Mixed platelet and coagulation disorders: Pathology review

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Case study0:00–1:05

At the emergency department, a 70 year old male named Max is admitted because of high fever with chills, and hypotension.
He complains of having urinary urgency, frequency and dysuria, or painful urination, for the last few days. A few hours after admission, he rapidly deteriorates and starts to bleed from venipuncture sites.
Urine and blood cultures are ordered and are both positive for gram negative rods. Lab tests show low platelet count, and bleeding time, PT and PTT are prolonged, fibrinogen is decreased and d-dimers are elevated.
Peripheral blood smear shows schistocytes. Now, there’s also an 18 year old female, named Sylvia, that came in with recurrent severe nose bleeds.
She also complains of heavy menstrual periods. Family history reveals her father also suffered from bleeding diathesis.
Lab tests show normal platelet count, prolonged bleeding time and PTT, and normal PT. Both Max and Sylvia are suffering from a hemostasis disorder.

Pathology1:05–2:01

Hemostasis disorders, also known as bleeding disorders, can be broadly divided into three groups. The first includes problems with primary hemostasis, which is the formation of the weak 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.
Okay, in this video, we will focus on mixed platelet and coagulation disorders, that include disseminated intravascular coagulation, or DIC, and von Willebrand disease.

Disseminated intravascul2:01–3:41

Alright, so let’s take a closer look at these disorders, starting with DIC, which is a massive overactivation of the coagulation system including both platelets and clotting factors.
For your exams, it’s important to know that DIC can occur in response to serious conditions including gram negative bacterial sepsis, trauma, and obstetric complications such as abruptio placenta and retained dead fetus in utero, acute pancreatitis, malignancies such as adenocarcinomas and promyelocytic leukemia, nephrotic syndrome, snakebites, and transfusion reactions.
Okay, whatever the cause, there is a release of a procoagulant that tips the scales in favor of clot formation. Procoagulants could be enzymes that help to proteolytically cleave and activate clotting factors or proteins like bacterial components such as lipopolysaccharide or tissue factor also known as thromboplastin.
For your test, remember that the release of tissue factor from abruptio placenta into the maternal circulation, is, in fact, the most common cause of DIC in pregnancy.
DIC leads to widespread clotting, which can block off small arteries leading to organ ischemia. These clots also act like jagged rocks in a river and damage the red blood cells floating by, causing microangiopathic hemolytic anemia.
These damaged RBCs can be seen on a blood smear as schistocytes but sometimes they get destroyed completely. At the same time, excessive clot formation depletes platelets and clotting factors, which paradoxically, leads to increased bleeding.Now, let’s move onto von Willebrand disease, the most common inherited bleeding disorder.

Von Willebrand disease3:41–4:38

It’s usually caused by autosomal dominant mutations of von Willebrand factor. These proteins normally serves as the glue between the platelet receptor Gp1b and the collagen underneath the endothelial cells.
So, for the test remember that if there’s a problem with von Willebrand factor, it’s hard for platelets to adhere to collagen in damaged blood vessels, leading to impaired platelet function.
Inherited von Willebrand disease is subclassified into type 1, which is a decrease in the quantity of von Willebrand factor, and type 2, which is a decrease in the function of von Willebrand factor.
Meanwhile, von Willebrand factor also stabilize factor 8 of the intrinsic coagulation pathway. So without von Willebrand factor, there’s less functioning factor 8 around, leading to decreased activation of the coagulation cascade.

