Heme Emergencies 1 Flashcards
All of procoagulants are synthesized in the liver except?
WV
Intrinsic pathway?
- think which test?
- Think which factors? 4
Extrinsic?
- Think which test?
- Think which factors? 2
- Intrinsic pathway? Think PTT (partial thromboplastin time)
- Think VIII, IX, XI, and XII
- Extrinsic pathway? Think PT
(prothrombin time) - Think II and VII
Note: **Both pathways converge on the activation of factor X, which subsequently results in prothrombin activator converting prothrombin into thrombin
Which factors are vit K dependant?
Factors VII, X, and prothrombin (Factor II) are vitamin-K dependent and are altered by warfarin (Coumadin) which is why we use the PT-INR to monitor warfarin therapy
Antithrombotic Termination
The termination phase of the coagulation process involves two circulating enzyme inhibitors. What are these? 2
1) Antithrombin (formerly called antithrombin III)
2) Tissue factor pathway inhibitor
AND
Clotting-initiated inhibitory process, the protein C pathway
Hemostasis Physiology
Antithrombin does what? 2
- activates coagulation factors and neutralizes thrombin (the last enzyme in the pathway for the conversion of fibrinogen to fibrin)
- complexes with naturally occurring heparin to accelerate and provide protection against uncontrolled thrombus formation on endothelial surfaces.
Hemostasis Physiology
- What does Protein C do?
- Protein s?
- Protein C
A plasma protein
Acts as an anticoagulant protein by inactivating factors V and VIII - Protein S
A plasma protein
Breaks down fibrin into fibrin degradation products that act as anticoagulants
Fibrinolysis
3 steps
- Plasminogen binds fibrin and tissue plasminogen activator (tPA)
- Complex leads to conversion of the proenzyme plasminogen to active, proteolytic plasmin
- Plasmin cleaves polymerized fibrin strand at multiple sites and releases fibrin degradation products including D-Dimer
Bleeding Disorders
- Defects in Platelet number? 3
- Defects in Platelet function? 1
- Defects in the coagulation cascade? 4
- Defects in Platelet number
- ITP
- Thrombotic Thrombocytopenic Purpura
- Hemolytic-Uremic Sundrome - Defects in Platelet function
- Aspirin (drug-induced) platelet dysfunction - Defects in the Coagulation Cascade
- Hemophilia A
- Hemophilia B (Christmas Disease)
- von Willebrands Disease
- Vitamin K deficiency
- Normal platelet count?
- Thrombocytopenia?
- Milld?
- Severe?
- Normal 100,000-400,000 cells/mm
- less than 100,000 -Thrombocytopenia
- 50,000-99,999 Mild
- less than 50,000 Severe
Bleeding time normals?
2-8 minutes
PARTIAL THROMBOPLASTIN TIME
- Measures what?
- Normal value?
- Measures Effectiveness of the Intrinsic
Pathway - NORMAL VALUE
25-40 SECS
- What is thrombin time?
- Normal?
- Measure of what?
- Time for Thrombin To Convert Fibrinogen to Fibrin Monomer
- NORMAL VALUE
9-13 SECS - Measure of Fibrinolytic Pathway
Hemostasis is DEPENDENT UPON? 5
- Vessel Wall Integrity
- Adequate Numbers of Platelets
- Proper Functioning Platelets
- Adequate Levels of Clotting Factors
- Proper Function of Fibrinolytic Pathway
What questions should I ask in the history if I suspect a bleeding abnormality?
4
- Family History
- Medications
- Past Medical History
- Previous Challenges to Hemostasis
Clinical Features of anemia? 5
- Palpitations
- Dizziness
- Orthostatic Hypotension
- Exertional Intolerance
- Tinnitus
PE for anemia? 5
- Pale conjunctiva or skin
- Tachycardia
- Systolic murmurs
- Tachypnea at rest and
- hypotension
are late signs
- Presence of what are diagnostic of anemia? 3
- Determining the exact etiology of the anemia is not essential in the ED, except in when?
- Initial eval should include ? 5
- What are the initial studies needed in patients with suspected bleeding disorders?
3
- decreased RBC count,
- Hemoglobin, and
- Hematocrit
- the face of acute hemorrhage
- Hemoccult exam,
- CBC,
- retic count,
- Review of RBC indices, and
- smear
- A
- CBC with platelet count,
- PT and
- PTT
Disorders of Secondary Hemostasis
- These are problems with what?
