Coagulation disorders: Pathology review

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Case Study0:00–1:07

At the hematology ward, there’s Braden, a 5 year old male, who developed prolonged bleeding after circumcision. His mother is worried because he has a history of recurrent hemarthrosis after minor falls.
Family history reveals a relative of his mother who suffered from bleeding diathesis. Now, there’s also a 3 day old preterm baby, called Harlow, who is bleeding severely from the umbilicus.
Her mother states that she did not get the standard care after delivery. CBC, PT and PTT are ordered for both patients.
They both have normal platelet count. Now, Braden has normal PT but elevated PTT, while Harlow has both PT and PTT elevated.
Both Braden and Harlow are suffering from a hemostasis disorder. Hemostasis disorders, also known as bleeding disorders, can be broadly divided into three groups.

Pathology1:07–2:04

The first includes problems with primary hemostasis, which is the formation of the platelet plug, so they are also called platelet disorders.
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 so they’re 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.
Let’s focus on coagulation disorders that are usually due to a decrease in the number of clotting factors and causes include hemophilia and vitamin K deficiency.
So, let’s look at hemophilia first. They are a group of inherited bleeding disorders caused by deficiencies in various coagulation factors.

Hemophilia2:04–2:54

Hemophilia A and B are X-linked recessive disorders so a high yield fact is that they almost exclusively affect males while females are carriers.
A big hint for hemophilia is a family history of a maternal relative with a bleeding disorder. Hemophilia A causes a deficiency in factor VIII, while hemophilia B leads to a deficiency in factor IX.
Hemophilia C on the other hand is an autosomal recessive disorder, meaning it can affect both males and females, leading to a deficiency in factor XI.
Alright, onto another coagulation disorder, vitamin K deficiency. Vitamin K acts as a cofactor to an enzyme found in the liver called gamma glutamyl carboxylase, which converts the non-functional forms of coagulation factors II, VII, IX, and X into their functional forms.

Vitamin K Deficiency2:54–4:39

So without vitamin K, the loss of factor VII means that the extrinsic pathway won’t function; and without factor IX, the intrinsic pathway won’t function; and without factor X and II, the common pathway won’t function.
So, all pathways in the coagulation cascade are affected in vitamin K deficiency. Normally, vitamin K comes from the diet, like in leafy dark green vegetables, like spinach, kale and chard, or can be made by intestinal microbial flora.
So, it’s easy to see that vitamin K deficiency can occur in malabsorption syndromes like cystic fibrosis and celiac disease, or with prolonged use of broad-spectrum antibiotics that kill intestinal microbial flora such as fluoroquinolones and cephalosporins.
Now, deficiency is rare in adults but neonates are particularly susceptible because breast milk is low in vitamin K and at the same time, their intestinal flora is still unable to produce it.
That’s why every newborn gets an intramuscular injection of vitamin K. Whatever the cause, coagulation problems share some common symptoms and these are high yield!

Symptoms4:39–7:13

People with these disorders can get large bruises after very minor trauma, and this is called easy bruising. 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.
For hemophilia A, B and C, the symptoms are nearly clinically identical, which makes sense since factors VIIIa, IXa and XIa work together in the coagulation cascade to activate factor X.
The severity of the symptoms depends on the severity of the underlying mutation. Having 5 to 40% of normal factor activity is mild, 1 to 5% is moderate, and less than 1% is severe.
Unfortunately, most hemophiliacs have severe disease. Male infants often develop excessive bleeding from circumcision, or from dental procedures.
They can also develop a cephalohematoma which is bleeding under the scalp due to trauma from the delivery. There’s also an increased risk of getting hemarthrosis once they start walking and falling.
Repeated episodes of hemarthrosis can causing the joint to deform, severely restricting range of motion and causing chronic pain.
Now, bleeding in vitamin K deficiency can be mild or severe and basically can occur at any site. An important fact to remember for the exams is that babies with vitamin K deficiency, especially if they’re preterm, can develop a condition known as hemorrhagic disease of the newborn.
This usually occurs during the first days of life and is characterized by bleeding from the skin and mucous membranes, the umbilicus, GI bleeding or intracranial bleeding.
Alright, now let’s switch gears and look at diagnostic tests, and this is very high yield. People with hemophilia often have a prolonged partial thromboplastin time, or PTT, since factors VIII, IX and XI are part of the intrinsic pathway.

Diagnostic Tests7:13–8:56

They will have a normal prothrombin time, or PT, and platelet count. It’s important to also rule out von Willebrand disease in these patients, as it too may exhibit a prolonged PTT, since von willebrand factor carries factor 8.
Once von Willebrand disease has been ruled out, a mixing study is done to differentiate whether this PTT prolongation is because of true factor deficiency, or because of presence of a factor inhibitor, like an antibody.
The patient’s plasma is mixed with normal plasma that contains all the factors, and then the PTT is checked again. If the PTT normalizes, then the patient must have a factor deficiency, and is diagnosed with hemophilia.
If the PTT doesn’t normalize, then there must be a factor inhibitor involved. In vitamin K deficiency, Both PTT and PT are elevated since vitamin K-dependent factors are involved in both intrinsic and extrinsic pathways.
PT usually elevates first, since factor VII, which is part of the extrinsic pathway, has the shortest half-life. Now, if PTT and PT correct in response to giving vitamin K, the diagnosis can be confirmed.
Now, treatment includes concentrates of the missing clotting factor VIII, IX and XI for hemophilias A, B and C, respectively.

Treatment8:56–9:23

Desmopressin is also used in hemophilia A, as it stimulates the release of von Willebrand factor from endothelial cells.
In individuals with vitamin K deficiency, vitamin K is administered. All right, as a quick recap!

Review9:23–10:27

Coagulation, or secondary hemostasis, disorders can occur when there’s a decrease in the number of clotting factors, like in hemophilia A, B and C, where there’s deficiency of factor 8, 9 and 11, respectively, and in vitamin K deficiency where factors II, VII, IX, and X cannot be converted to their functional forms.
Now, hemophilia is an inherited disorder while vitamin K deficiency can occur when there are malabsorption syndromes, prolonged use of antibiotics, and in neonates.
A diagnosis can be made based on clinical presentation, patient’s history, CBC, PT, PTT, as well as specific lab tests such as a mixing study.
Treatment of hemophilias includes concentrates of the missing clotting factor plus desmopressin for hemophilia A, and vitamin K in deficient individuals.
Now, back to the patients! Both patients have a bleeding disorder and most probably a coagulation disorder, since PT or PTT are affected and platelet count is normal.

Summary10:27–11:16

Due to his sex, history of recurrent hemarthrosis, family history of a bleeding disorder and prolonged PTT, Braden probably has hemophilia.
A mixing study must be done to distinguish a true factor deficiency from the presence of a factor inhibitor. If hemophilia is confirmed, specific factor VIII, IX, and XI levels will be measured to determine the missing factor.
Meanwhile, Harlow, due to her age and prolonged PT and PTT, probably has hemorrhagic disease of the newborn. This makes sense because she did not receive vitamin K after birth.
...And that’s the coagulation disorders pathology in a nutshell.