Thrombosis and Hemostasis - lecture Flashcards
Primary hemostasis
Platelet adhesion is dependent on glycoproteins on the platelet surface and is mediated by vonWillebrand factor
Activated platelets have storage granules and secrete factors (ADP , serotonin, etc.) which recruit other platelets
formation of a platelet plug which blocks egress of blood from the site of vascular injury
Secondary hemostasis
Involves the serum coagulation factors which ultimately catalyze the development of a fibrin latticework which braces and supports the platelet plug (or thrombus under pathologic conditions)
Serum coagulation factors also function to recruit platelets and amplify both primary and secondary hemostasis
Assessment of bleeding disorders - history
Medical History
History of bleeding (gums, joints, urine, stool, nose) History of easy bruising
History of bleeding during or after surgery
Family History
Other family members with bleeding
History of hemophilia, vonWillebrand disease, hereditary hemorrhagic telangiectasia, etc.
Drug History
Full list of medications as well as over-the-counter meds.
Check for alcohol use (“cocktail purpura”)
“Have you had any bleeding problems related to medications before?”
Lab assessment for bleeding disorders
Complete blood count (CBC)
Allows rapid evaluation of the platelet count Thrombocytopenia is the most common cause of bleeding
Inverse relationship between the platelet count and the bleeding time
Prothrombin time (PT)
assesses the extrinsic system Normal 10-13 seconds
Prolonged in deficiencies of Factors II, V, VII, and X as well as fibrinogen deficiency
Prolonged in patients taking warfarin or dicoumarol
Partial thromboplastin time (PTT)
assesses the intrinsic system
Normal 25-40 seconds
Prolonged in deficiencies of Factors VIII, IX, XI, XII Prolonged in patients on heparin
Thrombin time (TT)—assesses for deficiency or abnormalities of fibrinogen
Platelet aggregation studies
Important in determining platelet abnormalities when platelets are normal in numbers (“qualitative platelet defects”)
Most common specific abnormality is seen in patients who have taken aspirin or NSAIDS due to impaired arachidonate metabolism
Assists in the diagnosis of patients with vonWillebrand disease, storage pool disease, Bernard-Soulier syndrome, and other congenital platelet disorders
Disseminated intravascular coagulation
A complication of medical, surgical, and obstetrical situations
The intrinsic and extrinsic coagulation systems are activated with resulting local and general escape of thrombin into the circulatory system, resulting in an initial thrombosis stage
-Thrombosis is often masked, and may not be seen clinically
As platelets and clotting factors are depleted, bleeding ensues, which is the major feature of the disease
Tx:
Correction of the underlying disorder—sepsis, bowel obstruction, etc.
Heparin—not usually used unless overt thrombosis occurs
Supportive care—platelet and factor replacement
Thrombotic Thrombocytopenic Purpura
thrombocytopenic purpura, microangiopathic hemolytic anemia, fluctuating neurological signs, renal dysfunction, and febrility
MAHA + thrombocytopenia (<50,000) + fever + neurologic symptoms = TTP
Add renal failure = Hemolytic uremic syndrome
s/s:
Microangiopathic anemia— schistocytes (RBC fragments), helmet cells, etc. known as the “Waring blender” effect
Pathologic lesion—hyaline thrombi which occlude the capillaries of virtually every organ in the body
ADAMTS13: hereditary or acquired (infection, malignancy, immune disorders)
-vWF-cleaving protease
Tx: treat underlying cause
Plasmapheresis save 100%, fatal without
vonWillebrand Disease
decreased platelet adhesion to vascular endothelium, as mediated by vonWillebrand factor
decreased or absent production of vWF
Labs:
Platelet aggregation tests are abnormal (especially to ristocetin)
Treatment:
Cryoprecipitate—replaces vWF (emergent)
DDAVP—causes release of vWF from endothelium
Hemophilia A
X-linked recessive deficiency of Factor VIII
Deficiency variable: modest amount to complete absence of the factor
Risk of bleeding corresponds to degree of factor deficiency
Disease is classified as being mild (6-25% normal activity), moderate (1-5% normal activity), or severe (less than 1% normal activity)
Clinical Features
Easy bleeding and bruisability
Hematomas from bleeding into soft tissues and muscles
