Chapter 2 Flashcards
How does the endothelium prevent propagation of a clot?
Thrombomodulin production results in activation of protein C and subsequent inhibition of factors Va and VIIIa, while local TFPI release reversibly inhibits factor Xa
Endogenous heparin and dermatan sulfate expression results in antithrombin III binding- thus inactivating thrombin and preventing propagation of clot
What is an early mediator of primary hemostasis during endothelial injury?
Vasoconstriction, as a result of neuromyogenic reflexes within the vascular smooth muscle
How is vascular contraction further augmented?
Paracrine signaling via ADP, thromboxane A2 and serotonin from nearby adherent platelets
What provides an avenue for platelet and leukocyte adhesion
Exposure of subendothelial tissue factor and collagen
What improves coagulation protein and platelet binding?
Increased endothelial cell production of vWF
Expression of cellular TF and platelet-activating factor (PAF)
Reduced thrombomodulin activity
Origin of platelets and lifespan
Derived from bone marrow megakaryocytes
Lifespan of 9-12 days
What percentage of the body’s platelet pool is stored in the spleen?
1/3
How is platelet adhesion further strengthened?
Presence of vWF, which mediates the binding of collagen with glycoprotein Ib/IX
When does platelet plug formation occur?
When does clot stabilization occur?
What is clot stabilization aided by?
Within 1-3 mins of injury
Within 10 mins of injury
Aided in part by negative feedback from endothelial cell PGI2 release
What occurs after platelet plug formation?
Procoagulant protein complexes (i.e, prothrombinase, tenase) form on platelet phospholipid surfaces and augment the production of thrombin via the coagulation cascade
What is responsible for the production of all coagulation factors with the exception of VIII and vWF?
Liver
VIII and vWF are produced by endothelial cells
How are factors II, VII, IX and X formed
Through vit K-dependent reactions
They are of particular importance in pharmacologic anticoagulation
Traditional coagulation pathway
Extrinsic (PT/INR) and intrinsic (aPTT) merge into a common pathway
More recent discovery of the coagulation pathway
Described in cell-based phases:
Initiation
Amplification
Propagation
Process of initiation
TF is released by the injured vascular endothelium
Binds to factor VII to form TF-VIIa complexes
Complex activates factors X and IX to form Xa and IXa
Factors Xa and Va form the Xa-Va complex (prothrombinase complex)
Prothrombinase complex converts small amts of factor II (prothrombin) to factor IIa (thrombin)
Process of amplification
Thrombin produced from initiation activates additional factor V, VIII, XI, and platelets through a pos feedback loop
Process of propagation
Factors IXa and VIIIa form the factor IXa-VIIIa complex (tenase complex)
Tenase complex converts additional factor X to Xa, which then forms more prothrombinase complexes
Large amts of thrombin are generated, leading to the formation of fibrin from fibrinogen
Fibrin weaves throughout the platelet plug to form a stable fibrin clot
What are important natural anticoagulants?
ATIII
Protein C
Protein S
What does ATIII do?
Directly inhibits factors IIa (thrombin), IXa, Xa, and XIa
What is protein C?
A vit-K dependent natural anticoagulant, which is activated by thrombin-thrombomodulin complexes on the endothelial cell surface following the formation of a clot
What is protein S?
A vit-K dependent cofactor in the formation of APC
What are important regulatory and precursor proteins necessary for fibrin degradation?
Plasminogen
tPA
a2-antiplasmin
What does tPA do?
Acts to convert plasminogen to plasmin, which in turn binds fibrin and degrades the polymer into soluble split products
What does a2-antiplasmin do?
Serves as a negative regulator of plasmin and binds and inactivates circulating excess plasmin
Binds continuously secreted plasmin, allowing early clot formation during vascular injury without immediate degradation
What is a nl platelet count?
150-450K/microL of blood
What occurs with a platelet count <50,000?
Pts are subject to easy bruising and bleeding?
When does spontaneous bleeding occur?
Does not typically occur unless platelet counts are <20K
What is considered a nl bleeding time?
Between 2-10 mins
What does bleeding time measure?
Qualitative platelet dysfunction
What is an abnormal bleeding time?
What is it associated with?
