BL 03-04-14 11am-Noon Thrombotic Disorders - Thienelt Flashcards Preview

Unit 3 B&L > BL 03-04-14 11am-Noon Thrombotic Disorders - Thienelt > Flashcards

Flashcards in BL 03-04-14 11am-Noon Thrombotic Disorders - Thienelt Deck (60):

Thrombosis of Veins & Arteries - Epidemiology & Reasons to ID

- among the most important causes of sickness & death in developed countries of world
- Substantial portion of pts (20-40%) w/recurrent arterial or venous thrombosis are now known to have a hereditary or acquired defect that promotes thrombosis

Important to ID patients w/ these abnormalities:
- can be protected during periods of thrombotic stress (surgical procedures)
- can ID affected family members
- can initiate specific therapy when indicated


Virchow’s triad

Vascular obstruction due to thrombosis results from 3 interrelated factors:
1. Decreased blood flow (venous stasis)
2. Inflammation of or near blood vessels (altered vessels)
3. Intrinsic alterations in nature of blood itself (altered coagulability)

Still relevant & instructive today, when considering both arterial and venous thromboses (see pic in notes)


Arterial Thrombosis - when occur

- occur under conditions of high shear stress (a condition where von Willebrand factor is critical for platelet adhesion)


Arterial Thrombosis - composition

Composed primarily of aggregated platelets, containing small amounts of fibrin & 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.


Affect of large arterial clots

If become large enough to lead to complete arterial occlusion
---> ischemia & infarction of downstream tissues


Clinical manifestations of arterial clots

Dependent upon organ involved:
- heart attack w/ coronary artery occlusion
- stroke w/ cerebral artery occlusion
- gut ischemia w/ mesenteric artery occlusion, etc.


Abnormalities of blood flow which can contribute to development of arterial thrombi

- turbulent blood flow at arterial branch points & at sites of focal atherosclerosis


Abnormalities of the blood vessel which can contribute to development of arterial thrombi

- intraluminal vascular endothelial cell injury
- atherosclerotic plaque rupture
- hyperhomocysteinemia
- aneurysm formation
- vessel dissection


Altered coagulability which can contribute to development of arterial thrombi

Can be due to...
- platelet activation
- hyperviscosity (occurs w/ certain malignancies)
- thrombocytosis


Venous thrombi - when occur

- typically develop under conditions of slow blood flow (low shear stress)
- Increased age also contributes to increased risk for thrombosis, likely due to multiple factors


Venous thrombi - compositions

Primarily composed of large amounts of fibrin containing numerous red cells (“red thrombi”)


Abnormalities of blood flow which can contribute to development of venous thrombi

Stasis can be due to numerous factors:
- right-sided heart failure
- pre-existing venous thrombosis
- extrinsic vascular compression by tumor
- immobility
- obesity
- chronic venous insufficiency, etc.


Abnormalities of the blood vessel which can contribute to development of venous thrombi

- direct trauma or surgery
- extrinsic compression
- presence of a foreign body such as an IV catheter,
- vascular endothelial cell injury due to exposure to toxins or excess levels of homocysteine


Altered coagulability which can contribute to development of venous thrombi

Can be due to...
- inherited or acquired disorders of procoagulant proteins
- deficiency of anticoagulant proteins
- deficient fibrinolysis

Can also be due to other factors such as:
- use of oral contraceptives
- pregnancy
- malignancy
- hyperhomocysteinemia
- hyperviscosity
- presence of antiphospholipid antibodies


Symptoms of deep vein thrombosis (DVT) and pulmonary embolus (PE)

= can be vague & non-specific, making it difficult to make a Dx at times & making it important to have a high index of suspicion
- up to 50% are asymptomatic or undetected


Clinical signs and symptoms of DVT - severe/complete obstruction

Complete obstruction of a proximal vein (such as a massive iliofemoral thrombosis)
---> nearly complete obstruction of venous outflow from an extremity
---> phlegmasia cerulean dolens
= an extremely swollen, blue, painful leg


