Disorders of Hemostasis

Hemostasis 3 main phases

vascular spams, platelet plug formation, blood clotting (coagulation)

Vascular spasm

blood vessel constricts immediately after injury

triggered by smooth muscle contraction and platelet-released chemicals

Platelet plug formation

platelets adhere to exposed collagen

vWF helps platelet adhesion

activated platelets release: ADP, thromboxane A2, serotonin

Blood clotting (coagulation)

coagulation factors become activated

prothrombin converted to thrombin converting fibrinogen into fibrin

fibrin strengthens platelet plug into stable clot

Platelets are

anuclear cell fragments produced from megakaryocytes in bone marrow

Under the influence of the hormone ________________, hemopoietic stem cells differentiate into megakaryocytes and form ____________

thrombopoietin; platelets

Normal platelet count

150,000 - 400,000/uL of blood

Thromboxane A2 is a

prostaglandin produced by activated platelets from arachidonic acid through cyclooxygenase (COX-1) pathway

How Thromboxane A2 works

promotes platelet aggregation (activates nearby platelets)

constricts injured blood vessel (reduced blood loss)

amplifies platelet activation through a positive feedback loop

ADP is a

chemical messenger released from the dense granules of activated platelets (recruits and activates additional platelets for platelet plug)

ADP stands for

adenosine diphosphate

Vascular Endothelial Cell

thin, elongated cells lining the blood vessels and release procoagulants and anticoagulants

Vascular endothelial cells release procoagulants

in response to an injury - vWF starts platelet aggregation and adhesion

Vascular endothelial cells release anticoagulants

to maintain blood fluidity and prevent abnormal clotting

Prostacyclin and nitric oxide

promote vasodilation, inhibit platelet aggregation

Thrombin inhibitors (antithrombin)

inhibits factor Xa, prevents thrombin formation

Tissue plasminogen activator (tPA)

converts plasminogen into plasmin, an enzyme that breaks down fibrin

Coagulation cascade converts

fibrinogen (soluble plasma protein) into fibrin (insoluble protein) and each factor activates the next one

Coagulatoin is regulated by:

procoagulation factors involved in pathways and promote clotting and anticoagulation factors

Examples of procoagulation factors

prothrombin, tissue factor, fibrinogen

Examples of anticoagulation factors

antithrombin, protein C and S (prevent clotting by inactivating plasma clotting factors)

Extrinsic coagulation pathway

activated when there is a vascular injury and blood escapes into tissue with activation of tissue factor (surrounding blood vessel)

Intrinsic coagulation pathway

activated when factor Xll contacts subendothelial substances exposed by vascular injury (in blood vessel)

Both intrinsic and extrinsic pathways lead to

activate factor X (common pathway)

What happens when factor X is activated?

prothrombinase catalyzes transformation of prothrombin to thrombin

thrombin converts soluble fibrinogen to fibrin

Clot retraction

occurs 20-60 minutes after clot formation and squeezes serum out of the clot and strengthen the clot (pulls edges of damaged blood vessel together)

Fibrinolysis

dissolves the blood clot once it is no longer needed

How fibrinolysis works

plasminogen converted into plasmin; plasmin dissolves blood clots, free plasmin rapidly inactivated by a2-plasmin inhibitor

Clot retraction with actin and myosin

actin and myosin in platelets that are trapped in the clog begin to contract and fibrin strands are pulled toward platelets causing shrinkage

Clot dissolution

plasminogen is trapped in the clot and slow release of tPA converts plasminogen to plasmin which digests the fibrin strands causing clot to dissolve

Hypercoagulability

an exaggerated state of hemostasis that increases the tendency for thrombus formation and may cause blood vessel occlusion

Two main forms of hypercoagulability

increased platelet function & accelerated coagulation system activity

Increased platelet function

platelets become overly active and promotes excessive platelet aggregation

Accelearted coagulation system activity

increased activation of clotting factors and leads to excessive fibrin formation and clot development

Thrombocytosis

an abnormal increase in platelet count which increases the risk of abnormal blood clot formation

Primary (essential) thrombocytosis

bone marrow disorder; abnormal thrombopoietin receptor function, platelets dysfunctional, increased risk of thrombosis and bleeding, platelet count extremely high > 1,000,000/uL

Secondary (reactive) thrombocytosis

caused by another disease; increased thrombopoietin production, platelets function normally, symptoms relate to underlying disease, platelet count usually (1,000,000/uL)

Clinical manifestations of essential thrombocytosis are result of

thrombosis (blood clot formation) and abnormal platelet function

Erythromelalgia is a condition characterized by

episodes of burning pain, redness, and warmth in the hands or feet which occurs when platelet aggregates block small arterioles, reducing blood flow to affected areas

Despite having an increased number of platelets, patients may also experience ___________ because the platelets often function abnormally

bleeding

Low-dose _______ is effective in relieving symptoms because it reduces platelet aggregation

aspirin

Thrombus

blood clot that forms and remains attached to the wall of a blood vessel or the heart; partially or completely obstructs blood flow at the site where it forms

Embolus

detached intravascular material that travels through the bloodstream and lodges in another vessel

How embolus works

usually originates from a thrombus that breaks loose and moves through the circulation until it becomes lodged in a smaller blood vessel; blocks blood flow at a distant site, causing sudden ischemia or infarction

