PHAR 505 Exam III Lecture Review (3/9) Huynh Lecture: Pathophysiology of Clotting Disorders Hemostasis is designed to stop bleeding at the site of vascular injury through complex interactions. Mechanisms include:

- Vascular constriction: Constrict near site of injury to reduce blood loss Vasoconstrict - Primary Hemostasis: Formation of the primary platelet plug Plug - Secondary Hemostasis: Propagation of the clot via fibrin Coagulate

Primary Hemostasis – Platelet Aggregation - Following vascular injury, clotting factors are released to promote platelet aggregation. These factors include

collagen, thrombin, PAF, ADP, and TXA2 - Responding to the clotting factors, the platelet adheres to sub-endothelial regions of the vessel and becomes

activated, promoting the release of substances to activate nearby platelets. Aggregation forms the primary plug Secondary Hemostasis – Coagulation

- Injured blood vessels also expose Tissue Factor (TF), which initiates a coagulation system implemented by Thrombin (factor IIa)

- Factor IIa converts nearby fibrinogen to fibrin, reinforcing the platelet aggregate, and anchoring it to the vessel wall. In addition, further platelet activation is induced

A closer look at the coagulation cascade - Clotting factors: Primarily synthesized in the liver, they circulate in

the blood in the inactive state. When needed, they are converted into their active state to catalyze the next reaction in the cascade.

o Contact activation factors o Vitamin K dependent factors o Thrombin-sensitive factors

- Both the intrinsic and extrinsic pathways are simultaneously activated upon injury. They have different roles in factor activation

o Extrinsic: TF converts VII to VIIa and X to Xa which together promote Thrombin (IIa) generation

o Intrinsic: Initiated by XII, cascade à XI à IX à X - Fibrin formation is the final step of coagulation. IIa is responsible for converting fibrinogen to fibrin - Inhibitors of the coagulation cascade = Anticoagulants

o Anticoagulants § Antithrombin III: Inactivates serine proteases (IIa, IXa, Xa, XIa, XIIa) § Protein C § Protein S § Physical Prevention: Nitric Oxide (NO) and prostacyclin (PGI2) induce vasodilation to inhibit

platelet activation and aggregation o Normally, thrombosis is not occurring due to prevention by regulatory mechanisms. Defects in this

regulatory mechanism may lead to increased thrombosis. The most common defect in the anticoagulant system is in factor V. A mutation called factor V Leiden leads to resistance to inactivation by Protein C/S

Thrombosis: The formation of an inappropriate fibrin-platelet aggregate on the endothelium of a blood or lymphatic vessel (mural thrombus), within the heart (cardiac thrombus), or free in the lumina (thromboembolus)

- Venous thromboembolism (VTE): Is the formation of a clot within the venous circulation. It can also be referred to as deep vein thrombosis (DVT) and/or pulmonary embolism (PE).

o DVT: 70-80% involve the proximal veins. If left untreated, the clot can grow bigger, threatening blood circulation in the extremities. If it enters the lung, it can become a PE

o African Americans are at the highest risk or VTE > Caucasian > Asian - Stroke: A thrombus that forms in the left atrial appendage which can

embolize in the brain. CHAD scores can be used to determine the need for antiplatelet therapy for stroke prevention

o Risk factors: Cardiac Thrombus Hx, Atrial fibrillation, Valve replacement (Check CHAD scores).

- Reason to Intervene: The rate of recurrent VTE is the highest during the first 180 days, which gives us a target for therapy. The 10-year cumulative risk is ~25%. Additionally, PE commonly follows DVT, and is a common cause of sudden cardiac death.

Deep Vein Thrombosis (DVT) - DVT s/sx: Fairly nonspecific, PMHx is the most telling, otherwise swelling, redness, tenderness, and edema of the

infected limb are most indicative. - DVT Dx Diagnostic testing may be initiated if DVT is suspected, often related to PMHx

o Step 1: Wells Score (WS) o (WS > 2) Step 2a: Proximal CUS – since 70-80% of DVT occur in proximal, ultrasound can confirm o (WS < 2) Step 2b: DVT may be rules out using a D-dimer test, for low Wells Scores. Additionally, for

Proximal CUS exams that come back negative, a D-dimer test is used to confirm ruling out DVT. § If Proximal is (-), but the D-dimer is (+), a full leg CUS will need to be performed § Blood Test: D-dimer is a fibrin clot degradation product that is elevated in patients with acute

thrombosis. It is an extremely sensitive marker that, although not conclusive, is critical for ruling out dx of VTE (-).

• Falsely elevated readings: Recent surgery/trauma, increasing age, pregnancy, cancer [VTE Risk Factors] Virchow’s Triad Blood Stasis Hypercoagulable State Vascular Injury

- Blood stasis: Damaged valves or prolonged periods of immobility can result in stasis, and potentially DVT. This abnormality in blood flow can occur in populations with heart disease, paralysis, left ventricular dysfunction, valve damage from hypoxemia, compromised blood flow, or venous obstruction

- Hypercoagulable State: Activation of clotting cascade, clotting factor deficiencies, malignancies, pregnancy, hormone replacement, history of blood clots

o Patients with Cancer are at 4-7x higher risk of VTE o Pregnancy also increases the risk of VTE 4-5x, occurring most frequently in the first half of pregnancy.

