Stroke prevention in sickle cell anemia

STOP I demonstrated transfusions reduced stroke risk by 92 % in high risk children and TCD is used to select patients for transfusion. STOP II showed rising TCD velocities, especially above 200 cm/s cutoff, led to more strokes upon transfusion discontinuation.

Eleven percent stroke by age 20.
25 percent by age 45

Recommend at least annual TCD between ages 2-16

mortality with hemorrhage is 24-65 percent
Associations with hemorrhage: Hypertension, recent transfusion last 14 days, steroids, possibly NSIAA

nonatherosclerotic
point mutation valine for glu in Beta polypeptide chain

younger patients tend to get ischemic strokes, older patients hemorrhagic strokes, two thirds recur

Treatment of AF based on risk stratification

ACC

ASA 325 or no therapy- lone AF, age <60
ASA 325-- Age <> 60, no risk factors;

Anticoagulation
1. Age> 60, coexistant DM or CAD (optional addition of ASA)
2. Age >75-- especially women
3. Heart failure
4. LVEF<.35
5. thyrotoxicosis
6. HTN
7. RHD
8. Prosthetic heart valves
9. Prior thromboembolism
10 Persistent atrial thrombus on TEE

Intensity for anticoagulation:
Numbers 1-6 keep INR 2-3
Numbers 7-10 keep INR 2.5-3.5

ICH due to anticoagulants

Pearls
1. In SPAF virtually all ICH was due to INR > 3
2. Oral anticoagulants increase risk of parenchymal hemorrhage 7-10 times
3. In patients >60, actual risk of ICH was 0.3 - 1.0 per year.

Stroke therapy in pregnancy

Pearls
1. Evaluation is similar to nonpregant patients
2. Low dose ASA (80-150 mg) in second and third trimesters in high risk women is safe for mother and fetus
3. VKA's are dangerous especially 6-12 weeks due to embyopathy, fetal wastage and are dangerous in second and third trimesters due to neurodevelopmental problems. Postpartum is believed safe.
4. UFH and LMWH does not cross the placenta or enter breast milk and is believed safe for fetus, although it can cause bleeding at uteroplacental junction.
5. ASA and heparin can be used combined during pregnancy.

Antiphospholipid antibodies

Spectrum in order of increasing risk is
asymptomatic individuals with positive antibody tests
women with pregnancy loss alone (1 fetal loss after 10 wks or 3 before 10 wks)
patients with thrombosis
rapidly progressive multisystem vascular occlusion
lab - need 2 titers 6-12 weeks apart, of present LA, ACL AB's, or anti beta 2 glycoprotein 1 . LA is more sensitive than APL testing. You CAN run aPTT or DRVVT on warfarinized sample if diluted 2:1 prior to testing.

Factors increasing the risk are
high titers especially lupus anticoagulant
smoking
use of oral contraceptives
surgery
immobilization
pregnancy
inherited coagulable states

APASS showed relation of ACL's with first ischemic stroke. Study within WARRS trial showed no increased risk of thromboocclusive events in patients with antibodies on coumadin.

Other pearls : venous strokes are more common than arterial strokes, and cardiac emboli also occur. Large and small vessel disease can occur. Chorea is more common in primary APL than secondary APL syndrome ( ie lupus) and is usually bilateral

Associations of secondary APL:  CTD esp SLE

Aortic arch atheroma

1. Independent risk factor for stroke especially plaques greater than 4-5 mm, ulcerated plaques and MOBILE COMPONENTS BY TEE. Annual risk in these risk factor settings are 11.9--33 %. Role of warfarin in under study.

2.Bob Brown believes its indicated

Cardiomyopathy, reduced EF, CHF and stroke

Pearls
1. Cardiomyopathy is second most common cause of cardioembolic stroke with a 3/ relative risk.

2. Ventricular thrombus occurs is 3-4 % of dilated cardiomyopathy with an annual risk of systemic embolism of 3-4 %. Further risk factors for emboli are stasis, low ventricular flow velocity, and hemostatic abnormalities and low EF.

3. CHF has an annual stroke risk of 1-4 % and anticoagulation is recommended for EF of < 35 % regardless of cause. WARCEF will study warfarin v. aspirin for this indication.

