1
Q
Excessive bleeding can result from:
A
- Vessel abnormalities
- Platelet abnormalities (deficiency or dysfunction)
- Coagulation derangements
2
Q
Primary Hemostasis
A
- Platelet/ vascular problem
- Onset: spontaneous, immediate after trauma
- Sites: skin, mucous membranes
- Form: petechiae, ecchymosis
- Mucous membrane: common (nasal, oral, GI, GU)
- Other sites: rare
- Clinical examples: Thrombocytopenia, platelet defects, vWD, scurvy
3
Q
Secondary Hemostasis
A
- Coagulation factor problem
- Onset: delayed after trauma
- Sites: Deep tissues
- Form: hematomas
- Mucous membrane: less common
- Other sites: joint, muscle, CNS, retroperitoneum
- Clinical examples: Factor deficiency, liver disease, acquired inhibitors
4
Q
Vascular abnormalities
A
- Infections
- Drug reactions (often related to hypersensitivity vasculitis due to immune complex deposition)
- Scurvy, Ehler-Danlos (collagen defects in vessel walls)
- Henoch-Schonlein purpura (immune complex deposition)
- Hereditary hemorrhagic telangiectasia (Weber-Osler-Rendu Syndrome - dilated tortuous vessels that bleed easily
- Amyloidosis (weakens vessel walls)
5
Q
Causes of thrombocytopenia
A
Decreased production
Decreased survival
Sequestration
Dilution
6
Q
Immune thrombocytopenia
A
> Destruction caused by deposition of antibodies or immune complexes on platelets
>Can be autoantibodies (recognize self antigens)
>Can be alloantibodies
7
Q
Where do alloantibodies for thrombocytopenia come from?
A
> Can arise when platelets are transfused
Can arise when platelets cross placenta
>IgG from mother can cause fetal thrombocytopenia
8
Q
Non-immune causes of decreased platelet survival in thrombocytopenia
A
> Mechanical injury- heart valves
Disseminated intravascular coagulation (DIC)
Thrombotic microangiopathies
9
Q
Chronic Immune Thrombocytopenic Purpura (ITP)
A
> Caused by autoantibody mediated platelet destruction
|»_space;Primary or idiopathic (diagnosis of exclusion)
10
Q
Secondaries for Chronic ITP
A
> Systemic lupus erythematosis
HIV
B-cell neoplasms such as chronic lymphocytic leukemia
Many others
11
Q
Pathogenesis of chronic ITP
A
> Autoantibodies most often directed against platelet surface glycoproteins IIb/IIIa or Ib-IX (typically IgG)
Anti-platelet Ab act as opsonins
>IgG Fc receptor recognition by macrophages in the reticuloendothelial system (spleen)
>Megakaryocytes may also be affected → further thrombocytopenia
>Splenectomy seems to help many patients (no more phagocytosis or autoantibody)
12
Q
Clinical aspect of chronic ITP
A
- Females <40
- Insidious onset
- Cutaneous bleeding (petechiae, ecchymoses, melena, hematuria, menorrhagia)
- History of…easy bruising, nosebleeds, gum bleeding, soft tissue hemorrhages (with minor trauma)
- Complications: subarachnoid or intracerebral hemorrhage
- Uncommon: splenomegaly, lymphadenopathy
13
Q
Labs of chronic ITP (diagnosis of exclusion)
A
- low platelet count
- large platelets on peripheral blood smear
- normal or increased megakaryocytes in bone marrow
- normal PT and PTT
- platelet autoantibody tests
14
Q
Treatment/prognosis of chronic ITP
A
> glucocorticoids (inhibit phagocyte function) (may respond, many relapse)
spontaneous remission within one or more years possible
splenectomy for severe thrombocytopenia (increased risk of infections)
immunomodulation (if splenectomy fails or is contraindicated)
>IVIG
>rituximab (anti-CD20 antibody)
peptides mimicking thrombopoietin (TPO-mimetics)
15
Q
Acute ITP
A
- mainly in children
- likely triggered by viral illness (1-2 weeks post-illness)
- self-limited mostly
16
Q
Mechanisms of drug-induced thrombocytopenia
A
Direct destruction
Immune-mediated destruction
Drug instigates autoantibody (rarer)
17
Q
Most common drugs causing drug-induced thrombocytopenia
A
> Bind platelet glycoproteins (IIb/IIIa)→ antibody recognition of antigenic determinants
>Quinine
>Quinidine
>Vancomycin
18
Q