Between 10-15 mins
Associated with low-mod risk for bleeding
>15 mins is serious risk for spontaneous bleeding and severe platelet dysfunction or thrombocytopenia
What does prothrombin time (PT) measure?
The function of the extrinsic and common pathways of the ex vivo coagulation cascade
Measures the function of VII, V, X, II and I
What is a nl INR?
1.0
What prolongs INR? Why?
Warfarin
Due to depletion of vit K-dependent factors II, VII, IX, and X
What does aPTT measure?
The ex vivo intrinsic coagulation cascade, compromising high molecular weight kininogen, prekallikrein, and factors XI, IX, VIII, V, X, II, and I
What is activated clotting time?
ACT is a test similar to aPTT but used in clinical situations requiring high-dose heparin administration (cardiopulmonary bypass, endovascular interventions, ECMO)
What is TEG?
Thromboelastography Provides a quantitative measure of all aspects of hemostasis, including: Platelet aggregation Clot strengthening Fibrin cross-linking Fibrinolysis
Advantages of TEG
Quantification of thrombodynamics
Ability to differentiate between platelet and plasma coagulative disorders
Rapidity of its results
What is the MC congenital bleeding disorder?
vWD
Lab findings of vWD
Prolonged bleeding time
Mildly prolonged aPTT
Abnl platelet binding as measured by a depressed ristocetin cofactor assay
Type I vWD inheritance pattern
Autosomal dominant
Characterized by quantitative reduction in vWF levels with nl protein structure and function
Type II vWD
Variable inheritance pattern
Characterized by abnl qualitative protein function
Type III vWD
Autosomal recessive inheritance pattern
Associated with severe bleeding with absent vWF production
First-line therapy for type I and II vWD
DDAVP
Tx for type III vWD
Surgical prophylaxis or bleeding
Transfusion with cryoprecipitate or factor VIII: vWF concentrate
What is Glanzmann’s thrombasthenia?
A rare congenital platelet disorder that is a result of defective or decreased synthesis of glycoprotein IIb/IIIa
Platelets are unable to bind fibrinogen and lack the ability to form platelet aggregates
Why does platelet dysfunction occur in renal dz?
It’s a result of numerous changes to protein function and intraluminal fluid dynamics
What bleeding problems are found in uremic pts?
Dysfunctional vWF
Decreased thromboxane A2
Altered platelet granules
What does anemia cause in renal dz pts?
Decreased platelet adhesion and aggregation
Tx of uremic pts
Depends on severity of sx/bleeding risk
Dialysis
Epo
DDAVP/cryoprecipitate
What is extracorporeal circuitry?
What does it give rise to?
Cardiopulmonary bypass, ECMO
Abnl platelet activation in part d/t fibrinogen accumulation within the oxygenation membrane
What does consumption and loss of platelets from the circulating pool result in?
Thrombocytopenia as well as qualitative dysfunction
How are therapeutic anticoagulation levels maintained with extracorporeal circulation?
Systemic unfractionated heparin given IV and intermittently into the extracorporeal circuit
Type I HIT
May occur in as many as 10% of pts receiving unfractionated heparin
Typically resolves spontaneously within 96 hrs of heparin cessation
Type II HIT
Unusual immunologic complication affecting 1-3% of pts
Pathology of HIT
Heparin binds with PF4, which is released from platelet alpha granules normally.
in HIT, IgG antibodies form against the heparin-PF4 complex within 5-10 days of exposure that in turn, strongly activates platelet adhesion and aggregation
When should you raise clinical concern for HIT?
When platelet counts decrease by >50% from preheparin levels
What does massive platelet activation and platelet plug formation predispose the pt to?
Venous thrombosis Thromboembolism Limb ischemia Stroke MI
Labs for HIT
Serotonin release assay (SRA)
Heparin-induced platelet aggregation assay (HIPA)
ELISA
What is one of the more common screening tests in clinical use for HIT?
ELISA
Tx of HIT
Immediate cessation of all heparin therapies
Non-heparin-based anticoagulation strategies unless clinical CI
Avoidance of platelet transfusion is appropriate to help propagation of white clot
Idiopathic thrombocytic purpura (ITP)
An acquired d/o rising from pathologic destruction of platelets d/t autoantibody formation
When does ITP commonly occur?
