Ch. 24 Coagulation

Bleeding into skin, organs or membranes.

Small, pinpoint bleeding into skin

• Something wrong with platelets but platelet counts usually normal.
• EXAMPLE: Wiscott-Aldrich syndrome, Bernand-Soulier Syndrome, Glanzemann's, Thrombasthenia, Aspirin ingestion.

• Low production
• High Destruction or Consumption
• Common Causes: Cancer treatment, Damage to the bone marrow by miscellaneous drugs or toxins, 80% of hospitalized alcoholics mild thrombocytopenia, Vitamin B12 and Folic Acid deficiency, autoimmune diseases, leukemias.

A bacterial infection of the blood

• Increased platelets
• Acute blood loss, infections, inflammation

• Makes the body system avoid excessive blood flow.
• People without Vitamin K prone to excessive bleeding and bruising.
• Group 2 (2,7,9,10)

Refers to a group of bleeding disorders in which it takes a long time for a blood clot to form.

• DVT, PE, Strokes, and Heart attacks
• High procoagulants
• Low Fibrinolysis
• Low natural anticoagulants activity (ATIII, Protein C)

Usually auto antibodies directed against plasma coagulation proteins.

• Can have specificity against a specific protein or non-specificity against multiple different proteins.
• Lupus inhibitors
• Factor VIII inhibitors

Term used for venous thrombosis of upper and lower extremities associated with: visceral cancer.

Artificial DNA sequence resulting from the combining 2 other DNA sequences in a plasmid.

• Non-specific anti-phospholipid antibodies. Found in 10% SLE
• Associated: HIV, Medications, Cancers

Directed against plasma coagulation proteins.

• vWF proteins are normally broken down into smaller, inactive fragments by an enzyme.
• Deficiency: accumulation of vWF multimers (Abnormally large vWF molecules)
• Causes: Genetic, others acquired

• Synthesized by megakaryocytes and vascular endothelium
• 95% of Factor VIII composed of vWF
• Stabilizes Factor VIII and promotes platelet adhesion

• Types of clotting disease
• Hypercoagulable conditions

• Oral, slow
• 72 hours
• Effects Group 2 (2,7,9,10) because it's a Vitamin K inhibitor.

• IV
• Inhibits thrombin by enhancing ATIII
• Fast Acting
• 1/2 life= 1 hour

• Excessive thrombin activation and clotting
• Procoagulant activity exceeds anticoagulant activity.
• All hemostasis system activated.

• Genetically acquired but not sex linked.
• Males and Females
• More common than Hemophilia A
• Factor VIII lowered.
• Abnormal platelet function
• 85%: Vascular endothelial cells
• 15%: Platelet alpha granules

• Factor VIII Absent/decreased synthesis
• 85% of Hemophilias
• 66% cases acquired from inheritance of defective X chromosome
• 33% acquired from spontaneous mutations
• Females are carriers

• Factor IX deficiency
• Christmas disease
• Sex linked, Genetically acquired
• 20% spontaneous mutations

• Factor XI deficiency
• Genetically acquired, non-sex linked males and females affected.
• Most common in E.European Jews

ATIII: Decreased

Protein C: Decreased

Types of clotting diseases

• Auto-immune anti platelet antibodies
• Chronic=Adults
• Acute-transient=Children
• Treatment: Steroids, splenectomy, plasmapheris (REMOVES ANTIBODIES)

• vWF proteins are normally low into smaller inactive fragments by an enzyme.
• Synthesized by megakaryocytes and vascular endothelium.
• Def. of ADAMTS-13 enzyme promotes an accumulation of vWF multimers.
• High plasma BUN, Creatinine
• Low LDH
• High Bilirubin
• Low Haptoglobin (RBC Hemolysis)

• Related to TTP but with renal failure associated from vascular ischemia (blockages to renal blood vessel)
• ADAMTS-13

• Qualitative Platelet
• Dohle Bodies with large platelets
• Missing platelet GP receptors (Ib, V, IX) with impaired platelet.

• Qualitative platelet disorder
• PFA: Increased
• Genetic disorder
• End stage kidney disease

• PFA: Increased
• Missing platelet GP receptors (IIb/IIIa) with impaired platelet adhesion.

• Seen in 1% of heparinized patients.
• Thrombocytopenia begins 5-7 days after therapy.
• Heparin mediated immune platelet destruction
• Heparin interacts with platelet antigens.

Treatment: Discontinue heparin

• Most common in post partum females
• Anti-platelet antibodies from previous pregnancies or transfusions
• Thrombocytopenia 5-10 days post transfusion.

