Coagulation Flashcards
Hemostasis : primary vs secondary hemostasis
Integrity of the blood vessel is peccary to cary blood to tissues. Damage to the wall is repaired by hemostasis, which involves formation o f a
thrombus (clot) at the site o f vessel injury.
B. Hemostasis occurs in two stages: primary and secondary.
1. Primary hemostasis forms a weak platelet plug and is mediated by interaction
between platelets and the vessel wall. 2. Secondary hemostasis stabilizes the platelet plug and is mediated by the
coagulation cascade.
Primary Hemostasis Step
Step 1 - Transient vasoconstriction o f damaged vessel
1. Mediated by reflex neural stimulation and endothelin release from endothelial cells
B. Step 2 - Platelet adhesion to the surface of disrupted vessel
1. Von Willebrand factor (vWF) binds exposed subendothelial collagen. 2. Platelets bind vWF using the GPIb receptor. 3 vWF is derived from the Weibel-Palade bodies of endothelial cells and α- granules o f platelets.
C. Step 3 - P l a t e l e t degranulation
1. Adhesion induces shape change in platelets and degranulation with release of
multiple mediators. i. ADP is released from platelet dense granules; promotes exposure of GPIIb/
IIIa receptor on platelets. ii. TXA2 is synthesized by platelet cyclooxygenase (COX) and released;
promotes platelet aggregation
Step 4 - P l a t e l e t aggregation
1. Platelets aggregate at the site o f injury via GPIIb/IIIa using fibrinogen (from
plasma) as a linking molecule; results in formation o f platelet plug 2. Platelet plug is weak; coagulation cascade (secondary hemostasis) stabilizes it.
Disorders of primary hemostasis
Usually due to abnormalities in platelets; divided into quantitative or qualitative
disorders B. Clinical features include mucosal and skin bleeding.
1. Symptoms o f mucosal bleeding include epistaxis (most common overall
symptom), hemoptysis, GI bleeding, hematuria, and menorrhagia. Intracranial
bleeding occurs with severe thrombocytopenia. 2. Symptoms o f skin bleeding include petechiae (1-2 mm, Fig. 4.1), purpura
(> 3 mm), ecchymoses (> 1 cm), and easy bruising; petechiae are a sign o f
thrombocytopenia and are not usually seen with qualitative disorders.
Useful laboratory studies include
1. Platelet count - normal 150-400 K/µL; < 50 K/µL leads to symptoms.
2. Bleeding time - normal 2-7 minutes; prolonged with quantitative and qualitative
platelet disorders 3. Blood smear - used to assess number and size of platelets 4. Bone marrow biopsy - used to assess megakaryocytes, which produce platelets
Disorders of Primary Hemostasis: ITP
Immune thrombocytopenia purpura
Autoimmune production of IgG against platelet antigens (e.g., GPIIb/IIIa)
1. Most common cause of thrombocytopenia in children and adults B. Autoantibodies are produced by plasma cells in the spleen. C. Antibody-bound platelets are consumed by splenic macrophages, resulting in
thrombocytopenia.
Types of ITP
D. Divided into acute and chronic forms
1. Acute form arises in children weeks after a viral infection or immunization;
self-limited, usually resolving within weeks of presentation 2. Chronic form arises in adults, usually women of childbearing age. May be
primary or secondary (e.g., SLE). May cause short-lived thrombocytopenia in
offspring since antiplatelet IgG can cross the placenta.
ITP lab findings
E. Laboratory findings include
1. ↑ platelet count, often < 50 K/µL 2. Normal PT/PTT - Coagulation factors are not affected. 3. ↓ megakaryocytes on bone mar row biopsy
ITP treatment
F. Initial treatment is corticosteroids. Children respond well; adults may show early
response, but often relapse. 1. IVIG is used to raise the platelet count in symptomatic bleeding, but its effect is
short-li ved. 2. Splenectomy eliminates the primary source of antibody and the site of platelet
destruction (performed in refractory cases).
Disorders of primary hemostasis: microangiopathic hemolytic anemia
Pathologic formation of platelet microthrombi in small vessels
1. Platelets are consumed in the formation of microthrombi. 2. RBCs are “sheared” as they cross microthrombi, resulting in hemolytic anemia
with schistocytes (Fig. 4.2).