- Intrinsic pathway? 3
- Extrinsic? 1
- Problem with the coagulation factors themselves
- Instrinsic Pathway
- Hemophilia A
- Hemophilia B
- vWF - Extrinsic Pathway
- Vitamin K deficiency
Approach to the thrombocytopenic patient
- HX? 6
- assess the number and function of platelets with what? 2
History
- Is the patient bleeding?
- Are there symptoms of a secondary illness? (neoplasm, infection, autoimmune disease)
- Is there a history of medications, alcohol use, or recent transfusion?
- Are there risk factors for HIV infection?
- Is there a family history of thrombocytopenia?
- Do the sites of bleeding suggest a platelet defect?
Assess the number and function of platelets
- CBC with peripheral smear
- Bleeding time or platelet aggregation study
Clinical manifestations: Hemophilia
(hemophilia A & B are indistinguishable)
Symptoms? 7
- Hemarthrosis (most common): Fixed joints
- Soft tissue hematomas (e.g., muscle)
- Muscle atrophy
- Shortened tendons
Other sites of bleeding - Urinary tract
- CNS, neck (may be life-threatening)
- Prolonged bleeding after surgery or dental extractions
Hemophilia signs?
- Swollen, painful joints
- Local bleeding out of proportion to injury
- Subcutaneous bleeding
- Bleeding from mucous membranes
- Abdominal pain, distension
- Hematemesis, melena
Hemophilias
- Prolongation of what?
- Hemophilia A deficiency in?
- B?
- Prolongation of the aPTT (the PT will remain normal)
- Hemophilia A (deficiency in factor VIII)
- Hemophilia B (deficiency in factor IX) (Christmas Disease)
Hemo A etiology?
X-linked recessive pattern of inheritance
Describe the PP of Hemophilia A?
What is the kind of bleeding we are really worried about in these pts?
The blood of a person with hemophilia does not clot normally.
He does not bleed more profusely or more quickly than other people; however, he bleeds for a longer time.
External wounds are usually not serious.
Far more important is internal bleeding
These hemorrhages are in joints, especially knees, ankles and elbows; and into tissues and muscles
Signs and Symptoms
Hemophila A
? 7
- Petechiae and ecchymosis are characteristically absent.
- Bleeding into joints- Knees, ankles, elbows
- Bleeding into muscles- Spontaneous hemarthoses in severe disease
- GI bleeding
- Those with mild disease bleed after major trauma or surgery.
- Those with moderately severe disease bleed with mild trauma or surgery.
- Those with severe disease bleed spontaneously.
Hemophilia A
Lab findings? 5
- PTT is prolonged
- Factor VIII:C is reduced
- vWF is normal
- PT, Fibrinogen levels are normal.
- Diagnosis is confirmed by decreased Factor VIII levels.
Hemophilia A
Treatment? 4
- Avoid ASA
- Factor VIII replacement: Recombinant Factor VIII concentrate
- Cryoprecipitate
- For mild hemophilia
DDAVP
**Can use EACA (Amicar) along with the above
Hemophilia B
- AKA?
- Caused by?
- How common?
- Prolonged what?
- Dx confirmed by?
- Also called Christmas disease
- X-linked bleeding disorder caused by deficiency of Factor IX.
- Less common than hemophilia A.
- PTT is prolonged.
- Diagnosis is confirmed by demonstrating decreased Factor IX levels.
Hemophilia B
TX? 2
- Avoid ASA
- Factor IX concentrates
Factor VIII concentrates are INEFFECTIVE
Von Willebrand’s Disease
- Etiology?
- What is it?
- What is VW required for?
- Also carries what?
- Autosomal dominant pattern
- Disorder of platelet function and coag pathway
- Deficiency of von Willebrand Factor (vWF) - vWF is required for adequate platelet adhesion
- Also a carrier molecule for Factor VIII in the plasma
- Factor VIII is rapidly degraded, limiting its availability for coagulation with vWF deficiency.
Von Willebrand’s Disease (vWD)
Clinical presentation?
- Easy bruising
- Skin bleeding
- Prolonged bleeding from mucosal surfaces (eg, oropharyngeal, gastrointestinal, uterine).
