Heme: Hemostasis and Thrombosis

What does clinical hemostasis involve?

1. interactions btwn broken blood vessels, supporting structure, and circulating platelets

2. platelet aggregation and adhesion -platelet plug (primary)

3. activation of coagulation cascade -fibrin clot (secondary)

4. activation of coagulation factor inhibitors (tertiary)

5. fibrinolysis after remodeling and repair -clot destroyed

How can the coagulation cascade by initiated?

intrinsic pathway or extrinsic pathway

What starts the intrinsic cell pathway?

damage to cell surface

What activates the extrinsic pathway?

tissue factor released due to tissue damage

What do the intrinsic and extrinsic pathway both lead to?

prothrombin activator → starts the common pathway

Which pathway is a slower reaction and involves factors XII, XI, Ca, IX, VIII, X, platelet factor & V?

intrinsic pathway

Which pathway is a faster reaction and invovles tissue thromboplastin, factors VII, X, Ca, & V?

extrinsic pathway

What is the end product of the common pathway?

blood clot

Hemophilia A is a deficiency of what factor?

Factor VIII

Hemophilia B is a deficiency of what factor?

Factor IX

What are Acquired Factor Deficiencies?

physiological conditions

What is von Willebrand’s Disease?

platelet dysfunction

What is DIC?

consumptive coagulopathy

What measures the time to form fibrin clot through the extrinsic pathway?

PT; Factors II, V, VII, X, or fibrinogen (deficiency prolongs)

What measures the time to form fibrin clot through the intrinsic pathway?

PTT; Factors II, V, VIII, IX, X, XI, or XII (deficiency prolongs)

What is useful to distinguish between an abnormally prolonged clotting time due to a factory deficiency vs a factor inhibitor?

mixing study

In a mixing study, normal plasma is added to a pt’s w/ a prolonged PT or PTT. What is confirmed if this corrects the clotting time?

presence of a Factor Deficiency

In a mixing study, normal plasma is added to a pt w/ a prolonged PT or PTT. What is confirmed if this does NOT corrects the clotting time?

presence of a Factor Inhibitor

Hemophilia is what type of bleeding disorder? Who does it most commonly affect?

X-linked recessive; males

A male presents to the clinic w/ Hemophilia. What is his expression of the gene affected?

homozygous for the gene

Which form of Hemophilia is the 2nd most common congenital coagulopathy, caused by a defect in the intrinsic pathway, and associated w/ spontaneous or excessive hemorrhage?

Hemophilia A (classic hemophilia)

What form of Hemophilia is milder and common in Ashkenazi Jews?

Hemophilia B (Christmas Disease)

What patients would you suspect Hemophilia in?

neonate w/ +FMHx, unexplained neonatal bleeding w/ -FMHx, unexplained post traumatic or post-surgical bleeding later in life

What labs would confirm a dx of Hemophilia?

prolonged PTT, norm PT & plts

What treatments are available for Hemophilia?

Factor Concentrates (Recombinate & BeneFIX), Antifibrinolytics (Amicar), DDAVP, Gene Therapy

What are possible causes of Acquired Factor Deficiency?

Factor VIII inhibitors (most common), PTT prolonged (factor inhibitor), Auto-antibodies (autoimmune disorders), Allo-antibodies (hereditary factors deficiencies)

How do you detect the presence of Allo-antigens causing an Acquired Factor Deficiency?

Bethesda Test

How do you manage Acquired Factor Deficiencies?

challenging, high levels of Factor replacement (when antibody titers are low), FEIBA & NovoSeven (when antibody titers are high)

How do FEIBA and NovoSeven help in Acquired Factor Deficiencies?

bypasses intrinsic pathway

What labs would be seen in Vit K deficiency?

inc PT/PTT

inc liver enzymes

dec Vit K & Factors II, VII, IX & X

How would treat Vit K deficiency?

treat underlying disorder, parenteral vitamin K, FFP for hemorrhage

What is the most common inherited bleeding disorder?

Von Willebrand Disease

How are most cases of Von Willebrand’s transmitted?

autosomal dominant trait (M=F)

How does the Von Willebrand Factor contribute to hemostasis?

binding plts to plts, binding plts to endothelium, binding plts to Factor VIII

What is the Von Willebrand Factor?

large multimeric glycoprotein synthesized both in plts and in the endothelium

What factors would point to a dx of vWD?

FMHx, Hx of muco-cutaneous bleeding, Post surgical bleeding, confirmatory labs

What labs would you order to confirm a vWD dx?

aggregation assays (RIPA), multimeric patters, functional activity assays (VWF:AG, VWF:RCo, VWF:CB, Factor VIII)

What are the tx options for vWD?

vWF concentrates or Desmopressin Acetate (DDAVP) (causes releases of VWF and F8 from storage)

How would you prescribe DDAVP?

.3 mcg/kg IV q 12 hrs during bleed or 300 mcg puff intranasal (Stimate) prophylaxis

What is the best tx for Type 1 vWD?

