Platelet disorders: Pathology review
AssessmentsPlatelet disorders: Pathology review
USMLE® Step 1 style questions USMLE
A 9-year-old boy is brought to the emergency department by his parents due to prolonged bleeding following a tooth extraction earlier in the day. Past medical history is noncontributory. Temperature is 37.5°C (99.5°F), pulse is 88/min, respirations are 14/min, and blood pressure is 112/62 mmHg. Physical exam shows gingival bleeding and petechiae. Laboratory testing is obtained, and the results are shown below.
|Prothrombin time (PT)||12 seconds|
|Activated partial thromboplastin time (aPTT)||29 seconds|
|Bleeding time*||15 minutes|
Which of the following conditions is the patient at greatest risk of developing?
Content Reviewers:Yifan Xiao, MD
Contributors:Tanner Marshall, MS, Alex Aranda, Maria Emfietzoglou, MD, Robyn Hughes, MScBMC
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.
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.
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. ITP is caused by autoantibodies that bind to the platelet receptor GpIIbIIIa, 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 GpIb and the collagen underneath the endothelial cells.
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.
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.
The term thrombasthenia literally means “weak platelets”.
And it’s caused by a deficiency in the platelet receptor GpIIbIIIa, 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 GpIb.
GpIb 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.
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.
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