Bleeding Disorders & Hypercoagulable States

What are the types of platelet disorders?

impaired production, accelerated destruction, von willebrand disease, drugs (ASA, Plavix, NSAIDs)

What are the types of clotting disorders?

Hemophilia A and B

What are the types of hypercoagulable states?

Factor V Leiden mutation, antithrombin III deficiency, protein C deficiency

What are the symptoms of platelet disorders?

Epistaxis, gum bleeding, menorrhagia, gastrointestinal, bleeding, purpura, petechiae

What are the symptoms of coagulopathy?

hematomas, spontaneous hemarthroses, petechiae, purpura, and ecchymosis

what is the most common hereditary disorder of hemostasis?

Von Williebrand Disease

What is Von Willebrand Disease (vWD)?

Autosomal dominant disorder with a deficiency of von Willebrand factor (vWF)

What is Type I vWD?

MC type with quantitative decrease in vWF that is autosomal dominant

What are Types IIa, Type IIb, Type IIm,

Type IIn?

production of abnormal vWF that is qualitative abnormality

What is Type II vWD?

Rare, autosomal recessive disorder with absent vWF and is most severe

What are the symptoms of vWD?

mucosal bleeding, menorrhagia, prolonged bleeding post procedure

What are the labratory findings of vWD?

- normal platelet number and morphology

- prolonged platelet function (increased with ASA admin)

- normal PT and PTT

Which initial diagnostic tests are used for vWD?

- Plasma vWD antigens

- Plasma vWF activity

- Factor VIII clotting activity

What diagnostics are used for confirmatory assay of vWD?

- gel electrophoresis

- Ristocetin induced platelet aggregation (RIPA)

What is the management of Type I vWD?

Desmopressin (DDAVP)

What is the management of Type II/III?

vWF replacement either concentrates or recombinant

What factors promote vitamin K deficiency?

interference with bile production/secretion, malabsorption, drug therapy, cystic fibrosis

What are the symptoms of vitamin K deficiency?

mucosal bleeding, hematoma, GI bleeding, menorrhagia, hematuria, venipuncture oozing, easy bruising

What labs are seen in vitamin K deficiency?

- elevated PT and normal aPTT

- abnormal II, VII, IX, X, protein C

What is the treatment for vitamin K deficiency?

Phytonadione (PO or SC) that will decrease INR in 6 to 12 hours

What are the 3 causes of platelet disorders?

Impaired production, splenic abnormalities, and accelerated destruction

What causes impaired production of platelets?

Leukemia, bone marrow dysfunction (leukemia, aplastic anemia, myelofibrosis), cytotoxic drugs/radiation

What are the types of splenic abnormalities?

postsplenectomy (thrombocytosis), splenomegaly/hypersplenism, thrombocytopenia

What causes accelerated destruction of platelets?

drugs, ITP, DIC, TTP, HUS, HELLP

What drugs cause TCP?

Heparin, glycoprotein binders, bactrim, quinine, ASA, plavix, vancomycin, viruses, COVID vaccine, thrombotic TCP

What is Type I Heparin Induced TCP (HIT)?

mild transient drop in PLT count first few days and returns to normal with no sequela

What is Type II Heparin Induced TCP (HIT)?

significant and is caused by antibodies directed at PLT factor 4 forminga PF4/heparin complex that lead to TCP and thrombosis

When is HIT more common?

women after ortho surgeries

How is HIT managed?

D/C all heparin products and treat with argatroban or dabigatran

What is Immune or Idiopathic Thromcocytopenic Purpura (ITP)?

Autoimmune disorder with antibodies against own platelets causing massive phagocytosis of platelet antibody immune complexes in the spleen

What are the risk factors for ITP?

children (preceded by viral infection), AIDS, and COVID

What are the symptoms of ITP?

mucosal and skin bleeding, menorrhagia, antecedent viral infection

What are the physical exam symptoms of ITP?

Petechiae, purpura, and epistaxis; NO splenomegaly

What is the laboratory finding of ITP?

Thrombocytopenia (up to 100,000) with a normal PT, aPTT, D-dimer

What diagnostic is required for ITP?

Bone marrow biopsy

What is the treatment for ITP?