Heparin-induced thrombocytopenia (HIT)
A
Potentially deadly, arterial and venous thrombosis, limb loss or threatened loss, and/or pulmonary thromboembolism
19
Q
Two types of HIT
A
> Type I: not usually clinically significant
>Rapid onset after therapy, likely secondary to platelet aggregating effect
Type II: (clinically significant - less common)
>Occurs 5-14 days after therapy initiation, sooner if pre-sensitized
20
Q
Type II HIT
A
> Causes (paradoxical) thrombosis, not bleeding
(unfractionated heparin, but may still occur with LMWH -
almost never occurs with fondaparinux)
Mechanism
>Antibodies to heparin-platelet factor 4 (PF4) complex
»>PF4 is produced by activated platelets
>Antibody binding causes further platelet activation, even if thrombocytopenia
>Get aggregation and consumption, leads to prothrombotic state
21
Q
HIV-Associated thrombocytopenia pathophysiology
A
> CD4 and CXCR4 on megakaryocytes
(can become HIV-infected >
leads to apoptosis and impaired platelet production)
B-cell hyperplasia/dysregulation leading to autoantibody formation against platelet GPIIb-IIIa (destruction in spleen)
22
Q
Thrombotic Microangiopathies
A
> Caused by insults that lead to excessive platelet activation
>Deposit as thrombi in small blood vessels
>Cause microangiopathic hemolytic anemia
>Leads to widespread organ dysfunction
>Results in thrombocytopenia secondary to consumption
PT, PTT usually normal
23
Q
Thrombotic Thrombocytopenic purpura (TTP) pentad
A
Fever microangiopathic hemolytic Anemia Thrombocytopenia Renal insufficiency Neurologic symptoms (FATRN)
24
Q
Hemolytic-uremic syndrome (HUS)
A
- Children
- Lacks fever and neurologic symptoms
25
TTP pathophysiology
>ADAMTS13 (vWF metalloprotease) deficiency
>>ADAMTS13 is normally responsible for degrading very high-molecular-weight multimers of von Willebrand factor (vWF)
>>Without degradation, persistent multimers promote platelet activation and aggregation
26
Acquired form of TTP
- More frequent
| - Typically due to autoantibody that inhibits ADAMTS13
27
Hereditary form of TTP
- Onset typically in adolescence, episodic symptoms
| - Endothelial cell injury caused by other conditions may instigate or aggravate TTP
28
HUS pathophysiology
-Normal levels of ADAMTS13
-Typical: gastroenteritis with E. Coli
>>produces Shiga-like toxin>
absorbed into circulation from damaged/inflamed GI mucosa >alters endothelial cell function >leads to platelet activation and aggregation
-Atypical: associated with defects, inherited or acquired, in:
>>complement factor H (CFH)
>>membrane cofactor protein (MCP or CD46)
>>complement factor I (CFI)
>>basis of platelet activation is unclear
29
HUS clinical/symptoms/treatment/pronosis
-Typical
>>Mostly children and older adults
>>Present with bloody diarrhea, followed by HUS a few days later
>>Complete recovery with supportive care, but some may have irreversible renal damage or death
-Atypical
>>Often remitting, relapsing course
>>Treatment:
-Antibodies that inhibit activation of complement factor 5 for some inherited forms
-Immunosuppression for those with inhibitory autoantibodies
30
Bernard-Soulier Syndrome
- Inherited adhesion defect
- Autosomal recessive
- deficiency in GPIb
- clinically significant bleeding
- Labs: markedly increased platelet size, moderate decrease in numbers
31
Glanzmann thromboasthenia
- Inherited aggregation defect
- Autosomal recessive
- Deficiency or dysfunction in GPIIb/IIIa
- bleeding tendency can be severe
- Labs: platelets normal in number and size, solo w/o clumping
32
Secretion defects of storage pool disorders
Hermanski-Pudlak syndrome
| Chediak-Higashi syndrome
33
Acquired platelet function disorders
Aspirin or nonsteroidal anti-inflammatory drugs
-Inhibits COX >> required for TXA2
-Aspirin = irreversible inhibitor
Uremia
-impairs adhesion, aggregation, and granule secretion
34
Thrombin activates factors...
XI, V, and VIII
35
Factor VIII made in....
