Disorders of hemostasis and red blood cells

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Hemostasis is…

the processes involved with stopping blood flow

Conjugated bilirubin is…

– H2O soluble

• Secreted in bile

Unconjugated bilirubin is…

plasma insoluble

Unconjugated bilirubin accumulated in blood leads to…

Jaundice

what is NOT involved in the formation of a platelet plug?

agranulocytosis

A nurse is reviewing a HCP orders for a child with sickle cell anemia. what type of order is NOT appropriate

fluid restriction

A pt w iron deficiency anemia is refusing to take the prescribed oral iron medication due to constipation. What type of anemia is this classified as?

Microcytic hypochromic

afterload is….

the pressure / resistance a ventricle has to overcome during systole

Normal hemostasis involves…

a blood vessel sealing to stop a hemorrhage (bleed)

when discussing the sequence of clot dissolution, an instructor will highlight ____ as the item that begins the process

plasminogen

Abnormal hemostasis involves…

inappropriate blood clotting, or blood clot being unable to stop hemorrhage

The transformation of blood into a semisolid clot, meaning RBCs are then trapped in fibrin meshwork

Thrombosis

Inappropriate formation of blood clots

Bleeding

The failure to form a blood clot in the presence of bleeding

3 stages of hemostasis

vascular constriction

formation of platelet plug

blood coagulation

Vascular constriction

occurs when vessel spasm constricts vessel and ↓ blood flow

Formation of (unstable) platelet plug

Platelet driven formation of plug

Blood coagulation

forms stable blood clot, driven by clotting factors

Fibrin

aka clotting factor Ia

Rope or hair-like substance that wraps around platelet plugs to form structural basis of clot

End result of 3 stages of clot formation

Fibrin wraps around platelet plug to form structure

blood becomes gel-like and wraps RBCs + other blood components in clot

Clot and fibrous tissue to grow together to seal hole in vessel wall

components of hemostasis include…

Thrombocytes, plasma clotting factors, clotting cascade, endothelial cells, fibrinolysis

Thrombocytes

Platelets!

Anuclear cell fragments of megakaryocytes (Myeloid stem cell)

Normal level: 150,000-400,000 cells/μL

What proliferates thrombocytes in the liver?

Thrombopoietin (THPO)

Function of thrombocytes

Aggregate, promote blood coagulation and blood vessel repair

essential components of thrombocytes

Glycoprotein IIb/IIIa (GPIIb/IIIa), ADP, serotonin, TXA2

plasma clotting factors include…

• Factor I to XII, mostly synthesized in liver

• Vitamin K required to make several clotting factors (II,VII,IX,X)

• When clotting factors activated, they start the “Clotting Cascade”

factor X is…

where both pathways in clotting cascade converge

Factor 1 is…

fibrinogen

Factor 1a is…

fibrin

factor II is…

prothrombin

factor IIa is…

Thrombin

Factor IV is….

Calcium

Clotting cascade: Intrinsic pathway occurs..

inside the wall of the blood vessel

Characteristics of intrinsic pathway

• Slow (1 to 6 minutes)

• Begins in circulation

• Factor XII activated

Clotting cascade: extrinsic pathway occurs..

outside the wall of the blood vessel

Characteristics of extrinsic pathway

• Faster (15 seconds)

• Exposed tissue (trauma)

• Tissue factor (Factor III) activated

Both clotting cascade pathways converge at….

Factor X

What also occurs as pathways converge?

Factor II turns to IIa (Prothrombin → Thrombin)

Factor I turns to Ia (Fibrinogen → Fibrin)

Endothelial cells characteristics in hemostasis

• Play major role in hemostatic functions: platelet adhesion and blood clotting

• Promote blood clotting by synthesizing von Willebrand factor (vWf) → platelet aggregation when cell wall integrity is disrupted

• Promote blood flow by blocking platelet adhesion, inhibit coagulation, break up blood clots (clot lysis)

Fibrinolysis means….

clot dissolution

Endogenous Anticoagulants includes..

Antithrombin III, proteins C and S, Plasminogen, Plasmin

Antithrombin III, proteins C and S do what?

They inactivate clotting factors (Stops clotting)

Plasminogen is..

Proenzyme: normally inactive in the blood. Converted to plasmin by tissue plasminogen activators (t-PA)

Plasmin is…

the active form of plasminogen

digests fibrin strands of the blood clot

Step 1 of hemostasis is..

