Thrombosis syndromes (hypercoagulability): Pathology review

Definitions & Key takeaways

Thrombosis syndromes, also known as hypercoagulability, are a group of disorders characterized by an increased tendency to develop blood clots. These disorders can be inherited or acquired, and they can affect different parts of the body, including the veins and arteries. Thrombosis syndromes can be inherited, like factor V Leiden, prothrombin gene mutation, protein C and S deficiency, antithrombin III deficiency, or acquired like antiphospholipid syndrome.

Diagnosis can be made based on clinical presentation, coagulation studies, more specific lab tests like ELISA for antiphospholipid antibodies, as well as genetic testing to detect the specific mutations. Treatment involves a combination of anticoagulant therapy, lifestyle modifications, and management of the underlying conditions. Anticoagulant medications, such as warfarin and heparin, can help prevent blood clots from forming or growing.

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Case Study0:00–0:48

At the emergency department, a 30 year old Caucasian female named Celia came in with pain and swelling in her right calf.
She has a history of pregnancy loss and her mother has a history of recurrent episodes of venous thromboembolism. Her medical history is otherwise unremarkable.
Coagulation studies show normal PTT. Next to Celia, there’s a 60 year old male called Nicholas who developed a painful lesion on his arm after starting anticoagulation therapy with warfarin.
Now, there’s also a 26 year old African American female named Mary who has recurrent pregnancy losses. She was diagnosed with systemic lupus erythematosus about a year ago.
She has no family history of thrombophilic disorder. All of them suffer from thrombophilic disorders, or thrombosis syndromes, which are inherited or acquired diseases that predispose an individual to clot formation.

Pathology0:48–2:56

Inherited disorders include factor V Leiden, prothrombin gene mutation, protein C and S deficiency, and antithrombin III deficiency, while the most important acquired disorder is antiphospholipid antibody syndrome.
But before going into the individual thrombophilic disorders, let’s go through the normal coagulation system. The coagulation pathway is divided into an extrinsic and an intrinsic pathway, which join into a common pathway that ultimately result in the formation of fibrin clots.
The extrinsic pathway starts when trauma damages a blood vessel, and exposes the cells under the endothelial layer, which have tissue factor in their membrane.
Activated factor VII binds to tissue factor, forming a complex that then binds to and activates factor X. The intrinsic pathway starts when a circulating factor XII, activates factor XI, which then activates factor IX.
Finally, factor IX forms a complex with factor VIII, and this complex binds to and activates factor X. In the common pathway.
Activated factor X activates factor V, which converts prothrombin, or factor II, into thrombin. Thrombin then converts fibrinogen, or factor I, into fibrin, which cross-links to form a fibrin mesh that stabilizes the platelet plug.
Now, prothrombin time, or PT assesses the extrinsic and common coagulation pathways, and partial thromboplastin time, or PTT assess the intrinsic and common coagulation pathways.
Alright, but in order to prevent over-coagulation, the liver makes proteins C and S, which are vitamin K-dependent anticoagulant factors.
In the presence of protein S as a cofactor, protein C acts by enzymatically inactivating factors V and VIII. Finally, a protein called antithrombin III inhibits factor X and factor II.
Alright, now let’s take a closer look at the different thrombophilic disorders, starting with the inherited ones. Factor V Leiden is the most common hypercoagulable disorder in people of caucasian descent, and was named after the town Leiden in Holland, where the disease was first described.

Factor V Leiden2:56–3:23

It results from an autosomal dominant point mutation in the gene encoding for factor V, causing it to become resistant to inactivation by protein C.
And when factor V can’t get inactivated, there’s increased blood clot formation.Next up, is the second most common inherited thrombophilia, the autosomal dominant prothrombin G20210A mutation.

Prothrombin G20210A Mutation3:23–3:46

This mutation involves the substitution of adenine for guanine at position 20210 in the noncoding region of the prothrombin gene, causing an increase in the circulating levels of prothrombin.

Protein C & S Deficiency3:46–4:39

Okay, now onto protein C and S deficiency that results in an inability to inactivate factors V and VIII. There are two types and both are inherited in an autosomal dominant manner.
If a person suffers from type I disease, they don’t make enough protein C or protein S, so they have a quantitative defect.
In type II disease, there’s enough of protein C and S, but they don't function properly, which means the proteins have a qualitative defect.
There are also acquired forms of deficiency, which include impaired production due to liver disease, anticoagulation therapy with warfarin, which is a vitamin K antagonist, or when protein C and S get lost in the urine due to nephrotic syndrome.
Proteins C and S can also become deficient in disorders like disseminated intravascular coagulopathy, or DIC, where widespread clotting leads to depletion of both coagulation and anticoagulation factors.
Next up is antithrombin III deficiency that results in inability to inhibit factor X and factor II and can be acquired, or inherited.