PLT < 30,000: Prednisone, IVIG

> 3 months: thrombopoietin agonists, rituximab, fostanib

+/- splenectomy

What is Microangiopathic Hemolytic Anemia (MAHA)?

syndrome of traumatic intravascular hemolysis causing fragmentation of the RBCs seen on peripheral blood smear (schistocytes)

What are the possible causes of MAHA?

TTP, HUS, DIC, Mechanical Heart Valve, Malignant HTN

What is Thrombotic Thrombocytopenic Purpura (TTP)?

Endothelial layer of small vessels is damaged leading to fibrin deposition & platelet aggregation (platelet consumption).

What causes TTP?

deficiency of ADAMTS13

What are the risk factors of TTP?

autoimmune disease, HIV, malignancy, pregnancy, obesity, drugs

What is the triad of TTP?

1) Hemolytic Anemia

2) Thrombocytopenia

3) Neurologic effects (confusion, HA, focal neuro deficits, stroke, coma)

What are the associated symptoms of TTP?

purpura, fevers, chest pain, N/V

What are the labratory findings of TTP?

- thrombocytopenia (< 20,000)

- schistocytes/helmet cells

- elevated BUN/Cr, LDH, reticulocytes

- decreased ADAMTS13 activity

How is the PLASMIC Score calculated for TTP?

* One point for each feature *

- platelets < 30,000

- hemolysis

- no active cancer

- no solid organ or transplant

- MCV < 90 fL

- INR < 1.5

- Creatine < 2.0mg/dL

What are the severity scales for PLASMIC score?

6-7: high probability of TTP

5: intermediate probability

0-4: low probability

What is the treatment of TTP?

Corticosteroids, Rituximab, Plasmapheresis, Caplacizumab-monoclonal drug

What is Hemolytic Uremic Syndrome (HUS)?

Microangiopathic hemolytic anemia & thrombocytopenia

What is the pathogenesis of HUS?

Rapid destruction of RBCs causes acute kidney injury, in part due to obstruction of small renal arteries

What are the risk factors of HUS?

E. coli, STEC, S. pneumoniae

What are the symptoms of HUS?

abdominal pain, bloody diarrhea, anemia, thrombocytopenia +/- AKI and CNS involvement

What is the laboratory finding of HUS?

Increased reticulocyte count, thrombocytopenia, schistocytes, elevated BUN/Cr, Hematuria or proteinurea

What is the treatment of HUS?

plasma exchage, platelet and red cell transfusion, supportive therapy, ecluizumab

What is Disseminated Intravascular Coagulation (DIC)?

microthrombi cause infarcts & massive consumption of platelets, fibrin & coagulation factors → results in uncontrolled bleeding

What are the risk factors for DIC?

sepsis, OB complications, malignancy, trauma, pancreatitis, severe transfusion

What are the symptoms of DIC?

spontaneous oozing, digital ischemia, gangrene, recurrent DVTs, tender nodules in affected veins

What are some physical exam signs of DIC?

Jaundice, hemoptysis, delirium, Waterhouse-Friderichsen syndrome, and Purpura fulminans

What are the characteristic lab findings of DIC?

- low fibrinogen

- thrombocytopenia

- prolonged PT, aPTT

- elevated fibrin degradation

- normal fibrinogen (4 days) that rapidly declines

- decreased Antithrombin III

What is the management of DIC?

treat underlying cause, supportive care +/- transfusion, heparin, protein C concentrate (purpura fulminans)

What is Hemophilia A?

Classic hemophilia; deficiency of factor VIII that can also be X linked

What are the symptoms of Hemophilia A?

Hemarthrosis, Hematomas, recurrent mucosal bleeding, hematuria, intracranial hemorrhage

What is the classification of Hemophilia A?

Mild - >5%

Moderate - 1-5%

Severe - <1%

What are the laboratory findings of Hemophilia A?

- prolonged PTT

- decreased Factor VIII

+/- Factor VIII inhibitors

What is the treatment of Hemophilia A?

Factor VIII replacement infusion, Emicizumab, DDAVP (mild), avoid trauma/ASA

What is Hemophilia B?

Christmas disease, factor IX deficiency that is X-linked

What is the severity scales of Hemophilia B?

<1%: severe bleeding

1-5%: moderate bleeding

5-40%: mild disease

What are the lab findings of Hemophilia B?

- prolonged aPTT

- decreased factor IX

+/- Factor IX inhibitors

What is the treatment of Hemophilia B?

