2.1 Coagulation disorders highlights Flashcards
Clinically significant iron overload causes increased serum ____________ and transferrin saturation (TSAT)
ferritin
Hereditary Hemochromatosis (HH):
1) What is the pattern of inheritance? What gene is affected?
2) What makes up 95% of cases?
1) Autosomal recessive; HFE gene on chromosome 6
2) Most (95%) are homozygous for the C282Y variant (type 1a hemochromatosis).
Hereditary Hemochromatosis (HH):
1) What protein is thought to be important in the process by which duodenal crypt cells sense body iron stores?
2) Variant gene leads to increased iron absorption from where?
3) Accompanied by decrease in what?
1) HFE protein
2) Duodenum
3) Hepcidin
HH:
Characterized by increased accumulation of iron as ___________________ in the liver, pancreas, heart, adrenals, testes, pituitary, and kidneys (iron overload > tissue damage)
hemosiderin
HH
1) What is a Nonspecific symptom?
2) What are the other Sx?
1) Fatigue without anemia, lethargy, apathy, generalized pain
2) Symptoms attributable to iron overload: especially in the liver, heart, and pituitary gland
List 6 organs/ areas affected by HH
1) Liver
2) Heart
3) Endocrine
4) CNS
5) Arthropathy
6) Bronze skin
For each of the following, list manifestations of iron overload:
1) Liver
2) Heart
3) Endocrine
4) Bronze skin
1) Increase hepatic transaminases; cirrhosis; Hepatocellular cancer (HCC)
2) HF, arrhythmias
3) Type 2 DM
4) Skin hyperpigmentation
List and describe 2 complications of HH
1) Increased risk of infection: siderophilic bacteria like Yersinia enterocolitica, Vibrio vulnificus, and Listeria monocytogenes
2) Increased CA risk: Hepatocellular carcinoma (HCC): 15-20% frequency if cirrhosis
HH:
1) Initial test is usually iron studies to identify iron overload (high _______ and/or ________).
2) If iron overload, also perform liver function tests and _______ genetic testing
3) MRI is often used to quantify liver and/or ____________ iron if ferritin is very high (>1000 ng/mL), with liver biopsy in some cases
1) TSAT; ferratin
2) HFE
3) cardiac
HH
1) HH diagnosis is confirmed if what 2 conditions are met?
2) HFE genetic testing is appropriate for those with what?
1) Iron overload + homozygosity for HFE C282Y
2) A positive family history of HH, even without current iron overload
Phlebotomy treatment of HH:
1) Who should you recommend this for?
2) How often can it be?
1) Symptomatic or iron overload (if no anemia/hemodynamic instability)
2) Weekly
What are 2 rare alternatives for phlebotomy for HH?
1) Iron chelation
2) Erythrocytapheresis
Patients with genetic deficiencies of____________________________ exhibit lifelong recurrent bleeding episodes into joints, muscles, and closed spaces, either spontaneously or following an injury.
plasma coagulation factors
1) What is the most common inherited bleeding disorder?
2) The most common inherited factor deficiencies are what?
1) Von Willebrand disease
2) Hemophilias
Differentiate between hemophilia A, B, and C
Hemophilia A: Factor 8
Hemophilia B: Factor 9
Hemophilia C: Factor 11
1) What pathway does PT/INR look at?
2) What about PTT?
3) What are the vitamin K dependent coag. factors?
1) Extrinsic (+ common)
2) Intrinsic (+ common)
3) 2, 7, 9, 10 + proteins C, S, Z
What helps platelets link together to form fibrin plug and extends half-life of factor 8?
vWF
Hemophilia A & B:
1) True or false: People with hemophilia do not bleed any faster than normal, but they can bleed for a longer time
2) Inheritance is ______________________, leading to affected males and carrier (affected) females with variable bleeding tendencies. What does this mean?
1) True
2) X-linked recessive
-Daughters of all affected males are obligate carriers
Hemophilia is classified according to the level of factor activity in the plasma; list the different classifications
1) Severe hemophilia: <1% factor activity
2) Moderate
3) Mild
4) With activity >25% of normal, the disease is discovered only by bleeding after major trauma/routine pre-surgery laboratory tests.