Antithrombin III Def.4:39–5:15

Acquired deficiencies are more common, and result from impaired production of antithrombin III due to liver disease, or protein losses such as nephrotic syndrome, or DIC.
Antithrombin III deficiency can also be inherited via an autosomal dominant inheritance pattern and is further divided into two types.
Just like with protein C and S deficiency, with type I there is a quantitative defect, while in type II disease there is a qualitative defect.

Antiphospholipid Syn.5:15–5:53

Alright, onto the acquired causes of thrombophilia, the most important of which is antiphospholipid antibody syndrome. In antiphospholipid antibody syndrome, individuals produce antibodies, which attack the phospholipids in the cell membrane of their own cells, or attack proteins that are bound to those phospholipids.
So it’s an autoimmune disease, and it can occur as a primary disease, or in the setting of an underlying disease, like systemic lupus erythematosus.
Just like most autoimmune diseases, antiphospholipid antibody syndrome is more common in young females. The most common presentation of all thrombophilic disorders is venous thromboembolism.

Symptoms5:53–10:53

This includes deep vein thrombosis of the lower or upper limbs which can present with pain and swelling in the affected limb.
Now, parts of the clot can break off and travel to other organs, like the lungs, the brain, the liver and the kidneys, cutting off blood flow to those organs and causing organ failure.
Now, each of these thrombophilic disorders also have specific symptoms that can help you identify them. Alright, let’s start with the inherited diseases.
For the exams, remember that Factor V Leiden, especially in homozygotes or those who have two copies of the factor V Leiden gene, as well as prothrombin 20210A predispose mainly to deep vein thrombosis, but also cerebral vein thrombosis.
Αlso, they are both associated with pregnancy loss due to blood clotting in placental vessels, leading to placental infarction.
The risk of recurrent venous thromboembolism is only mildly increased but can increase when there’s an additional risk factor, like surgery, pregnancy, prolonged immobility, or oral contraceptive use.
Now, most people with protein C or S deficiency also present with venous thromboembolism, but a more serious condition that could result from severe protein C or S deficiency in homozygotes is called neonatal purpura fulminans, which is a condition where a newborn suffers massive arterial and venous thromboembolisms with hemorrhagic skin necrosis.
Now, a high yield topic that is frequently tested on the exams is warfarin induced skin necrosis. This is a condition where tiny thrombi form in the blood vessels of the skin while a person is on warfarin therapy.
Warfarin prevents the synthesis of vitamin K-dependent factors including the procoagulant factors II, VII, IX, and X, as well as the anticoagulant factors, protein C and S.
But the thing is, protein C and S have the shortest half-life out of all of these factors. As a result, there’s a transient period of time after starting warfarin in which the patient doesn’t have much protein C and S but still has adequate levels of factors II, VII, IX, and X.
So during this transient period a patient is slightly hypercoagulable! Normally, this transient period is not significant enough to cause any problems.
But in a person with protein C or S deficiency, the hypercoagulability can cause them to develop tiny clots in cutaneous blood vessels, which leads to warfarin-induced skin necrosis.
Μοving onto antithrombin III deficiency, the major consequences is increased risk of venous or arterial thrombosis and heparin insensitivity.
Heparin works as an anticoagulant by binding and increasing the activity of antithrombin III which normally inhibits factor X and factor II, and as a result, heparin causes a rise in the partial thromboplastin time, or PTT.
However, in a patient with antithrombin III deficiency, there not enough antithrombin III for heparin to bind to, so the rise in PTT is less than expected.Alright, let’s continue on to the acquired thrombophilic disorders.
Individuals with antiphospholipid antibody syndrome can present with venous or arterial thrombosis. Venous thromboembolism is more common in females, while arterial thrombosis is more common in males, and can cause heart attack, stroke, or limb ischemia.
In addition, individuals might develop Libman-Sacks endocarditis, which is where antigen-antibody complexes and blood clots settle in the endocardium and vegetations form.
These vegetations can happen anywhere on the valve surface or chordae tendineae, but typically form on the mitral valve, leading to mitral valve regurgitation.
A typical skin finding in antiphospholipid syndrome is livedo reticularis, which is caused by swelling of the venules due to clots obstructing them, and appears as a mottled purplish discoloration of the skin.
Women affected by antiphospholipid syndrome tend to have pregnancy-related complications that can lead to a miscarriage.
Also, for reasons that aren’t completely understood, antiphospholipid antibodies are thought to cause neurologic symptoms like headaches and seizures.
In rare cases, antiphospholipid syndrome leads to rapid organ failure due to generalized thrombosis; this is called catastrophic antiphospholipid syndrome and can lead to death.Okay, now a key concept that is frequently tested on the exams is knowing when to screen for these rare thrombophilias in a person with venous thromboembolism.
Risk factors include having it at a young age, having more than one episode, or having a venous thromboembolism at an odd location, like in the cerebral, portal, or mesenteric veins.
Another situation when screening for causes of thrombophilia is indicated in a woman with recurrent miscarriages. Finally, the risk of having a venous thromboembolism in some of the thrombophilias can be quite low, but that risk can increase when there’s an additional risk factor, like surgery, pregnancy, prolonged immobility, or oral contraceptive use.Alright, now let’s look at specific clues that can help you diagnose each thrombophilic disorder, and this is very high yield!

