Thrombosis Flashcards
- Identify the components of Virchow’s triad and their pathophysiologic contribution to thrombosis.
- Compare and contrast the cause and mechanism of a thrombus occurring in the arterial circulation (such as acute coronary artery thrombosis) from one that develops in a deep vein of the leg. Include the instigating factor(s) and composition of the clot.
Arterial circulation
Occur during what conditions?
Composed mainly of ______ and small amounts of fibrin and a few red blood cells.
What are some clinical manifestations?
What are some abnormalities of blood flow that can contribute to the development of thrombi?
What are some abnormalities related to the blood vessels?
What are some altered coagulability conditions?
Arterial thrombi occur under conditions of high shear stress, a condition where von Willebrand factor is critical for platelet adhesion.
They are composed primarily of aggregated platelets, containing small amounts of fibrin and few red cells, making them appear white in color (“white thrombi”).
If they become large enough to lead to complete arterial occlusion, ischemia and infarction of the downstream tissues occurs.
Clinical manifestations are dependent upon the organ involved (heart attack with coronary artery occlusion, stroke with cerebral artery occlusion, gut ischemia with mesenteric artery occlusion, etc).
*Abnormalities of blood flow which can contribute to development of thrombi include hypertension and turbulent blood flow at arterial branch points and at sites of focal atherosclerosis.
**Abnormalities of the blood vessel can include intraluminal vascular endothelial cell injury, atherosclerotic plaque rupture, hyperhomocysteinemia, aneurysm formation, and vessel dissection.
***Altered coagulability can be due to platelet activation, hyperviscosity such as may occur with certain malignancies, and thrombocytosis.
- Compare and contrast the cause and mechanism of a thrombus occurring in the arterial circulation (such as acute coronary artery thrombosis) from one that develops in a deep vein of the leg. Include the instigating factor(s) and composition of the clot.
Venous thrombosis
In contrast to arterial thrombosis, venous develop under conditions of _______ blood flow.
Primarily composed of large amount of ______ and _____.
In contrast, venous thrombi typically develop under conditions of slow blood flow (low shear stress).
They are primarily composed of large amounts of fibrin containing numerous red cells (“red thrombi”).
Stasis can be due to numerous factors, such as right‐sided heart failure, pre‐existing venous thrombosis, extrinsic vascular compression by tumor, immobility, obesity, and chronic venous insufficiency.
Vascular factors contributing to venous thrombosis can include direct trauma or surgery, extrinsic compression, presence of a foreign body such as an IV catheter, and vascular endothelial cell injury due to exposure to toxins or excess levels of homocysteine.
Altered coagulability can be due to inherited or acquired disorders of procoagulant proteins, deficiency of anticoagulant proteins, deficient fibrinolysis, and other factors such as use of oral contraceptives, pregnancy, malignancy, hyperhomocysteinemia, hyperviscosity, and the presence of antiphospholipid antibodies. Increased age also contributes to increased risk for thrombosis, likely due to multiple factors.
- Describe at least three major clinical symptoms that occur when a patient suffers from an acute iliofemoral thrombosis of the leg, and indicate the pathophysiologic reason for each one (for example, dilated superficial veins of the calf due to obstruction of venous return in the occluded deep veins).
- Describe at least three major clinical symptoms that occur when a patient suffers from an acute iliofemoral thrombosis of the leg, and indicate the pathophysiologic reason for each one (for example, dilated superficial veins of the calf due to obstruction of venous return in the occluded deep veins).
Pulmonary embolism
Diagnosis of Venous Thrombosis
Treatment
- Treatment for acute clot is heparin
- Heparin inactivates activated clotting factors
- Minimum time: 5 days and until warfarin is fully therapeutic
- Warfarin used to prevent additional clots.
- Warfarin does NOT treat the acute clot-do not give alone for acute event!
- Reduction of vitamin K dependent factors takes at least 4-5 days regardless of INR
- List three clinical clues suggesting an inherited hypercoagulable disorder.
- First thrombosis age <50
- Recurrent episodes of thrombosis
- Family history of thrombosis
- Thrombosis at unusual sites
- Neonatal thrombosis
Thrombosis without apparent antecedent thrombogenic event (idiopathic)
- Briefly describe at the molecular level the pathophysiologic reason that patients with deficiencies of antithrombin, protein C, protein S, factor V Leiden or the prothrombin gene mutation are likely to have thrombosis. Explain what tests are used to identify these patients.
Factor V Leiden
Resistance to inactivation leads to what?
Due to an autosomal dominant mutation of the factor V gene that leads to partial resistance to inactivation through proteolytic cleavage by protein C.
Factor V Leiden is inactivated 10 times more slowly than normal factor Va.
Resistance to inactivation leads to increased risk for thrombosis.
- Factor V Leiden is the most common inherited predisposition to hypercoagulability in Caucasian populations of northern European background (up to 15%). Heterozygotes have a 4‐ to 7‐fold increased lifetime relative risk of developing venous thromboembolism, and homozygotes are estimated to have an 80fold increased lifetime relative risk.
- Long‐term anticoagulation therapy is not necessary for heterozygotes unless they experience more than one thrombotic event or life‐threatening thromboembolism. Asymptomatic patients should not be treated but should be informed of increased thrombotic risk associated with other risk factors such as surgery, oral contraceptive use, or pregnancy.
Factor V Leyden
Is it a deficiency?
What changes are seen?