Postpartum VTE risk is 20x, due to hypercoagulability associated with increased concentrations of factor VII, VIII, X, vWf, and fibrinogen. Hormones reducing venous outflow or uterine obstruction may also contribute.

o OCP: Directly associated with the dose of estrogen, contraceptives increase the risk of VTE in the first 6-12mo of use and decrease thereafter – completely reversible 3mo post-d/c. It is suggested the mechanism involves increased prothrombin, factor VII, VIII, X.

- Vascular injury: Trauma, surgery, heart valve replacement, atherosclerosis, indwelling catheter o Surgical patients have higher rates of VTE than medical patients, with the highest risk 7-10days post-op.

The greatest contributors include: total hip arthroplasty (THA), hip fracture surgery (HFS) § Newer technology has lowered this risk, by shortening both surgery and recovery time.

Mechanical prophylaxis functions by facilitating blood flow. o Hospitalized Medical patients are scored for VTE risk by using the Padua prediction score. Score-able

elements include: cancer, mobility, age, obesity, medical history, etc § < 4, low risk, involves a case-by-case decision about whether or not to intervene with anticoags § ³ 4, high risk, thromboprophylaxis should be used

Post-Thrombotic Syndrome - Post-Thrombotic Syndrome is the development of s/sx of chronic venous insufficiency following DVT. It occurs

as a consequence of long-standing thrombotic obstruction, valvular incompetence, and venous hypertension - Sx: Pain, vein dilation, edema, skin pigmentation (purple), venous ulcers

VTE Prophylaxis - Prevention is best. At least one-third of hospitalized patients are at high VTE risk, they will require prophylactic

anticoagulation therapy. Pulmonary Embolism (PE)

- PE s/sx: Not too direct, but primary sx include chest pain, dyspnea, tachycardia, pass-out from hypoxemia, syncope

- PE Dx o Step 1: CT Pulmonary Angiogram – has high sensitivity and

specificity, it is the gold standard o Transthoracic Echocardiography (TTE): Noninvasive, TTE offers a

nice visualization of the heart to assess the RV and LV size, systolic function, and check for valvular abnormalities.

o Ventilation-Perfusion Scintigraphy (V/Q Scan): An older tool that gives 3 potential results, none of which are conclusive which is why it is no longer favored. It can rule out PE with a 0.9% failure rate.

- PE can be classified temporally into Acute, Subacute, and Chronic categories - PESI Scores

o Once dx with PE, a 30-day mortality risk can be calculated using the PESI scores

o £ 65: Low risk – consider outpatient therapy if clinically appropriate o > 65: High risk – patient will require close monitoring and potentially admittance into the ICU

(3/12) Kim Lecture: Heparin-Induced Thrombocytopenia Heparin-Induced Thrombocytopenia (HIT)

- Get injected with Heparin, there’s a few things that can happen - No Ab: Most patients receiving heparin will not form the antibody - Subclinical: A subset will form Ab, but not show symptoms - Thrombocytopenia: The next subset will have a significant depletion

of platelet, which is the first major concern and a thrombotic complication. Bleeding Risk

- Thrombotic Complication: Risk still elevated 4 weeks post-d/c o If untreated, the risk increases 50-89% o Mortality: 17-30% associated with severely low platelet

- Pathophysiology o Once exposed to heparin, circulating platelet factor IV (PF4) adheres to the heparin product o Complex formation stimulates production of IgG and other Ig against

Heparin-PF4 o IgG binding to Heparin-PF4 produces a substrate, IgG-Heparin-PF4, which

can activate platelets at the Fc receptor. Binding to the Fc receptor will cause the release of micro particles and pro-coagulants

o The micro particles can activate other platelets, leading to further PF4 release o Overall, this activity involves the burst generation of thrombin and may

damage the blood vessel - Clinical Presentation of HIT

o Venous: DVT, PE, Cerebral venous thrombosis, venous limb gangrene o Arterial: Limb artery thrombosis + amputation, thrombotic stroke, MI

- Risk Factors for Immune-mediated mechanism o Duration of heparin exposure (> 4 days), o Heparin type ~ Bovine > porcine, IV > SubQ, UFH > LMWH o Patient Population: Cardiac surgery, purpose for hospitalization (orthopedic > medical) o Gender: F > M

Isolated HIT HIT ± Thrombotic Syndrome Reversible – Not-immune mediated Fast onset, 1-2 days Transient reduction in platelet during Heparin therapy, occurring 10-20%

More serious, Immune-mediated Delayed onset, 5-10 days Characterized by ³ 50% drop in platelet count, which will recover upon d/c