Hemophilia A and B
1) In the moderate and severe forms, the disease is characterized by bleeding into the _________________, soft tissues, and muscles after minor trauma or even spontaneously.
2) Patients with mild disease experience infrequent bleeding that is usually secondary what?
1) joints (hemarthrosis)
2) Trauma (with initiation of menses, may have menorrhagia/“abnormal uterine bleeding [AUB])
Hemophilia A & B
1) Early in life, bleeding may present after circumcision or rarely as _____________ hemorrhages.
2) Acute ______________ are painful, and clinical signs are local swelling and erythema.
1) intracranial
2) hemarthroses
Hemophilia A & B
1) With acute hemarthrosis, what may a pt adopt to avoid pain?
2) Very young children unable to communicate verbally show ____________ and a lack of movement of the affected joint.
1) A fixed position, which leads eventually to muscle contractures.
2) irritability q
Hemophilia
1) What 3 types of bleeding are life threatening?
2) What are 3 side effects of hemophilia?
1) Bleeding into oropharyngeal spaces, intracranial bleeding, or retroperitoneal bleeding
2) Retroperitoneal hemorrhages, pseudotumors, hematuria
Hemophilia A & B:
1) What are debilitating?
2) After a joint has been damaged, recurrent bleeding episodes result in the clinically recognized “____________,” which then establishes a vicious cycle of bleeding; this Results in progressive joint deformity that in critical cases requires surgery as the only therapeutic option.
1) Chronic hemarthroses
2) target joint
Hemophilia A & B
1) ________________ into the muscle of distal parts of the limbs may lead to external compression of arteries, veins, or nerves that can evolve to a _____________ syndrome.
2) It is important to measure the level of factor activity of _____________ to recognize those at risk of bleeding and to optimize preoperative and postoperative management.
1) Hematomas; compartment
2) carriers
Hemophilia:
1) aPTT is markedly prolonged in ___________ hemophilia.
2) What is PT with hemophilia? What abt platelet counts/platelet function tests?
3) The diagnosis is made after specific determination of what activity levels?
1) severe
2) Normal; normal
3) Factor 8 or 9
Hemophilia:
An isolated abnormal PT suggests what?
Factor 7 deficiency
Hemophilia A and B
1) Hemophilia A or B is diagnosed by an isolated reproducibly low factor _______ (Hemophilia A) or ______ (Hemophilia B) activity level, in the absence of other conditions.
2) Identifying a pathogenic variant in these factor’s genes is the best test for diagnosis/exclusion of ________________ status (factor levels are still important for management).
3) Verify there is a normal___________________ to eliminate possibility of some forms of VWD
1) 8; 9
2) hemophilia carrier
3) VWF antigen (VWF:Ag)
Factor activity testing should be measured in what 3 settings?
1) Male infants with a hemophilic maternal pedigree
2) Daughters of affected males or of carrier mothers
3) Anyone who experiences unexpected excessive bleeding with trauma/invasive procedures
Hemophilia A & B
1) The preferred method for carrier detection is genetic testing for a gene variant that has been identified in ___________________.
2) All potential carriers, aka all __________ first-degree relatives of an affected individual, should get genetic testing
1) an affected family member
2) female
Name a non-factor Tx for hemophilia A
Emicizumab(SQ)
Hemophilia
1) What are 2 reasons to give factor replacement therapy
2) Desmopressin (DDAVP) (IV or intranasal) may be given as needed for mild hemophilia ____ (not ___).
3) What does DDAVP do?
1) In response to a bleeding episode or as a prophylactic treatment
2) hemophilia A (not B)
3) Promotes release of endogenous factor 8 and von Willebrand factor
Hemophilia Txs:
1) What may be useful as adjunctive agents for mucosal bleeding or procedures to control local hemostasis (prevent the breakdown of clots)?
2) _____________ clinical trials are showing promise and may eliminate spontaneous bleeding and need for factor replacement
1) Antifibrinolytics
2) Gene therapy
Complications of hemophilia:
1) Antibodies that interfere with factor activity or half-life are called what? (hint: major complication of hemophilia Tx)
2) When is this Dx suspected?
1) Factor inhibitors
2) When patients do not respond to factor replacement at therapeutic doses.