Arterial thrombi

form in superficial or deep arteries

Venous thrombi

form in superficial or deep veins

Arterial thrombi are associated with

conditions that produce turbulent blood flow and platelet adherence

Venous thrombi associated with

conditions that cause stasis of blood flow with increased concentrations of coagulation factors (e.g. during pregnancy to prevent excessive bleeding during parturition)

Factor V Leiden

most common inherited thrombophilia (increased tendency forming thrombus)

Cause of Factor V Leiden

activated protein C resistance - prevents the normal breakdown of Factor V, leading to increased blood clotting

Factor V Leiden increases the risk of

venous thromboembolism (VTE)

Antiphospholipid syndrome

autoimmune disorder causing increased blood clotting

Autoantibodies attack _____________________________ and activate endothelium, platelets, and coagulation pathway in antiphospholipid syndrome

phospholipid-binding proteins

Antiphospholipid syndrome increase the risk of

venous or arterial thromboembolism

Thrombocytopenia

a decrease in the number of circulating platelets below 150,000/uL

Three major mechanisms of thrombocytopenia

1. decrease platelet production

2. increased sequestration (pooling) in the spleen

3. Increased platelet destruction or reduced survival

Decreased platelet production

bone marrow cannot produce enough megakaryocytes - in leukemia replacement of bone marrow by malignant cells

Increased sequestration (pooling) in the spleen

in splenomegaly (enlarged spleen), up to 90% of platelets may become trapped

Normally, the spleen stores ________ of platelets

30-40%

Increased platelet destruction or reduced survival

antiplatelet antibodies attack platelet membrane proteins: autoimmune disorders, blood transfusions

Immune thrombocytopenic purpura (ITP)

an autoimmune disorder characterized by increased destruction of platelets and thrombocytopenia and increased risk of bleeding

Pathophysiology of Immune thrombocytopenic purpura (ITP)

• immune system produces antiplatelet antibodies

• antibodies target platelet membrane glycoproteins

• antibody-coated platelets are recognized and removed by phagocytes in the spleen

• results in reduced number of circulating placements

Individuals with ITP often experience __________ due to a _____ platelet count

bleeding; low

ITP common manifestations

easy bruising, bleeding gums, epistaxis, melena, menorrhagia

Epistaxis

nosebleeds

Melena

black, tarry stools from gastrointestinal bleeding

Menorrhagia

heavy or abnormal menstrual bleeding

Petechiae

tiny, pinpoint red or purple spots caused by bleeding under the skin

Purpura

larger purple discolorations resulting from bleeding beneath the skin

Von Willebrand disease is

the most common inherited bleeding disorder caused by a deficiency or dysfunction of vWF

The vWF results in

impaired platelet adhesion and may also reduce factor Vlll, leading to prolonged bleeding

vWF has two major functions

promotes platelet adhesion & carries and protects factor Vlll

VWD type 1

autosomal dominant

accounts for about 70% of cases

reduced amount of vWF, usually mild

VWD type 2

autosomal dominant

accounts for about 25% of cases

normal or near-normal amount of vWF, but it functions abnormally

causes mild to moderate bleeding

VWD Type 3

autosomal recessive

extremely low levels of functional vWF

rare, causes severe bleeding

Clinical manifestations of VWD

epistaxis, bleeding from mouth, menorrhagia, prolonged bleeding after surgery or dental extraction, prolonged bleeding time despite normal platelet count

Management of vWD

most patients (types 1 & 2) do not require routine treatment, just avoid medications that increase bleeding risk (aspirin)

severe cases may include vWF factor replacement and Factor Vlll concentrates

Hemophilia

inherited X-linked recessive disorder; primarily affects males

Hemophilia A

most common from about 80-85% of cases

mutations in the F8 gene cause deficiency or defect of clotting factor Vlll

Hemophilia B

also known as Christmas disease (about 15-20% of cases)

mutations in the F9 gene cause deficiency of Factor lX

Hemophilia results in

impaired blood clotting and prolonged bleeding

Hemophilia common symptoms

hematoma formations, persistent bleeding from relatively minor traumatic lacerations, hemarthrosis

Hemarthrosis

bleeding into joints

Lab findings of hemophilia

prolonged activated partial thromboplastin time (aPTT)

normal prothrombin time (PT)

Treatment of hemophilia

recombinant factor Vlll (A)

recombinant factor lX (B)

Disseminated Intravascular Coagulation

a serious disorder of hemostasis characterized by simultaneous widespread clotting and bleeding

Complication of various clinical conditions that release tissue factor DIC

sepsis, acute leukemia, trauma, blood transfusion, obstetric complications

Massive activation of the coagulation cascade (DIC) leads to

widespread clot formation, consumption of clotting factors and platelet, severe bleeding

Pathophysiology of DIC characterized by

a cycle of intravascular clotting followed by active bleeding

Excessive clot formation

• excessive generation of thrombin

• formation of microthrombi in small blood vessels

• vessel occlusion, reduced blood flow and tissue ischemia

Excessive bleeding

• consumption of clotting factors and platelets

• increased fibrinolysis producing fibrin degradation products (FDPs)

• severe hemorrhage

Clinical manifestations of bleeding

petechiae, ecchymoses, bleeding from intravenous or surgical sites, nosebleeds, gastrointestinal bleeding, hematuria

Thrombotic complications due to vascular occlusion (DIC)

tissue ischemia, renal failure, respiratory distress, neurological dysfunction, multiple organ failure