Factor IX replacement, avoid IM injections, trauma, and ASA

What is Hemophilia C?

Autosomal recessive, factor XI

What are congenital causes of hypercoagulable states?

Factor V Leiden mutation, Antithrombin III deficiency, Protein C deficiency, and Protein S deficiency

What is Virchow's Triad?

stasis of blood flow, endothelial

injury, hypercoagulability

What is Factor V Leiden Mutation?

resistance to activated protein C (anticoagulant) resulting in venous thrombosis, thromboembolism

What is the result of Antithrombin III deficiency?

inability to inactivate surplus thrombin leading to venous thrombosis and thromboembolism

What leads to the development of Antithrombin III deficiency?

Autosomal dominant inheritance or acquired from liver disease, DIC, or HUS

What is the result of Protein C deficiency?

inherited or acquired deficiency leading to the inability for clot lysis

What is the characteristic symptoms of Protein C deficiency?

Coumarin Necrosis (warfarin induced)

What is the typical role of protein S and what happens when it is deficient?

Cofactor for activated protein C and tissue factor pathway inhibitor that has a 10x increase for VTE when deficient

What is prothrombin gene mutation?

Mutation of nucleotide substitution of the gene which leads to greater function of prothrombin (Factor II)

What is Lupus Anticoagulant/Antiphospholipid Syndrome?

Autoimmune multisystem disorder that can lead to VTE's, pregnancy loss, arterial clots, and cytopenias

What are the manifestations of LAC/APS?

stroke/TIA, mesenteric occlusion, DVT/PE, cerebral sinus

What is the symptoms of LAC/APS?

livedo reticularis

what diagnostics are used for LAC/APS?

LAC test, anti-cardiolipin, and beta 2 glycoprotein antibodies

When is inherited thrombophilia testing indicated?

VTE & at least one 1st degree relative with documented VTE before age 45 OR patients <45 with VTE or thrombosis in unusual locations

What is included in the thrombophilia testing?

1) Levels of protein S, C, and antithrombin II

2) Factor V Leiden & prothrombin gene mutations

3) CBC with differential and a peripheral smear

4) Coagulation sudies

What is the managment of hypercoagulation?

heparin (acute), warfarin (chronic), DOACs, Pradaxa, prophylaxis when indicated (avoid OCPs, HRT)

What are the indications for indefinite anticoagulation?

- > 1-2 spontaneous thromboses

- 1 spontaneous life-threatening VTE

- 1 spontaneous thrombosis at an unusual site (mesenteric or cerebral)

- 1 genetic defect predisposing to thromboembolic event

What is screened in transfusion medicine?

HIV, hepatitis, HTLV-I and II, West Nile, and syphilis

When are packed red blood cells transfused?

symptomatic anemia; acute blood loss from trauma or surgery (Hgb <7 to 8 or 7-10 for acute MIs)

When is whole blood tranfused?

massive hemorrhage when rapid volume and clotting is life-saving

When are platelets transfused?

stop or prevent bleeding when < 10k or < 15-20k if feverish

When is flash frozen plasma transfused?

Bleeding in pts' with factor deficiencies, liver disease, DIC,

Coumadin overdose

When is cryoprecipitate transfused?

fibrinogen <100, post-partum hemorrhage or DIC

When is albumin transfused?

severe burns, shock, or liver failure

When is prothrombin complex concentrate (PCC) transfused?

rapid reversal of anticoagulants (warfarin) in life-threatening bleeding

When should leuko-reduced transfusion be given?

febrile non-hemolytic transfusion reactions, frequent transfusions, future transplants, neonates, or high CMV risk

When should irradiated transfusion be given?

pts at risk for transfusion associated graft vs host disease (monitor K+)

What are the types of transfusion reactions?

Hyperkalemia, Hypocalcemia, hemolysis, fever, anaphylaxis, transfusion related acute lung injury (TRALI), tranfusion associated circulatory overload (TACO)

What is the most common cause of acute hemolytic transfusion?

Blood bank error regarding ABO antigens most often with PRBC's (i.e. Type A getting blood from a Type B donor)

What are the characteristics of delayed hemolytic tranfusion?

Due to lab errors that predominantly causes extravascular hemolysis and fever

What are the symptoms of acute hemolytic transfusion reaction (AHTR)?

back/flank pain, fevers, chills, hypotension, oozing from IV sites or epistaxis, hematuria, or AKI