B. Seen in thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic
syndrome (HUS)
What is TTP
TTP is due to decreased ADAMTS13, an enzyme that normally cleaves vWF
multimers into smaller monomers for eventual degradation.
Large, uncleaved multimers lead to abnormal platelet adhesion, resulting in
microthrombi. 2. Decreased ADAMTS13 is usually due to an acquired autoantibody; most
commonly seen in adult females
- microagniopathic hemolytic anemia
What is HUS
HUS is due to endothelial damage by drugs or infection.
1. Classically seen in children with E coli O157:H7 dysentery, which results
from exposure to undercooked beef 2. E coli verotoxin damages endothelial cells resulting in platelet microthrombi.
- microagniopathic hemolytic anemia
clinical findings of HUS and TTP
Clinical findings (HUS and TTP) include
1. Skin and mucosal bleeding
2. Microangiopathic hemolytic anemia
3. Fever
4. Renal insufficiency (more common in HUS) - Thrombi involve vessels of the
kidney. 5. CNS abnormalities (more common in TTP) - Thrombi involve vessels of the
CNS.
lab findings microangiopathic hemolytic anemia (TTP and HUS)
Laboratory findings include
1. Thrombocytopenia with ↑ bleeding time
2. Normal PT/PTT (coagulation cascade is not activated)
3. Anemia with schistocytes
4. ↑megakaryocytes on bone marrow biopsy
TX for TPP and HUS
Treatment involves plasmapheresis and corticosteroids, particularly in TTP.
Qualitative Platelet Disorders
Bernard-Soulier syndrome is due to a genetic GPIb deficiency; platelet adhesion is
impaired.
1. Blood smear shows mild thrombocytopenia with enlarged platelets.
B. Glanzmann thrombasthenia is due to a genetic GPIIb/IIIa deficiency; platelet
aggregation is impaired.
C. Aspirin irreversibly inactivates cyclooxygenase; lack of TXA2 impairs aggregation.
D. Uremia disrupts platelet function; both adhesion and aggregation are impaired
Secondary Hemostasis
A. Stabilizes the weak platelet plug via the coagulation cascade
1. Coagulation cascade generates thrombin, which converts fibrinogen in the
platelet plug to fibrin. 2. Fibrin is then cross-linked, yielding a stable platelet-fibrin thrombus.
B. Factors of the coagulation cascade are produced by the liver in an inactive state.
Activation requires
1. Exposure to an activating substance
i. Tissue thromboplastin activates factor VII (extrinsic pathway). ii. Subendothelial collagen activates factor XII (intrinsic pathway).
2. Phospholipid surface of platelets
3. Calcium (derived from platelet dense granules)
Disorders of Secondary hemostasis - clinical features
Usually due to factor abnormalities
B. Clinical features include deep tissue bleeding into muscles and joints (hemarthrosis)
and rebleeding after surgical procedures (e.g., circumcision and wisdom tooth extraction).
lab findings for disorders of secondary hemostasis
- Prothrombin time (PT)-measures extrinsic (factor VII) and common (factors
II, V, X, and fibrinogen) pathways of the coagulation cascade - Partial thromboplastin time (PTT)-measures intrinsic (factors XII, XI, IX,
VIII) and common (factors II, V, X, and fibrinogen) pathways of the coagulation
cascade
Hemophilia A
A. Genetic factor VIII (FVIII) deficiency
1. X-linked recessive (predominantly affects males) 2. Can arise from a new mutation (de novo) without any family history
B. Presents with deep tissue, joint, and postsurgical bleeding
1. Clinical severity depends on the degree of deficiency.
Hemophilia A lab findings and tx
Laboratory findings include
1. ↑ PTT; normal PT
2. ↓ FVIII
3. Normal platelet count and bleeding time D. Treatment involves recombinant FVIII.
Hemophilia B (Christmas disease)
Genetic factor IX deficiency
1. Resembles hemophilia A, except FIX levels are decreased instead of FVIII
Coagulation factor inhibitor
A. Acquired antibody against a coagulation factor resulting in impaired factor function;
anti-FVIII is most common. 1. Clinical and lab findings are similar to hemophilia A. 2. PTT does not correct upon mixing normal plasma with patient’s plasma (mixing
study) due to inhibitor; PTT does correct in hemophilia A.