Hemophilia complications;
1) Intensive replacement therapy such as for major surgery, intracranial bleeding, or trauma increases the risk of what for patients of all ages and degree of clinical severity?
2) Because early detection of an inhibitor is critical to a successful correction of the bleeding or to eradication of the antibody, most hemophilia centers perform screening for inhibitors how often?
1) Inhibitor formation (which requires close laboratory monitoring in the following weeks).
2) annually
Hemophilia complications: Plasma-derived concentrates given in the 1970’s to early 1990’s caused many ______, ________, & ___________ infections in those with hemophilia
HBV, HCV, and HIV
Hemophilia complications from the 70s:
1) Hepatitis C virus (HCV) infection is the major cause of morbidity and the second leading cause of death in hemophilia patients exposed to ____________________ concentrates.
2) Co-infection with ______ and _____, present in almost 50% of hemophilia patients, is an aggravating factor for the evolution of liver disease
1) older clotting factor
2) HCV and HIV
Elderly hemophilia patients have different problems compared to the younger generation; describe
1) More severe arthropathy and chronic pain
2) High rates of HCV and/or HIV
3) Cancer (HCC)
Hemophilia
1) All patients with hemophilia should be seen regularly in a comprehensive ____________ treatment center.
2) Patients who need to have _________________ procedures should be admitted
1) hemophilia
2) major invasive
Hemophilia:
Among those with high-risk HCV: a semiannual or annual liver ultrasound and alpha-fetoprotein (AFP) to screen for __________
HCC
Hemophilia C
1) Frequency of hemophilia C (Factor XI deficiency) is rare; what pattern of inheritance does it have?
2) ________________________ such as bruises, gingival bleeding, epistaxis, hematuria, and menorrhagia are common, especially following trauma
1) Autosomal recessive
2) Mucocutaneous hemorrhages such as
What are the functions of Von Willebrand Factor (vWF)?
1) Bridging platelets to the subendothelial matrix + to linking them together in the platelet plug
2) Prolonging factor 8 half-life (has a binding site)
Differentiate between the 3 types of vWD
1) Type 1 (majority): quantitative, mild or moderate platelet-type bleeding
2) Type 2: qualitative, moderate to severe bleeding in childhood/ adolescence
-2B: thrombocytopenia
-2N: resemble hemophilia A
3) Type 3: quantitative; very low levels of vWF, severe infancy/ childhood bleeding
aPTT and PT are most commonly ___________ in patients with vWD
normal
Von Willebrand Disease:
1) What 2 things does initial testing include?
2) Screening tests for VWD include what 3 things?
3) Platelet-dependent VWF activity or VWF antigen <______% confirms VWD
1) CBC and coag. studies
2) VWF antigen, VWF activity, and factor 8 activity
3) <30%
Von Willebrand Disease Tx:
1) When is DDAVP useful?
2) DDAVP causes release of ____ and factor ______ from storage sites.
3) Due to tachyphylaxis (decrease in response after repeated administration) and the risk of significant hyponatremia secondary to fluid retention, more than two doses should not be given in a 48-hour period
1) Mild bleeding Tx
2) vWF; factor 8
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Von Willebrand
1) When bleeding is not controlled with DDAVP: administer what?
2) _________________ agents (e.g., aminocaproic acid, tranexamic acid) may be used adjunctively for mucosal bleeding or procedures
1) vWF-containing factor VIII concentrates or recombinant VWF products
2) Antifibrinolytic
Von Willebrand
1) Pregnant patients with type I vWD usually do not require treatment at the time of delivery because of the natural physiologic increase in what?
2) Patients are at risk for significant bleeding ______ weeks postpartum when vWF levels fall secondary to the fall in estrogen levels.
1) vWF levels (observed by parturition.)
2) 1–2 weeks
Vit. K deficiency:
1) Mild to moderate vitamin K deficiency typically features a prolonged ____ (high); _______ can become prolonged with more severe deficiency
2) Why is this the case?
3) Activity levels of individual clotting factors II, VII, IX, and X typically are _______
1) PT ; PTT
2) PT becomes prolonged prior to PTT because Vit. K deficiency first affects the activity of factor 7
3) low
Vitamin K Deficiency: Treatment
1) For treatment, _______________ may be administered via IV or PO routes.
