s stored in ‘Weibel-Palade bodies’, but where are they? Are they in the vessel wall, in the platelet, free-floating in the blood? It’s confusing me a little bit.

A. First, a little background. Von Willebrand Factor is a huge multimeric protein that is made by megakaryocytes and endothelial cells. It functions in both the initial, platelet-plug phase of hemostasis (in which it glues the platelets to the endothelium), and in the second, fibrin-forming phase of hemostasis (in which it serves as a carrier molecule for factor VIII that keeps factor VIII from being prematurely degraded).

In Von Willebrand disease, von Willebrand factor is either decreased or abnormal. This means that patients have a hard time gluing platelets to their endothelium during clot formation (so the initial platelet plug doesn’t form as well). They also may have a hard time forming fibrin, since von Willebrand factor is a carrier (degradation-preventing) molecule for factor VIII, and factor VIII is a critical factor in the coagulation cascade.

So. Where is von Willebrand factor stored? In a few different places, it turns out:

1. Endothelial cells. Endothelial cells synthesize von Willebrand factor and store it in little organelles called Weibel-Palade bodies (named after the two scientists who discovered them). The main things found in Weibel-Palade bodies are von Willebrand factor (described above) and P-selectin (a cell-adhesion molecule that endothelial cells use to catch passing leukocytes, allowing them to leave the blood vessel and migrate into the surrounding tissue).

2. Platelets. Megakaryocytes (big cells in the bone marrow that give rise to platelets) synthesize von Willebrand factor, and it gets stored in the alpha granules of platelets.

This is a good idea, because the main job of von Willebrand factor is to act as the glue that sticks the platelets down onto the subendothelium! So it’s stored in places near the place it’s needed most.

Image credit: kodama (home) (http://www.flickr.com/photos/kodama/4541652/), under cc license.

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 fibrin-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)

Here’s a good question about two entities that sound the same (but aren’t).

Q. What is the difference between heparin associated thrombocytopenia (HAT) and heparin induced thrombocytopenia (HIT)?

A. Heparin-induced thrombocytopenia (HIT) is defined as a decrease in platelet count during or shortly after heparin exposure. There are two types of HIT:

1. HIT type I (used to be called heparin-associated thrombocytopenia) – a benign, probably non-immune form of HIT that is not associated with an increased risk of thrombosis. It is mild, with platelet counts rarely dipping below 100,000. It affects up to 10% of patients receiving heparin treatment, and it disappears with withdrawal of heparin.

2. HIT type II – an immune-mediated type of HIT that is associated with an increased risk of thrombosis. It is associated with significant morbidity and mortality if unrecognized.

Here is a good article that goes into greater depth on HIT, especially the second type:
http://www.thrombosisjournal.com/content/3/1/14

Photo credit: Amanda Dowling (http://www.flickr.com/photos/tinkerroll21/3279134315/)

Here’s a nice boards – type question that requires you to put together some clinical and laboratory data to form a diagnosis, and then describe what the blood smear would look like.

—————————————————————————————–

A previously-healthy 32-year-old woman presents with recurrent headaches. She develops nausea, vomiting, weakness, and easy bruisability. Her laboratory values are as follows:

Hgb = 6.9
MCV = 80
Plt = 30,000
WBC=15,000

She is immediately admitted to the hospital. Over a two day period, she becomes lethargic, and lapses into a coma. A peripheral blood smear is most likely to show which of the following?

A. Macrocytes
B. Spherocytes
C. Schistocytes
D. Sickle cells
E. Target cells

—————————————————————————————–

This question describes a patient with marked anemia and thrombocytopenia (but the WBC is normal – even above normal – so you can rule out the causes of pancytopenia). Her clinical symptoms include various non-specific findings, like nausea and vomiting, but also the specific finding of neurologic deficits.

Her symptoms and laboratory values are consistent with TTP (thrombotic thrombocytopenic purpura), which is a disorder that’s part of a group of disorders called “thrombotic microangiopathies.” Thrombotic microangiopathies are a group of syndromes, including TTP and HUS, in which something triggers platelet activation, and the patient ends up with thrombi all over the place – with resultant thrombocytopenia (the patient is using the platelets up in making the thrombi) and microangiopathic hemolytic anemia (red cells are getting snagged on the fibrin strands as they go through the thrombi-laden vessels).

In TTP, the “something” that triggers platelet activation is abnormal von Willebrand factor. It turns out that normally, when von Willebrand factor is released into the circulation, it’s in a big, long multimer (called “unusually large vWF.” In this state, it causes platelet aggregation! But we have an enzyme called ADAMTS13 that cleaves unusually large vWF into smaller, less active pieces, which work well (but not too well).

Patients with TTP lack this enzyme (either they’re making antibodies to it, or they are missing it from birth) – so they have this unusually large vWF floating around, which traps platelets and causes thrombi.

