Platelet disorders: Pathology review

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Case study0:00–0:37

At the family medicine center, a mother came in with her 5 year old child, Alana. Several days ago, Alana developed bloody diarrhea after eating undercooked ground beef and her mother noticed her face was pale and she only urinated once in the past 12 hours.
Next to her, there’s a 30 year old person named Danika, who came in complaining of increased bruising for the past several months.
She has no other symptoms and physical examination shows multiple ecchymoses on the extremities. Both Alana and Danika are suffering from a hemostasis disorder.

Pathology0:37–2:34

Hemostasis disorders, also known as bleeding disorders, can be broadly divided into three groups. The first includes problems with primary hemostasis, which is when there’s a problem forming the initial platelet plug, and so, they’re referred to as platelet disorders.
Now, the second group includes problems with secondary hemostasis, which is making a strong fibrin clot through activation of the intrinsic, extrinsic and common coagulation pathways, and are also known as coagulation disorders.
And the last group includes disorders that affect both primary and secondary hemostasis and are known as mixed platelet and coagulation disorders.
For this video, let’s focus on the platelet disorders. These can be further subdivided into two categories.
In the first category, there’s thrombocytopenia, which is defined as a platelet count below 150,000 per microliter, with the normal range being between 150,000 and 450,000.
Thrombocytopenia can be caused by increased platelet destruction, which can be immune-mediated, like in heparin induced thrombocytopenia, or HIT, and immune thrombocytopenic purpura, or ITP.
Other cases can be non-immune mediated, like thrombotic thrombocytopenic purpura, or TTP, and hemolytic-uremic syndrome, or HUS.
Thrombocytopenia from these cases is often due to an increased consumption of platelets during the formation of abnormal clots.
And as a result, there are fewer platelets left in circulation. Alright, now, in the second category of platelet disorders, there’s a decrease in platelet function, while the platelet count can be normal, like in Glanzmann thrombasthenia, Bernard-Soulier syndrome, and uremic platelet dysfunction.
Okay, so let’s take a closer look at these different platelet disorders, starting with the immune-mediated causes of platelet destruction.

Heparin induced thromboc2:34–3:16

First, there’s heparin induced thrombocytopenia, or HIT, which is a reaction that develops 5 to 15 days after starting either unfractionated or low-molecular weight heparin.
Remember for your exams that the risk for HIT is greater with unfractionated heparin. HIT is caused by an IgG antibody that binds to an antigen complex made of heparin and the endogenous cytokine platelet factor 4.
The antibody then binds to and activates platelets, causing them to get used up when they form numerous blood clots. Alright, next we have immune thrombocytopenic purpura, or ITP.

Immune thrombocytopenia3:16–3:59

ITP is caused by autoantibodies that bind to the platelet receptor Gp2B3A, and target platelets for destruction in the spleen.
It’s like the platelet equivalent of autoimmune hemolytic anemia, where antibodies and complement are directed against RBCs, targeting them for destruction.
In fact, some patients develop both conditions together and that’s called Evan’s syndrome. When ITP occurs by itself, it’s called primary ITP, but when it’s triggered by another condition like hepatitis C, HIV, or lupus - it’s called secondary ITP.
Now, let’s move onto non-immune mediated causes of platelet destruction. So, normally, endothelial cells store and release Von Willebrand factor, which serves as the glue between the platelet receptor Gp1b and the collagen underneath the endothelial cells.

Thrombotic thrombocytope3:59–5:09

Many individual von willebrand factors can clump together, forming large multimers. Eventually, to prevent the clot from getting too big, a metalloproteinase called ADAMTS-13 comes along and breaks down the multimers.
In thrombotic thrombocytopenic purpura, or TTP, there can be a genetic deficiency of ADAMTS-13, or an autoantibody against ADAMTS-13.
Sometimes autoantibodies to ADAMTS-13 develop after exposure to antiplatelet medications like ticlopidine and clopidogrel, or chemotherapeutic agents like cyclosporine and gemcitabine.
Alternatively, they can be associated with diseases like systemic lupus erythematosus. Ultimately, the result is an accumulation of von willebrand factor multimers, and that causes excessive platelet adhesion and clot formation within small blood vessels throughout the body.
Alright, now HUS is clinically similar to TTP, and there are two types of HUS; typical and atypical. The typical type is also called shiga-toxin producing Escherichia coli HUS, or SPEC-HUS.

Hemolytic uremic syndrom5:09–6:29

It classically occurs in children and develops after an episode of gastroenteritis caused by shiga toxin producing organisms, like enterohemorrhagic Escherichia coli subtype O157:H7 and Shigella dysenteriae.
This shiga toxin destroys colonic epithelial cells, causing bloody diarrhea. It then enters the circulation, where it damages the endothelial cells, triggering a massive release of von willebrand factor.
This leads to excessive platelet adhesion, and clot formation throughout the body. Typical HUS carries a good prognosis and usually isn’t life-threatening.
On the other hand, atypical HUS is not associated with shiga-toxin producing Escherichia coli, may occur at any age, and has a relatively poor prognosis.
Atypical HUS is linked to a genetic mutation in factor H, a protein that normally controls the complement system. Without factor H, the complement system goes wild, causing damage to the endothelial cells.
Okay, now let’s move onto disorders with platelet dysfunction. Glanzmann thrombasthenia is an autosomal recessive bleeding disorder.