Symptoms4:38–6:33

So mixed platelet and coagulation disorders affect both primary and secondary hemostasis, and as a result they can present with symptoms caused by dysfunctions in both pathways.
Primary hemostatic, or platelet, problems 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.
In contrast, secondary hemostatic, or coagulation, problems can present with large bruises after minor trauma, like bumping into a door.
They also suffer from ecchymoses, which is discoloration caused by bleeding under the skin, deep tissue hematomas, hemarthrosis, which is bleeding inside the joint space, posterior epistaxis, which causes a severe nosebleed, GI bleeding, urinary bleeding, and persistent bleeding after surgical procedures.Now, a dangerous complication is intracerebral hemorrhage, or bleeding into the brain, which can cause a stroke or increased intracranial pressure.
Okay, so mixed platelet and coagulation disorders can present with a mix of symptoms of platelet and coagulation disorders, but other symptoms can help you identify the specific disease.
In DIC, initially, the patient is more likely to clot, and that leads to overconsumption of the coagulation factors and platelets.
Then, there’s a period in which the patient is more likely to bleed from everywhere, including from venipuncture sites. Moving onto von Willebrand disease.
Although patients usually have mucocutaneous bleeding that’s characteristic of primary hemostatic problems, some people can also have deep tissue bleeding characteristic of secondary hemostatic disorders.

Diagnosis6:33–9:11

Alright, now let’s switch gears and look at diagnosis. Individuals with DIC will 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. Bleeding time is rarely measured nowadays, because they’ve been replaced by another screening tool called platelet function analyzers, but this could still come up on your exams!
People with DIC will also have a prolonged prothrombin time or PT, which is caused by the decreased levels of coagulation factors used in the extrinsic and common coagulation pathways.
They also have a prolonged partial thromboplastin time or PTT, which is caused by a decreased level of coagulation factors in the intrinsic and common coagulation pathways.
So patients with DIC will have prolonged bleeding time, PT and PTT. For red blood cells, we have microangiopathic hemolytic anemia and a clue for this is the presence of schistocytes on peripheral blood smear.
Another high yield fact you need to remember is that the levels of clotting factors like fibrinogen, factors V and VIII, are also decreased, while there are elevated d-dimer levels that indicate accelerated clot lysis.
Finally, an important clue for the diagnosis of DIC is a recent history of serious medical conditions like sepsis that could have triggered the condition.
Now, Von Willebrand disease is a chronic disorder, so CBC might show macrocytic or normocytic anemia due to recurrent bleeding.
There’s usually a normal platelet count since it’s a qualitative platelet problem, not a quantitative one. There’s also a prolonged bleeding time which is an indicator of platelet function and PTT may be normal or elevated in patients with decreased factor VIII activity that is part of the intrinsic coagulation pathway.
PT is always normal since the extrinsic pathway is not affected. So we have prolonged bleeding time, normal to high PTT and normal PT.
Another test called the von Willebrand factor ristocetin cofactor assay can also be done. In this test, a patient’s blood is mixed with an antibiotic called ristocetin.
Normally, ristocetin helps brings von Willebrand factor and platelet receptor Gp1B together creating platelet aggregation.

Treatment9:11–9:32

But in von Willebrand disease, von Willebrand factor is either decreased or dysfunctional, so the ristocetin cofactor assay shows decreased platelet aggregation.
Finally, since it’s an inherited disorder, a family history can also be an important clue on the exams.Moving on to treatment, for DIC, it focuses on treating the underlying cause and supporting the various organs.

Review9:32–10:06

And then, for von Willebrand disease, it is high-yield to know that it includes desmopressin, which help releases von Willebrand factor stored in the endothelium into the circulation.
Okay, to review! Mixed platelet and coagulation disorders can occur when there’s a defect in both primary and secondary hemostasis, like in DIC where there’s an over consumption of platelets and clotting factors, and in von Willebrand disease, which is caused by impaired platelet adherence.

Summary10:06–10:47

A diagnosis can be made based on clinical presentation, CBC, peripheral blood smear, lab findings, but also more specific lab tests like the ristocetin cofactor assay.
Treatment is supportive for DIC and desmopressin for von Willebrand disease.Now, back to the patients! Both of them have a mixed platelet and coagulation disorder.
Due to his history of urinary tract infection symptoms and positive urine and blood cultures, Max has a UTI complicated by gram negative sepsis.
After that, he developed DIC since he has thrombocytopenia,
Mixed platelet and coagulation disorders: Video | Osmosis