DDAVP

What is the best tx for Type 2 vWD?

vWF concentrates (most effective), DDAVP may be insufficient

What is the best tx for Type 3 vWD?

always vWF concentrates

What causes DIC?

abnormal activation of coagulation and fibrinolysis leading to ongoing coagulation and fibrinolysis

DIC leads to?

excessive thrombi formation, end organ damage, death

DIC can be triggered by exposure of blood to a large source of tissue factor. This can happen in conditions?

malignancy, obstetric complications, mechanical tissue injury, endotoxins and cytokines in infection (sepsis)

What labs would you see in a pt that has DIC?

markedly inc D-dimer, dec fibrinogen, thrombocytopenia, prolonged PT/PTT, markedly dec protein C

How would you treat DIC?

identify trigger → resolve, supportive therapy, replete platelets or clotting factors, cryoprecipitate transfusion to correct low fibrinogen, anticoagulant therapy (if life threatening and hyper coagulability), wait and watch

What is HELLP Syndrome?

intravascular hemolysis (H), elevated liver enzymes (EL), low platelet count (LP)

HELLP Syndrome is seen in what population?

preeclamptic/eclamptic pts in their third trimester; typically have epigastric or RUQ pain, nausea, and vomiting

How is Hemolytic Uremic Syndrome (HUS) different from TTP?

much less neurologic sx and more likley renal failure, more common in kids

HUS primarily affects what population?

children <10 yo or elderly

What is HUS associated with?

infection of E. Coli 0157:H7

What are the symptoms of HUS?

acute renal failure, bloody diarrhea, thrombocytopenia, anemia

What is the tx for HUS?

supportive, hemodialysis w/ plasma exchange

HUS has higher mortality rates for what population?

older children and adults

What are the similarities of TTP & HUS?

plt destruction, appear suddenly & spontaneous w/o cause, can be life threatening

What are the causes of TTP & HUS?

enterohemorrhagic infection, idiopathic

How is TTP different from HUS?

less likely to involve renal failure, more likely to involve neurologic symptoms

What is sufficient to make a dx of TTP or HUS?

presence of microangiopathic hemolytic anemia w/o other cause

What leads to clinical thrombosis?

balance is tied in favor of clotting → thrombophilic or hyper coagulable state

What are the two types of venous thromboembolisms (VTE)?

DVT and PE

Which form of VTE is most common and causes 5x more death than breast cancer?

DVT

What are signs of a PE?

SOB, tachypneic, CP, hemoptysis

What are some Acquired Hypercoagulable States?

HIT, antiphospholipid antibody syndrome, malignancy, nephrotic syndrome

What are some Inherited Hypercoagulable States?

Proteins S deficiency, Protein C Deficiency, Factor V Leiden

A genetic thrombophilia defect coupled with a acquired thrombogenic stimulus often leads to what?

thrombosis

What is the role of Proteins S and C?

down-regulate the coagulation cascade by proteolytic degradation of Factors V and VIII

Proteins S and C deficiency is an autosomal inherited trait. What happens if an individual is homozygous for the trait?

neontal purpura fulminans, DIC, severe VTE

What happens in Protein S & C deficiency?

dec in proteolytic regulation of Factors V & VIII leads to uncontrolled fibrin clot formation and a hyper coagulable state

How do you treat neonatal purpura fulminans?

protein concentrates

What causes Factor V Leiden gene polymorphism?

specific point mutation rends factor V resistant to proteolysis by activated Protein C

What is the most common known inheritable risk factor for VTE w/ DVT as the most common manifestation?

Factor V Leiden

What is the tx for VTE?

anticoagulation (duration depends on clinical situation)

How long is the anticoagulation tx for an idiopathic DVT?

6 months

How long is the anticoagulant tx for idiopathic VTE + hereditary risk factor?

lifelong

How long is the anticoagulant tx for a massive PE ± hereditary risk?

lifelong 😕

How long is the anticoagulant tx for a DVT w/ a transient risk factor?

3-6 months after risk factor ceases

What are some initial anticoagulant tx options?

unfractionated heparin (IV, very quick)

LMW heparin (enoxaparin or Lovenox, SubQ, quick)

Coumadin (Warfarin, block vit K dependent factors, slow, long acting)

How do you monitor Coumadin therapy?

PT/INR (target 2-3)

How can you reverse Coumadin in emergent situations?

vit K injection (slow), FFP, Prothrombin-complex concentrates (fastest)

What are the new oral anticoagulants?

Direct Factor Xa inhibitors (Xarelto, Eliquis) and Direct Thrombin Inhibitors (Pradaxa)

What is the benefit/drawback of the new age oral anticoagulants?

no labs needed; costly, higher risk of bleeding

What are thrombolytic agents?

plasminogen activators that promote clot lysis by converting plasminogen to the fibrinolytic enzyme plasmin

What are thrombolytic agents used for?

acute coronary artery thrombosis, ischemic stroke, peripheral artery occlusion, rarely VTE

Which type of blood loss affects the integrity of the BV & O2 supply to tissue and can induce hypovolemic shock?

acute

Which type of blood loss causes Hgb levels to fall compromising O2 delivery to vital organs and depletes iron stores causing iron deficiency anemia?

gradual

How does the body respond to blood loss?

rapid inc RBC production, vasospasm redistributes blood flow, Albumin → inc plasma V, RBCs inc transfer of O2 to tissues

What is the Bohr effect?

RBCs inc O2 transfer to tissue by shifting the O2 dissociation curve to the right

What % of blood loss causes HF and death unless replaced ASAP?

~ 50%

What should be done in a severe hemorrhage?

IV access for fluid and volume expanders, plt and coag factor replacement to maintain homeostasis

What electrolyte solutions can be used as volume expanders? How long can they be used?

Ringer’s lactate and Normal Saline; pts cannot be sustained for longer periods (1-2 hrs)

What do colloid solutions do?

provide reliable volume expansion

What do FFP do?

provide clotting factors needed for hemostasis in a massive bleed; also act as a protein containing expander

What is heparin-induced thrombocytopenia (HIT)?

associated w/ arterial and venous thrombosis, activation of plts and injury → thrombosis