Von Willebrand disease
A. Genetic vWF deficiency
1. Most common inherited coagulation disorder
B. Multiple subtypes exist, causing quantitative and qualitative defects; the most common type is autosomal dominant with decreased vWF levels.
C. Presents with mild mucosal and skin bleeding; low vWF impairs platelet adhesion.
vWBD lab findings
Laboratory findings include
1. ↑bleeding time
2. ↑PTT; normal PT - Decreased FVIII half-life (vWF normally stabilizes FVIII);
however, deep tissue, joint, and postsurgical bleeding are usually not seen. 3. Abnormal ristocetin test - Ristocetin induces platelet agglutination by causing
vWF to bind platelet GPIb; lack of vWF → impaired agglutination →abnormal test.
vWBD tx
Treatment is desmopressin (ADH analog), which increases vWF release from
Weibel-Palade bodies of endothelial cells.
Vitamin K deficiency
Disrupts function of multiple coagulation factors
1. Vitamin K is activated by epoxide reductase in the liver. 2. Activated vitamin K gamma carboxylates factors II, VII, IX, X, and proteins C
and S; gamma carboxylation is necessary for factor function.
B. Deficiency occurs in
1. Newborns - due to lack of GI colonization by bacteria that normally synthesize
vitamin K; vitamin K injection is given prophylactically to all newborns at birth
to prevent hemorrhagic disease of the newborn. 2. Long-term antibiotic therapy - disrupts vitamin K-producing bacteria in the GI
tract 3. Malabsorption - leads to deficiency of fat-soluble vitamins, including vitamin K
Other cases of abnormal secondary hemostasis
A. Liver failure - decreased production of coagulation factors and decreas
ed activation of vitamin K by epoxide reductase; effect of liver failure on coagulation is followed using PT
B. Large-volume transfusion - dilutes coagulation factors, resulting in a relati
ve
deficiency
Heparin-Induced Thrombocytopenia
Platelet destruction that arises secondary to heparin therapy
B. Fragments of destroyed platelets may activate remaining platelets, leading to
thrombosis.
Disseminated intravascular coagulation
A. Pathologic activation of the coagulation cascade
1. Widespread microthrombi result in ischemia and infarction. 2. Consumption of platelets and factors results in bleeding, especially from IV sites
and mucosal surfaces (bleeding from body orifices).
B. Almost always secondary to another disease process
1. Obstetric complications - Tissue thromboplastin in the amniotic fluid activates
coagulation. 2. Sepsis (especially with E coli or N meningitidis) - Endotoxins from the bacterial
wall and cytokines (e.g., TNF and IL-1) induce endothelial cells to make tissue
factor. 3. Adenocarcinoma - Mucin activates coagulation. 4. Acute promyelocytic leukemia - Primary granules activate coagulation. 5. Rattlesnake bite - Venom activates coagulation.
DIC lab findings
Laboratory findings include
1. ↓ platelet count
2. ↑ PT/PTT
3. ↓ fibrinogen
4. Microangiopathic hemolytic anemia
5. Elevated fibrin split products, particularly D-dimer
i. Elevated D-dimer is the best screening test for DIC. ii. Derived from splitting of cross-linked fibrin; D-dimer is not produced from
splitting of fibrinogen.
DIC tx.
Treatment involves addressing the underlying cause and transfusing blood products
and cryoprecipitate (contains coagulation factors), as necessary.
Disorders of fibrinolysis
B. Disorders of fibrinolysis are due to plasmin overactivity resulting in excessive cleavage
of serum fibrinogen. Examples include
1. Radical prostatectomy - Release of urokinase activates plasmin. 2. Cirrhosis of liver - reduced production of α2-antiplasmin
C. Presents with increased bleeding (resembles DIC)
D. Laboratory findings include
1. ↑ PT/PTT - Plasmin destroys coagulation factors. 2. ↑ bleeding time with normal platelet count - Plasmin blocks platelet aggregation. 3. Increased fibrinogen split products without D-dimers - Serum fibrinogen is
lysed; however, D-dimers are not formed because fibrin thrombi are absent.