The symptoms in TTP are usually described as a pentad: 1) hematuria and jaundice (from the microangiopathic hemolytic anemia), 2) bleeding and bruising (from the thrombocytopenia), 3) fever (who knows why), 4) bizarre behavior or neurologic deficits (from thrombi in the brain), and 5) decreased urine output (from thrombi in the kidneys leading to kidney failure). In reality, not all patients have all of the symptoms – so you don’t need to have all 5 by any means to diagnose it. Treatment depends on whether it’s acquired or hereditary. Acquired cases tend to be more severe for some reason, and the treatment involves daily plasmapheresis (to get rid of the antibodies to ADAMTS13). The hereditary cases are usually treated with plasma infusions every three weeks or so (to replace the missing enzyme).

So: the answer to the question is C, schistocytes. Schistocytes are a special type of fragmented red cells (they are small, with pointy outlines, and no central pallor) that are characteristic of microangiopathic hemolytic anemia (you can see a whole bunch of these in the image above!). Sometimes you can see things that look sort of similar to schistocytes in other anemias – such as the bite cells you see in glucose 6 phosphate dehydrogenase deficiency. But any time you see something you even think might be a schistocyte, you need to explore the possibility of a microangiopathic hemolytic process, because some of the things that cause microangiopathic hemolytic anemia are very dangerous (like TTP!), and you would not want to miss them.

Note: the very nice image of a microangiopathic hemolytic anemia (see all the schistocytes?) was taken by Ed Uthman and can be found at http://commons.wikimedia.org/wiki/File:DIC_With_Microangiopathic_Hemolytic_Anemia_(301920983).jpg.

Another great board-type review question, this time on von Willebrand disease and hemophilia:

A 34-year-old male presents with excessive bleeding. He has a family history of bleeding, and his laboratory results are as follows:
1. PTT (partial thromboplastin time): increased
2. Bleeding time: increased
3. Platelet aggregation studies: abnormal (no aggregation with ristocetin)
4. Factor VIII level: decreased.

Which of the following is the most likely diagnosis?
A. Hemophilia A
B. Hemophilia B
C. von Willebrand disease
D. Factor V Leiden
E. Antiphospholipid antibody syndrome

————————————————–

This question is asking you to a) identify which of the distractors is, in fact, a bleeding disorder, and b) decide based on laboratory tests which is the most likely diagnosis. Let’s take the answers one by one.

Answer A (hemophilia A) is wrong. But if you were in a hurry, you might see the “decreased factor VIII level” part of the question and rush right toward A, because in hemophilia A, the whole problem is that you don’t have enough factor VIII around. However, this is the wrong answer for a few reasons. Although the PTT result is consistent with hemophilia A (if you don’t have enough factor VIII, the intrinsic arm of your coagulation pathway will not be working properly, and the PT will be prolonged), the other lab tests are not. The bleeding time is normal in hemophilia, because this test only measures the how the platelets function in vivo – it has nothing to do with coagulation! Kind of counterintuitive, but it’s true. The bleeding time is really measuring how fast you can form your intitial platelet plug; the test ends at that point. Whether you have enough factor VIII to make fibrin or not is immaterial – the test is over and done by that point. See our previous post on what the bleeding time measures for more information on this. Also, platelet aggregation studies are normal in hemophilia (it’s the coagulation cascade that is abnormal, not the platelets).

Answer B (hemophilia B) is incorrect for all the above reasons; plus, hemophilia B involves factor IX, not factor VIII.

Answer C is correct.  The lab test results in this question are all consistent with von Willebrand disease. Patients with von Willebrand disease have decreased amounts of (or functionally abnormal) von Willebrand factor, which is the factor that glues platelets down onto the subendothelium. In addition, factor VIII is decreased (von Willebrand factor is the carrier for factor VIII, so if there’s less vWF around, there will be less factor VIII around). So, in von Willebrand disease, the PTT is increased (less factor VIII leads to a prolonged PTT). The bleeding time is also increased in von Willebrand disease (in vWD, the platelets are less able to stick to the subendothelium, so it takes longer to form the initial platelet plug). Finally, in von Willebrand disease, platelet aggregation studies are abnormal (the platelets don’t aggregate with ristocetin in von Willebrand disease, because ristocetin causes platelets to express their little GP Ib receptors, which are the receptors that bind vWF. If you don’t have enough vWF around, or it’s functionally abnormal, giving ristocetin won’t do squat to the platelets – they will remain unaggregated.

Answer D is wrong on many levels. First, Factor V Leiden is a thrombotic disorder, not a bleeding disorder. Also, coagulation tests are normal in Factor V Leiden! So are the bleeding time and platelet aggregation studies (not that you’d order these tests – you’d be too smart for that). And the factor VIII level is normal, obviously.

Answer E is wrong too. Antiphospholipid antibody syndrome is a disorder that – if anything – causes thrombosis in patients! Many times, these antibodies do nothing at all in the patient; sometimes they can cause thrombosis. But when you run coagulation tests, the antiphospholipid antibodies bind to the reagent (for example, thromboplastin), effectively using it up and removing it from the test tube – so the coagulation test result looks prolonged! Weird. The patient is either normal or is clotting excessively, and the test results say the patient should be bleeding. So in this question, the PTT result fits with antiphospholipid antibody syndrome. However, none of the other test results are consistent with this disease.

Note: the image of a different type of review was taken by Anna Majkowska and can be found at http://www.flickr.com/photos/majkowska/2622920603/.