Dr



Dr. Cobos

ICM

April 16 – 9:00 am

Jody Haigood/Joseph Cordova

Thromboembolic Disease

Dr. Cobos started with the hypercoagulability handout first.

“Magnitude of the problem”

• He read this slide word for word. Basically, this is a major problem. It seems to be a bigger problem now than it was 100 years ago. Our body is made to balance between not bleeding to death and not clotting to death. There is a slight tip towards thrombosis due to the current life style of being sedentary, higher weight, high cholesterol, and hypertension. This is why there is more of a problem with thromboembolism now.

“Differential Diagnosis of a patient with a thrombotic Diathesis”

• Any patient that has a thromboembolic event is considered to be hypercoagulable by definition. If the patient is at bed rest or has prolonged immobilization from trauma they will be hypercoagulable. You can develop a clot from a secondary factor (secondary state) that is well explained or you can develop a clot from a genetic abnormality (primary state). He will focus mainly on the primary state.

• 80% of patients with a thromboembolic event will be due to an acquired (secondary) hypercoagulability state. Dr. Cobos then read the causes of secondary hypercoagulability states.

• The Lupus anticoagulant really has nothing to do with Lupus and it is not an anticoagulant (He said that it is a procoagulant). These are antibodies that we have in our body against phospholipid. The antibodies are what initiate the thrombosis. It is also called the antiphospholipid syndrome. It was first seen in patients with Lupus and it caused an elevation of the PTT. This is why it was originally called Lupus anticoagulant (remember, it really doesn’t have anything to do with Lupus).

• Hyperhomocysteinemia – it is an inherited disease. It has been found to be a major cause of vascular and arterial thrombosis. It occurs in about 15% of the cases. The patient is unable to clear homocysteine, which is an amino acid, from our body. He compared it to hypercholesterolemia, where the patient cannot clear cholesterol from the body. Hyperhomocysteinemia is probably even more important than cholesterol in rendering us hypercoagulable.

He then skipped to the Venous Thromboembolism handout.

“Coagulation Pathway”

• The different factors are proteins, which we have 12 of in our bodies. If you cut yourself or injure yourself, the factors will be activated. There is a cascade that activates each subsequent factor in the pathway. The end result is the formation of a fibrin clot. The first way to activate the pathway is to start with Factor 12 and work down. The other way to activate the pathway is to start with Factor 7. It goes to activate Factors 5 and 10, which then activates prothrombin, etc. Ultimately, fibrinogen is converted to fibrin.

• The body has a mechanism to tell itself to shut off the coagulation pathway. This involves the natural anticoagulants – protein C, protein S, antithrombin 3, APC, and the fibrinolytic system. Protein C and protein S are manufactured in the liver. Once thrombin is activated, it has two jobs. The first is to act on fibrinogen and the second job is to activate protein C. Protein C and protein S then form a complex that act on Factor 5 to shut off the coagulation pathway. Antithrombin 3 acts on thrombin and several other points to shut down the pathway.

• There is usually a balance between the procoagulation factors and the anticoagulation factors. If you are lacking in any one of these, there will be clinical manifestation. Example – A patient that is deficient in Factor 8 or Factor 9 will tend to bleed because they cannot form fibrin. This is hemophilia. Another example is a deficiency in protein C or protein S will lead to clot formation.

• A common mutation that occurs in Factor 5 will render the factor resistant to activated Protein C. Therefore, protein C will be unable to shut the pathway down. The patient will be hypercoagulable. This is also called Factor V Leiden.

“Venous Thromboembolism etiology and pathogenesis”

• Venous thromboembolism and pulmonary embolism are venous thrombi that are composed mostly of fibrin. They also have RBCs with a variable platelet and leukocyte component. Once the fibrin is laid down in the lumen of the venous vessel and it propagates, it will form an occlusion which leads to a venous thrombosis. The venous thrombosis can dislodge and embolize to the lung, which is the pulmonary embolism. These are red thrombi, whereas arterial thromboembolisms are composed of platelets and fibrin.

• The white thrombi are the arterial thromboembolism. These are composed predominately of platelets and fibrin. An arterial thromboembolism in a coronary artery is the main cause of an MI. These can also cause a stroke when the thromboembolism is in a cerebral artery.

• Pulmonary embolism remains the most common preventable cause of hospital deaths.

