lecture 11: hypercoaguable states

•Diminished blood flow

•Damage to the Vascular Wall

•Thrombotic shift

define virchow's triad

deep vein thrombosis, pulmonary embolus, cerebral infarction, myocardial infarction, organ infarcts

problems associated with thrombophilia

pulses

in assessing for thrombophilias, always check for

loss of limb

Both venous and arterial clots can cause limb pain, but missing an arterial clot can cause

-atherosclerotic lesion with active inflammation

-composed of fibrin and platelets

characterize arterial thrombosis

-red blood cell and fibrin rich

-composed of red blood cells and fibrin fibers

characterize venous thrombosis

thrombosis in the setting of an atherosclerotic plaque

#1 cause of death in the world

Factor V Leiden mutation

-but it is generally a weak hypercoaguable risk factor, needs associated athersclerosis, immobilization, etc

most common inherited disorder leading to DVT

•Activated Protein C Resistance- impaired down regulation of procoagulant activity, normally protein C inactivates factor Va thus reducing thrombin generation. Prevents factor V over activity by protein C

pathogenesis of Factor V Leiden disorder

heterozygous form of factor V leiden mutation

-homozygous increases risk by 90x

nearly 1/4 pts with initial DVT have this mutation

•cancer, lupus anticoagulant, pregnancy, oral contraceptives, hormone replacement

acquired activated protein C resistance may be seen with

Prothrombin G20210A mutation

•Mutation leads to higher prothrombin levels due to increased mRNA leading to increased circulating prothrombin levels

-low vitamin K

-inherited deficiency

Protein C and S deficiency may be due to

•Starting warfarin Tx can result in a hypercoagulable state initially due to inhibition of protein C and S early before vitamin K factors inhibited (II, IX, X) known as warfarin-induced skin necrosis, start LMWH or heparin before instituting warfarin therapy

do NOT treat protein C deficienct pt with warfarin bc

purpura fulminans

•neonatal homozygous form of protein C or S deficiency seen as widespread venous thrombosis and skin necrosis (also seen with meningococcus and gram-negative infections, DIC)

warfarin induced skin necrosis

- due to protein C deficiency which is exacerbated

- protein C deficiency can be acquired or inherited

1) stop warfarin, start heparin

2) give vitamin K

3) If needed, proceed to Protein C concentrate or FFP which has protein C

Dysfibrinogenemia

-abnormal fibrinogen protein

-usually bleed, but can get hypercoaguable

-associated with liver disease, tho can be congenital

autosomal dominant

inheritance of antithrombin deficiency

antithrombin III

complexes with heparin sulfates to inhibit both formed thrombin and Xa

almost exclusively venous

thrombosis type associated with antithrombin deficiency

nephrotic syndrome by proteinuria, hepatic veno-occlusive disease or ascites in liver disease and multiple other diseases

causes of acquired antithrombin III deficiency

elevated homocysteine lead to premature atherosclerosis of coronary, peripheral and cerebral vessels

how would a folate metabolism variant lead to thrombus?

severe elevations of homocysteine---> severe premature atherosclerosis and thromboembolism

genetic cystathionine beta synthetase deficiency causes

B12, B6, and folate supplement

most common treatment of hyperhomocysteinemia associated with premature atherosclerosis

MTHFR gene (worst form homozygous)

gene mutation associated with folate metabolism variant

an L-methylfolate supplement when treating depression

pts with mutated genotypes of folate metabolism have been sugugested to benefit frorm

group O

-greater risk off bleeding

factor VIII and vWF levels lower in this blood group

Risk of thrombosis greater in AA, AB, BB than AO, BO, OO

risk of thrombosis is greater in these blood groups

atrial fibrillation and heart disease

heart defect associated with acquired venous thrombosis

-protein C resistance acquired

-protein S levels decrease throughout pregnancy

why do OCPs and pregnancy increase risk off venous thrombosis?

nephrotic syndrome & extreme liver ascites

__________ can cause ATIII loss by proteinuria

crohn's and ulcerative colitis

bowel conditions that may lead to acquired venous thrombosis

Trousseau's syndrome

a migratory thrombophlebitis - presents with redness and tenderness on palpation of extremities. associated with a visceral malignancy mostly pancreatic adenocarcinoma or adenocarcinoma of the colon and lung etc.

essential thrombocythemia

•arterial and venous thrombosis, wholly characterized by an elevated platelet count. Low dose aspirin and hydroxyurea may prevent thrombocytosis

-myeloproliferative disorder

Chronic Myelogenous Leukemia (CML)

•clonal disorder. Increased number of WBCs at different levels of maturity

-myeloproliferative disorder ---> hypercoaguability

polycythemia vera

•high incidence of venous thrombosis in mesenteric, portal and hepatic systems. Literally, too many red blood cells.

-myeloproliferative disorder---> hypercoaguability

•May decrease counts with hydroxyurea and anagrelide. Antiplatelet agents may cause bleeding so caution with aspirin.

management of platelet disorders causing hypercoaguability

secondary thrombocytosis

response to hemorrhage, disease process (IDA, chronic infection, RA), or splenectomy

-less thrombogenic

•Compression stockings,

•activity and ambulation,

•heparin or low-molecular-weight heparin,

•inferior vena cava filters may be used for recurrent thrombosis prevention before surgery

surgical prophylxis mechanisms to avoid thrombosis

antiphospholipid syndrome

characterized by recurrent arterial or venous thrombosis, thrombocytopenia and recurrent fetal loss resulting from placental vascular insufficiency, primary or secondary to autoimmune diseases (especially systemic lupus erythematosus).

-anticardiolipin antibodies

-lupus anticoagulant (misnomer)

-paradoxical prolonged PTT

lab findings associated with anti-phospholipid syndrome

•Strong family history

•Unprovoked thrombotic event

•3 or more first trimester losses

•1 or more late fetal losses

consider screening for hypercoaguable disorder if

heparin

this anticoag MAY impart a survival benefit in cancer pts

heparin

•the stalwart for anticoagulation: it is inexpensive, easy to monitor and has a short half-life

easier to administer

why prefer LMWH over heparin

warfarin

treatment of choice of long term anticoagulant therapy

Andexanet alfa

med to stop bleeding secondary to thrombotic disorder

warfarin

treatment of choice of long term anticoagulant therapy