Von Willebrand’s Disease
Signs and symptoms? 6
- Excessive menstrual and postpartum bleeding
- GI bleeding
- Epistaxis
- Gingival bleeding
- Easy bruising
- UNCOMMON for joints to be involved
VW Laboratory Findings? 6
- Prolonged bleeding time
- PTT may be prolonged
- PT and platelets are normal
- Factor VIII:C levels decreased
- vWF plasma level low
- Measured by factor VIII antigen - May need to distinguish subtype
Von Willebrand’s Disease (VWD) DX testing? 1. Why might you see a prolonged PTT? 2. Why might you see low Factor VIII? 3. What is the bleeding time a measurement of?
Factor VIII activity and aPTT
1. Since normal VWF protects factor VIII from proteolysis, you may see a prolonged activated partial thromboplastin time (aPTT)
2. Factor VIII levels are often in the low normal range in mild cases of VWD (but nevertheless they’ll be normal)
3. Bleeding time
The bleeding time (BT) is a measure of the interaction of platelets with the blood vessel wall. It is prolonged in patients with moderate and severe VWD, but is often normal in those with mild VWD
Helpful if abnormal
Keep in mind…
1. In patients with mild vWD, the ingestion of what drugs can precipitate bleeding that may not have occurred otherwise? 2
- Some patients remain asymptomatic, with the diagnosis being made during the course of screening studies because?
- aspirin or
- other antiplatelet medications such as nonsteroidal antiinflammatory
- because of a family member with newly-diagnosed severe VWD.
Von Willebrand’s Disease
1. Tx?
- More severe VW tx? 3
- Treatment:
If bleeding disorder is characteristically mild
Avoidance of ASA and NSAIDS - More severe vWD Treatment:
- Desmopressin acetate (DDAVP)
-Factor VIII concentrates: Humate-P (Armour)
-E-amincaproic acid (EACA)
Good with dental procedures
- Desmopressin acetate (DDAVP) for VW
1. Causes what?
2. Increases what?
3. Can be administered how?
- Causes release of stored vWF from endothelial cells
- increases factor VIII levels
- Can be administered IV, subq, or intranasally
Replacement therapy with VWF containing concentrates
Several products are available that contain VWF in high concentration including:
4
- “Intermediate purity” factor VIII concentrates (contains VWF as well)
- Highly purified VWF concentrates
- Recombinant VWF products (still in development)
- Cryoprecipitate (not recommended)
Vitamin K deficiency:
- Source of vitamin K ?
- Synthesized by?
- Required for synthesis? 6
- Causes of deficiency ? 4
- Treatment? 2
- Green vegetables 2. Synthesized by intestinal flora
- Factors II, VII, IX ,X Protein C and S
- Malnutrition -Biliary obstruction -Malabsorption -Antibiotic therapy
- Vitamin K -Fresh frozen plasma
Major clotting factors for the extrinsic pathway (II, VII, and X) depend on what? 2
- healthy liver and
2. adequate dietary intake of vitamin K.
Vit K defieicny
Condition is commonly seen in:
6
- Alcoholics
- Chronic liver disease
- Biliary obstruction
- Intestinal malabsorption
- Poor dietary intake
- Long term use of antibiotics
Laboratory Findings:
Vit k deficeincy?
Tx?
PT/PTT is prolonged
PT more so than PTT
Treatment? Vitamin K supplementation (but doesn’t work with liver disease………coag factors do not respond appropriately)
Idiopathic Thrombocytopenia Purpura (ITP)
- Etiology?
- PP? 3
- Common occurs in childhood when?
- In adults its often chronic. what gender?
- Often results from? 4
- Autoimmune disease (Aquired)
- Pathologic antibodies bind to platelets, resulting in accelerated platelet clearance
- Spleen rapidly removes the autoantibodies from circulation
- Splenic macrophages with Fc receptors bind to antibody coated platelets.
3. Commonly occurs in childhood Abrupt onset within 2-21 days after a viral infection 4. In adults, often chronic, females > males 5. Often results from: -Blood transfusions -IV drug use -Graves disease -Can be chronic
Idiopathic Thrombocytopenia Purpura (ITP) s and s
9
Signs and symptoms:
- Easy bruising, Petechiae, Purpura: Lesions will be painless, flat, and nonpruritic
- Epistaxis
- Bleeding from gums
- Melena
- Hematuria
- Excessive menstrual bleeding
- Spontaneous hemorrhage rarely occurs
- Wet purpura (blood blisters in mouth)
- Retinal hemorrage
ITP - Immune/Idiopathic Thrombocytopenic Purpura
- Dx of?
- Platelet counts?
- What should be present in marrow?