“Clinical risk factors”

• Surgical and nonsurgical trauma – this disrupts the vasculature and activates the coagulation pathway.

• He then just read the rest of the risk factors.

“Inherited abnormalities”

• He read them and just said that you need to know that these are inherited risk factors.

• The most common ones are Activated Protein C resistance, prothrombin gene mutation (for venous thrombosis), and hyperhomocysteinemia (often seen in young people who have an MI).

“Clinical Features (venous thrombosis)”

• Leg pain is common, but it does not have to be present. You can have swelling, but many times the patient will complain of pain.

• Sometimes you can palpate the cord (thrombosed vessel).

• Discoloration of the lower leg.

• Venous distension and prominence of the superficial veins.

• Cyanosis is seen only in bad cases.

“Clinical Features (pulmonary embolism)”

• He read straight from the slide.

• Because of the pulmonary infiltrate, it is sometimes hard to differentiate it from pneumonia.

• In any cardiovascular event that occurs suddenly, you should consider pulmonary embolism (PE).

“Pulmonary Embolism”

• 90% of PE originate from thrombi in deep veins of the leg, especially in the popliteal vein or the more proximal veins of the leg.

• Pulmonary embolism occurs in 50% of patients with objectively documented proximal vein thrombosis. However, the proximal vein thrombosis is not what will kill you. The pulmonary embolism is what will kill you. You can develop a deep vein thrombosis and never develop a pulmonary embolism. However, even if you get treated for the thrombosis, you will still have abnormal vasculature. The blood will not flow as adequately and you will have to form neovascularization. You can also have swelling when you exercise and chronic pain. Therefore, the patient will have significant morbidity, even if it didn’t end in death.

• He then read the rest of the slide.

• Right now, they use some sort of imaging study to document an occlusion in the deep venous system. An example of this is a venogram. In a venogram they inject dye into the venous system and then take X-rays. This is considered to be fairly invasive. A non-invasive way to do it is to use ultrasound. This is probably the most common imaging study used.

• For pulmonary embolism, you can use an angiogram. You can also use CT scan or MRI, which are both non-invasive.

• Based on the symptoms that the patient presents with (look back at clinical features), you can decide which imaging study to use. From this, you can start the proper treatment.

“Laboratory Features”

• There is still no lab test that can be used reliably to predict development of VTE.

• He skipped the second point on the slide.

“Objectives of Treatment”

• Prevent death from pulmonary embolism. So if the patient has a deep venous thrombosis in his leg, he is at risk of dying from the thrombus dislodging and going to his pulmonary vasculature.

• Prevent recurrent venous thromboembolism.

• Prevent the postphlebitic syndrome. This refers to a clot in the lower extremity that develops. It may partially resolve, but it leaves the patient with impaired venous flow. The extremity will have swelling and pain and this will be life-long. This is why you want to diagnose it and start treatment early.

“Treatment of VTE”

• The anticoagulant of choice initially is Heparin. Heparin works immediately. You also have to keep Coumadin (Warfarin) in mind. Coumadin takes about 5-7 days to reach the therapeutic level. This is why it is not ideal for a deep vein thrombosis.

• So initially, you start with Heparin. You want to anticoagulate someone and prolong their PTT to 1.5 times the control value for at least 5-7 days. Then you will switch to oral Coumadin. This is the way they used to do it.

• Now, they are able to use the low molecular weight Heparin. He read the 5 points about (LMWH). This allows the patient to be treated on an outpatient basis; no hospitalization is required. The other Heparin is given IV and requires hospitalization.

• If Coumadin is given to the patient, it is continued for 3-12 months (usually 6 months) for the first, uncomplicated episode. In selected cases, anticoagulation may be required for life.

He switched back to the Hypercoagulability handout.

“Prevalence of Defects in Patients with Venous Thrombosis”

• Activated Protein C Resistance is seen in 10-40% of the cases. This is seen during pregnancy and when a female starts birth control pills.

• He read the rest of the slide.

“Molecular Basis of Hereditary Thrombophilia”

• A mutation develops in one of the factors that leads to an abnormal gene. For example, Factor 5 mutation is one dominant mutation. This leads to a Factor 5 that is very resistant to being inactivated by protein C. This is seen in about 15% of Northern Europeans and only about 5% of Asians. If a mutation occurs in a high percentage of people (like 15%), it tells you that there must have been some genetic advantage for the mutation to be selected out. If you think about 500 years ago when the medical care was not adequate, it was to our advantage to be slightly hypercoagulable. The patient would not bleed to death if they cut themselves. In today’s society since we are all sedentary and have high cholesterol and blood pressure, a gene that was previously advantageous is now a problem.