2) The oral dose is __________mg/day and absorption is typically excellent
3) What form of Vit. K results in faster normalization of a prolonged PT?
1) vitamin K1
2) 5–10
3) Intravenous (IV)
Immune Thrombocytopenic Purpura (ITP)
1) What is it?
2) Differentiate between it in kids and adults
1) acquired autoimmune disorder in which there is immune-mediated destruction of platelets and possibly inhibition of platelet release
2) Kids: an acute disease, most commonly following a viral infection
Adults: chronic
Immune Thrombocytopenic Purpura
ITP is termed “secondary” if it is associated with an underlying disorder, such as what 2 things?
Autoimmune disorders + infections
Immune Thrombocytopenic Purpura/ ITP:
1) ITP is characterized by _________________ bleeding.
2) Patients usually present either with _____________ and ___________, or with thrombocytopenia incidentally found on a routine CBC
1) mucocutaneous bleeding (skin/mucous membranes)
2) ecchymoses and petechiae
Immune Thrombocytopenic Purpura (ITP) lab findings:
1) Typically, patients have isolated _____________.
2) Laboratory testing is performed to evaluate for secondary causes of ITP and should include testing for what 3 things?
3) What may show large platelets, with otherwise normal morphology?
1) thrombocytopenia
2) HIV infection and hepatitis B and C
3) Peripheral blood smear
Immune Thrombocytopenic Purpura (ITP):
1) When is Tx indicated? (know this)
2) What is the mainstay of Tx?
3) What should you do if active bleeding?
1) Platelet counts <25,000-30,000/mcL or significant bleeding
2) Corticosteroids (prednisone) +/- IV immunoglobulin (IVIG)
3) Platelet transfusions
1) Thrombotic Microangiopathies (TMA) include what 2 things?
2) TMAs are characterized by a combination of which two findings?
3) TMA pts may have ________ dysfunction (more common/severe in HUS), ____________ impairment, and/or _________ , but these are not required for diagnosis of TMA
1) Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS)
2) Thrombocytopenia + Microangiopathic hemolytic anemia (MAHA)
3) kidney, neurologic, and/or fever
What is the mnemonic for the pentad of TTP findings?
(TTP = Thrombotic Thrombocytopenic Purpura)
FAT RN
Fever
Anemia
Thrombocytopenia
Renal dysfunction
Neurologic abnormalities
In acquired (vs. inherited) TTP, an ________________ inhibitor can be detected
(need to know this)
ADAMTS-13
(Autoantibodies against ADAMTS-13 lead to accumulation of ultra-large vWF multimers)
Hemolytic uremic syndrome (HUS):
1) How is it often contracted? (need to know the types)
2) Most pts (esp kids) have what?
1) Undercooked ground beef contaminated with E. coli (esp. types O157:H7 or O145)
2) Recent or current diarrheal illness (often bloody)
Thrombotic Microangiopathies (TMAs): Give some typical TTP and HUS lab findings
1) Thrombocytopenia
2) Elevated creatinine (if renal involv.)
3) Routine coag studies usually normal
Thrombotic Microangiopathies (TMAs):
1) What is found on periph. blood smear with MAHA?
2) What about with shiga-toxin mediated HUS?
1) Schistocytes
2) Positive stool culture for E. coli O157:H7 or stool assays for Shiga toxin
Which is more of a devastating disease if not diagnosed and treated promptly, ITP or TTP?
TTP
1) What remains the mainstay of treatment of TTP?
2) What is a Tx for acquired TTP?
3) Name another thing used to Tx TTP
1) Therapeutic plasma exchange (TPE) (aka, plasmapheresis)
2) immunosuppression
3) Caplacizumab
True or false: Children or adults with endemic diarrhea-associated HUS generally recover with supportive care alone (IV fluid hydration, etc.)
True
Platelet transfusions are relatively ____________ in TMAs
contraindicated
(may worsen TMA, possibly due to propagation of platelet-rich microthrombi)
True or false: You should admit all patients with newly suspected/diagnosed TMA (TTP or HUS)
True
Heparin-Induced Thrombocytopenia (HIT):
1) What is the end result of its pathology?
2) What is uncommon?
3) How does it usually present?