- Autosomal dominant genetic mutation (1994 in the Dutch city of Leiden).
- This is not a deficiency! but a structural change in the Factor V
- Factor V (G to A at nucleotide 1691; argenine to glutamine at amino acid 506).
- Diagnosis by DNA analysis ( heterozygotes vs homozygotes)
- Briefly describe at the molecular level the pathophysiologic reason that patients with deficiencies of antithrombin, protein C, protein S, factor V Leiden or the prothrombin gene mutation are likely to have thrombosis. Explain what tests are used to identify these patients.
Prothrombin gene mutation:
This is the second most common inherited predisposition to hypercoagulability and has an autosomal dominant inheritance pattern.
- The mutation appears to lead to elevated concentrations of plasma prothrombin.
- Heterozygotes have a 2‐6‐fold increased lifetime relative risk of VTE. Indications for treatment are similar to those for factor V Leiden. –
- Heterozygotes for both mutations (factor V Leiden and prothrombin G20210A) should have long‐term anticoagulation following a first thrombotic event.
- Briefly describe at the molecular level the pathophysiologic reason that patients with deficiencies of antithrombin, protein C, protein S, factor V Leiden or the prothrombin gene mutation are likely to have thrombosis. Explain what tests are used to identify these patients.
Antithrombin
Homozygous deficiency is usually fatal in _______.
How does a deficiency in antithrombin affect the effcicacy of heparin?
Antithrombin III regulates coagulation by inactivating thrombin as well as factors Xa, IXa, XIa and XIIa.
AT‐III deficiency is inherited in an autosomal dominant fashion. Most patients are heterozygous, having ~50% of normal activity levels.
Homozygous deficiency is usually fatal in utero.
The estimated increased lifetime relative risk of thrombosis is up to 40‐fold.
Deficiency of AT‐III can sometimes lead to heparin resistance, since heparin acts as a cofactor for AT‐III and, thus, lack of AT‐III limits the therapeutic effectiveness of heparin.
****Asymptomatic patients should not be treated.
Patients with a single thrombotic event should receive at least 3‐6 months of anticoagulation. Patients with massive VTE or PE should be considered for thrombolytic therapy.
-Pregnant patients or patients undergoing surgery should receive prophylaxis, including AT concentrate administration.
Antithrombin deficiency
- Briefly describe at the molecular level the pathophysiologic reason that patients with deficiencies of antithrombin, protein C, protein S, factor V Leiden or the prothrombin gene mutation are likely to have thrombosis. Explain what tests are used to identify these patients.
Protein C
Homozygous deficiency of protein C leads to _________, an often fatal disease ar birth associated with extensive venous or arterial thrombosis at birth and levels of protein C less than 5 %.
Why does warfarin-induced necrosis develops in heterozygotes?
Protein C is a vitamin K‐dependent plasma protein that, when activated, inactivates factors Va and VIIIa to inhibit coagulation.
Deficiency is inherited in an autosomal dominant fashion.
Most affected patients are heterozygotes with ~50% of normal protein C levels. The estimated increased lifetime relative risk of VTE is up to 31‐fold.
-Homozygous deficiency of protein C leads to neonatal purpura fulminans, an often fatal disease associated with extensive venous or arterial thrombosis at birth and levels of protein C <5% of normal.
Heterozygotes can also develop warfarin‐induced skin necrosis. This problem typically occurs in patients started on large doses of warfarin in the absence of concomitant heparin therapy. Warfarin decreases the already low protein C levels more rapidly that the vitamin K‐dependent procoagulant factors, leading to exacerbation of the basal hypercoagulable state.
Asymptomatic patients should not receive anticoagulation but should avoid other risk factors and should receive prophylaxis for high‐risk procedures such as surgery. Those with a single thrombotic event should receive 6‐12 months of anticoagulation and those with more than one event, a single life‐threatening event, or a strong family history of thrombosis should receive long‐term anticoagulation. Protein C concentrates are available for those with homozygous deficiency.
Protein C deficiency testing:
- Briefly describe at the molecular level the pathophysiologic reason that patients with deficiencies of antithrombin, protein C, protein S, factor V Leiden or the prothrombin gene mutation are likely to have thrombosis. Explain what tests are used to identify these patients.
Protein S
Protein S is another vitamin K‐dependent plasma protein that facilitates the anticoagulant activity of activated protein C. As with protein C, deficiency is inherited as an autosomal dominant trait.
Patients can present with VTE or with arterial thrombosis, including stroke. Risk for thrombosis is higher when combined with other risk factors. Neonatal purpura fulminans and warfarin‐induced skin necrosis can be seen. The estimated lifetime increased relative risk of thrombosis is up to 36‐fold. Treatment principles are the same as those for protein C deficien
- Describe the clinical features and criteria for diagnosis of antiphospholipid antibody syndrome.
- Describe the clinical features and criteria for diagnosis of antiphospholipid antibody syndrome.
- Describe the clinical features and criteria for diagnosis of antiphospholipid antibody syndrome.
Antiphospholipid antibody syndrome pathophysiology
-exact mechanism by which antibodies induce thrombotic/obstetric complications are unclear
-Hypotheses:
- activation of endothelial cells
- oxidant-mediated injury of the vascular endothelium
- antibodies interfere with function of phospholipid-binding proteins involved in regulation of coagulation
Summary:
Managing hypercoagulable States
- Explain the key factor in determining how long someone should be anticoagulated for a venous thrombosis.