Liver sinusoidal and Kupffer cells and other areas
36
vWF made by...and is circulated and secreted into...
endothelial cells and megakaryocytes; subendothelial matrix
37
vWF plays a role in primary and secondary hemostasis, which involve ________ and ___________, respectively
platelet adhesion; stablizing fVIII
38
Von Willebrand Disease (VWD)
- Most common inherited bleeding disorder
- Generally associated with mild bleeding tendency
- Clinically and molecularly heterogeneous
- Mostly autosomal dominant, but rare autosomal recessive forms
- VWF gene on chromosome 12p
39
Type 1 VWD
- quantitative defects
- Most common
- Autosomal dominant (spectrum of mutations, including point substitutions that interfere with maturation or result in rapid clearance)
- Mild to moderate vWF deficiency, generally mild disease
40
Type 3 VWD
- quantitative defects
- Autosomal recessive (usually deletions or frameshift mutations involving both alleles)
- Very low levels of vWF, correspondingly severe clinical disease (some bleeding characteristics of hemophilia due to decreased stability of factor VIII)
41
Type 2 VWD
- Qualitative defects
| - 2A (most common, autosomal dominant, normal quantities of vWF > missense mutations lead to defective multimers)
42
VWD Labs
-Patients with vWD have platelet function defects despite normal platelet numbers (prolonged bleeding time)
-Plasma levels of active vWF are reduced
>>Secondary decrease in factor VIII
>>Prolonged PTT
-Wide variability in clinical expression, even within families
43
VWD Treatment
-typically prophylactic
>>Desmopressin (DDAVP) – stimulates vWF release
>>Plasma concentrates with factor VIII and vWF
44
Hereditary derangements typically involve....
A single factor
45
Hemophilia A is a deficiency in...
Factor VIII
46
Hemophilia B is a deficiency in...
Factor IX
47
Acquired coagulation derangements involve....
Multiple coagulation factors
48
Vitamin K deficiency infleunces coagulation factors...
Factors II, VII, IX, and X
| Proteins S and C
49
Disseminated intravascular coagulation involves...
Consumption of multiple factors
50
Hemophilia A
-Most common hereditary disorder associated with life-threatening bleeding
-Factor VIII mutation(s) on chromosome X
>>X-linked recessive inheritance
>>Mostly affects males, with rare bleeding in heterozygous females
-30% without a family history (de novo mutation)
51
Severity of Hemophilia A
<1% VIII activity: severe
2-5%: moderate
6-50%: mild
52
Most severe mutation of Hemophilia A
Inversion involving X chromosome that abolishes synthesis of factor VIII
53
Clinical signs of Hemophilia A
- Easy bruising
- Massive hemorrhage after trauma or procedures
- Spontaneous hemorrhage (includes into joints - recurrent can cause joint deformities)
- Petechiae absent
54
Labs of Hemophilia A
- Normal PT
- Abnormal PTT
- Factor VIII-specific assays required for diagnosis
55
Hemophilia A treatment
- Recombinant factor VIII (some develop antibodies>>therapeutic challenge)
- Previously, transfused with plasma-derived factor VIII>>HIV
56
Hemophilia B Characteristics
- Not as common
- Wide spectrum of mutations (X-linked recessive), variable severity
- Prolonged PTT, normal PT (need factor IX testing)
- Treat with RF IX
- Christmas Disease
57
Liver disease may be associated with...
-Reduced synthesis of factors and prolonged TT
-Decreased production of anticoagulant proteins
>>can be associated with thrombotic or bleeding complications
-Severe = prolonged PT and PTT
-vitamin K-dependent proteins decreased
-can get inhibitor-like activity from abnormal fibrinogens
58
Factors that limit coagulation
- Dilution –blood flow washes out factors
- Need for negatively charged phospholipid (provided by activated platelets)
- Factors expressed by intact endothelium adjacent to injury
- Fibrinolytic cascade
59
Fibrinolytic cascade
- Limits size of the clot, contributes to later dissolution
- Plasmin – breaks down fibrin, interferes with its polymerization
- Fibrinogen breakdown products (fibrin degradation/split products, fibrin-derived D-dimers) can be measured in thrombotic states
60
Plasmin
-Generated from plasminogen by intrinsic pathway or plasminogen activators (t-PA)
61
t-PA
- Synthesized by endothelium
- Active when bound to fibrin
- Useful therapeutic agent – activity confined to sites of recent thrombosis
62
Plasmin controlled by counter-regulatory factors once activated, like....
Alpha2-plasmin
63
Three major anticoagulant systems that regulate enzymes of the coag protein system
Protein C/S system
-When activated, reduces thrombin formation, stimulates fibrinolysis, initiates inflammation to reduce thrombosis risk
Plasma serine protease inhibitor system – mainly antithrombin (AT III)
- Inhibits factors IIa (thrombin) and Xa
- Heparin interaction
TFPI- Tissue factor pathway inhibitor
64
How does the endothelium limit coagulation?