1) Thrombosis (clots; present in up to 50% of cases) and thrombocytopenia
2) Bleeding
3) New-onset thrombocytopenia within 5-14 days of initial exposure to heparin
Heparin-Induced Thrombocytopenia (HIT): Treatment
1) Immediately discontinue all forms of __________ (avoid future exposures)
2) Alternative ______________ (such as a direct thrombin inhibitor [argatroban, bivalirudin]) should be administered due to prothrombotic nature of HIT
1) heparin
2) anticoagulant
Disseminated Intravascular Coagulation (DIC)
1) Caused by uncontrolled local or systemic activation of coagulation & leads to depletion of coagulation factors and __________.
2) Often results in _____________penia
3) Describe the progression of this condition
1) fibrinogen
2) thrombocytopenia
3) Widespread clotting > consumption of coagulation factors/platelets > widespread bleeding
Disseminated Intravascular Coagulation (DIC)
1) Where does bleeding usually occur?
2) Malignancy-related DIC may manifest as ___________ (Trousseau syndrome)
1) multiple sites (e.g., IV catheters, incisions),
2) thrombosis
Disseminated Intravascular Coagulation (DIC): Describe what labs will look like (worsen as it progresses)
1) Thrombocytopenia
2) Prolongation of PT and aPTT
3) Low/declining fibrinogen
4) Elevated D-dimer
5) May have schistocytes
(know at least the first 4)
The most common inherited thrombophilia is what?
Factor V Leiden (FVL) / Activated Protein C Resistance
(a hypercoag. disorder)
Factor V Leiden (FVL) / Activated Protein C Resistance:
1) What typically causes it?
2) FVL renders both the activated and inactive forms of factor ____ [a procoagulant] insensitive to the actions of activated protein C (aPC) [a natural anticoagulant], leading to __________________/___________
1) Resistance to activated protein C aka factor V Leiden
2) 5; hypercoagulation/thrombosis
Venous Thromboembolism (VTE) is the major manifestation of what?
Factor V Leiden
Factor V Leiden:
1) What is the major manifestation? What are the most common sites for this?
2) Less commonly may have _____________ in the cerebral, mesenteric, or portal veins or superficial lower extremities
1) Venous Thromboembolism (VTE); PE or DVT
2) thrombosis
Factor V Leiden:
1) Some effect in relation to ________ thromboembolism (MI, stroke/TIA) and _________ complications.
2) The presence of FVL generally does not alter decision-making regarding what?
1) arterial; pregnancy (unexplained recurrent late pregnancy loss)
2) the duration of anticoagulation
Protein S Deficiency (hypercoag. disorder):
1) Protein S deficiency is an inherited thrombophilia associated with an increased risk of what?
2) Protein S is a _____________-dependent glycoprotein and is a natural anticoagulant.
3) How is it diagnosed?
1) Thromboembolism
2) vitamin K
3) Low protein S levels
In addition to PROS1 gene mutations (hereditary), reduced protein S levels have been seen in what settings?
1) Pregnancy
2) OCP
3) DIC
4) HIV
5) Nephrotic syndrome
6) Liver disease
7) L-asparaginase chemotherapy
Protein S deficiency:
1) What is the major clinical manifestation of protein S deficiency?
2) What are 2 complications assoc. with protein C and protein S deficiencies?
1) Venous thromboembolism (DVT/PE)
2) Purpura fulminans and warfarin-induced skin necrosis
Protein S Deficiency mgmt:
1) What do you do for asymptomatic individuals with protein S deficiency who have not had a thromboembolic event?
2) The initial management of acute VTE in patients with inherited protein S deficiency is the same as that in the general population, which is what?
1 Do NOT Tx with routine anticoagulation
2) Anticoagulation for at least 3-6 months
Protein C is a vitamin K-dependent anticoagulant protein synthesized in the __________
liver
True or false: inherited protein C deficiency can be subdivided into 2 groups
True
List non-inherited causes of protein C deficiency
1) DIC
2) Liver disease
3) Infection
4) Uremia
5) Cancer/ cancer therapy
Warfarin-induced skin necrosis can occur with either ___________ or _________ deficiency
protein c or protein s
Why can warfarin induced skin necrosis occur with protein C or S deficiencies?
Transient hypercoagulable state during initial warfarin administration
