hypercoagulable states Flashcards
(15 cards)
Plasma-based protein that inhibits several activated coagulation factors
* Thrombin, factor Xa, and factor IXa
* Unfractionated heparin and low-molecular-weight heparin possess anticoagulant activity by increasing the rate by which
antithrombin inhibits these factors
antithrombin (antithrombin III)
Vitamin K-dependent plasma protein, is a cofactor that increases the inhibitory action of activated protein C by about 20-
fold
protein S
- Vitamin K-dependent plasma protein that binds to the endothelial cell surface and is activated by thrombin
- Activated protein C cleaves both factor Va and factor VIIa, inhibiting both the common pathway and the intrinsic pathway
protein C
- Early thrombosis (age 45 y and younger)
- Recurrent thrombotic events or fetal loss
- Family history of thrombosis or recurrent fetal loss
- Thrombosis in unusual location (mesenteric, cerebral, axillary, or portal veins)
features suggestive of thrombophilia
- Prothrombin gene mutation
- Leads to increased prothrombin biosynthesis with about 30% increase in circulating
prothrombin levels creates a prothrombotic state - Inherited in an autosomal dominant manner
- Heterozygotes account for up to 10% of patients with initial episodes of DVT
- Have increased risk of venous thromboembolism and pregnancy complications
Prothrombin G20210A
- Activated protein C resistance caused by factor V Leiden mutation is the most prevalent inherited
hypercoagulable disorder - The gene for factor V has a single point mutation that makes factor Va resistant to inhibition by activated
protein C (factor V Leiden) - Leads to overabundant conversion of prothrombin to thrombin
- Factor V Leiden is inherited in an autosomal dominant pattern – most patients heterozygous for the
mutation - Heterozygotes for this have 7-fold increased risk of DVT compared with noncarriers
- Homozygotes have 20-fold increase in risk
- DVT > PE
- Can produce pregnancy complications severe preeclampsia, placental abruption, fetal growth restriction, and stillbirth
activated protein C resistance (factor V Leiden)
- Transmitted in an autosomal dominant fashion – has more varied clinical presentations
- Not all patients with heterozygous defects develop inappropriate thrombosis
- Homozygous deficiency is rare and presents as neonatal purpura fulminans
- Higher risk for venous thromboembolism
- Associated with either decreased total amount of protein C or S or decreased functional
activity - In general, lower function is associated with higher risk and frequency of thrombotic
events - Higher risk for warfarin-induced skin necrosis (rare)
- Warfarin inhibits protein C and S synthesis
protein C and S deficiencies
- Several mutations to the antithrombin gene exist– many leading to deficiency
- 2% of patients with history of thrombosis have antithrombin deficiency
- Inherited in an autosomal dominant fashion
- Heterozygotes have 5-fold increased risk of thrombotic events
- Typically, pregnancy complications and venous thromboembolism
- Homozygous deficiency is incompatible with life
antithrombin (III) deficiency
- Coagulation changes in pregnancy represent an adaptive measure to prevent excessive
hemorrhage with delivery - Changes promoting thrombosis are similar but less profound in women taking oral
contraceptives and hormone replacement therapy - Estrogen use has been associated with:
- Modest increases in procoagulant proteins:
- Factor VII, VIII, and X, prothrombin, and fibrinogen
- Decreases in anticoagulant proteins:
- Antithrombin, protein S, and protein C
- Use of OCP or HRT in patient with known heterozygosity for factor V Leiden puts them at
an even higher risk for thrombosis (15-fold increase)
pregnancy and estrogen use
Autoimmune disorder defined by development of venous and/or arterial thrombosis and
pregnancy morbidity in the presence of antiphospholipid antibodies
* Most common specific antibodies associated with antiphospholipid syndrome are:
* lupus anticoagulant, β2-glycoprotein I, and anticardiolipin antibodies
* Up to 5% of normal, healthy young people have antiphospholipid antibodies; this number
increases with age and comorbid conditions, but only a minority of these patients
develop antiphospholipid syndrome (40-50 per 100,000 persons)
- Most patients have no predisposing conditions (primary antiphospholipid syndrome)
- Minority have conditions thought to be associated with their antiphospholipid syndrome
(secondary antiphospholipid syndrome) - Rheumatologic or autoimmune disorders (systemic lupus)
- Infections
- Drug exposures (phenytoin, hydralazine, cocaine)
- Most present with isolated, recurrent thrombotic events
- 1% have a rapidly progressive form known as catastrophic antiphospholipid syndrome
- Acceleration in the pathophysiologic process with widespread small-vessel occlusion
in multiple organs - Common triggers:
- Infection, surgery, oral anticoagulant withdrawal, OCP use, obstetric complications,
cancer - Mortality is 50% despite treatment
antiphospholipid syndrome
Exact mechanisms for increased risk are not completely understood
* For patients with new diagnosis of cancer, risk of venous thromboembolism is highest in
first 3 months after diagnosis
* Some types of cancer are more likely to promote thrombosis including:
* Pancreatic, brain, AML, gastric, esophageal, gynecologic, kidney, lung
* Chemotherapy can also affect coagulation downregulation of protein C and S,
induction of tissue factor production by endothelial cells, and direct cell damage
malignancy (risk factor for clots)
malignancy treatment
- Use LMWH for initial treatment of venous thromboembolism in patients with active
cancer - Long-term anticoagulation following the diagnosis of venous thromboembolism in these
patients uses LMWH for 6 months as opposed to warfarin - Prophylactic anticoagulation for primary prevention of VTE in ambulatory medical
oncology patients is not recommended
- Warfarin inhibits production of vitamin D-dependent coagulation factors
- Upon initiation of warfarin, protein C is decreased before most of the procoagulant proteins
- Leads to transient relative protein C deficiency can lead to clinically significant hypercoagulability
- Presents with painful, red lesions usually located over the extremities, breasts, trunk, or penis
- Typically start with an initial central erythematous macule, extending over hours to a localized edema, developing central purpuric zones and then necrosis
- Thrombin inhibitors (LMWH) are administered and continued until therapeutic anticoagulation is achieved with warfarin to prevent this complication
warfarin induced skin necrosis
antiphospholipid syndrome treatment
- Patients should be given warfarin to maintain INR of 2.0-3.0
- DOACs are not recommended because they are less effective than warfarin in APS
- Pregnancy-associated APS
- Combination of prophylactic doses of LMWH and low dose aspirin is the usual
approach to prevent pregnancy complications - If history of thrombotic events outside of pregnancy full dose LMWH is needed
- Use of steroids and IV immunoglobulin not recommended
- Catastrophic APS
- IV immunoglobulin or plasmapheresis PLUS IV heparin and high doses of
corticosteroids are administered