E. Treatment is aminocaproic acid, which blocks activation of plasminogen.
Normal fibrinolysis
A. Normal fibrinolysis removes thrombus after damaged vessel heals.
1. Tissue plasminogen activator (tPA) converts plasminogen to plasmin. 2. Plasmin cleaves fibrin and serum fibrinogen, destroys coagulation factors, and
blocks platelet aggregation. 3. α2-antiplasmin inactivates plasmin.
Thrombosis basics
BASIC PRINCIPLES
A. Pathologic formation of an intravascular blood clot (thrombus)
1. Can occur in an artery or vein 2. Most common location is the deep veins (DVT) of the leg below the knee.
B. Characterized by (1) lines of Zahn (alternating layers of platelets/fibrin and RBCs,
Fig. 4.3) and (2) attachment to vessel wall
1. Both features distinguish thrombus from postmortem clot.
C. Three major risk factors for thrombosis are disruption in blood flow, endothelial cell
damage, and hypercoagulable state (Virchow triad).
Disruption of normal blood flow
A. Stasis and turbulence of blood flow increases risk for thrombosis.
1. Blood flow is normally continuous and laminar; keeps platelets and factors
dispersed and inactivated
B. Examples include
1. Immobilization - increased risk for deep venous thrombosis
2. Cardiac wall dysfunction (e.g., arrhythmia or myocardial infarction)
3. Aneurysm
Endothelial cell damage
A. Endothelial damage disrupts the protective function of endothelial cells, increasing the risk for thrombosis.
B. Endothelial cells prevent thrombosis by several mechanisms.
1. Block exposure to subendothelial collagen and underlying tissue factor 2. Produce prostacyclin (PGI2) and NO - vasodilation and inhibition of platelet
aggregation
3. Secrete heparin-like molecules - augment antithrombin III (ATIII), which
inactivates thrombin and coagulation factors 4. Secrete tissue plasminogen activator (tPA) - converts plasminogen to plasmin,
which (1) cleaves fibrin and serum fibrinogen, (2) destroys coagulation factors,
and (3) blocks platelet aggregation 5. Secrete thrombomodulin - redirects thrombin to activate protein C, which
inactivates factors V and VIII
Causes of endothelial cell damage
Causes of endothelial cell damage include atherosclerosis, vasculitis, and high levels of
homocysteine.
1. Vitamin B12 and folate deficiency result in mildly elevated homocysteine levels,
increasing the risk for thrombosis.
i. Folic acid (tetrahydrofolate, THF) circulates as methyl-THF in the serum.
ii. Methyl is transferred to cobalamin (vitamin B12), allowing THF to participate
in the synthesis of DNA precursors. iii. Cobalamin transfers methyl to homocysteine resulting in methionine. iv. Lack of vitamin B12 or folate leads to decreased conversion of homocysteine to
methionine resulting in buildup of homocysteine
Cystathionine beta synthase (CBS) deficiency results in high homocysteine levels
with homocystinuria.
i. CBS converts homocysteine to cystathionine; enzyme deficiency leads to
homocysteine buildup. ii. Characterized by vessel thrombosis, mental retardation, lens dislocation, and
long slender fingers.
hyper coagulable state
A. Due to excessive procoagulant proteins or defective anticoagulant proteins; may be
inherited or acquired B. Classic presentation is recurrent DVTs or DVT at a young age.
1. Usually occurs in the deep veins of the leg; other sites include hepatic and cerebral
veins.
Protein C or S Deficiency
causes hypercoagulable state
Protein C or S deficiency (autosomal dominant) decreases negative feedback on the
coagulation cascade.
1. Proteins C and S normally inactivate factors V and VIII. 2. Increased risk for warfarin skin necrosis
i. Initial stage of warfarin therapy results in a temporary deficiency of proteins C
and S (due to shorter half-life) relative to factors II, VII, IX, and X ii. In preexisting C or S deficiency, a severe deficiency is seen at the onset of
warfarin therapy increasing risk for thrombosis, especially in the skin.