Clinical signs and symptoms of DVT - less obstruction

- pain
-pitting edema of distal extremity
- warm, dusky, reddish-blue discoloration of skin caused by enhanced superficial venous blood flow

Sometimes these physical signs can be very subtle, requiring good light & asking pt to stand for a few minutes to appreciate differences in size, warmth, color, or edema between normal & involved legs


Postthrombotic syndrome

= one consequence of extremity DVT
- due to chronic venous insufficiency & chronic venostasis
---> Affected extremities become chronically swollen & painful & show dark skin discoloration
---> Cutaneous ulcers can develop, usually around the ankle when a leg is affected
---> Recurrent bouts of leg pain & swelling can occur due to intermittent obstruction of blood flow in the absence of formation of new thrombi.


Pulmonary embolism - what is it

= dreaded complication of DVT
= occurs when part of a thrombus breaks off & travels through major veins, past right heart, & into pulmonary artery circulation until it becomes lodged

--->Lung tissue past the thrombus cannot participate in gas exchange & can infarct


Saddle emboli

= clot involving both pulmonary arteries
---> cardiovascular arrest & death can occur


Location of DVT & likelihood of causing a PE

DVT restricted to the calf veins
- uncommonly results in clinically important PE
- rarely associated w/ fatal outcome

DVT involving popliteal or more proximal leg veins
- if inadequately treat, is associated w/ 20-50% risk of clinically relevant recurrence
- strongly associated w/ symptomatic & fatal PE


Signs/Symptoms of PE

Classic signs & symptoms include:
- sudden chest pain
- dyspnea
- anxiety
- cough
- syncope
- cyanosis

Hemoptysis can occur uncommonly

Patients can present w/ cardiac arrest & sudden death.

Patients w/ small but recurrent PE can develop chronic dyspnea & chronic pulmonary HTN with elevated right heart pressures.

Significant mortality can occur if an unrecognized PE goes untreated.


Diagnosis of Venous Thrombosis

B/c of often vague or non-specific signs/symptoms, Dx of DVT or PE based on history & physical alone can be difficult & unreliable.

Once venous thrombus is suspected, further testing is required to make a definitive Dx.

Evidence-based algorithms using test sensitivity & specificity & pretest probability developed to aid in diagnosing DVT & PE
- one useful screening test in these algorithms is the D-dimer assay


D-dimer - how it works

= very useful screening test for venous thrombi

D-dimers can only be formed when cross-linked fibrin has been degraded by plasmin via fibrinolysis
- So, there must be formation of a clot if D-dimers are present, making D-dimer assay an indirect measure of clot formation.


Sensitivity & Specificity of D-dimer test

- Very sensitive (high negative predictive value for DVT...negative results rule out DVT)
- NOT specific (positive result does not confirm DVT)

W/ a positive D-dimer screening test, further studies should be performed.
- Venous ultrasound +/- US-Doppler
- Spiral CT scan of chest & ventilation/perfusion (V/Q) scans (for Dx of PE)


- Venous ultrasound +/- US-Doppler in DVT Dx

- can measure blood flow & pressure in blood vessels
- has >95% sensitivity & specificity in patients w/ symptomatic DVT


Spiral CT scan in Dx of PE

Spiral CT scan of the chest
- CT scan for embolus in pulmonary artery circulation --> directly visualized


Ventilation/perfusion (V/Q) scans to Dx PE

Two types of imaging are done.
- A gaseous radionuclide is inhaled to evaluate which parts of lungs are being aerated w/ breathing.
- Then, another radionuclide is injected to assess how well blood circulates through lungs.
- Mismatch btwn ventilation & perfusion (i.e., a localized area that ventilates well but is not perfused) may indicate a PE


Treatment of arterial thromboses in the acute setting

In acute setting:
- Heparin (to prevent further clot formation)
- Fibrinolytic agent like tPA (to lyse existing clot)

Time is of the essence due to the risk for tissue ischemia & infarction w/ delay in initiation of treatment.


