Plasminogen Activator Inhibitor Type 1 Deficiency

Clinical Manifestation

Age at presentation: There does not appear to be a typical average age at which symptoms first appear or manifest. In fact, the age of diagnosis ranges from four months to 76 years of age.20,52

Clinical history: Decreased PAI-1 activity may be caused by qualitative or quantitative defects. PAI-1 deficiency is a mild to moderate delayed bleeding disorder. The most common bleeding symptoms include those following surgery, injury, or trauma and in women include menorrhagia, rarely hemorrhagic rupture of ovarian cysts, antenatal bleeding and post-partum hemorrhage.20 (Please refer to “Special consideration in women” section for details).

In general, bleeding is expected to be more pronounced after trauma/surgical procedures especially involving the oral and urogenital areas owing to the increased concentration of local fibrinolytic activity in saliva and urine, respectively. Spontaneous bleeding is rarely observed. Post-surgical bleeding after dental procedures in individuals with PAI-1 deficiency has been reported in a number of studies.20,56-58,60 In fact, recurrent oral bleeding, along with a history of childhood posttraumatic and postsurgical bleeding, was responsible for the diagnosis of PAI-1 deficiency in the proband in the Old Order Amish population.53 Additionally, there have been reports of easy bruising, epistaxis, and muscle hematomas after injury or trauma.20,59,60 Follow-up evaluations have also revealed intracranial hemorrhage, hemarthrosis, and prolonged wound healing.56,61

Special consideration in women: Menorrhagia and pregnancy require special consideration in women with PAI-1 deficiency.49,56,61,62,67 Menorrhagia can lead to significant blood loss in this bleeding disorder. In fact, one report indicates the requirement of packed red blood cell transfusion in an Amish woman after significant blood loss during menstruation.49 Another report details a massive hemorrhage (6 L) from a 15 year old girl during her first menstruation who was diagnosed with complete PAI -1 deficiency upon genetic analysis and found to be homozygous for one base pair duplication on exon 3 at the age of 47 years.61 In this case, physicians instituted estrogen/progesterone therapy to prevent menses ten months out of the year. She was subsequently hospitalized twice yearly to induce menses to allow for appropriate uterine and ovarian growth.

During these hospitalizations she required up to 10 L of blood due to significant blood loss. This individual also suffered significant pregnancy-related complications. At 26 years of age she suffered a miscarriage at 19 weeks’ gestation due to massive bleeding. A year later, a second pregnancy occurred, and bleeding was observed at 11 weeks’ gestation. Fresh frozen plasma (FFP) was administered 2-3 times per week until 28 weeks’ gestation at which time FFP was administered daily. At 32 weeks’ gestation she had uncontrolled uterine contractions with grade 2 placental abruption and a 1736 gram female infant was born via emergency caesarean section. Perioperative blood loss was 4500 ml for which 42 units of FFP were administered. Finally, her third pregnancy occurred at 29 years of age. The patient was given FFP periodically after the 8th week of gestation and then daily beginning at 20 weeks’ gestation. Despite this intensive treatment regimen, she had a placental abruption at 27 weeks with 1037 ml of blood loss during cesarean section and a 978 gram female infant was delivered. It is speculated that large amounts of FFP were needed to maintain both pregnancies because: 1) there is an increasing demand for PAI-1 as a pregnancy progresses; 2) even large amounts of FFP are only able to provide limited quantities of PAI-1; and 3) PAI-1 has a very short half-life (6 minutes).68

In Indiana, there are two female siblings in the Amish community with homozygous complete PAI-1 deficiency who have had controlled menstrual blood flow and achieved successful pregnancies with the use of antifibrinolytic agents, epsilon-aminocaproic acid (EACA) and tranexamic acid (TA).

Amish women have identified an herbal over-the-counter progesterone containing cream, Progesta-Care (Life-Flo, that patients utilize during menses in addition to the oral EACA which results in an improvement of bleeding symptoms.  The cream contains 20 mg of progesterone per pump with the patient using one pump daily applied to abdomen and thighs.  The pregnancies were complicated with intermittent abnormal bleeding in the antenatal period and preterm labor although the newborns were healthy. These women also used antifibrinolytics during pregnancy and in the postpartum period.

The dose of EACA used in pregnancy was 3 grams orally every 6 hours, which was started at the first sign of vaginal bleeding and continued throughout pregnancy. However, the women reported using it intermittently to control their symptoms and for up to 6 weeks postpartum. Both these women experienced preterm deliveries occurring around 30-34 weeks. One of the women had a miscarriage at 6 weeks, and after her second pregnancy had a hemorrhagic rupture of an ovarian cyst, which was treated with oral EACA with symptom improvement.

Another woman in the Amish community with complete PAI-1 deficiency had a non-pregnancy related follicular cyst rupture resulting in hemoperitoneum requiring hospitalization and packed red blood cell transfusion.69

The most recently reported case is that of a 70-year old Japanese woman with life threatening bleeding episodes and a new mutation c.1189G>C;p.Gly397Arg resulting in dysfunctional PAI-1 protein. She had heavy menstrual bleeding and had three pregnancies which resulted in spontaneous miscarriages or preterm labor with excessive uterine bleeding or preterm labor with life-threatening uterine hemorrhage.63

From these cases, it is evident that women with complete PAI-1 deficiency are fertile and can have successful pregnancies, although complications of intermittent antenatal bleeding, preterm labor, postpartum hemorrhage and miscarriages should be anticipated.