- Balance between anti- and pro-coagulant activities
- Determines whether clot formation, propagation, or dissolution occur
- Normal endothelium – antithrombotic effects via platelet inhibitory, anticoagulant, and fibrinolytic effects
- Injured endothelium - loses many antithrombotic properties
65
Platelet inhibitory effects of normal endothelium
- Shields platelets from subendothelial collagen and vWF
- Releases inhibitory substances – prostacyclin, NO, adenosine diphosphatase
- Bind and alter activity of thrombin
66
Anticoagulant effects of normal endothelium
>Shields from tissue factor in vessel wall
>Expresses factors that actively oppose coagulation
>>Thrombomodulin and endothelial protein C receptor
>>>Bind thrombin and protein C in a complex (causes thrombin to lose ability to activate factors and platelets, cleaves and activates protein C (with protein S, potent inhibitor of FVa and FVIIIa)
>>Heparin-like molecules
>>>Bind and activate antithrombin III, which inhibits thrombin and FIXa, Fxa, FXIa, FXIIa
>>>Heparin works by stimulating antithrombin III activity
>>Tissue factor pathway inhibitor (with protein S, binds and inhibits tissue factor /factor VIIa complexes)
67
Fibrinolytic effects of normal endothelium
Synthesize t-PA
68
Primary abnormalities involved in abnormal clotting (Virchow's triad)
Endothelial injury
Stasis or turbulent blood flow
Hypercoagulability
69
Prothrombotic changes in endothelial injury
- Downregulate expression of thrombomodulin – modulator of thrombin activation
- Downregulates other anticoagulants, such as protein C and tissue factor protein inhibitor
70
Antifibrinolytic effects of endothelial injury
- Activated endothelial cells secrete plasminogen activator inhibitors – limit fibrinolysis
- Downregulate expression of tissue plasminogen activator
71
Turbulence
causes endothelial injury and dysfunction
72
Stasis
venous thrombi
73
Both turbulence and stasis
- Promote endothelial activation, enhance procoagulant activity
- Disrupt laminar flow, platelets contact endothelium
- Prevent washout and dilution of clotting inhibitors
74
Examples of alterations to normal blood flow
- Ulcerated atherosclerotic plaques
- Aneurysms
- Atrial dilation
- Hyperviscosity
75
Hypercoagulability/Thrombophilia
- Any disorder that predisposes to thrombosis
| - Primary (genetic) or secondary (acquired)
76
Primary thrombophilias
- Most common involve factor V Leiden and prothrombin
- Also includes disorders with increased levels of factors VIII, IX, XI or fibrinogen
- Less common include antithrombin III, protein C and protein S deficiencies
77
Secondary thrombophilias
- Frequently multifactorial
| - Risks include stasis, vascular injury, hyperestrogenic state, malignancy, others
78
Factor V Leiden
- single nucleotide mutation in factor V
- Not a factor deficiency, but an abnormal (mutated) form
- Among those with recurrent DVTs, up to 60% have it
- Mutation renders factor V resistant to cleavage by protein C, lose antithrombotic regulatory pathway
- Heterozygotes – 5x increase of venous thrombosis
- Homozygotes – 50x increase
79
Prothrombin gene mutation
- Single nucleotide change in prothrombin gene
| - Leads to elevated PT levels, 3-fold increase of venous thrombosis
80
Antithrombin deficiency
- Hereditary – can present with DVT, PE
| - Acquired – in DIC, liver disease, nephrotic syndrome, heparin therapy
81
Protein C or S deficiencies
- Both with genetic and acquired deficiencies
| - Increased risk of thrombosis
82
Antiphospholipid syndrome
-binding of antibodies to epitopes on proteins that are induced or "unveiled" by phospholipids
>>Possibly associated with β2-glycoprotein I – associates with surfaces of endothelial cells and trophoblasts, and thrombin
>>Induces a hypercoagulable state through uncertain mechanisms
83
Clinical manifestations of antiphospholipid syndrome
- recurrent thromboses
- repeated miscarriages
- cardiac valve vegetations
- thrombocytopenia
- Presentation can include pulmonary embolism, pulmonary hypertension, stroke, bowel infarction, renovascular hypertension, renal microangiopathy
84
Primary Antiphopholipid syndrome
- Hypercoagulable state, but no evidence of autoimmune disorder
- Can follow exposure to certain drugs or infections
85
Secondary antiphospholipid syndrome
-autoimmune diseases (SLE)
86
Labs and Treatment for antiphospholipid syndrome
- Prolonged PTT
- Clotting, not bleeding
- Treatment: anticoagulation and immunosuppression
87
Arterial thrombosis
- Usually begin at sites of turbulence or endothelial injury
| - Frequently occlusive
88
Venous thrombosis
- Typically in areas of stasis
- Almost invariably occlusive
- Typically have more red cells than arterial – red or stasis thrombi
89
Lines of Zahn
Laminations of a thrombosis that are pale platelet and fibrin deposits alternating with darker red cell-rich layers
90
Postmortem lines of Zahn look like..