Time of infection (often viral) OR
altered immune homeostasis (malignancy, lymphoproliferative d/os, concurrent autoimmune dz)
Dx of ITP
Clinical and one of exclusion
Tx of ITP
With platelet count of <30K, initially prevention of bleeding
Include glucocorticoids and IVIG
2nd line is splenectomy
If surgery is CIed, rituximab
Pathology of hemophilia A/B
A is deficiency of factor VIII
B is deficiency of factor IX
Impaired formation of tenase (VIII-IXa) complex, impacting the amplification phase of coagulation and leading to decreased factor Xa and thrombin creation
Sx of hemophilia A/B
Mucosal bleeding
Excessive bleeding during circumcision
Hemarthrosis
Intracranial hemorrhage
Labs for hemophilia A/B
Elevated aPTT
Decreased factor VIII or IX levels
Tx of hemophilia A
Recombinant factor VIII
Cryoprecipitate transfusion
Desmopressin
Tx of hemophilia B
Recombinant factor IX
FFP or cryoprecipitate transfusion
DIC
Results from unchecked activation of the normal coagulation response with loss of localization
Sepsis is the MCC of DIC
Pathophys of DIC
Stems from systemic microvascular activation of platelets, diffuse activation of clotting factors, deposition of fibrin with microangiopathic thrombosis, and subsequent fibrinolytic pathway inactivation
Dx of DIC
Clinical dx of exclusion
Schistocytes on peripheral blood smear
Tx of DIC
Maintain an INR <1.5 and platelet count >50K
Tx of bleeding secondary to hepatic failure
Correction of factor and platelet deficiencies with blood component management
When is hypothermia commonly seen?
Altered coagulation as a result of:
Trauma
Massive resuscitation
Extended exposure to open body cavities during procedures
Iatrogenic hypothermia for cerebral or myocardial protection
What is hypothermia associated with?
Impaired platelet function
Decreased collagen-induced platelet aggregation
Tx of hypothermia
Treat underlying cause
Limit evaporative heat loss
Mild (>34 degrees Celsius)- passive rewarming techniques
Moderate (30-34 Celsius)- active rewarming
Severe (<30 Celsius)- External passive and active rewarming, internal rewarming
Definition of massive transfusion
Replacement of a pts blood volume with packed RBCS (pRBCs) in a 24-hr period or acute transfusion of over half the pt’s blood volume per hr
What is the massive transfusion protocol?
1:1:1 ratio of pRBC, FFP and platelet administration
What is the MC hereditary procoagulant d/o?
Factor V Leiden
Pathology of factor V Leiden
Mutation of the factor V protein prevents APC-mediated inactivation, thereby increasing risk for uncontrolled clot formation
Dx of factor V Leiden
aPTT with and without APC
Tx of factor V Leiden
No lifelong anticoagulation, only in thromboembolic events
What does ATIII do?
Inactivates thrombin and factors Xa, IXa, and XIa
What is the MC site of thrombosis in an ATIII deficiency?
Iliofemoral DVT
Dx of ATIII deficiency
ATIII-heparin cofactor assay
Tx of ATIII deficiency
FFP transfusion or ATIII concentrate
Dx of protein C/S deficiency
Serum protein C and S levels below the nl limits
What is the MC clinical manifestation of C/S deficiency?
Venous thromboembolism
What is a known RF for pts with decreased protein C and S levels d/t a transient procoagulant state during initiation of the drug?
Warfarin-induced skin necrosis
When should postponement of surgery occur?
Postpone beyond 6 wks for bare-metal stenting and 6 mos for drug-eluting stenting for noncardiac surgery pts
If not possible, continue dual antiplatelet therapy
MOA of ASA
NSAID that irreversibly inhibit clyclooxygenase isoforms (COX-1 and COX-2)
Maintains its effects for the lifespan of the platelet
MOA of ticlopidine, prasugrel and clopidogrel
Irreversibly inhibit activity of the ADP-P2Y receptor on the platelet membrane, which in turn impairs glycoprotein IIb/IIIa-mediated platelet cross-linking and aggregation
When to use clopidogrel
ACS
Recent MI or CVA
Established PAD
When to use prasugrel
ACS during PCI
It is found to inhibit platelet aggregation more rapidly and consistently compared to clopidogrel
When to use cilostazol
Intermittent peripheral arterial claudication
Prevents vasoconstriction and smooth muscle proliferation
May require up to 1 yr before symptomatic relief is noticeable
CIs of cilostazol
Dx of heart failure
What are abciximab, eptifibatide, and tirofiban used for?