Diagnosis10:53–14:34

Let’s start with factor V Leiden. In patients with factor V Leiden, PTT, that assesses intrinsic and common coagulation pathways, is shortened or normal.
The best initial test is to mix activated protein C with the person’s plasma and to measure PTT before and after. In individuals without factor V Leiden, there’s usually a prolongation of the PTT after protein C is added since protein C inactivates factors V and VIII which are part of the intrinsic and common pathways.
But in individuals with factor V Leiden, PTT stays the same because factor V Leiden is resistant to protein C. And that’s something you absolutely have to remember for the exams!
Factor V Leiden can be confirmed by looking for the mutation in the factor V gene using PCR. Now, for prothrombin 20120A, the diagnosis is straightforward; use PCR to detect the mutation.For protein C or S deficiency, assays are performed that reveal protein C activity below the lower limit.
Protein S deficiency is more difficult to diagnose, and like protein C deficiency there are a number of different assays to diagnose the condition.
The most common and best assay checks for the levels of free protein S in the serum since it’s the active form. Now, antithrombin III deficiency can be confirmed with a functional assay for plasma antithrombin activity called the antithrombin-heparin cofactor assay.
During this test, the ability of heparin to inhibit thrombin or factor Xa gets measured. Antithrombin III deficiency is diagnosed when antithrombin activity is less than 80% of the normal range in AT-heparin cofactor assay.
Genetic testing for this disorder is still being researched and is not routinely available. Moving onto antiphospholipid antibody syndrome.
The three antibodies associated with antiphospholipid antibody syndrome are anti-cardiolipin, anti-beta-2 glycoprotein I, and lupus anticoagulant.
Anti-cardiolipin and anti-beta-2 glycoprotein I antibodies can be measured directly using enzyme-linked immunosorbent linked assay, or ELISA.
Another high yield fact you should remember is that anticardiolipin antibodies can cause a false-positive test when the person has syphilis.
On the other hand, lupus anticoagulant is quite possibly the worst misnomer in medicine. First, lupus anticoagulant antibodies are not indicative of lupus.
Second when lupus anticoagulant is inside the body, it actually acts as a procoagulant, which is why it’s associated with thrombophilia.
But it’s called “anticoagulant” because in vitro, it actually acts as an anticoagulant, and prolongs the PTT, so when a mixing study is done, which is when normal plasma is added to the tube, the PTT does not correct.
To confirm the antibody’s presence, the Russell viper venom test is done. It assesses the ability of this snake’s venom to induce thrombosis, which requires the presence of phospholipids.
So if lupus anticoagulant were present, it would bind to the phospholipids and interfere with the venom’s ability to induce thrombosis.
The diagnosis of antiphospholipid antibody syndrome includes having one or more of the clinical criteria which include; a venous or arterial thromboembolic event, or three or more spontaneous abortions in the first trimester or even just one spontaneous abortion after the first trimester.
In addition, one or more of the three antibodies must be present. It’s also important to consider looking for lupus, by testing for antinuclear antibody or ANA, and extractable nuclear antigen antibodies or ENA.
All right, as a quick recap! Thrombophilic disorders can occur when the normal physiological balance between clot formation and clot lysis is tipped towards clot formation.

Review14:34–15:08

They can be inherited, like factor V Leiden, prothrombin gene mutation, protein C and S deficiency, antithrombin III deficiency, or acquired like antiphospholipid syndrome.
A diagnosis can be made based on clinical presentation, coagulation studies, more specific lab tests like ELISA for antiphospholipid antibodies, as well as genetic testing to detect the specific mutations.
Now, back to the patients! Celia most probably has an inherited thrombophilic disorder due to her age, her history of pregnancy loss, family history of vein thrombosis, and absence of an obvious acquired hypercoagulable state.

Summary15:08–16:06

The most common in individuals with Caucasian descent is factor V Leiden. Now, her PTT is normal but if we measure PTT after protein C is added PTT will be the same and that’s another indication for the diagnosis.
In order to confirm it, PCR for the mutation should be ordered. Now, Nicholas most probably developed warfarin induced skin necrosis which is caused by acquired protein C and S deficiency.
Assays for the levels of protein C and S must be done to confirm diagnosis. Now, due to her history of recurrent pregnancy losses, presence of SLE and absence of family history of inherited thrombophilia, Mary most likely has antiphospholipid antibody syndrome secondary to SLE.
To confirm the diagnosis one or more of the three antiphospholipid antibodies must be present.