• Prothrombin gene mutation is also a single mutation.

• The other three deficiencies have many mutations. This becomes a problem when the patient is screened genetically.

• Question: In the antiphospholipid syndrome, why do you see an increase in PTT? Answer: We have an antibody against phospholipid. Once the Ab attaches to the phospholipid, it activates the coagulation pathway and leads to a clot. It can be idiopathic or in association with another condition. In patients with Lupus, you see an elevated PTT, but they never bled. So they thought it was a misnomer. It was also seen in patients who did not have Lupus. It was later discovered that it was a procoagulant. The way you check the PTT is to take blood and then time it to see how long it takes the fibrin to form a clot. One of the reagents to run the PTT contains phospholipid. When you draw blood you are also getting some of the antiphospholipid Ab which interacted with the reagent. This caused the PTT to be elevated outside the body. (Inside the body the PTT was actually normal).

• Therefore, it is called the Lupus anticoagulant, BUT it has NOTHING to do with LUPUS or ANTICOAGULATION. Could that be any more confusing? ( Dr. Cobos said to be careful if you are consulted on a patient who has an elevated PTT. It could be from Lupus antiphospholipid or from a factor deficiency. The difference is that with the Lupus antiphospholipid disorder you will have a clotting history and with the factor deficiency (ex. – hemophilia) you will have a bleeding history.

At this point, he went pretty fast and he only said select things on several slides that he wants us to know. He skipped quite a few slides.

“Physiology of the Natural Anticoagulant Mechanisms”

• For Antithrombin III, he wants us to know the three points on this scribe. He read them word for word.

• If a patient has a blood problem and they are taking heparin, but they are not adequately anticoagulating you need to think about an antithrombin III deficiency.

• For protein C, know that it is a vitamin K-dependent protein.

• When protein C is activated, it is called APC and it is activated by thrombin. It then forms a cofactor with protein S. This complex will inactivate Factor 5 mainly but also Factor 8.

• For protein S, it is also a vitamin K-dependent protein. It exists as a free form and as an inactive form. It is a cofactor for the expression of APC’s anticoagulant activity.

“Clinical Features of Inherited Deficiencies…”

• He read the three numbers in the Type I row for each of the deficiencies.

“Common Causes of Acquired Deficiencies…”

• He said not to memorize these, but to be familiar with them.

“Warfarin (Coumadin)-Induced Skin necrosis”

• He definitely wants us to know this. If Coumadin is an anticoagulant, why do we see patients with skin necrosis? It is because some of the microvasculature becomes occluded.

• Coumadin inactivates the vitamin K-dependent factors. Protein C is also vitamin K-dependent. Protein C has the shortest half-life. If the patient has a clot and you start him on Coumadin you would expect the Coumadin to inactivate the vitamin K-dependent factors and make him anticoagulated. Before this can happen, the protein C is affected first. The protein C drops before the patient can be adequately anticoagulated. For a period of time, the patient will be more hypercoagulable because they are protein C deficient. This is a reason that you would want to start with Heparin and then switch to Coumadin.

• Therefore, you can associate warfarin-induced skin necrosis with protein C deficiency.

“Hyperhomocysteinemia”

• It causes both arterial and venous thrombosis. It does this by direct endothelial cell damage. It also activates the coagulation factors and inhibits the anticoagulants.

• It is important to recognize this condition because you can decrease the level of the homocysteine in the body by giving folic acid.

• He read the second slide for Hyperhomocysteinemia. A mutation in the MTHFR causes the mild, persistent form of hyperhomocysteinemia seen in 5-15% of the people.

• He read the third slide for hyperhomocysteinemia. This condition was discovered only about 5 years ago. Therefore, there have been no long-term studies done on it.

“Treatment of DVT/PE in patients with a hereditary…”

• Same as for patients who do not have a hereditary thrombotic disorder.

• You will use heparin and then warfarin. Warfarin can actually be started on the same day as heparin. It is important to reach a therapeutic level, which can be measured by an INR test. The INR needs to be between 2-3.

• It is important to tell female patients that Warfarin is teratogenic.

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