Vessel Spasm/Vasoconstriction

what happens during Vessel Spasm/Vasoconstriction?

• INJURY: blood vessel contracts vascular smooth muscle → ↓ blood flow from rupture

• Nerve reflexes and humoral factors cause short spasm

• Platelets release thromboxane A2 (TXA2), a vasoconstrictor

Step 2 of hemostasis is….

Formation of Platelet Plug

What happens during the formation of a platelet plug?

Activation, adhesion, aggregation of platelets

Activation of platelets involves….

platelets being attracted to damaged vessel wall

What causes adhesion of platelets for platelet plug

Endothelial cells releasing von Willebrand factor (vWF) which binds platelet receptors (GPIIb/IIIa) to vessel wall

what causes aggregation of platelets for plug

Platelets release mediators (ADP and TXA2) that attract platelets

step 3 of hemostasis is..

Blood Coagulation (clotting cascade)

What is involved in Blood Coagulation (clotting cascade)?

• Conversion of fibrinogen (H2O soluble) into fibrin strands (H2O insoluble)

• Intrinsic pathway

• Extrinsic pathway

• PT/PTT/INR

PT/PTT/INR is…

• Measure time (seconds) that it takes for blood to clot

Prothrombin time (PT and INR) is linked with…

the extrinsic pathway

Partial thromboplastin time (PTT) is linked with…

the intrinsic pathway

Elevated PT/PTT/INR is..

• ↑ amount of time for blood to clot

• ↑ risk of bleeding

Decreased PT/PTT/INR

• ↓ amount of time for blood to clot

• ↑ risk of clotting

higher risk for stroke, covid

what is step 4 of hemostasis

Clot retraction

What happens during clot retraction

• Edges of injury pulled together with actin and myosin from the platelets

• Actin and myosin contract, pulling the fibrin strands of the clot towards the platelets in the platelet plug

• Squeezes plasma (liquid) out of clot, causes clot to shrink

What is step 5 of hemostasis

Clot dissolution

what happens in clot dissolution?

activation of plasminogen by t-PA

Tissue plasminogen activator (t-PA) release from endothelial cells converts plasminogen to plasmin

Plasmin digests fibrin strands and clot dissolves

Bleeding disorders include..

Thrombocytopenia (low platelet count)

Thrombocytopathia (Impaired platelet function)

Hemophilia A

von Willebrand disease

Disseminated intravascular coagulation

Thrombocytopenia (low platelet count) is…

↓ in number of circulating platelets (< 150,000/μL)

Commonly seen in small vessels when platelet count < 20,000/μL

a cause of bleeding in pts

Thrombocytopenia (low platelet count) causes

drug-induced, malignancies, immune response, sequestering of platelets in the spleen

Thrombocytopathia (Impaired platelet function) is caused by…

• ASA and NSAID use

• Irreversibly affects platelet COX activity, inhibits thromboxane A2 (TXA2) synthesis for life of platelet (8-12 days)

• May also be caused by disorders of adhesion (von Willebrand disease)

hemophilia A is…

a coagulation disorder

x linked recessive

a Factor VIII deficiency - Works together with vWF to promote clotting and platelet adhesion

if Mild – bleeding with trauma/injury

if Severe – spontaneous, severe bleeding

Hemophilia A treatment

Factor VIII replacement therapy

von Willebrand disease is…

a coagulation disorder

• Autosomal dominant disorder

• Deficiency or defect in vWF

• Mild - moderate bleeding

von Willebrand disease treatment

treat with DDAVP (desmopressin acetate), an analog of vasopressin (ADH)

Disseminated intravascular coagulation is…

Widespread coagulation and bleeding due to underlying disorder – not a primary disease

MASSIVE/SYSTEMIC activation of the clotting pathway

Disseminated intravascular coagulation occurs as..

Occurs as complication of obstetric disorders, malignant neoplasms, systemic infections, severe trauma, surgery, burns (extrinsic pathway)

Endothelial injury (intrinsic pathway) e.g., infections, type 3 hypersensitivity disorders, burns, hypoxia, acidosis, shock, vasculitis

Disseminated intravascular coagulation pathophysiology

Excessive thrombin generation leads to fibrin deposition in microvasculature (capillaries) → systemic microvascular clots

Vicious cycle of clotting, dissolution of clots (bleeding), clotting, dissolution of clots (bleeding)

Disseminated intravascular coagulation (cascade)

• DIC activates intrinsic pathway and extrinsic pathway of clotting cascade

• Both pathways end in the Final Common Pathway at Factor X

• With help of prothrombin activator, prothrombin → thrombin and fibrinogen → fibrin

Fibrinolysis cascade

• Thrombin stimulates release of t-PA.