Bleeding into skin, organs, membranes

Small, pinpoint bleeding into skin

• Bacterial toxins
• Malignancies (Trousseau's Syndrome)
• Antibody-Antigen reactions
• Trauma
• OB complications
• Diabetes
• DIC

• 150-450 (10³/mm³)
• Decreased plts: Thrombocytopenia
• Increased plts: Thrombocytosis

• >100: for normal clot formation
• < 50: abnormal bleeding and bruising
• < 20: Cerebral bleeding (death)
• < 10: Spontaneous bleeding (Death)

• Petechaie,
• purpura
• epistaxsis (nosebleeds)
• Cerebral hemorrhage
• Excessive surgical bleeding

• Defective platelet dense granule storage
• Abnormally small platelets

• Missing platelet GP receptors (Ib, V, IX)
• Impaired platelet adhesion

Missing platelet GP receptors (IIb,IIIa) with impaired platelet adhesion

• Aspirin inhibits platelet function
• Aspirin inhibits the synthesis of naturally occuring substances (Thromboxane A₂) that promote platelet aggregation.

• Common cause: Cancer treatment (Therapeutic irradiation and chemotherapy)
• Damage to the bone marrow by miscellaneous drugs or toxins
• 80% of hospitalized alcoholics have mild thrombocytopenia.
• Vitamin B12 and Folic Acid deficiency
• Viral infections (EBV, HIV, Mumps, Chicken pox, others)
• Autoimmune diseases
• leukemias

• Heparin mediated immune platelet destruction.
• Heparin interacts with platelet antigens
• Seen in 1% of heparinized patients
• Thrombocytopenia begins 5-7 days after therapy
• Checked for platelet counts

Treatment: stop heparin

• Ab-ag complexes (immune complexes) attach to platelets
• Removal of platelets from the peripheral blood
• Associated with: Sepsis (bacteria in the blood) and drugs

• Most common in post partum females
• Anti-platelet antibodies from previous pregnancies or transfusions
• Thrombocytopenia 5-10 days post transfusion
• (Exposed to antigen in child birth make antibodies)

• Auto-immune anti platelet antibodies
• Thrombocytopenia (low platelets)
• Cause: UNKNOWN (perhaps associated with viral infections)
• Acute to transient symptoms in children
• Chronic=Adults

• Treatment: Splenectomy, Steroids, Plasmapheresis (removes antibodies)
• Titer: way of measuring concentration

• vWF is synthesized by megakaryocytes and vascular endothelium.
• Deficiency of ADAMTS-13 promotes an accumulation of vWF multimers (abnormally large vWF molecules
• vWF multimers adhere to the endothelium lining and promote platelet adhesion and aggregation.

• Causes of ADAMTS-13 deficiencies:
• Genetic, Acquired

• Thrombocytopenia
• Microangiopathic (abnormal circulation in blood vessels) hemolytic anemias (schistocytes)
• High: Plasma BUN and Creatinine (Renal failure), LDH, Bilirubin,
• Low: Haptoglobin (RBC hemolysis)
• Vascular occlusions (renal and neurological damage)

Treatment: Plasmaphoresis to remove vWF multimers from the plasma. Support patient with Platelet transfusions

• Keep blood vessels clear of vWF.
• Weeds keep growing and platelets get stuck because ADAMTS-13 can't cut it down.

• Type of TTP, but with renal failure associated from vascular ischemia
• (Blockages to renal blood vessels)

• Enlarged spleen
• Abnormal increased removal of platelets from the peripheral blood.
• Treatment: Splenectomy

• Acute blood loss
• Infection
• Inflammation
• Pathological thrombocytosis can be associated with thrombotic events (clotting)

• Vitamin K deficiency=Decreased group II (2,7,9,10)
• Liver disease=all coagulation proteins are decreased.
• Hemophilia
• Autoimmune antibodies against coagulation proteins.
• Excessive consumption and depletion of coagulation proteins.
• 30-40% of circulating proteins is still sufficient to produce normal clotting.
• There must be a significant factor deficiency before the PT/PTT tests are abnormally elevated.

Genetic deficiencies of coagulation protein synthesis

• Absent or decreased synthesis of Factor VIII
• Most common hemophilia (85% of all hemophilias)
• 66% of cases acquired from inheritance of a defective X chromosome.
• 33% of cases acquired from spontaneous mutation of X chromosome.
• Disease is almost found in 1/10,000 males.
• Females are carriers (carry the defective gene, but don't have symptoms of the disease)
• Found in all ethnic groups.

Caused by decreased or absent VIII:C component of the Factor VIII molecule.

• vWF (Von Willebrand Factor)
• VIII:RCo (Platelet aggregation)
• VIII: Ag (Antigenic site)

• VIII: C (procoagulant)
• VIII: Ag (Antigenic Site)

• Males: XY sex Chromosomes
• Females: XX sex chromosomes

• The genetic mutation responsible for defective Factor VIII synthesis is on the X chromosome, not the Y
• A male with a defective X chromosome inherits the disease because he has no genetic capacity to synthesize Factor VIII.
• A female with a defective X chromosome is a carrier of the disease and has no symptoms because she still has an additional normal X chromosome that can still synthesize Factor VIII.