Hemarthroses—one or two “target joints” which have recurrent bleeds
Patients are at significantly increased risk for bleeding during and after surgery
Hemophilia B
decreased serum Factor IX
X linked recessive
Easy bleeding and bruisability
Hematomas from bleeding into soft tissues and muscles
Hemarthroses—one or two “target joints” which have recurrent bleeds
Tx: replacement of Factor IX for hemorrhage or prophylactically for surgery
Vit K dependent factors - deficiency
Bleeding/hemorrhage
Prolonged PT
Deficiency of Factors II, VII, IX, X, Protein C and S
Hereditary Hemorrhagic Telangiectasia
a.k.a. Osler-Weber-Rendu syndrome
AD
Chr 9 mutation in endoglin (CD105) - membrane glycoprotein expressed on endothelial cells
The only endothelial syndrome associated with hemostatic complications
Caused by thinning of vessel walls with telangiectatic formations, arteriovenous malformations, and aneurysmal dilatations throughout the body
Clinical features:
Telangiectasias—gradually appear throughout life located in skin, mucous membranes, and visceral tissues
Bleeding—to mild or inapparent trauma; epistaxis is the most frequent symptom (80%)
Benign course, recurrent bleeds frequent
Tx: surgery or laser photoablation
AT-III Deficiency
Clinical presentation:
variable from minimal symptomatology to early death from recurrent pulmonary emboli
Recurrent lower extremity thrombophlebitis and deep vein thrombosis, venous insufficiency, and chronic leg ulcers
50% of affected patients have DVT and/or PE by age 30
Significantly increased risk for DVT in pregnant women—due in part to pregnancy-induced hyper coagulability
Dx: diminished levels of AT-III in serum - less than 50% normal activity
Tx:
Prophylactic treatment with anticoagulants
Patients with DVT should receive heparin but much higher doses are required
AT-III replacement therapy is available for known AT-III deficient patients with DVT who do not respond initially to heparin
Deficiency of protein C and S
vitamin K-dependent zymogens
Protein C—inactivates factors V and VIII
Protein S—cofactor for protein C
Use warfarin to decrease risk of thromboembolic dz
Like AT-III deficiency presentation and course
Most common cause of hypercoagulable state from deficiency of these proteins is initiation of warfarin therapy!
Proteins C and S are depleted prior to the other factors, resulting in a temporary increase in coagulability
Factor V Leiden
Abnormality of Factor V at binding site for activated Protein C
Heterozgotes at increased risk for thromboembolic disease
Homozygotes have excessively high risk for thromboembolism
Treatment:
No prior episodes: monitor; DVT prophylaxis and risk reduction
Prior episodes: consider lifelong anticoagulation
Prothrombin 20210
G-A mutation resulting in increased activity for prothrombin and inability to de-activate prothrombin
Risk of thrombosis very high—combined with Factor V Leiden may account for most cases of hereditary thrombophilia
Treatment: along the same guidelines as Factor V Leiden
Antiphospholipid syndrome - associated terms and features
Circulating Ab to phospholipid
Associated terms:
Anticardiolipin antibody syndrome
Lupus anticoagulant—actually a misnomer as risk of thrombosis is major feature of dz
False positive VDRL antibody syndrome
Associated features:
Thromboembolic phenomena
Miscarriage
Thrombocytopenia
Cerebral ischemia and recurrent stroke (especially in young patients!)
UBO (“Unidentified Bright Objects”) on MRI scans
Connective tissue disease—present >50% of cases but not required for diagnosis
Prolonged PTT, which fails to correct with mixing studies
Valvular heart disease in some
Coronary artery disease in some
Antiphospholipid syndrome dx and tx
Tests:
- A prolonged phospholipid-dependent coagulation test (PTT)
- Lack of correction in mixing studies using normal plasma
- Neutralization of inhibitor with excess phospholipid
Dilute Russell viper venom time (DRVVT) more specific than PTT-related test
Tx:
no benefit for anticoagulation in those without a history of thromboembolic disease
with a history: lifelong anticoagulation
don’t base on single test! Multiple positive tests over a 3-12 month period are required to make diagnosis
Anticoagulation during pregnancy may be accomplished with SC heparin
Hydroxychloroquine—consensus report indicated it may help reduce thromboembolism in patients with APS and SLE