4. RHD with valve disorder has 1.5 to 4.7 % annual risk of emboli, with 12 % presenting with emboli as first sign of. 30-65 % of cases have recurrent emboli, usually within 6-12 months. Anticoagulation reduces annual stroke risk in old observational studies from 10 to 0.8-3 %.

5. MVP has stroke risk in young adults of about 1:6000.

6. Mitral annular calcification has 2.1 increase stroke risk and associates with AF.

7. Mechanical valves embolize at a rate of 2-4 % /year WITH anticoagulation. Further risk factors of thrombus formation are LAE, atrial stasis, AF, valve type and position (tilting disc), and in one study ventricular pacers.

8. Patients with bioprosthetic valves without anticoagulation have a risk of emboli of 6% in first 3 months.

9. Combined therapy of antiplatelet plus anticoagulation therapy risk is 1.3 to 24.7 % for major hemorrhage.

10. Anticoagulation may be continued in setting of infective endocarditis although opinion is divided on efficacy in this setting.

Anticoagulation pearls

1. Effects of heparin include interaction with Antithrombin 3, charge dependent interaction, and modulation of factor Xa generation. The low affinity for AT3 leads to greater effect when it binds PF4, which may lead to heparin antibodies (IgG) which activate platelets and lead to HIT. Heparin also binds to plasma proteins, macrophages, and endothelial cells, causes increased vessel wall permeability, and supression of smooth muscle proliferation, and activation of osteoclasts. It can be reversed with protamine, 1 mg per 100 units of UFH received over several hours.

Pearls on HIT
arterial OR venous clots occur
AB's against Factor 4 platelets complexes PF$ and heparin
10X more common with heparin than with LMWH

Mechanisms of heparin:  binds tissue factor and F VIIa at site of injury. Inhibits propagation of clot when F IXa binds to coafactor, and F VIIIa (intrinsic pathway)

2. LMWH's preferentially inactivate Xa with less HIT, and has a more predictable dose response relationship due to decreased binding to endothelial cells, proteins and macrophages. Protamine neutralizes only 60 % of anti Xa activity of LMWH's.

3. Prothrombin time (PT) to monitor VKA's is performed by adding calcium and thromboplastin to citrated plasma. INR is international normalized ratio where = (patient P/mean normal PT)*ISI (international sensitivity index).

4. Ximelegatran can use fixed dose, has no food or drug interactions,

Heparin, LMWH are indirect thrombin inhibitors
hirudin, argabotan, inactivate bound thrombin and are direct inhibitors

Statins and stroke

Heart protection study showed benefit in patients with statins. LDL triggers macrophage transition to foam cells, promotes metalloproteinase production, inflammatory adhesion molecule expression, platelet adhesion, NO synthase.

Landau analysis/critique (Neurology, letter 73;817 2009)

risk reduction of atorvastatin for 72.5 year old was 0.4 % (NNT>200) from 3.3 to 2.9 %. this is annual second stroke risk. The risk of having a stroke for those not taking drug is 96.7%. Vital statistics show death rate from any cause is 3.2 % at age 72, 4.2 % at age 75, 6.7 at age 80, and 10.2 at age 85. Treatment group with atorvastatin had twice as many hemorrhagic strokes, larger death rate from all causes, and some occurrence of hepatotoxicity and rhabdomyolosis.

Michael Strupp (Munich) opined that the primary endpoint, risk of fatal aor nonfatal stroke, was reduced in treatment group by ten percent which was not significant. Bianchi et al. differentiated effects in younger and older patients. They compared in SPARCL the 25 % reduction in younger patients, the 10 % reduction in older patients, and lack of significant interaction between age and treatment group. They argued effect diminishes with age.

Therapy of hypertension and stroke

Lowering sbp 10-12 points and DBP 5-6 points leads to 38 % fewer strokes . PROGRESS trial of ACEi v indapamide v. plac showed 9/4 bp reduction led to 28 % fewer strokes. HOPE randomized 9297 patients to ramipril or placebo, leading to 3/2 bp reduction and 32 % less strokes. LIFE (losartan ) trial showed 25 % reduction in stroke without change in blood pressure with ang II blocker. ALLHAT showed more strokes in patients getting lisinopril v. thiazide . Rec is for ACEi + diuretic to get bp < 140/90, or less than 130/80 in diabetics.

Or each 20/10 increase in BP over 115 to 185 doubles risk of stroke