L-12 Coagulation Disorders: Clinical Aspects

• Clinical Aspects of Disorders of Coagulation II covers hemophilia, von Willebrand disease, disseminated intravascular coagulation, and hemorrhagic viruses.
• The objectives include describing the clinical presentation, pathophysiology, diagnosis, and treatment considerations for hemophilia and von Willebrand disease.
• Other objectives are to describe the clinical presentation, pathophysiology, diagnosis, and treatment consideration of disseminated intravascular coagulation (DIC).
• Finally, to describe the physiology, pathogenesis, epidemiology, diagnosis, and prevention of hemorrhagic viruses including Hanta virus, Lassa, Yellow fever virus, Dengue virus, Marburg virus and Ebola virus.

Presentation of a Young Male Patient

• A 9-year-old male arrives at the emergency room due to weakness in his right knee joint, bruising, and inability to walk.
• He noticed "something weird" in his knee after soccer practice in the park.
• The patient then felt a "tingling feeling" in his knees, particularly the right one, that night.
• Over the subsequent days, his knees swelled up, accompanied by increased pain.
• He is unable to bend his knee very well.

Patient History

• The patient has no past medical or surgical history, allergies, or current medications.
• Family history reveals that an uncle died of a bleeding problem, and his mother bleeds heavily during her periods.

Hematologic Observations

• The patient bruises very easily, particularly after soccer practice.
• Two months prior, a dentist experienced difficulty stopping the bleeding after a tooth extraction.

Musculoskeletal Exam

• The right knee shows swelling, erythema, increased warmth, and tenderness to palpation, with inability to fully extend or flex.
• Notable bruising is present on the right lower lateral thigh and a bruise is present on the left leg, without petechiae.
• Arthrocentesis shows that it is a blood tap.

Dental Context

• Platelet adhesion uses Gp-lb Receptor.
• Platelet aggregation is done by Thromboxane A2, a platelet aggregator and vasoconstrictor, using Gpllb-Illa Receptor.
• Primary platelet plug is formed.
• Coagulation factors convert soluble fibrinogen into an insoluble fibrin web.

Understanding Intrinsic and Extrinsic Pathways

• Partial Thromboplastin Time (PTT) is associated with the intrinsic pathway and usually takes 25-35 seconds.
• Prothrombin Time (PT) is associated with the extrinsic pathway and usually takes 10-15 seconds.
• The common pathway includes factors I, II, V, and X.
• Fibrinogen is factor I and prothrombin is factor II.
• The extrinsic pathway will influence prothrombin time (PT).
• Tissue factor activates factor VII.
• Intrinsic pathway will influence Partial Thromboplastin Time (PTT).
• Intrinsic pathway involves factors XII, XI, IX, and VIII.

Labs and Results

• Labs to order include: platelet count, prothrombin time (PT), partial thromboplastin time (PTT), bleeding time or platelet function assay.
• Platelet count is normal.
• Bleeding time is normal, indicating no platelet function problem.
• Prothrombin time (PT) is normal.
• Partial thromboplastin time (PTT) is prolonged suggesting problems elsewhere in the coagulation system.

Understanding Prolonged PTT

• Prolonged PTT can relate to issues within the intrinsic pathway, extrinsic pathway, or platelets.
• Mixing the young boy's blood with normal blood normalized the PTT.
• After this we check an immunoassay of the deficient factor(s) in the intrinsic pathway (PTT).
• A deficiency in factor VIII, which is called Hemophilia A, is found.
• Hemophilia A is an X-linked recessive genetic disorder.

Hemophilia A Treatments

• Desmopressin (DDAVP) can increase factor VIII stores by stimulating von Willebrand factor release from endothelial cells, primarily beneficial in mild cases.
• Factor VIII can be given several times a week depending on the severity of hemophilia A.
• If autoantibodies against factor 8 are present, Factor 7 (NovoSeven) or a prothrombin complex concentrate such as FEIBA (factor Eight Inhibitor Bypass Agent) may be necessary.

