Thrombosis and Hemostasis - lecture

Question 1

Primary hemostasis

Answer 1

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

Question 2

Secondary hemostasis

Answer 2

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

Question 3

Assessment of bleeding disorders - history

Answer 3

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?”

Question 4

Lab assessment for bleeding disorders

Answer 4

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

Question 5

Prothrombin time (PT)

Answer 5

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

Question 6

Partial thromboplastin time (PTT)

Answer 6

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

Question 7

Platelet aggregation studies

Answer 7

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

Question 8

Disseminated intravascular coagulation

Answer 8

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

Question 9

Thrombotic Thrombocytopenic Purpura

Answer 9

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

Question 10

vonWillebrand Disease

Answer 10

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

Question 11

Hemophilia A

Answer 11

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

Question 12

Hemophilia B

Answer 12

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

Question 13

Vit K dependent factors - deficiency

Answer 13

Bleeding/hemorrhage
Prolonged PT
Deficiency of Factors II, VII, IX, X, Protein C and S

Question 14

Hereditary Hemorrhagic Telangiectasia

Answer 14

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

Question 15

AT-III Deficiency

Answer 15

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

Question 16

Deficiency of protein C and S

Answer 16

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

Question 17

Factor V Leiden

Answer 17

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

Question 18

Prothrombin 20210

Answer 18

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

Question 19

Antiphospholipid syndrome - associated terms and features

Answer 19

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

Question 20

Antiphospholipid syndrome dx and tx

Answer 20

Tests:

1. A prolonged phospholipid-dependent coagulation test (PTT)
2. Lack of correction in mixing studies using normal plasma
3. 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