- Morphology?
- Prognosis for kids?
- In adults, they require therapy when?
- Diagnosis of exclusion
- Very low platelet counts
- Megakaryocytes should be present in marrow.
- Normal morphology
- In children, usually provoked by viral illness.
Spontaneously remits
No specific therapy usually required. - In adults, specific therapy required if platelet count is
Secondary Idiopathic Thrombocytopenia Purpura (ITP)
1, Meds? 4
2. Others? 4
- Sulfonamides/
- Thiazides/
- Cimetidine/
- Heparin
- SLE,
- other autoimmune,
- hepatitis,
- HIV
Idiopathic Thrombocytopenia Purpura (ITP)
Labs? 5
- Thrombocytopenia
- Prolonged bleeding time
- Very mild anemia, if at all
- PT/PTT are normal
- Bone marrow biopsy
- Normal or increased number of megakaryocytes
Idiopathic Thrombocytopenia Purpura (ITP)
1. Tx mild?
- Tx Severe?
- Mild acute ITP (platelet count >30,000 and no mucosal bleeding ) may not require treatment other than trauma protection (especially head) and avoiding ASA.
- More severe ITP (platelet count less than 30,000 with mucosal bleeding)
- treated with Prednisone 1-2mg/kg/day.
Prednisone tx for ITP:
- Decreases the affinity of what for what?
- How should you manage this?
- Bleeding diminishes within how long?
- Platelet count improves within how long?
- splenic macrophages for antibody-coated platelets.
- High dose until platelet count is normal, then gradually tapered.
- days (often 1 day).
- 2 weeks.
Idiopathic Thrombocytopenia Purpura (ITP)
Severe of failure to respond to prednisone? 2
Treatment:
Patients who fail to respond to prednisone
1. Splenectomy
-Most definitive treatment
2. IV immunoglobulin
-Should be reserved for bleeding emergencies such as preparing a severely thrombocytopenic patient for surgery
ITP
Patients who fail to respond to prednisone AND splenectomy
Danazol 600mg/d
Thrombotic Microangiopathy
Which are these? 2
- Thrombotic thrombocytopenic purpura
2. Hemolytic Uremic Syndrome
TTP - Thrombotic Thrombocytopenic Purpura
What is it?
A process, characterized by abnormal activation of platelets and endothelial cells, with fibrin deposition in the microvasculature, and peripheral destruction of platelets and red cells.
TTP - etiology
- May be associated with what?
- Can be induced by?
- Increased incidence with? 2
- May be associated with
- an antibody against or a deficiency of the protease which cleaves the very high molecular weight multimers of von Willebrand’s factor - Can be induced by
- drugs, including ticlopidine, quinine, cyclosporine, tacrolimus, rapamycin, mitomycin C, and bleomycin - Increased incidence with pregnancy or HIV
Thrombotic Thrombocytopenic Purpura (TTP)
Multiple Organ abnormalities? 5
- Microangiopathic hemolytic anemia -Anemia that results when capillaries are partially occluded by fibrin
- Thrombocytopenia, often with purpura but not usually severe bleeding
- Acute renal insufficiency that may be associated with anuria and may require acute dialysis
- Neurologic abnormalities, usually fluctuating
- Fever
Thrombotic Thromboytopenic Purpura (TTP)
- Seen primarily in young adults between what ages?
- Gender?
- Occasionally precipitated by? 4
- 20-50
- Slight female predominance
- Occasionally precipitated by:
- Estrogen use
- Pregnancy
- Drugs
- Infections
Thrombotic Thromboytopenic Purpura (TTP)
6
Signs and symptoms
- Patient appears acutely ill
- Febrile
- Pallor
- Purpura
- Petechiae
- Signs of neurological dysfunction
TTP - Diagnostic Features
(aka “The Pentad”)
5
- Microangiopathic Hemolytic
- Low platelets - MUST BE PRESENT
- Fever
- Neurologic Manifestations - headache, sleepiness, confusion, stupor, stroke, coma, seizures
- Renal Manifestations - hematuria, proteinuria, elevated BUN/Creatinine
Microangiopathic Hemolytic will show? 4
- Anemia (MAHA)
- Elevated LDH,
- elevated bilirubin
- Schistocytes on the peripheral smear
MUST BE PRESENT
Thrombotic Thromboytopenic Purpura (TTP)- Laboratory Findings: 7
- Thrombocytopenia
- Marked anemia
- Reticulocytosis
- Occasional circulating nucleated RBC’s
- Schistocytes, helmet cells
- Hemolysis (microangiopathic hemolytic anemia)
- Coags
TTP - Treatment
- Tx relies on what?