Glanzmann thrombasthenia6:29–6:58

The term thrombasthenia literally means “weak platelets”. And it’s caused by a deficiency in the platelet receptor Gp2b3a, which is necessary for platelets to stick to each other via fibrin.
So even though the platelet count can be normal, there’s diminished platelet aggregation. Moving on, Bernard-Soulier is a rare autosomal recessive disorder caused by a deficiency or absence of the platelet receptor Gp1b.

Bernard-Soulier syndrome6:58–7:25

Gp1b normally binds to von Willebrand factor which it self is bound to the collagen exposed in the damaged endothelial lining.
So here, platelets can’t adhere to the damaged blood vessels and they won’t activate the platelet plug formation process.
Finally, there’s uremic platelet dysfunction which occurs in individuals with chronic kidney disease. The pathophysiology isn’t fully understood, but it’s thought that there’s an accumulation of toxins which interferes with the normal platelets - endothelium interaction.

Uremic platelet dysfunct7:25–7:43

Symptoms7:43–10:47

Whatever the cause, platelet problems, or primary hemostatic disorders, usually present with petechiae, which are pinpoint superficial skin bleeds, anterior epistaxis, which are usually mild nosebleeds, immediate bleeding after surgical procedures, like tooth extraction, or bleeding from mucosal surfaces, like gingival, gastrointestinal, or vaginal bleeding.
Now, when there’s thrombocytopenia like in ITP, the lower the platelet count, the higher the risk of bleeding or bruising.
Spontaneous bleeds start to happen when the platelet count falls below 30,000, with spontaneous intracranial bleeds developing when the platelet count falls below 10,000.
Finally, most surgical procedures can be performed as long as the platelet count is above 50,000. Alright, but other symptoms can help you identify the specific disease.
Let’s start with HIT, which is the most common cause of thrombocytopenia in hospitalized individuals. For your exams, it’s important to know that individuals with HIT more often develop paradoxical thrombotic events, rather than bleeding.
Thrombotic events can be life threatening and are most often venous, causing deep vein thrombosis, pulmonary embolism, or cerebral venous sinus thrombosis or less often arterial, causing limb gangrene, stroke, or myocardial infarction.
Other individuals simply have thrombocytopenia on a CBC. Now, ITP is most of the time asymptomatic, but in severe cases it can cause petechiae and mucocutaneous bleeding.
Next up is TTP that classically presents with five symptoms: thrombocytopenia, microangiopathic hemolytic anemia, which occurs due to destruction of the red blood cells by large clots, and causes fatigue; fever, renal insufficiency, which can cause hematuria and decreased urine output; and neurologic symptoms like headache and confusion.
However, only some individuals get all five symptoms. Now, the classic presentation of HUS is a triad of thrombocytopenia, renal insufficiency, and microangiopathic hemolytic anemia.
It’s super important to remember for the exams that typical HUS occurs in children, usually under 10 years old, and appears five to ten days after an episode of gastroenteritis often associated with eating undercooked ground beef, drinking unpasteurized milk or swimming in contaminated water.
Another high yield fact to remember is that, unlike TTP, HUS doesn’t usually cause a fever or neurological symptoms, and instead the renal insufficiency symptoms predominate.
Now, Glanzmann thrombasthenia and Bernard-Soulier syndrome present in childhood with mild, mucocutaneous bleeding. Finally, uremic platelet dysfunction often presents with abnormal bleeding in individuals with end-stage renal disease, which improves after dialysis.
Alright, now let’s switch gears and look at diagnosis. Individuals with platelet disorders often have a prolonged bleeding time, which involves mildly pricking the patient, and then timing how long it takes for them to stop bleeding - normally, this occurs within two to five minutes.