Factor V Leiden
causes hyper coagulable state
Factor V Leiden is a mutated form of factor V that lacks the cleavage site for
deactivation by proteins C and S.
1. Most common inherited cause of hypercoagulable state
Probrombin 20210A
causes hypercoagulable state
Prothrombin 20210A is an inherited point mutation in prothrombin that results in
increased gene expression.
1. Increased prothrombin results in increased thrombin, promoting thrombus
formation.
ATIII deficiency
causes hypercoagulable state
ATIII deficiency decreases the protective effect of heparin-like molecules produced by
the endothelium, increasing the risk for thrombus.
1. Heparin-like molecules normally activate ATIII, which inactivates thrombin and
coagulation factors. 2. In ATIII deficiency, PTT does not rise with standard heparin dosing.
i. Pharmacologic heparin works by binding and activating ATIII.
ii. High doses of heparin activate limited ATIII; coumadin is then given to
maintain an anticoagulated state.
oral contraceptives
causes hypercoagulable state
Oral contraceptives are associated with a hypercoagulable state.
1. Estrogen induces increased production of coagulation factors, thereby increasing the
risk for thrombosis.
Embolism
Intravascular mass that travels and occludes downstream vessels; symptoms depend on the
vessel involved.
thromboembolus
Thromboembolus is due to a thrombus that dislodges; most common type of embolus
(>95%)
atherosclerosis embolus
Atherosclerotic embolus is due to an atherosclerotic plaque that dislodges.
1. Characterized by the presence of cholesterol clefts in the embolus
fat embolus
Fat embolus is associated with bone fractures, particularly long bones, and soft tissue
trauma.
1. Develops while fracture is still present or shortly after repair
2. Characterized by dyspnea (fat, often with bone marrow elements, is seen in pulmonary
vessels, Fig. 4.4B) and petechiae on the skin overlying the chest
Gas embolus
Gas embolus is classically seen in decompression sickness.
1. Nitrogen gas precipitates out of blood due to rapid ascent by a diver.
2. Presents with joint and muscle pain (‘bends’) and respiratory symptoms
(‘chokes’). 3. Chronic form (Caisson disease) is characterized by multifocal ischemic necrosis of
bone. 4. Gas embolus may also occur during laparoscopic surgery (air is pumped into the
abdomen).
amniotic fluid embolus
Amniotic fluid embolus enters maternal circulation during labor or delivery
1. Presents with shortness of breath, neurologic symptoms, and DIC (due to the
thrombogenic nature of amniotic fluid) 2. Characterized by squamous cells and keratin debris, from fetal skin, in embolus (Fig.
4.4C)
pulmonary embolism
Usually due to thromboembolus; the most common source is deep venous thrombus
(DVT) of the lower extremity, usually involving the femoral, iliac, or popliteal veins. B. Most often clinically silent because (1) the lung has a dual blood supply (via pulmonary
and bronchial arteries) and (2) the embolus is usually small (self-resolves)
Sudden death occurs with a large saddle embolus that blocks both left and right
pulmonary arteries or with significant occlusion of a large pulmonary artery (Fig.
4.5); death is due to electromechanical dissociation. E. Pulmonary hypertension may arise with chronic emboli that are reorganized over
time.
pulmonary infarction
Pulmonary infarction occurs if a large- or medium-sized artery is obstructed in
patients with pre-existing cardiopulmonary compromise; only 10% of PEs cause
infarction.
1. Presents with shortness of breath, hemoptysis, pleuritic chest pain, and pleural
effusion 2. V/Q lung scan shows mismatch; perfusion is abnormal. 3. Spiral CT shows a vascular filling defect in the lung. 4. Lower extremity Doppler ultrasound is useful to detect DVT. 5. D-dimer is elevated. 6. Gross examination reveals a hemorrhagic, wedge-shaped infarct.
Systemic embolism
A. Usually due to thromboembolus
B. Most commonly arise in the left heart
C. Travel down systemic circulation to occlude flow to organs, most commonly the
lower extremities