Lack organization, not attached to underlying wall, "chicken fat" upper portion
91
Mural thrombi
Those occuring in hear chambers or aorta
92
Heart valve thrombi
Vegetations
93
Fate of the thrombus
>Propagation – accumulate additional platelets and fibrin, grow
>Embolization – dislodge and travel to other sites
>Dissolution
--Fibrinolysis, can lead to rapid shrinkage
--More resistant once cross-linking occurs (explains why t-PA works only early on)
>Organization and recanalization - ingrowth of endothelial cells, can eventually re-establish continuity of a vessel
94
Venous thrombosis (phlebothrombosis)
- Most common in superficial or deep leg veins
- Can cause congestion, swelling, pain, tenderness, lead to overlying ulceration
- Deep veins thromboses can embolize – pulmonary embolism
- Can be associated with hypercoagulable states, bed rest/immobilization, congestive heart failure, trauma, surgery, pregnancy, malignancy
95
Arterial thrombosis
Atherosclerosis most common etiology – endothelial injury and abnormal blood flow
96
Disseminated Intravascualr Coagulation (DIC)
-An acute, subacute or chronic thrombohemorrhagic disorder
-Characterized by excessive activation of coagulation and formation of thrombi in microvasculature
-Occurs as a secondary complication of many disorders
-Results in consumption of platelets, fibrin, and coagulation factors
>>Secondary activation of fibrinolysis
97
DIC Etiology and Pathogenesis
1. exposure of tissue factor
2. Combines with factor VII to activate Factors X and IX
3. Activation of X leads to generation of thrombin
4. Thrombin converts fibrinogen to fibrin
5. Feeds back to activate factors IX, VII, and V
6. Stimulates fibrin crosslinking
7. Inhibits fibrinolysis
8. Activates platelets
9. Leads to stable clot
-Thrombin is also bound to thrombomodulin, anticoagulant
>>Activates protein C, which inhibits factors V and VIII
98
Widespread injury to endothelial cells can happen through...
- Necrosis
- Sepsis - mediated by TNF, induces tissue factor expression, decreases thrombomodulin, upregulates expression of adhesion molecules (attracts leukocytes)
- Deposition of antigen-antibody complexes
99
DIC most frequently associated with...
obstetric complications, malignancy, sepsis, major trauma
100
Consequences of DIC
-Widespread deposition of fibrin in microvasculature (can lead to ischemia, microangiopathic hemolytic anemia)
-Consumption of platelets and clotting factors, activation of plasminogen (leads to hemorrhagic diathesis)
>>Plasmin cleaves fibrin, digests factors V and VIII
>>Fibrin degradation products inhibit platelet aggregation, fibrin polymerization, and thrombin
101
Lab findings of DIC
-Prolonged PT, PTT
-Thrombocytopenia (generally mild)
-Presence of both thrombin and plasmin formation
>>D-dimer test - measures plasmin-cleaved, insoluble, cross-linked fibrin that originally arose from thrombin cleavage
>>Previously measured fibrin degradation (split) products – not as specific
102
DIC Morphology
- Thrombi (Brain, heart, lungs, kidneys, adrenals, spleen, liver, (decreasing order) but may be anywhere
- Can cause infarcts, hemorrhage
103
Clinical features of DIC
-Can be sudden
>>50% associated with pregnancy, can be reversible with delivery
>>33% with carcinomatosis
-Can get:
>Microangiopathic hemolytic anemia
>Dyspnea, cyanosis, respiratory failure
>Acute renal failure and oliguria
>Circulatory failure and shock
-Waterhouse-Friderichsen syndrome in meningococcemia (massive adrenal hemorrhages)
-Kasabach-Merritt syndrome (unusual DIC associated with giant hemangiomas)
-Best treated by managing the underlying disorder
-Variable prognosis
B & L
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