Diagnosis10:47–15:25

Bleeding time is rarely measured nowadays, because it’s been replaced by another screening tool called platelet function analyzer.
An important fact to remember is that markers of secondary hemostasis like prothrombin time or PT, and partial thromboplastin time or PTT are normal, since they’re not involved in formation of the platelet plug.
Okay! Now, let’s look at specific lab tests that can help you identify the cause of the primary hemostatic disorders.
Diagnostic testing for HIT includes an ELISA serological assay to detect the antibodies. Unfortunately, many individuals that have received heparin form these antibodies but don’t have HIT, so the test is not very specific.
A more specific test is the serotonin release assay, which is the gold-standard for diagnosing HIT. In the serotonin release assay, the patient’s serum is mixed with heparin and donor platelets.
Activated platelets release serotonin. So in a positive test, the patient’s serum has antibodies that bind to heparin and the platelets, and cause those platelets to release serotonin.
For ITP, it’s important to remember that this is a diagnosis of exclusion, so there’s no specific test that confirms the diagnosis.
Interestingly, the CBC usually shows isolated thrombocytopenia, with a normal hematocrit and leukocyte count. Also, the megakaryocytes start releasing large platelets, which makes the mean platelet volume increase.
Now, in some cases, if there’s significant bleeding, it can lead to anemia. And in the minority of patients who have concurrent autoimmune hemolytic anemia, there can be spherocytes on the peripheral blood smear.
An abdominal ultrasound is often done to rule out splenomegaly, and hepatitis C virus and HIV testing are done, since ITP can be triggered by those infections.
Alright, now to diagnose TTP, thrombocytopenia and microangiopathic hemolytic anemia have to be present. A CBC will show low platelet count and normocytic normochromic anemia, and a peripheral blood smear will show schistocytes, which are fragmented red blood cells.
Because there’s a hemolytic anemia, the unconjugated bilirubin and lactate dehydrogenase levels are elevated. In addition, haptoglobin levels are decreased, because haptoglobin binds to free hemoglobin in the circulation.
Also, since the hemolysis is not immune mediated, a Coombs test is often negative. Creatinine levels may be elevated if there is kidney damage.
Now, laboratory studies in HUS are similar to TTP, with a CBC showing anemia and thrombocytopenia, the peripheral blood smear showing schistocytes, and elevation of lactate dehydrogenase, unconjugated bilirubin and creatinine levels, as well as decreased haptoglobin levels.
When typical HUS is suspected in a child, stool cultures can be sent off to look for E. coli or Shigella dysenteriae.
Next up is Glanzmann thrombasthenia. A CBC may show anemia due to bleeding, and a normal platelet count.
Peripheral blood smear shows no platelet clumping which can be an important hint. Also, unlike von Willebrand disease and Bernard-Soulier, platelets do aggregate in response to ristocetin, since there’s nothing wrong with von Willebrand factor or Gp1b.
Now, in Bernard Soulier syndrome, a CBC can show anemia from bleeding, and there may also be a thrombocytopenia. That’s because the megakaryocytes in the bone marrow make really large platelets that aren’t properly counted by the platelet counting machine, resulting in a low platelet count.
These giant platelets don’t aggregate in response to ristocetin. However, addition of normal plasma to the test sample does not correct platelet aggregation, because there’s a defect in the platelet receptor, and not von Willebrand factor.
Finally, uremic platelet dysfunction. Oddly, chronic kidney disease leads to anemia of chronic disease due to erythropoietin deficiency.
Evidence of kidney disease like an elevated blood urea nitrogen and creatinine help confirm the diagnosis. Alright, now, let’s discuss treatment.

Treatment15:25–16:48

For HIT, it’s simply stopping heparin and starting anticoagulation with a non-heparin anticoagulant, like argatroban, which is a thrombin inhibitor.
For ITP, treatment starts with corticosteroids or intravenous immunoglobulin, both of which help stop the formation of new autoantibodies.
In harder cases, a splenectomy can be done to get rid of the splenic macrophages that are destroying the platelets. As an alternative, other medications can be tried, like rituximab, an anti-CD20 monoclonal antibody, or eltrombopag and romiplostim, which are thrombopoietin receptor agonists.
Next, TTP is treated with corticosteroids like prednisone and plasmapheresis, which gets rid of the patient’s plasma along with all of the large von willebrand factor multimers, and replaces it with new plasma.
Similarly, plasmapheresis is done in HUS, the patient’s plasma is exchanged with plasma that has a normal amount of ADAMTS13 and lacks the antibodies that might be destroying it.
Now, Then, most patients with Glanzmann’s thrombasthenia and Bernard-Soulier don’t require any treatment, but in more serious bleeding, platelet transfusions can be done.
Finally, for uremic platelet dysfunction, the main thing is to address the chronic kidney disease. All right, as a quick recap.

Review16:48–17:23

Platelet disorders can occur when there’s decreased platelet count or decreased platelet function. Decreased platelet count can be due to immune-mediated platelet destruction like in HIT and ITP, or due to non-immune mediated destruction like in TTP and HUS.
Now, disorders with platelet dysfunction include Glanzmann thrombasthenia, Bernard Soulier syndrome, and uremic platelet dysfunction.
A diagnosis can be made based on clinical presentation, CBC, peripheral blood smear, lab findings, but also more specific lab tests.

Summary17:23–18:18

Now, back to the patients! Alana has the classic presentation of HUS where an episode of infectious gastroenteritis lead to signs of anemia and renal failure.
Laboratory studies will reveal anemia with elevation of lactate dehydrogenase and unconjugated bilirubin, thrombocytopenia, and increased creatinine levels.
Peripheral blood smear will show schistocytes and stool cultures can be sent off to look for E. coli or Shigella dysenteriae.
Meanwhile, Danika has isolated thrombocytopenia most probably caused by ITP which is a diagnosis of exclusion. CBC will show thrombocytopenia with increased mean platelet volume, normal hematocrit and white leukocyte count, peripheral blood smear will be normal, and an ultrasound should be done to exclude splenomegaly.
...And that’s the platelet disorders pathology in a nutshell.
Platelet disorders: Video, Causes, and Symptoms | Osmosis