Considerations Differential Diagnosis

• The findings show increased bleeding time, normal PT, prolonged PTT, and low levels of factor VIII, which can indicate Von Willebrand disease.
• Von Willebrand factor accompanies factor VIII and stabilises factor VIII.
• Reduced levels of von Willebrand factor can lead to factor VIII disintegration.
• VWD is important with platelet adhesion.
• Bleeding time will be prolonged with von Willbrand Disease.
• Factor VIII is unstable alone and will degrade rapidly in the blood without VW.
• The bleeding time AND PTT will therefore also be prolonged in VWD.

Distinguishing Other Diagnoses

• Hemophilia A and B can be ruled out if petechiae and prolonged bleeding.
• In the best selection has to be Bernard Soulier the only deficit is the bleeding time.
• In Bernard Soulier disease there is a defect with platelet "adhesion", specifically affecting GP lb.
• Bernard Soulier is defined as platelets sticking to a non-platelet substance and also has low platelet levels in cases.
• Glanzmann's thrombasthenia is a defect of platelet aggregation, specifically affecting GP Ilb-Illa.
• Glanzmann's thrombasthenia is responsible for platelets sticking to each other "aggregation".

Warfarin and Factor Effects

• Warfarin inactivates Vitamin K, thereby inactivating vitamin K-dependent coagulation factors.
• The vitamin K dependent factors are: 2,7,9,10 (C&S)
• Warfarin use will the affect both PT and PTT.
• The best test for warfarin is PT.

Heparin and Factor Effects

• Heparin activates anti-Thrombin III which then inactivates II and X.
• Heparin use will the affect both PT and PTT.
• Partial thromboplastin time (PTT) is a better measured test when using heparin.

Disseminated Intravascular Coagulation (DIC) Case

• A 66-year-old male with a history of chronic prostatitis develops fever, chills, tachycardia, and hypotension with leukocytes and nitrates presents in his urine.
• A digital rectal exam reveals bogginess and pain upon palpating the prostate, leading to a suspicion of acute-on-chronic prostatitis.
• Hospital urine and blood cultures confirm E coli infection.
• Over the hospital stay, he experiences shortness of breath, rectal bleeding, hematemesis, bleeding from his IV line, elevated prothrombin time, partial thromboplastin time, bleeding times, decreased platelet count and schistocytes on the peripheral smear.
• His fibrin degradation products and D-dimer elevate significantly.
• Disseminated Intravascular Coagulopathy (DIC) is likely.

Understanding DIC

• Disseminated: affects all over the body,
• Intravascular: located in the vessels,
• Coagulopathy: involves thrombosis and the consumption of coagulation factors.
• DIC is also called a consumptive coagulopathy.

Acute DIC Blood Profile

• Bleeding time is increased.
• Partial thromboplastin time (PTT) is increased.
• Prothrombin time (PT) is increased.
• D-dimer is increased.
• Fibrin split products are increased.
• Fibrinogen is decreased.
• Platelets are decreased.
• Peripheral smear reveals presence of Schistocytes.

Common Causes of Acute DIC

• Gynecological complications such as postpartum bleeding, amniotic fluid embolism, which can release tissue factor and activate the extrinsic pathway are common.
• Sepsis is especially associated with Gram-negative bacteria.
• Endotoxins can activate tissue factor which can trigger sepsis.
• Cancer leads to TNF release and may trigger acute promyelocytic leukemia (M3).
• Trauma, acute pancreatitis, and rattlesnake bites can each result in cases of DIC.
• It is most important to treat the underlying condition that is causing DIC.

Hantavirus

• A group of friends in Colorado clean up mouse droppings in a cabin.
• Two weeks later, the friends develop a fever, malaise, back ache and headache.
• One week after that, petechial rash develops on all three.
• It is revealed that all have evidence of renal failure, blood in the urine, and proteinuria.
• Bunyavirus is Hantavirus, Hemorrhagic Fever with Renal Syndrome (HFRS).
• Rodent feces and urine "scat" is associated with Hantavirus.
• It is detected through serological testing but can also be detected by serologic test or PCR testing.
• It can be treated with IV ribavirin and supportive care.