Adjuncts to heparin and ASA therapy
What do heparin and LMWH do?
Increase ATIII activity
Primarily affects intrinsic and common pathways of in vitro coagulation
How do you measure heparin and LMWH efficacy?
aPTT needs to be 1.5-2.5x the baseline aPTT value
What is the onset of therapeutic warfarin anticoagulation
Takes at least 24-72 hrs
Principally affects extrinsic and common pathways of in vitro coagulation
How to measure effect of warfarin
PT and INR
MOA of direct thrombin inhibitors (DTI)
Examples of DTI
Inactivates circulating and clot-bound thrombin
Argatroban and bivalirudin
Dabigatran
When to use argatroban
Those with contraindication to heparin
Monitoring of argatroban
aPTT
What is bivalirudin approved for?
Pts with ACS undergoing PCI
What is dabigatran used for?
Tx/prevention of DVT, PE, non-valvular atrial fibrillation-associated stroke
What are apixaban, roxaban, and edoxaban approved for?
VTE and nonvalvular a fib
Measurement of apixaban, roxaban, and edoxaban
Anti-factor Xa activity
What is r-tPA approved for?
Acute STEMI
Acute ischemic stroke
Acute massive PE
Use of oxidized regenerated cellulose products
Frequently used as topical mesh placed on sites of bleeding to promote coagulation
Use of gelatin matrix products
Can absorb blood up to 40x their weight and serve as the foundation of a hemostatic plug
Use of topical thrombin and fibrin sealants
Commonly used bioactive topicals that augment hemostasis via directed factor II (topical thrombin) or fibrinogen (fibrin) application
MOA of aminocaproic acid
Interferes with fibrinolysis by competitively blocking the fibrin-binding site on plasminogen, thereby preventing conversion to plasmin
Use of aminocaporic acid
Prevention of fibrinolytic bleeding d/t: Cardiac surgery Congenital hematologic dz Cirrhosis Malignancy
Use of tranexamic acid
Hemophiliac pts undergoing dental procedures
Tx of menorrhagia
Uses of desmopressin
DI
Nocturia
Management of bleeding secondary to hemophilia A, type I and 2 vWD, and prevention of surgical bleeding in hemophiliac pts
Dosing of desmopressin in perioperative vWD and hemophilia A pts
30 mins IV or 2 hrs IN prior to the procedure
What does protamine sulfate do?
Reverses the effects of heparin
What does phytonadione (vit K) do?
Antagonizes the effects of warfarin
What does each unit of pRBCs contain?
200 mL of RBC concentrate and an additional 100 mL of preservation solution
What do pRBCs do?
Raise the recipient hematocrit approximately 3-4%
Derivation of FFP and FP-24
Donor whole blood that has been separated and frozen within 8 (FFP) and 24 (FP-24) hrs
When are FFP and FP-24 indicated?
Tx of multiple coagulation factor deficiencies, massive transfusion protocols, and when specific factor concentrates are not available
What are components of cryoprecipitate?
Fibrinogen
Factor VIII
Factor XIII
vWF
Indications of cryoprecipitate
Massive transfusion protocols
Hypofibrinogenemia
Factor VIII deficiencies when factor concentrates are not available
Bleeding associated with vWD when factor concentrates or DDAVP are not available
Platelet concentration dose and efficacy
Contain around 7 x 10 to the 6th platelets per 50 mL
Each unit should increase platelet levels by at least 5K
Indications for platelet transfusions
Massive transfusion Hereditary platelet dysfunction Drug-induced platelet dysfunction Cardiopulmonary bypass surgery-related platelet destruction Platelet underproduction
What should platelet counts be in preparation for surgical procedures?
> 50K
What are isolated and recombinant factors currently available?
Fibrinogen concentrate Recombinant thrombin Recombinant factors VIII and IX vWF concentrate Antithrombin concentrate Of particular note in surgical populations: prothrombin complex concentrates (PCCs) and recombinant factor VIIa