• All daughters of a hemophiliac father will be carriers.
• Sons of female carriers have a 50% chance of being hemophiliacs.
• Daughters of female carriers have a 50% chance of becoming carriers.
• For practical considerations, females can transmit the disease but cannot become hemophiliacs themselves

• Easy bleeding and bruising, even from normal activities.
• The absence of normal clotting often results in painful and crippling bleeding into joints.
• Normal cuts and injuries can be life threatening.

• An artifical DNA sequence resulting from the combing of DNA sequence in a plasmid.
• Proteins that are produced by different genetically modified organisms following insertion of the relevant DNA into their genome.
• As this recombines the DNA of 2 different organisms.

• PT: Normal
• PTT: Increased (only measures Factor 8)
• FIB: Normal
• PFA: Normal
• Plt #: Normal
• D-dimer: =
• FDP:=

• Defective or absent vWF.
• 95% of Factor 8 is composed of the vWF
• vWF stabilizes Factor 8 and promotes platelet adhesion.
• Genetically acquired, but not sex linked (males and females affected)
• More common than Hemophilia A
• VWF synthesis (85% endothelial cells + 15% platelet alpha granules)
• vWF is an adhesive protein that binds with platelet GP IIb/IIIa receptors (its the rope that ties onto the platelets)
• Affects 1-2% of population
• 80% mortality if untreated
• Factor 8 activity is decreased in both Hemophilia A and VWD

• Unstable Factor 8 is removed from the plasma.
• Poor platelet adhesion

• Bleeding from abnormal platelet adhesion.
• Bleeding from decreased Factor 8 activity

• Normal platelet function
• Abnormal

• PT: normal
• PTT: Increased (decreased Factor 8)
• FIB: normal
• PFA: Prolonged (Decreased plt. function)
• Plt #: normal
• D-dimer: =
• FDP: =

• Factor 9 deficiency
• X-mas disease
• Sex linked, genetically acquired like Hemophilia A
• 20% are spontaneous mutations
• Frequency: 1/30,000 males
• Similar symptoms as Hemophilia A,but usually not as severe

• Factor 11 deficiency
• Genetically acquired, non sex-linked, Males and Females affected
• Frequency: 1/100,000
• Most common in Eastern European Jews
• 8% frequency among Israeli Ashkenazi Jews

Balance between clotting and bleeding

• Too much clotting
• The coagulation factors get used up=Bleeding

• Abnormal activation without fibrin formation (Primary fibrinolysis)
• Activation with fibrin formation (Secondary fibrinolysis)

• Excessive thrombin activation and clotting
• Pro-coagulant activity exceeds anticoagulant activity
• All components of the hemostasis system are activated: (Pro-coagulants, Platelets, Vascular System, Fibrinolysis )

• Childbirth (33%)
• Malignancies (33%)
• Bacterial infections
• Trauma=Burns, surgery, injuries
• Snake bites
• RBC hemolysis

• Petechia/Purpura
• Bleeding/cozing from surgical incesions
• IV
• Needle sticks
• coagulation proteins and platelets are depleted in excessive clotting.
• Excessive fibrinolysis produces increased FDP
• Increased FDPs inhibit platelet aggregation/adhesion
• Excessive clotting depletes the natural anticoagulant activity

• excessive clotting
• Treatment: Stop the clotting= Anticoagulant therapy (Heparin)
• Can be supported with blood transfusions until the root cause is controlled (RBCs, Platelets, FFP)

• PT: Increased
• PTT: Increased
• FIB: Decreased
• PFA: Prolonged (Decreased Platelet Function)
• Plt #: Decreased
• Blood smear: Schistocytes
• FDP: +
• D-Dimer: + (most specific indicator)
• ATIII and PC: Decreased

• Increased procoagulants
• Decreased fibrinolysis
• Decreased natural anticoagulant activity (ATIII and Protein C)
• Damaged vascular systems and stasis
• 300,000 annual deaths in US hospitals
• More deaths from clotting than bleeding

• DVT: Deep Vein Thrombosis
• PE: Pulmonary Embolisms
• Strokes and heart attacks from vascular occlusions
• Traveler's thrombosis

ATIII: Decreased

Protein C: Decreased

FDP: +

D-dimer: +

Treatment: Warfarin, Heparin, Aspirin. DVT and PE involves the use of "clot busting" drugs, usually plasminogen activators (TPA). Plasminogen activated plasmin. Activated plasmin dissolves fibrin.

• Substances that inhibit plasma coagulation proteins
• Circulating anticoagulants (inhibitors) are usually auto antibodies directed against plasma coagulation proteins.
• Found in 1% of the population
• Inhibitors can have specificity against a specific protein or non-specificity against multiple different proteins.
• Most circulating anticoagulants only cause bleeding disorders when they are associated with another coagulation disorder

• Non-specific anti-phospholipid (components of membranes) antibodies
• Found in 10% of Systemic Lupus Erythromatosis
• Also associated with HIV, cancers, and medications

• Anti-factor 8 antibody
• Found in 10-15% of Hemophilia A patients
• Hemophilia A patients with less than 1% activity often have anti-factor 8