Lassa Hemorrhagic Fever

• Lassa virus is an Arenavirus.
• Lassa virus is found in West Africa: Guinea, Sierra Leon, Liberia, Nigeria areas.
• It is transmitted through rodents "multi-mammated rat" through human ingestion or inhalation of virus from urine/feces.
• Is also transmitted person to person by blood, tissue, secretions and excretions.
• Symptoms: flu like symptoms: headaches, vomiting, diarrhea, and eventually bleeding.

Dengue Hemorrhagic Fever

• A PMH includes dengue fever (serotype DENV-1) 1 year ago where she was relatively asymptomatic except for mild body aches and a rash.
• Five days after coming back to Florida, she now complains of sudden fever, severe body aches and headache.
• One week passes and she shows liver function tests markedly elevated and she has thrombocytopenia of 40,000.
• Petechiae is noted under her hard palate.
• She is hypotensive, tachycardic and has nasal bleeding vomiting bloody emesis and bleeding from the inserted CVP line is noted.
• Dengue virus serotypes: DENV-1, 2, 3, 4.
• Anti-Dengue IgM can be used to identify it.
• The family of Dengue include those with an enveloped, single stranded RNA virus.
• Spread by Aedes aegyptii and Aedes albopictus.
• Those who have been infected with one serotype may give lifelong immunity however contracting another type of serotype may have worse outcomes.
• Immimunizing against dengue ESPECIALLY if one has contracted dengue prior is very important.

Yellow Fever

• Multiply in liver, spleen and lymph nodes.
• LIVER AND KIDNEY FAILURE manifests with elevated liver function test and decreased urine output.
• Hemorrhage manifests hematemesis, epistaxis, petechiae, thrombocytopenia, decreased coagulation.
• Yellow fever is a Flaviviridae Family.
• Transmission happens from human to human by the virus or infected monkey to human.
• It is spread by Aedes aegyptii in Africa, and in S. America by Aedes aegyptii and Haemagogus species.
• A 50 year old male from Angola.
• Had custom of preparing bodies for the funeral.
• Has symptoms abrupt fever and chills, malaise and severe weakness.
• One week later confusion, hypertension and severe bleeding namely: epistaxis, hematemesis, and melena occurs.
• Also petechiae and ecchymosis are noted throughout.

Marburg virus

• Marburg virus is a Filoviridae.
• Marburg virus has a 80-90% mortality.
• The virus infects macrophages/dendritic cells, then moves to the lymph nodes, next organs.
• It has an 1 week incubation period, with abrupt flu like symptoms, with severe headache, nausea, vomiting, diarrhea, confusion, seizure and coma.
• severe bleeding up-regulates tissue factor -> leading to DIC.
• The diagnosis: RT-PCR or ELISA.
• There is supportive treatment.
• Fruit bat is the reservoir with Transmission from bat fluids from handling bush meat.
• Also has person to person with Bodily fluids: eyes nose mouth transmission.

Ebola virus

• Ebola virus is a a Filoviridae, with 50% mortality.
• Signs of infection include meningitis or encephalitis.
• Also pericarditis and myocarditis could also develop.
• Then bleeding by impairing the coagulation cascade: hematochezia and melena.
• It is often accompanied by AMS which stands for: Skin with petechia, purpura, ecchymosis, mucosal bleed.
• Most cases result in Organ failure leading to death.
• The diagnosis: PCR, ELISA, ebola virus antibodies.
• There is supportive treatment: fluids, antipyretics, remdesivir, monoclonal antibodies.
• The only preventions is a vaccine.
• All bodily fluids like: sweat, saliva, feces, urine, milk, blood, semen can transmit the disease.
• Infections occur through eyes, nose, mouth.
• Incubation lasts for 2-21 days.
• Then patients develop and abrupt fever, chills, myalgia, rash, Nausea, vomiting, watery diarrhea manifesting Hypotension shock.
• Bats and apes/chimps may be zoonotic transmitters.
• Infection starts in humans by handling bushmeat before human to human transmission.