Treatment of arterial thromboses in the long-term setting

The pathophysiology of arterial thrombus formation is primarily related to platelet activation & aggregation.
Thus, in long-term setting where prevention is main goal of therapy, antiplatelet agents are indicated in most situations.
- aspirin (inhibits COX)
- thienopyridines such as ticlopidine (Ticlid) & clopidogrel (Plavix)(ADP receptor antagonists)
- glycoprotein IIb/IIIa inhibitors such as abciximab (Reopro)


Treatment of venous thromboses in acute setting

Activation of coagulation cascade & formation of fibrin clot is main pathophysiologic mechanism

So, agents that inhibit coagulation are indicated:
= Unfractionated or low molecular weight heparin used initially
---> act as cofactors to potentiate activity of antithrombin III


Treatment of venous thromboses in longterm setting

- Low molecular weight heparin can be continued (requiring twice daily subcutaneous injections)
- Pt can be switched to oral anticoagulation w/ warfarin (Coumadin)


Warfarin action

- inhibits activity of vitamin K dependent enzymes (Factors II, VII, IX, X, Protein C, Protein S)
- B/c it doesn’t affect coagulation factors that have already been synthesized & released into circulation, not effective until enough time has passed to allow turnover of the factors


Factor half-life & treatment w/Warfarin

Of factors affected by Warfarin, factor VII has the shortest half-life (5 hours; others = 24 to 48 hours)
---> VII will have greatest effect on PT/INR
---> PT/INR will be prolonged before full anticoagulation has taken place
==> For that reason, important to maintain patients on heparin anticoagulation therapy at least 5 days after starting warfarin to insure full anticoagulation has taken place


Caution w/ Warfarin

Warfarin has a long half-life which is affected by many drugs & foods
- Careful & regular monitoring of PT/INR necessary to prevent under- or overdosing.


Duration of anticoagulation therapy

= Determined on individual basis based on several factors

- Goal of treatment is prevention of DVT recurrence or clot extension & prevention of PE.

- Key in decision-making process is determining if DVT occurred due to transient risk factors (surgery, temporary immobilization, trauma, or pregnancy) or if pt has underlying hypercoagulable disorder or ongoing risk factors that require longer treatment.

- Location & severity of clot also influences


Inherited Thrombotic Disorders

Patients often have a combo of defects.

Not everyone w/ an inherited hypercoagulable state will develop an overt thrombosis

Not everyone w/ thrombosis will have an identifiable hypercoagulable state.

>60% of pts presenting w/ idiopathic venous thrombosis will be found to have an inherited hypercoagulable state.

Many of the remaining 30-40% may have an acquired condition such as cancer or antiphosphlipid antibodies.


Hypercoagulable State (increased risk for thrombi) - Causes

Factor V Leiden
Prothrombin G20210A
Protein C deficiency
Protein S deficiency
Antithrombin deficiency
Mild hyperhomocysteinemia
Elevated factor VIII
Lupus anticoagulant
Elevated anticardiolipin antibodies


Factor V Leiden (Activated Protein C Resistance) - basic process

- Due to autosomal dominant mutation of factor V gene
---> leads to partial resistance to inactivation through proteolytic cleavage by protein C
---> increased risk for thrombosis


Factor V Leiden

= inactivated 10x more slowly than normal factor Va.
= most common inherited predisposition to hypercoagulability in Caucasian populations of N. European background (up to 15%)
- Heterozygotes have 4- to 7-fold increased lifetime relative risk of developing venous thromboembolism
- Homozygotes have 80-fold increased lifetime relative risk.


Treatment in Factor V Leiden

- Long-term anticoagulation therapy not necessary 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 w/other risk factors such as surgery, oral contraceptive use, or pregnancy


Prothrombin G20210A

= 2nd most common inherited predisposition to hypercoagulability
- autosomal dominant inheritance
- Mutation leads to elevated concentrations of plasma prothrombin.
- Heterozygotes have 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.


Protein C & Protein C Deficiency

Protein C
= vitamin K-dependent plasma protein
= when activated, inactivates factors Va & VIIIa to inhibit coagulation

Deficiency - autosomal dominant inheritance


Heterozygous vs. Homozygous Protein C Deficiency inheritance

= most affected patients
- ~50% of normal protein C levels.
- estimated increased lifetime relative risk of VTE is up to 31-fold.