- PLEX is done daily until plts > ?
- Follow which labs? 4
- Secondary measures if no response to plasma exchange include what? 3
- Avoid what?
- Treatment relies on PLASMA EXCHANGE.
- 150 x 2d
- Follow LDH, plts, H/H, Cr daily.
- vincristine,
- splenectomy,
- Rituximab.
- AVOID PLATELET TRANSFUSIONS - THEY “FUEL THE FIRE”–have been associated with CVA, death, lawsuits
TTP - Course and Prognosis
- Mortality without therapy?
- With it?
- Prognosis?
- > 90% fatal without therapy.
- 80-90% survive with therapy
- One third of patients will relapse within 10 yrs, most within one month of diagnosis.
HUS - Hemolytic Uremic Syndrome
- What makes this different from TTP?
- Usually precipitated by what?
- Seen in who more?
- In adults often precipitated by?
- Has fewer neurologic sequelae, more renal manifestations.
- Usually precipitated by diarrheal illness, especially E. coli O157:H7 or Shigella
- Seen more in pediatric patients, usually has better prognosis.
- In adults, often precipitated by estrogen use or by the post partum state.
Hemolytic-Uremic Syndrome (HUD)
Etiology and Pathogenesis
- Different what involved in TTP?
- Triad?
- Different vascular beds involved than TTP
- Similar pathogenesis of TTP
- Acute renal failure,
- microangiopathic hemolytic anemia and
- thromboctopenia
Hemolytic-Uremic Syndrome (HUD)
Differentiated from TTP by ?
renal failure and lack of neurologic findings.
HUS Laboratory Findings
6
- Microangiopathic hemolytic anemia
- Less severe thrombocytopenia
- Striking red blood cell fragmentation (the defining diagnostic finding)
- Elevated LDH
- PT/PTT normal
- Elevated fibrin degradation products
- D-Dimer
Hemolytic-Uremic Syndrome (HUD)
1. How is this distinguished from DIC?
Coags are normal!!
Hemolytic-Uremic Syndrome (HUD)
Tx?
- Children?
- Adults? 2
- Many adult pts have what?
Treatment:
1. In children
Self-limited, conservative management of renal failure.
- Adults
- Large volume plasmaphoresis with fresh-frozen plasma replacement
- Management of renal failure - Many patients have chronic renal insufficiency
DIC - Disseminated Intravascular Coagulation
What is it?
A process, characterized by abnormal activation of coagulation, generation of thrombin, consumption of clotting factors, destruction of platelets, and activation of fibrinolysis.
Disseminated Intravascular Coagulation (DIC)
1. PP?
- Associated with?
3.
- Release of tissue factor substances that activate extrinsic pathway of coagulation. Large scale intravascular aggregation of platelets and activation of the coagulation cascade.
- Associated with massive injury to the endothelial lining of blood vessels
Disseminated Intravascular Coagulation (DIC)
Causes?
9
- Placentae abruptio
- Septic abortion
- Sepsis and severe infections (Gram -)
- Cancers
- Trauma
- Burns
- Hemolysis
- Heat stroke
- Snake bites
Disseminated Intravascular Coagulation (DIC)
Signs and symptoms:
8
- Lead to both bleeding and thrombosis, although bleeding is far more common.
Bleeding
- Spontaneous bleeding and oozing at venipuncture signs or wounds
- Shock and widespread bleeding
Thrombosis
- Digital ischemia and gangrene
- Renal necrosis
- CNS dysfunction (seizures, delirium, coma)
- Respiratory failure
- Can lead to microangiopathic hemolytic anemia
Laboratory diagnosis DIC?
6
- Thrombocytopenia: platelet count
Disseminated Intravascular Coagulation (DIC)
Tx?
5
- Correction of underlying disease
Hemodynamic support as appropriate
For patients actively bleeding
2. PLT transfusions (PLT
Aspirin and NSAIDS 20,000 tons of aspirin used in the US. 1. Aspirin irreversibly inhibits what? 2. Effect lasts for as long as ? 3. What is prolonged in most? 4. Other NSAIDs have reversible effects lasting only how long?
- cyclooxygenase in platelets.
- 7 days.
- Bleeding time
- a few hours.
