S18C229 - Clotting disorders

Question 1

Virchow’s triad of thrombus

Answer 1

• venous stasis
• hypercoagulability
• endothelial injury

Question 2

Hypercoagulable states: inherited

Answer 2

• activated protein C resistance due to factor V leiden mutation
• prothrombin gene mutation 20210A
• protein c deficiency
• protein s deficiency
• antithrombin deficiency
• hyperhomocysteinemia

Question 3

Hypercoagulable states: acquired

Answer 3

• antiphospholipid syndrome
• pregnancy
• OCP/HRT
• malignancy
• HIT
• warfarin induced skin necrosis
• hyperviscosity syndrome

Question 4

Antithrombin

Answer 4

• inhibits thrombin, factor Xa, factor IXa

- UFH/LMWH cause anticoagulation by increasing the rate at which antithrombin inhibits these factors

Question 5

what does it mean if a behind factor? eg. Xa

Answer 5

that it is activated

Question 6

Protein C

Answer 6

• vit K dependent protein that binds to endothelial cells
• activated by thrombin
• cleaves factor Va and factor VIIIa, and therefore inhibits the common and intrinsic pathway
• homozygous is rare, presents as neonatal purpura fulminans
• higher risk for warfarin-induced skin necrosis

Question 7

Protein S

Answer 7

• cofactor for protein C
• also vit K dependent
• increases the inhibitory action of activated protein C

Question 8

Features suggestive of Thrombophilia

Answer 8

-early thrombosis (age

Question 9

Management of Inherited/Acquired thrombophilias (hypercoagulable)

Answer 9

• first episode: UFH/LMWH x5d until warfarin therapeutic
• continue AC tx for 6mo-2y, possibly life
• can just go straight onto a DOAC

-2nd episode : life long AC

• pregnancy: begin UFH or LMWH at diagnosis of pregnancy
• may use warfarin in post-partum period

Question 10

Factor V Leiden mutation - activated protein C resistancw

Answer 10

• most prevalent hypercoagulable d/o
• mutation in factor Va makes it resistant to inhibition by activated protein C and therefore there is an increase in conversion of prothrombin to thrombin` and more fibrin and excessive thrombus
• most are heterozygous
• have a 7x increase in DVT (homozygotes 20x)
• 21% of pts with first time DVT will have FVL deficiency/mutation

Question 11

Prothrombin gene mutation 20210A

Answer 11

• mutation leads to increased prothrombin biosynthesis with 30% increase in circulating prothrombin levels
• causes a hypercoagulable state

Question 12

Antithrombin Deficiency

Answer 12

-can be deficient in patients due to mutations
-2 main groups:
type 1: measured level of antithrombin is decreased
type 2: normal level of antithrombin but fxn diminished

Question 13

Hyperhomocysteinemia

Answer 13

• 3 enzymes involved in metabolism of homocysteine
• deficiency in 2 of the enzymes causes incr arterial/venous thrombosis and atherosclerosis
• if incr homocysteine in the blood this is a sign of functional enzyme deficiency
• can have mental retardation, dvpt delay as well
• unknown mechanism
• tx: folate, pyridoxine, vit B12

Question 14

Antiphospholipid Syndrome

Answer 14

• antibodies assoc with APS: beta2-glycoprotein I and Lupus anticoagulant
• procoagulant, causes thrombosis (clots)
• acquired
• occurs in 1 in 5 patients

Question 15

Clinical signs of APS

Answer 15

• venous: DVT
• arterial: premature atherosclerosis, ACS, CVA
• obstetric: fetal loss after 10w GA, preterm labor, low BW, preeclampsia
• neuro: stroke, migraine, seddon syndrome (Stroke, HTN, livedo reticularis), cognitive dysfxn, dementia, chorea, dysphagea, GBS, Sz, optic neuritis
• skin: livedo reticularis
• cardiac: syndrome X, valvular dz
• skeletal: osteonecrosis
• renal: microangiopathy, renal artery/vein thrombosis, stenosis with HTN
• pulmonary: PE, HTN
• GI: budd chiari syndrome, mesenteric ischemia, hepatic infarction, cholecystitis with gallbladder necrosis
• hematologic: bleeding deathesis (Rare), thrombocytopenia, hemolytic anemia

Question 16

APS Dx

Answer 16

• one or more thrombotic events or pregnancy losses and repeated positive results for one or more AP antibodes at least 6w apart
• presence of antibodies can be transient, therefore absence of lab findings should not dissuade the dx

Question 17

APS Tx

Answer 17

• IV heparin - keeping in mind that the activate thromboplastin time may not be useful for determining efficacy as this test is abnormal in APS
• if known hx but no thrombotic hx then do not treat prophylactically unless pregnant

Question 18

Pregnancy and hypercoagulability

Answer 18

• occurs to prevent excess hemorrhage during delivery
• increased estrogen is part of what increases coagulability (increases factors 7,8,10, prothrombin and fibrinogen) and decreases antigoagulant proteins (antithrombin, protein S, C)
• OCP also causes protein C resistance
• factors making pregnancy hypercoagulable: venous occlusion from uterus, increased thrombin and procoagulants, decreased protein C

Question 19

Malignancy and hypercoagulability

Answer 19

• pts with 1st time episode of VTE 10-20% will have new dx of cancer in previous 6mo or following year
• risk of VTE is highest in 1st 3mo after dx
• the following have increased risk of VTE: brain, pancreatic, AML, gastric, espophageal, gyne, kidney, lung
• cancer also increases risk of arterial clot (MI, CVA)

Question 20

HIT

Answer 20

• consumptive coagulopathy similar to TTP and DIC but in DIC coag factors are consumed and in HIT there is activation and consuption of platelets
• pts develop IgG Abs against the heparin-PF4 complex
• do not need to have been exposed to heparin to develop antibody
• heparin-Ab complex binds and activates platelets fomring clot and setting off cascade
• can be caused by unfractionated and LMWH
• occurs in 0.5-5% of pts

Question 21

HIT: Dx

Answer 21

• usually have low platelets (50) w/in 5-15d of starting heparin
• 10% will need amputation and 20-30% will die w/in 1mo
• lab dx, not clinical
• suspect if platelets have dropped by 50% in pt on or recently on heparin
• can have rapid onset w/in hours of initiating heparin
• platelets normalize 1w after stopping heparin

Question 22

HIT: Tx

Answer 22

• stop all heparin products
• will still need AC b/c risk of thrombosis highest in 1st wk after dx (argatroban) don’t use warfarin b/c this can increase microvascular thrombosis b/c transient protein C deficiency

Question 23

Warfarin induced skin necrosis

Answer 23

• inhibits production of vit K coag factors (1972, C)
• transient C deficiency can lead to hypercoagulability
• painful red lesions over extremities, breasts, trunk, penis
• initial central erythenatous macule then edema, then central purpuric zones then necrosis
• therefore bridge with heparin and avoid high loading doses of warfarin