- leads to neonatal purpura fulminans
= often fatal disease associated w/ extensive venous or arterial thrombosis at birth & levels of protein C <5% of normal


Heterozygous Protein C Deficiency & Warfarin

Heterozygotes can develop warfarin-induced skin necrosis.
- typically occurs in pts started on large doses of warfarin in absence of concomitant heparin therapy
- Warfarin decreases already low protein C levels more rapidly that vitamin K-dependent procoagulant factors
---> exacerbation of basal hypercoagulable state


Asymptomatic patients with Protein C deficiecy - treatment

- should not receive anticoagulation
- should avoid other risk factors
- should receive prophylaxis for high-risk procedures such as surgery


Treatment for Protein C deficient pts based on number of thrombotic event & severity

Single thrombotic event:
- 6-12 months of anticoagulation

More than one event, Single life-threatening event, OR Strong family Hx of thrombosis
- long-term anticoagulation

Protein C concentrates are available for those with homozygous deficiency.


Protein S

= another vitamin K-dependent plasma protein that facilitates anticoagulant activity of activated protein C


Protein S Deficiency

- As w/protein C, deficiency is inherited autosomal dominantly
- Patients can present w/ VTE or w/ arterial thrombosis, including stroke.
- Risk for thrombosis higher when combined w/ other risk factors.
- Neonatal purpura fulminans & warfarin-induced skin necrosis can be seen.
- Estimated lifetime increased relative risk of thrombosis is up to 36-fold.
- Treatment principles are the same as those for protein C deficiency.


Antithrombin III Antithrombin Deficiency

Antithrombin III
- regulates coagulation by inactivating thrombin as well as factors Xa, IXa, XIa and XIIa


Antithrombin Deficiency

- inherited in an autosomal dominant fashion
- estimated increased lifetime relative risk of thrombosis is up to 40-fold


Hetero vs. Homo zygotes in Antithrombin Deficiency

= most patients
- ~50% of normal activity levels

= usually fatal in utero


Antithrombin Deficiency & Heparin

Antithrombin deficiency can sometimes lead to heparin resistance
- heparin acts as cofactor for AT-III
- thus, lack of AT-III limits therapeutic effectiveness of heparin


Treatment of Antithrombin Deficiency

- should not be treated

Single thrombotic event
- should receive at least 3-6 months of anticoagulation

Massive VTE or PE
- should be considered for thrombolytic therapy

Pregnant pts or pts undergoing surgery
- should receive prophylaxis, including AT concentrate administration


Hyperhomocyteinemia & Thrombus risk

- can be inherited or acquired
- mechanism for increased thrombus risk may be enhanced platelet activation & adhesiveness due to endothelial cell injury


Increased factor VIII activity & Thrombus risk

Factor VIII activity >150%
---> 3-6 fold greater relative risk of VTE

Factor VIII activity >200%
---> Risk increases to 11-fold


Impaired fibrinolysis

= plasminogen deficiency, tPA deficiency, etc
--> can lead to increased risk for thrombosis


Lupus anticoagulants, anticardiolipin antibodies, and beta-2 glycoprotein 1 antibodies

= Additional important acquired risk factors for thrombosis (venous & arterial) as well as increased risk for obstetric complications & fetal death

Paradoxically, these Abs lead to prolongation of APTT in the lab (hence the name “lupus anticoagulant”)
= laboratory artifact due to in vitro inhibition of phospholipid-dependent coagulation assays
- does not reflect the way they act on coagulation system in vivo


Oral contraceptives

= well-recognized acquired risk factor for thrombosis since their introduction in 1960’s

Likely mechanism
= alteration in levels of coagulation factors
---> net increased risk for thrombosis

Risk greatly increased in combo w/ other risk factors.
- Factor V Leiden alone leads to 4-7 fold increased relative risk for thrombosis
- Factor V Leiden in combo w/ oral contraceptive use leads to a 30-35 fold increased risk