• t-PA converts plasminogen → plasmin

• Plasmin digests fibrin strands, causing blood clot to dissolve

Disseminated intravascular coagulation pattern and hemostasis experience

• Steps 3 and 5 of hemostasis are repeated over and over until all platelets and clotting factors have been used up

• Once clotting factors are depleted, patient bleeds and bleeds and bleeds

Disseminated intravascular coagulation (DIC) manifestations

• Bleeding

• Petechiae, oozing from puncture sites, or severe hemorrhage

• Hypoxia and organ damage

• Microemboli that obstruct blood vessels

  Renal, circulatory, or respiratory failure

  Convulsions, coma

Treatment of DIC includes…

• Manage primary disease

• Replace clotting components

• Administer heparin

DIC: Replace clotting components means using…

FFP (fresh-frozen plasma), platelets, cryoprecipitate

DIC: Administering heparin results in…

↓ risk of venous thromboemboli occluding microvasculature in end organs

RBCs / Erythrocytes is responsible for..

95-98% of O2 carried bound to hemoglobin (Hb)

• 4 globin protein chains: 2 alpha, 2 beta

What gives RBCs its red color??

Iron!

Each Hb molecule carries ___ molecules of O2

4 molecules

Hemoglobin Synthesis

• CBC – Hb (measure)

• Requires iron – stored in liver and bone marrow

• Source of iron: diet

Iron is recycled as aged RBCs are destroyed

Erythropoiesis is…

the production of RBCs (which are produced in bone marrow)

stimulated by decrease in blood oxygen content

erythropoietin is produced in the…

the kidneys

consider blasts (RBCs)….

toddler RBCs

consider Reticulocytes (RBCs)….

teenager RBCs

EPO/Epogen®/epoetin alfa (IV, subQ) does what?

increases production of RBCs

RBC Life Span

• ~120 days

• 1% of RBCs replaced/day

• Senescent RBCs → Hb → heme + globin

Anemia

↓ O2-carrying capacity in the blood due to ↓ number of RBCs, ↓ Hb level, or both

Etiology of Anemia

1. Excessive loss of RBCs due to bleeding

2. Destruction of RBCs (hemolysis)

3. Defective or inadequate RBC production

Manifestations of Anemia

Signs and symptoms relate to compensatory mechanisms:

• Dependent upon severity, onset, age and health status

• Efforts to ↑ O2 -carrying capacity in blood: ↑ RR, ↑ HR,↑ plasma volume

• Tissue hypoxia → Fatigue, weakness, dyspnea, maybe angina

• Brain hypoxia → Headache, faintness, dim vision

• Blood redistribution → Pale skin, mucous membranes, nail beds

• Hemolytic anemias → Jaundice

The fundamental pathophysiologic alteration seen in all forms of anemia is…

hypoxemia leading to tissue hypoxia

Anemia: Macrocytic/Megaloblastic cells

Impaired DNA synthesis, large, abnormally shaped, normal Hb concentration

Anemia: Microcytic and hypochromic cells

Small, abnormally shaped, pale, ↓ Hb concentration

Anemia: Normocytic and normochromic cells

Normal size and Hb concentration. Not enough RBCs

Macrocytic/Megaloblastic Anemia is..

Impaired DNA synthesis, large, abnormally shaped, normal Hb concentration

Vitamin B12 Deficiency Anemia

• Vitamin B12 essential for DNA synthesis, fat and protein metabolism, and myelin production in the CNS

• Absorbed in small intestine

• Absorption requires intrinsic factor secreted by parietal cells

• Loss of parietal cells due to autoimmune destruction, gastric mucosal atrophy, gastric bypass surgery

• Acidic environment required for secretion of intrinsic factor

Vitamin B12 Deficiency Anemia symptoms

Weakness, fatigue, lethargy, ataxia, paresthesias

Vitamin B12 Deficiency Anemia treatment

B12 IM injections